Organic Synthesis Highlights 5Vset

J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig

Organic Synthesis Highlights

OVC H Verlagsgesellschaft mbH, D-6940 Weinheim (Federal Republic of Germany), 1991 Distribution: VCH, P. 0. Box 101161, D-6940 Weinheim (Federal Republic of Germany) Switzerland: VCH, P. 0. Box, CH-4020 Basel (Switzerland) United Kingdom and Ireland: VCH (UK) Ltd., 8 Wellington Court, Cambridge CB1 1HZ (England) USA and Canada: VCH, Suite 909,220 East 23rd Street, New York, NY 10010-4606 (USA) ISBN 3-527-27955-5 (VCH, Weinheim)

ISBN 0-89573-918-6 (VCH, New York)

J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig

Organic Synthesis Highlights

VCH

Weinheim - New York - Base1 - Cambridge

Prof. Dr. Johann Mulzer Institut fiir Organ. Chemie der Freien Universitat TakustraBe 3 D-1000 Berlin 33

Prof. Dr. Hans-Josef Altenbach Fachbereich Chemie der Universitlt/Gesamthochschule Warburger StraBe 100 D-4790 Paderborn

Prof. Dr. Karsten Krohn Institut fur Organ. Chemie der TU Braunschweig Hagenring 30 D-3300 Braunschweig

Prof. Dr. Hans-Ulrich Reissig Institut fur Organ. Chemie PetersenstraBe 22 D-6100 Darmstadt

Prof. Dr. Manfred Braun Institut fiir Organ. Chemie UniversitatsstraBe 1 D-4000 Diisseldorf 1

This book was carefully produced. Nevertheless, authors and publisher do not warrant the information contained therein to be free oferrors. Readersare advisedto keep in mind that statements, data, illustrations, proceduraldetailsor other items may inadvertently be inaccurate.

Published jointly by VCH VerlagsgesellschaftmhH, Weinheim (Federal Republic of Germanv) VCH Publishers, Inc., New York, NY (USA)

_ I

Editorial Management: Karin von der Saal Production Manager: Elke Littmann Cover illustration: A starburst dendrimer Library of Congress Card No.: 90-13003 British Library Cataloguing-in-PublicationData: Organic synthesis highlights. 1. Organic compounds. Synthesis I. Mulzer, J. 547.2 ISBN 3-527-27955-5 Deutsche Bihliothek Cataloguing-in-PublicationData: Organic synthesis highlights I J. Mulzer ... - Weinheim ;New York ;Basel ; Cambridge : VCH, 1990 ISBN 3-527-27955-5 (Weinheim ...) ISBN 0-89573-918-6 (New York) NE: Mulzer, Johann OVCH VerlagsgesellschaftmbH, D-6940 Weinheim (Federal Republic of Germany), 1991 Printed on acid-free paper. All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition and printing: Krebs-Gehlen Druckerei, D-6944 Hemsbach. Bookbinding: J. Schlffer GmbH & Co. KG, D-6718 Grunstadt. Printed in the Federal Republic of Germany

Preface

Organic synthesis is as highly developed, versatile, and interdisciplinary branch of natural science. It allows the preparation of complex molecules and new materials with unexpected properties. Based on the accomplishments of modern analytical techniques (spectroscopy,Xray analysis, chromatography) and on the knowledge of quantum chemistry, the mechanistic understanding of organic reactions has been immensely enlarged and may now be used in the planning of more efficient synthetic routes. Novel, highly selective reagents appear every month. New reactions or modifications of old reactions have been devised to meet the ever-increasing demands of selectivity in modern synthesis. “Organic Synthesis Highlights” provides an overview of the rapid progress, the trends, and the accomplishments of synthetic organic chemistry over the past five years. It was written by five young authors, who are all active researchers in different fields of organic chemistry. “Organic Synthesis Highlights” in not another textbook on organic chemistry. It addresses university teachers, research chemists in industry, and advanced students. Instead of attempting to cover the entire subject in full-blown detail, its essay-like approach gives the reader an impression of the competitive atmosphere, the creativity, and resourcefulness which is so characteristic of organic synthesis today.

The book contains 49 articles on almost every aspect of modern organic synthesis. In the first part, methodology, reagents, and reactions are described, especially with respect to their chemo-, regio-, and stereoselectivity potential. Particular emphasis has been laid on the rapidly developing organometallic and biooriented procedures. Wherever necessary, mechanisms are discussed for a better understanding of the reaction. In the second part, this knowledge is applied to the synthesis of target compounds, mostly natural products with remarkable physiological properties such as pheromones, alkaloids, prostaglandins, and steroids. Frequent use is made of retrosynthetic analysis to show how a multi-step synthesis may be planned to avoid inefficient bond connections and isomeric mixtures. The syntheses are discussed with the aid of concise flowcharts aiming at the principal understanding of the sequence and leaving the details to the more than 1000 references which consider even the most recent literature. It is the hope of the authors that this volume might be helpful in many respects: for getting a quick introduction to a new research area, for preparing seminars, lectures, or examinations, for getting a hint of how to solve a specific problem in synthesis, or just for having fun with good new chemistry. Berlin, September 1990

J. Mulzer

Contents

Part I. Methods, Reagents and Mechanisms A. Various Aspects of Stereodifferentiating Addition Reactions Cram’s Rule: Theme and Variations ................................................... J. Mulzer

3

............................................

9

Stereoselective Reactions of Cyclic Enolates K. Krohn

Chiral Sulfoxides in the Synthesis of Enantiomerically Pure Compounds . . . . . . . . . . . . . . . . K, Krohn

14

......................................................

19

Syntheses with Aliphatic Nitro Compounds ............................................ M. Braun

25

Boron: Reagents for Stereoselective Syntheses .......................................... M. Braun

33

.............................................

40

..............................................................

45

Chiral Cyclic Acetals in Synthesis H.-J. Altenbach

a-Hydroxylation of Carbonyl Compounds H.- U. Reissig Electrophilic Aminations K. Krohn

Asymmetric Induction in Diels-Alder Reactions .................................. K. Krohn Chiral Lewis Acids .................................................................... H.-J. Altenbach

66

C-C Bond-Forming Reactions in Aqueous Medium ................................... H.- U . Reissig

71

Natural Product Synthesis via 1,3;Dipolar Cycloadditions .............................. J. Mulzer

77

VIII

Contents

[4 + 11 and [3 + 21 Cycloadditions in the Synthesis of Cyclopentanoids . . . . . . . . . . . . . . . . . K. Krohn

96

Recent Applications of the Paterno-Buchi Reaction ..................................... M . Braun

105

Diastereoselective Claisen Rearrangements ............................................. H.-J. Altenbach

111

Ester Enolate Claisen Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H.-J. Altenbach

116

B. Cyclization Reactions The Weiss Reaction . . . . . . . . . . . . . . . . . . . H.- U. Reissig

....................

Radical Reactions for Carbon-Carbon Bond Formation . . . . . . . . . M . Braun

. . . . . . . . . . . . . . . I21 ....................

. . . . . 131

Cyclization of Allyl- and Vinylsilanes ....................................... K. Krohn Nazarov and Pauson-Khand Reactions ............................... K. Krohn

126

. . . . . . . . . . . . . 137

Polyepoxide Cyclizations .............................................................. H.-J. Altenbach

145

Syntheses of Macrocyclic Ethers ....................................................... H.-J. Altenbach

151

Halolactonization: The Career of a Reaction J. Mulzer

.....

.........................

C. Organotransition Metals in Synthesis New Aromatic Substitution Methods .................................................. M. Braun

167

Palladium-Catalyzed Arylation and Vinylation of Olefins ............................... H.- U. Reissig

174

Regio- and Stereoselective Aryl Coupling .............................................. H.-J. Altenbach

181

Benzannulation Reactions Employing Fischer Carbene Complexes ...................... H.- U. Reissig

186

Methylenations with Tebbe-Grubbs Reagents .......................................... H.-U. Reissig

192

Contents

IX

D. Electrochemistry in Selective Synthesis Anodic Oxidation and Amidoalkylation ................................................ H.- U. Reissig

199

E. Bio-oriented Methodology Enzymes in Organic Synthesis, I ....................................................... J. Mulzer

207

Enzymes in Organic Synthesis, I1 ...................................................... J. Mulzer

216

Enzyme Chemistry - Valuable New Applications ...................................... H.-J. Altenbach

224

Biomimetic Natural Product Syntheses ................................................ M . Braun

232

F. Synthesis with Ex-Chiral-Pool Starting Materials ( R ) - and (S)-2,3-Isopropylidene Glyceraldehyde “Unbiased” Chiral Starting Materials .................................................. J. Mulzer

Chiral Building Blocks from Carbohydrates ............................................ K. Krohn

243 251

Part 11. Applications in Total Synthesis A. Synthesis of Classes of Natural Products Some Recent Highlights From Alkaloid Synthesis K. Krohn Synthesis of 0-Glycosides . . K. Krohn Cembranoid Syntheses H.-J. Altenbach

..

...

.............................

...........................

263

........................

277

.......................................

Optically Active Glycerol Derivatives H.-J. Altenbach

.............

.................................

Asymmetric Syntheses of a-Amino Acids ............................................... H.-J. Altenbach

286 292 300

X

Contents

B. Synthesis of Individual Natural Products Compactin and Mevinolin ....... M . Braun

.........

The Coriolin Story, or The Thirteen-Fold Way J. Mulzer

.................................

................................

..

.............

309 323

.....................................

335

Milbemycin /j3 ......................... H.- U . Reissig

.........................................

344

Daunosamine .......................... M. Braun

...........................................

351

Two Strategies, One Target: Swainsonine H.- U. Reissig

..................................

359

Syntheses of Statine ....................... H.-J. Altenbach

..................................

365

A Look at “Structural Pathologies” ....................................

371

“Starburst Dendrimers” and “Arborols” ............................................... K. Krohn

378

Author Index ..........................................................................

385

Subject Index.. ........................................................................

391

Fr ontalin M. Braun

C. Syntheses of Non-Natural Target Compounds Fenestranes K. Krohn

-

Abbreviations

9-BBN Bn = Bzl Bz DEAD DIBAH = DIBAL DH P DME DMF DMAP DMSO DBN DBU BOC BuLi LAH LDA MEM MOM MsCl MCPBA = mCPBA HMPA = HMPT NBS PCC PDC Phth PPA PPTS TBDMS TBDPS TMEDA TMM TMS Ts TH P

9-Bora-bicyclo[3.3.1]nonane

Benzyl Benzoyl Diethyl-azo-dicarboxylate Diisobutyl-aluminium-hydride Dihydropyrane Dimethoxy-ethane Dimethylformamide 4-N,N-Dimethylaminopyridine Dimethylsulfoxide

1,5-Diaza-bicyclo[4.3.O]nonene-5 1,5-Diaza-bicyclo[5.4.O]undecylene-5 tert-Butyloxy-carbonyl n-Butyllithium Lithiumaluminiumhydride Lithiumdiisopropylamide 2-Methoxyethoxymethyl Methoxy-methyl Methanesulfonylchloride m-Chloroperbenzoic acid Hexamethylphosphoric acid triamide N-Bromosuccinimide Pyridiniumchlorochromate Pyridinium-dichromate Phthaloyl Polyphosphoric acid Pyridinium-p-tosylate ter-Butyldimethylsilyl tert-Butyldiphenylsilyl Tetramethyl-ethylene-diamine Trimethylene methane Trimethylsilyl Tosyl Tetrahydropyranyl

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

I. Methods, Reagents and Mechanisms

A. Various Aspects of Stereodifferentiating Addition React ions

This chapter deals with various aspects of addition to sp2-carbons. Addition reactions permit C,C- and C-heteroatom bonds to be formed in such a way as to create new stereocenters, and hence enantiomers or diastereomers. The process is called “stereodifferentiation” and it must be performed with as much selectivity as possible; a stereoisomer ratio of 9:l- or better is desirable. Cycloadditions like the Diels-Alder reaction produce two bonds in one step with the potential for up to of 16 stereoisomers! It is one of the great achievements of modern synthetic methodology that such additions may be controlled to yield only one isomer by use of appropriate auxiliaries and conditions. Sigmatropic rearrangements like the Claisen rear-

rangement proceed with self-immolative stereochemistry, which means that a new stereocenter is generated at the cost of a previous one. In the Claisen case, a C - 0 bond is transformed into a C-C bond with a quantitative chirality transfer.

Literature: Asymmetric Synthesis (J. D. Morrison, Editor), Academic Press, 1983/84, Vol. 2 + 3. Natural Products Synthesis Through Pericyclic Reactions, G. Desimoni, G. Tucconi, A. Barco, G. P. Pollini, ACS Monograph 180, American Chemical Society, Washington, D. C.,1983. Stereodifferentiating Reactions, Y.Zzumi, A. Tui, Kodansha, 1911.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Cram’s Rule: Theme and Variations

Cram’s rule was formulated in the early fifties and has been an evergreen in organic stereochemistry ever since. In their original paper [l] Cram and Abd Elhafez studied the addition of various organometals and complex hydrides to prochiral carbonyl functions, summarizing their findings in the following postulate: “In non-catalytic reactions of this type that diastereomer will predominante which could be formed by the approach of the entering group from the least hindered side of the double bond when the rotational conformation of the C - Cbond is such that the double bond is flanked by the two least bulky groups attached to the adjacent center”. Despite its verbose formulation this so-called “Cram’s rule” soon became an indispensable ingredient of organic textbooks; the simple substituent classification according to effective size (L = large, M = medium, S = small) and the seductively clear influence of steric shielding on the direction of nucleophilic attack were responsible for this popularity. In today’s view, Cram’s rule - similar to Prelog’s rule [2] attempts a heuristic treatment of the problem of diastereoface selectivity. Owing to the vicinal chiral center, both faces of the carbonyl group are diastereotopic, which means that re- and siattack differ in energy [3] and unequal amounts of the adducts (2) and (3) are produced. Recently, general descriptions of these phenomena have been developed, resulting in the SeebachPrelog topicity concept [4]. In principle,

Cram’s rule has been applied to both 1,2- and 1,3-inductions; this article, however, will be restricted to the 1,2-case, following Cram’s original definition [l]. Ironically, concepts based on questionable premises frequently turn out particularly fruitful. In fact, Cram’s rule appears highly oversimplified in several respects: (a) No distinction is made between ground state and reactive conformation. The postulate that (I) is the ground state conformation of the metal carbonyl complex, is incorrect, as shown by Cornforth [S] and Karabatsos [6]. True, however, is that complexation is indispensable for the activation of the carbonyl group. An uncomplexed carbony1 group is unreactive towards organometallic attack. (b) In view of the low rotational barriers around C(0)- C-bond axes more than one reactive conformation may be involved, according to the Curtin-Hammett principle [7]. Among these, ( I ) is highly unfavorable, as it leads to the fully eclipsed arrangements (2) and (3) in the course of nucleophilic addition! (c) The substituents are classified as S , M, and L only with respect to their bulk. Any dipolar interactions with the nucleophile are neglected. This deficiency was partly remedied by Cornforth [S]; he suggested a “dipolar model” for electronegative ct-substituents (Cl, etc.), which he assumed would adopt the L-position in (1). A more general improvement was made by Felkin [S] who realized the importance of the transition state. To avoid eclipsing interactions

4

Stereodgferentiating Addition Reactions

-

Ooolt Met

Cram-Modell Met , ,*

M

R'- Met

(Met = Mg. Li. Zn, etc.)

o%+

I

R

L

+

(2)

(3) (minor)

(major)

Felkin model*) R'-Met I

R'-Met I M

&

S

RF-

(3) O ~ ~ i l M e4 t

Met

L

L (4) major

(5) minor

Felkin-Anh modello) R'-Met

-+

V :2 R Met

0

(2)

* r3)

L

L

(6) major

(7) minor

-

-

R'-M

/

Met

Burgi-Dunitz trajectory of R'-Met: S interaction R'-Met is smaller than interaction R'-Met M ++

Houk model")

n

Y

X

X

Y

I

I

I

I

L

L

(8) minor

(9) major

Felkin preferred the semi-staggered geometries (4)/(5)and postulated nucleophilic attack from

an antiperiplanar position with respect to substituent L. Thus, instead of considering one conformation and two modes of attack, as Cram and Cornforth had done, Felkin suggested two

reactive conformations (4)/(5) and only one mode of attack. L is generally the substituent with the highest repulsive effect, which may be of steric or dipolar (e.g. OR, NRJ origin. For electronegative substituents like OR or NR2the transition states (4)/(5) gain an extra stabiliza-

5

tion by electron transfer from the nucleophile into the low-lying o*-orbital of the C- L bond (“antiperiplanar effect” [9]. However, Felkin’s interpretation failed to explain why (4) is favored over (5). The answer to this problem was given by Biirgi/Dunitz and Anh [lo] who developed the concept of “nonperpendicular attack”. Due to repulsion from the carbonyl-oxygen, the nucleophile approaches the carbonyl-carbon at an angle of ca. 100” with respect to the carbonyl axis. Thus, (4) changes to (6) and (5) to (3, with (6) (R’M interacts with S ) clearly better than (7) (R’M interacts with M). This co-called Felkin-Anh model has been reconsidered by Heathcock in a series of papers [lOa]. He found that steric and electronic effects are sometimes comparable for two substituents (e.g. OMe and Ph), so that altogether four reactive conformations have to be considered: two for OMe and two for Ph in the role of L. Such considerations have also been the subject of ab-initio calculations by Houk [lob]. Some time ago, Houk extended the FelkinAnh concept to the stereochemistry of C=Cadditions (“Houk’s model” [ll]). In this case, the reactive conformations are (8) (= (6)) and (9)(= (7)). In contrast to the carbonyl addition, no repulsive interactions need here be considered. Hence, orthogonal quasicyclic transition states are postulated, and the reactive conformation must be so chosen that a minimum of steric interactions arises inside the cyclic framework. This means that (9)is a better geometry than (8). Despite this fascinating theoretical evolution, reported cases of high Cram-Felkin-Anh selectivity have been rare for some years. Only quite recently have new solutions to this problem emerged. One possibility is replacement of the traditional Grignard or organolithium compound by novel organometallics. For example, the trialkoxy titanates ( i f b ) / ( i f c )show a far superior Felkin-Anh selectivity in many cases [12,13]. High selectivity is also found for the

(11) M =

C r a m : anti-Cram

k j 2 2. HCI L HzC’ I

BnO

OH

Bn = Benzyl

OH

2 -Desoxy- L -1yxo-

hexose”)

6

Stereodifferentiating Addition Reactions

addition of tin(I1) or zinc diallyl to alkoxy aldehydes like (12) and (13). Fuganti [14] and Mukaiyama [lS] utilized this observation in certain monosaccharide syntheses. High Felkin-Anh selection was also found for 2-metallated furane [15a], thiazole [lsb] and chromium(I1) ally1 reagents [lSc]. Similarly, the Cram-Felkin-Anh selectivity of ester enolates may be dramatically enhanced by using the 0-silyl-derivatives (14b) under BF3catalysis instead of the lithium compounds (14a) [16].

<: H2C

(10)

CH,

(18)

0“““‘ CH3 CH3

@,,Y5fR*+ 0 OH

(19) anti-Cram

OH 0

(20) Cram

OSiMe3

(R)-(18) R’ = <.Ph

: (19) : (20) = 1 : 1.5

CH3

OSiMe3

(S)-(18) R‘

=

3 - c :~ (19) ~ : (20) = 8 : 1 Ph

+ P h C CbHO Z M e

entiation” is by no means restricted to carbonyl additions. It can be extended to any kind of addition between prochiral sp2-centers.

(16)

(15)

( 1 4 ~M )

CH,

( 14)

Ph$CO,Me OH

1

(W77)

Li:

(IS) : ( 1 6 )

=

3 :1

( 1 4 b ) M = SiMe,tBu: ( 1 5 ) : (16) = 1 5 :

A conceptually different approach makes use of “double stereodifferentiation”. This means that the effect of the chiral center in the carbony1 compound is superimposed upon a second stereodirecting effect from the nucleophile. If both effects operate in the same direction, “matched” stereocontrol is achieved, and the individual effects are mutually reinforcing. In the “mismatched case the individual effects are counteracting and stereocontrol is drastically reduced [17]. For example, in the addition of the chiral enolate (18) to the a-chiral aldehyde (S)-(17) the Cram product is hydroxy ketone (20). It can be seen that the influence of the enolate overrides the effect of (17): weak Cram selection is observed for (R)-(18),whereas (S)(18) strongly induces formation of the antiCram adduct (19). With (R)-(17) these selectivites are reversed, so that (R)-(18)leadsto weak anti-Cram and (S)-(18)to strong Cram selection [17a]. This principle of “double stereodiffer-

C = C-Additions Following “Houk‘s Model 79

Houk’s model has been applied to hydroborations [19], osmylations [20], and cycloadditions [21]. Significant stereoselection may be achieved by utilizing the “antiperiplanar effect” [9] of an OR-substituent, which adopts the position of substituent L. Thus, in the Diels-Alder addition of the in-situ diene (21) to acrylic ester (22) a 4:1-ratio is observed in favor of the “Houk product” (23). In a similar fashion, Houk’s model describes cuprate additions to enone systems like (25).The selectivity in favor of (26) may be explained via the transition state (27).

Chelate Cram Model In his original publication [l] Cram discussed a “cyclic model” in addition to the acyclic one. The cyclic model, now better known as the “chelate Cram model”, should be operative in

OAc

4

'& R

\

/

(23)

Cram's Rule: Theme and Variations

iMea Bu

+

AcO ' f & -Q iMe,tBu

\

OMe

4

:

l

/ OMe

(241

is thus opposite to the Felkin-Anh model. It turns out that the chelate model is far more reliable and efficient than the non-chelate model. In particular, ketones like (29) exhibit an extraordinary degree of stereoselection[23]. Applications in synthesis are manifold, one example being the conversion of diol (30) into racemic muscarine [24]. However, no reliable

(2-5)

HA

> 97% (26)

H

-

-

(30)

OMe

B n e O B n II

CH2

7

transition state

the case of a-alkoxy, a-hydroxy-, and a-aminocarbonyl compounds. Prior to organometallic addition the cation M forms a chelate (28) which is attack from the least hindered face, i.e. from the side of S.The correspondinginduction

BnO-0Bn

e

,.CHaNMe3

Chelate Cram Model

8'

HO

> 100 : 1

cle

muscarine chloride

XJ : 1 anti-Cram seiectivip)

8

Stereodifferentiating Addition Reactions

121M. T. Reetz, Top. Curr. Chem. Res. 106,l (1982). Monography: Organotitanium Reagents in Organic Synthesis, Springer, Berlin, 1986. 131 B. Weidmann and D. Seebach, Angew. Chem. 95, 12 (1983), Angew. Chem. Int. Ed. Engl. 22, 31 (1983). [14] G. Fronza, C. Fuganti, P. Grasselli, G. PetrocchiFanton, and C. Zirotti, Tetrahedron Lett. 23, 4143 (1982). [IS] T. Mukaiyama, T. Yamada, and K. Suzuki, Chem. Lett. 1983, 5. [l5a] S. Pikul, J. Raczko, K. Anker, and J. Jurczak, J. Am. Chem. SOC. 109,3981 (1987) and ref. cited. [ISblA. Dondoni, G. Fantin, M. Fagangnolo, A. Medici, and P. Pedrini, J. Org. Chem. 54, 693 (1989). [l 5c] J. Mulzer, Th. Schulze, A. Strecker, and W.Denzer, J . Org. Chem. 53, 4098 (1988). [16] C. H. Heathcock and L. A. Flippin, J . Am. Chem. SOC.105, 1667 (1983). [17] S. Masamune, W.Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 97, 1 (1985); Angew. Chem. Int. Ed. Engl. 24, 1 (1985). References [17a] S. Masamune, Sk. A. Ali, D. L. Snitman, and D. S. Garuey, Angew. Chem. 92, 573 (1980); Angew. Chem. Int. Ed. Engl. 19, 557 (1980). [I] D. J. Cram and F. A. Abd Elhafez, J. Am. Chem. SOC.74, 5828 (1952). For a discussion see: E. L. [18] D. A. Evans, J. V.Nelson, and T. R. Taber, Top. Stereochem. 13, l(1983). Eliel, in Asymmetric Synthesis (J. D. Morrison, Editor). Vol. 2A, p. 125, Academic Press, 1983. [19] Y.Kishi et al., J. Am. Chem. SOC.101,259 (1979), [2] V. Prelog, Helv. Chim. Acta 36, 308 (1953). 102, 7962 (1980), Tetrahedron Lett. 1979, 4343. [3] V. Prelog and G. Helmchen, ibid 55, 2581 (1972). [2O]J. K. Cha, W.J. Christ, and Y.Kishi, Tetrahedron [4] D. Seebach and V.Prelog, Angew. Chem. 94,696 Lett. 24, 3943 (1983). (1982), Angew. Chem. Int. Ed. Engl. 21, 654 [21] R. W . Franck, T. V.John, K. Olejniczak, and J. F. Blount, J. Am. Chem. SOC.104, 1106 (1982), cf. (1982). [5] J. W. Cornforth R. H. Cornfort, and K. K. MaD. Horton, T. Machinami, Y. Takagi, C. W.Bergthews, J . Chem. SOC.1959, 112. mann, and G. C. Chirstoph, J. Chem. SOC.,Chem. [6] G. J.. Karabatsons, J. Am. Chem. SOC.89, 1367 Commun. 1983, 1164. J. Mulzer, M. Kappert, G. Huttner, and I. Jibril, Tetrahedron Lett. 26, 1631 (1967). (1985). [7] cited in E. L. Eliel, Stereochemie der KohlenstoffVerbindungen, Verlag Chemie, Weinheim, 1966, [22] W . R. Roush, B. Lesur, Tetrahedron Lett. 24, 2231 (1983). p. 290. [23] W.C. Still and J. H. McDonald ZZZ,Tetrahedron [8] M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968, 2199. Lett. 21, 1031 (1980). [9] P. Caramella, N. G. Ronda, M. N. Paddon-Row, [24] W. C. Still and J. Schneider, J. Org. Chem. 45, K. N. Houk, J. Am. Chem. SOC.103, 2438 (1981). 3375 (1980). [lo] N. T. Anh, Top. Curr. Chem. 88, 145 (1980); H. [25] M. Asami and T. Mukaiyama, Chem. Lett. 1983, 93. B. Biirgi, J. D. Dunitz, J. M . Lehn, and G. Wipff; [26] M. T. Reetz, Angew. Chem. 96, 542 (1984), AnTetrahedron 30, 1563 (1974). gew. Chem. Int. Ed. Engl. 23, 556 (1984). [IOa] E. P. Lodge and C. H. Heathcock, J . Am. Chem. SOC.109, 2819, 3353 (1987). [27] G. E. Keck, S. Castellino, S. D. Kahn, and W. J. Hehre, Tetrahedron Lett. 28, 279, 281 (1987). [lob] Y. D. W u and K. N. Houk, J. Am. Chem. SOC. [28] M. T. Reetz, M. W. Drewes, and A. Schmitz, 109, 906, 908 (1987). [ I l l M . N. Paddon-Row, N. G. Rondan, and K. N. Angew. Chem. 99, 1186 (1987), Angew. Chem. Int. Ed. Engl. 26, 1141 (1987). Houk, J. Am. Chem. SOC.104, 7162 (1982).

criteria have yet been found for making a clear prediction whether a given substrate-reagent combination will follow the chelate or the nonchelate pathway. For example, Grignard additions to the dialkoxy aldehydes (12)/(13)are non-chelated, whereas aldehyde (31)shows high chelate-induced selectivity [25]. Important factors apparently are the Lewis acidity of the cation and the nature of the 0- or N-protecting group [26,27,28]. Its numerous deficiencies notwithstanding, Cram’s rule has triumphed as one of the central ideas in acyclic 1,2-~tereoinduction.It is quite likely that the weaknesses of the original formulation inspired many of the fascinating experiments reported in recent years.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Stereoselective Reactions of Cyclic Enolates

The search for stereoselective reactions, especially in noncyclic systems, is one of the more active areas of current research. There is hardly a single recent report of a natural‘product synthesis in which stereoselectivity is not claimed in the title. Often it is not enantioselectivity, but rather diastereoselectivity that poses the more difficult problems [l]! The quest for generally applicable principles to the understanding of stereoselectivity has almost certainly not ended despite the wealth of information to be found in a number of very useful reviews and books [2-41. According to McGarvey [S] the problem of stereoselectivity in kinetically controlled reactions of chiral enolates can be analyzed in terms of three models: chelate control (I),covalent control (2),and stereoelectronic control (3). Electronic influences can certainly not be excluded in cyclic models. However, steric effects - which are in a delicate balance with electronic interactions [6] in a case such as (3)

MO

- are more clearly defined in cyclic than in open chain models. Stereochemicalresults can be relatively easily predicted if the reaction conditions allow a choice between chelate control and non-chelate control [7, 81. This contribution presents examples that illustrate the possibility of stereocontrol with cyclic enolates on the basis of the covalent model (3).In all the cases described it is possible to transform cyclic compounds into open chain molecules by simple chemical operations (e. g. hydrolysis). We examine first the 0-lactones investigated by Mulzer et al., representing the smallest ring system meeting above requirements. Alkyl halides, and aldehydes [9] or Michael acceptors [lo] may be used as electrophiles.In both cases the electrophile - an aldehyde is shown in (4) - enters opposite the bulky substituent R’ (R’ = tert-butyl), which effectively shields one side of the rigid planar ring system. In addition, the third chiral center of the chiral alcohol (5) is generated with high selectivity due to steric interactions between R2 and R3,which favor transition state (4). Mulzer has called this phenomenon “Dreierdiastereoselectivitat”.

10

Stereodgferentiating Addition Reactions

Five-membered ring systems with various heteroatoms in the P-position relative to the chiral center have also been intensively investigated. Alkylation of the 0-amido butyrolactone (6),which can be converted into the dianon (7) by treatment with 2.2 equivalents of lithium diisopropylamide, was studied by McGarvey in the context of his synthesis of amphotericin B [S]. Addition of methyl iodide also occurs in this case preferentially from the top of the molecule, and the mono-alkylation products (8)and (9)are formed in a ratio of 11 : 1. H\

(6)

11

1

(8)

(9)

The center that transfers the chirality is situated y to the enolate. The investigations of Seebach et al. [I1 -141 have shown that effective stereoselectivity is also possible with chiral center in the P-position. The 1,3-dioxolanes ( I O U ) [Ill, 1,3-oxazolidines(fob) [12], and 1,3imidazolidinones (1Oc) [I 31 prepared from chiral a-amino or a-hydroxy acids have the structural features of both lactones or amides and acetals or aminals. The substituent R is derived from the substrate and may vary widely depending upon the chiral natural products available. In any case, the reaction is essentially the same, as illus-

:vxo

3’

R

(roa): X = Y = 0 ( l o b ) : X = 0; Y = NBz

(IOc): X = NCH,

Y = NBz

trated by the example of L-lactic acid (11)[ll]. Benzaldehyde and pivalaldehyde have been shown to be best suited for acetal formation with (11)due to the pronounced steric effect of the bulky tert-butyl or phenyl groups. Interestingly, the cis-acetal is the major product in kinetically controlled acetal formation. Diastereomeric purity of the acetal is a prerequisite to enantiomeric purity of the subsequent products. Fortunately, this is no problem since (12) is crystalline and can easily be purified. Although the original chiral center of (12) is destroyed by treatment with LDA in the subsequent enolization step, a base-stable chiral center is created in the position opposite, and here the introduction of an incoming electrophile can be directed from the Re side with high selectivity (typically > 97% ds). This process has been called “self-reproduction of chirality” by Seebach [14]. Acetal cleavage leads to enantiomerically pure tert-alcohols that are otherwise

“CH,

Reactions of Cyclic Enolates

11

r

E

not easily accessible. An elegant example appears in the frontalin synthesis described elsewhere in this book [lS]. In all the endocyclic enolates considered so far the ring system is flattened by at least two sp2-centers,and the electrophile adds from the rear of the molecule irrespective of the position of the shielding substituent. But what about exocyclic enolates such as (16) or (19),derived from the esters (IS)and (18)? Here the bicyclic chelate structure (16), in which the tert-butyl substituent is pushed more or less into an equatorial position, favors addition of the electrophile from the same side, afford the cis-adduct (17)[16]. Similar conditions prevail in enolate (19)of the acetonide (18).Nevertheless, reaction of (18)with alkyl halide leads to cis-product (20) [181, while aldehydes give trans-adducts (21) ~171. The extent of asymmetric induction does not necessarily decrease if the double bond of the enolate is situated one bond further from the ring. This has been demonstrated in the elegant asymmetric syntheses of amino acids by Evans [19] and Trimble and Vederas [20]. It is likely that the enolate derived from (22)also exists as the chelated structure (23).Conformational fixation in the chelate permits the substituent R’

to direct the approaching reagent quite emciently ( > 97% ds). Di-tert-butylazodicarboxylic esters are also interesting electrophiles, giving in enantiomerically pure form not only uamino acids [after reduction of (241 but also the corresponding physiologically relevant ahydrazino acids. Let us return, however, to the “covalent model”. A typical example of the application of six-membered endocyclic enolates occurs in the asymmetric synthesis of amino acids via bislactime ethers such as (25),as elaborated by Schollkopf and cowerkers [21]. The nearly planar ion pair (26) obtained by deprotonation of (25) reacts almost exclusively from the top of the molecule (>95% ds) to afford the top of the molecule (>95% ds) to afford the adduct (27).Methyl esters of valine and the desired amino acid bearing the variable substituents R’ and R2 are liberated by acidic hydrolysis in alcoholic solution in virtually enantiomerically pure form. Aldehydes, epoxides, and Michael acceptors can also be used successfully as electrophiles [21]. Dihydroazines such as (28) are obtained by condensation of chiral a-hydroxy acids and amino acids, such as phenylalanine and they can be deprotonated as in (29)with potassium tert-butoxide. Diastereoselectivity in this case

12

Stereodfferentiating Addition Reactions

0

0

BOC-N-N-BOC

BocNH-NBoc

OCH,

depends much more on the nature of the substituent R’ than in the case of the bislactime ethers (25). If alkylation is carried out with methyl halide only 60% ds is observed for R’ = isopropyl, but selectivity increases to 92% ds when R‘ = tert-butyl even with a residue as small as methyl. The fact that the steric influence of the substituent is so much less pronounced than in the case of the bislactime ethers may be a result of deviations from planarity in the dihydroazine system (26).

4 +

H 3 3 F H 3 CH30

(27)

Fortunately, organic chemists have more than just monocyclic compounds in their treasure chests. Bicyclic systems comprising two five-membered rings are also very popular. For steric reasons the ring fusion in such systems is necessarily cis, which leads to particularly ef-

(30)

fective shielding of the endo side. This circumstance has been elegantly exploited by Meyers et al. [24] in the synthesis of chiral cyclopentenones. Selectivity remains relatively high even if one of the rings is expanded to six-members as demonstrated by extension of the synthesis to cyclohexenones with quarternary chiral centers [24]. The commercially available aminodiol (31) condenses with 5-oxohexanoic acid to yield bicyclic lactam (32) as the major product (84: 14) together with other isomers. An endolexo mixture is obtained in the first alkylation of (32) with RX, but this center becomes planar with subsequent formation of the enolate and the decisive second alkylation occurs with > 97% ds from the exo side to afford (33).The neighbouring hydroxymethyl group serves only to facilitate reduction of the lactam to an intermediate aminal (anchimeric effect). Further treatment with Bu4NH2P04leads directly to the desired cyclohexenone (35) via the intermediate ketoaldehyde (34). One might still wish to inquire about the reliability of predictions based on the “covalent model” for the stereochemical outcome of cyclic enolate reactions. With the exception at the more flexible six-membered ring systems, in which other factors contribute to axial vs. equatorial attack [26a], the examples presented here show quite good agreement between theory and

Reactions of Cyclic Enolates

Ph

0

Ph

o

2. IDA-HMPA R’X

1 4 R‘

(33)

OHC O b -R ’

R‘

(34)

R’

R

(35)

experiment (for a recent theoretical treatment of enolate reactions see ref. 25). However, it is certainly dangerous to oversimplify, and factors such as enolate aggregation, the possibility of chelation, and the nature of the electrophile [e.g. (19)]must also be considered, as shown in the recent review by Seebach [26b].

References [I] B. K. Sharpless, lecture given at the Nobel Symposium on “Asymmetric Organic Synthesis” Karlskoga/Schweden, Sept. 1984. [2] C. H. Heathcock in J. D. Morrison (Ed.): “Asymmetric Synthesis”. Vol. 3, p. 111, Academic Press, Orlando. FL 1983. [3] D. A. Evans, J. V.Nelson, and T. R. Taber, Top. Stereochem. 13, l(1982). [4] a) T. Mukaiyama, Org. React. 28, 203 (1982);b) R. W. Hoffmann, Chem. Rev. 89, 1841 (1989). [5] G. J. McGarvey, J. M. Williams, R. N. Hiner, Y. Matsubara, and T. Oh, J. Am. Chem. SOC.108, 4943 (1986). [6] a) P. Delongchamps: “Stereoelectronic Effects in Organic Chemistry”, Pergamon Pres, Oxford

13

1983; b) A. S. Cieplak, B. D. Tait, and C. R. Johnson, J. Org. Chem. 54, 8447 (1989). [7] M. Reetz, Angew. Chem. 96,542 (1984).Angew. Chem. Int. Ed. 23, 556 (1984). [8] C. Siege1 and E. R. Thornton, J. Am. Chem. SOC. 111, 5722 (1989). [9] J. Mulzer and A. Chucholowski, Angew. Chem. 94,787 (1982), Angew. Chem. Int. Ed. Engl. 2f, 771 (1982). J. Mulzer and T. Kerkmann, J. A. Chem. SOC.102, 3620 (1980). [lo] J. Mulzer, A. Chucholowski, 0. Lammer, I. Jibrill, and G. Huttner, J. Chem. SOC.Chem. Commun. 1983, 869. [ I l l D. Seebach, R. NaeJ and G. Calderari, Tetrahedron 40, 1313 (1984). [I21 D. Seebach and A. Fadel, Helv. Chim. Acta 68, 1243 (1985). [I31 J. D. Aebi and D. Seebach, Helv. Chim. Acta 68, 1507 (1985). [14] D. Seebach, R. Irmwinkelried, and T. Weber in: “Modern Synthetic Methods 1986”. Vol. IV, p. 125. Springer Verlag, Berlin 1986. [l5] R. Naef and D. Seebach, Liebigs Ann. Chem. 1983,1930;M . Braun, Nachr. Chem. Tech. Lab. 33, 392 (1985). [I61 D. Seebach and M. Coquoz, Chimia 39, 20 (1985). [I71 W.Ladner, Chem. Ber. 116, 3413 (1983). [I81 R. W .Hoffmann and W.Ladner, Chem. Ber. 116, 1631 (1983). [19] a) D. A. Evans, T.C. Britton, R. L. Dorow, and J. F. Dellaria, J. Am. Chem. SOC. 108, 6395 (1986); b) D. A. Evans, J. S. Clark, R. Metternich, V.J. Novack. and G. S. Sheppard, J. Am. Chem. SOC.112, 866 (1990). [20] L. A. Trimble and J. C. Vederas, J . Am. Chem. SOC.108, 6397 (1986). [21] Review: U.Schollkopf in J. Streith, H . Prinzbach, and G. Schill (Eds): “Organic Synthesis, an interdisciplinary challenge” (Proc. 5th IUPAC Symp. Org. Synth., p. 101). Blackwell Scientific Publications, Oxforf 1985. [22] U. Schollkopf and R. Scheuer, Liebigs Ann. Chem. 1984, 939. [23] A. I. Meyers and K. T. Wanner, Tetrahedron Lett. 26, 2047 (1985). [24] A. I. Meyers, B. A. Lejker, K. T. Wanner, and R. A. Aitken, J . Org. Chem. 51, 1936 (1986). [25] Y. Li, M. N. Paddon-Row, and K. N. Houk, J. Am. Chem. SOC.110, 3684 (1988). [26] a) K. Tomioka, H. Kawasaki, K. Yasuda, and K. Koga, J. Am. Chem. SOC.110, 3597 (1988); b) D. Seebach, Angew. Chem. 100, 1685 (1988). Angew. Chem. Int. Ed. Engl. 27, 1624 (1988).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Chiral Sulfoxides in the Synthesis of Enantiomerically Pure Compounds

Linguistic purists may not appreciate it, but acronyms for chemical expressions are increasingly appearing in the chemical literature [13, and there can be no doubt that they facilitate rapid communication among specialists. Recently Seebach [2] introduced the expression “EPC synthesis” for the synthesis of “Enantiomerically Pure Compounds”. The advantage of this acronym is its conceptual breadth, which includes “synthesis of enantiomerically pure compounds via incorporation of chiral natural products” as well as “asymmetric synthesis” and “resolution of racemates”. The application of sulfoxides in organic synthesis has long been documented [3] but the new goal of EPC synthesis has opened the door to novel perspectives [4-61 that are highlighted here. Sulfoxides with two different alkylor aryl substituents [e.g., R. and R’ in (f)] are chiral; the remaining positions on the pyramidal structure are occupied by oxygen and a lone pair of electrons.

In contrast to the correspondingly substituted tertiary amines, thermal racemization normally occurs only above 200°C (AH’ = 150 to 180 kJ mol-‘). Pyrolytic elimination be-

gins at lower temperatures and can serve as the basis for synthesizing chiral olefins [7]. Ally1 sulfoxides rearrange to ally1 sulfenates [S], a fact that has recently been skillfully exploited by Grieco et al. [9] in a synthesis of (+)-cornpactin (Scheme 1). Noteworthy are the mild conditions (room temperature) under which the sulfoxide (6) rearranged to an allylic sulfenate, which was in turn reduced by trimethyl phosphite to the allylic alcohol (7). The chiral integrity of the neighboring centers was fully retained during the course of these reactions. The chiral building block (4) was derived from tri-0-acetyl-Dglucal [lo]. This was coupled via a Diels-Alder reaction with the enantiomerically pure dienophile (3), obtained by resolution of the corresponding racemate. Similarly, no racemization is observed in the treatment of sulfoxides with base, a decisive factor in this synthetic application. However, preliminary experiments (notably those of Tsuchihashi) [l 11 were disappointing. Rather low diastereoselectivitieswere observed in the reaction of carbanions from sulfoxides with carbonyl compounds. This was all the more disappointing since promising differences were measured in the kinetic acidities of the diastereomeric amethylene protons. For example, the observed rate differencefor base-catalyzed H-D exchange in the conformationally frozen centrosymmetric sulfoxide (8)is lo3 [12].

Chiral Sulfoxides

15

Scheme 1 A key step in the compactin synthesis of Grieco et al. [ 9 ]

+ 1. MPBA

0

SPh

S-Ph

1 rearragement 2 P(OME)~

#R [-]

0 O = S - Ph

f 7)

(6)

& .

R = M e o ~ o M e

i

Facile acid-catalyzed isomerization served Solladie as a way of escaping this dilemma. At the same time, the enantiomerically pure sulfoxides became readily available thanks to an equilibration technique [13]. Thus, the sulfinate menthyl esters (9)and (10)could be equilibrated with hydrochloric acid, and the pure (S)-isomer (10) was easily isolated by crystallization (Scheme 2).

o

H3C CH3

Scheme 2 Equilibration of diastereoisomeric sulfinate esters, synthesis of the enantiomerically pure sulfinyl acetate (ll),and stereoselective reaction of ( 1 1 ) with ketones.

(9) R

=

menthyl

(crystallin) (10)

16

Stereodifferentiating Addition Reactions

The enantiomerically pure sulfinyl acetate (11)was obtained in 90% yield by substituting the magnesium enolate of tert-butyl acetate for the 0-menthyl group [13]. The ester group enhances the acidity of the protons adjacent to the chiral sulfoxide, and excellent diastereoselectivity is observed in the reaction of the magnesium enolate of (If) with carbonyl compounds to afford (12).This high selectivity is once again due to formation of the magnesium chelate complex (14). Much better stereodifferentiation is possible here than with more conformationally flexible transition states [14]. The reversal of the normal stereochemical outcome in the reduction of P-ketosulfoxides with diisopropyl aluminum hydride (DIBAL) in the presence of zinc can be interpreted in a similar way [l5]. Finally, to conclude the general synthetic path outlined in Scheme 2, the P-hydroxy ester (13) is prepared with an ee of 66 to 95%

by reductive removal of the sulfoxide group using aluminum amalgam. Only the chiral information from the sulfoxide remains, and it is obtained at relatively low cost through use of the inexpensive reagent menthol. The relatively low a- C - H acidity of a sulfoxide (about midway between the acidity of benzylic protons and protons c1 to an ester) can also be increased by a phosphonate group. The so-called Mikolajczyk phosphonate (15) [16] was elegantly incorporated in Solladit's EPC synthesis of the chromane ring of vitamin E [17] (Scheme 3). Optically active sulfoxides result from the condensation of the doubly activated chiral sulfoxide (15) with the monoacetal of methylglyoxal. Unfortunately, however, the product is 1 : l mixture of E/Z-isomers. The route to the pure E-vinyl lithium compound (16) again involves an equilibration, this time under basic conditions with lithium diisopropylamine. The explanation for the shift of equilibrium in the direction of the E-vinyl compound (16) may lie in the favorable complexation of lithium with the two oxygen atoms of the neighboring acetal. The synthesis was completed as in the general reaction of Scheme 2, by diastereoselective ad-

Scheme 3 Synthesis of an enantiomerically pure formylchromane precursor to vitamin E.

(Equilibration)

Chiral Suljoxides

17

Scheme 4 (+)-Pentalene synthesis via chiral sulfinyl anions by Hua [18].

1. K2C03/CH30H 2. CH3MgBr

(24)

3. Deoxygenation 4. Dehydration

dition of the aldehyde derived from trimethyl hydroquinone, affording (17). The phenolic group was then deprotected by treatment with fluoride (R = SiR3) and the chromane ring closed by addition of the phenolate to the activated double bond. It is noteworthy that chirality is here transfered via a kind of allylic sulfoxide substitution to a center three atoms away! A third example of a-proton activation involves ally1 sulfoxides, which Hua [IS] used twice in the synthesis of (+)-pentalene (Scheme 4). Certain pentalenolactones derived from (25) show activity against both bacteria and tumors [19]. In the first application, enantioselective Michael addition of the allylsulfinyl anion (19) permitted kinetic resolution of racemic (20);the desired (S)-(20)remained unchanged in solution and could be isolated in 45% yield (Scheme 4). Enantiomerically pure (20) was subsequently converted to (23) in 91% yield and 82% ee by treatment with two equivalents of the racemic sulfinyl anion (22). In this case it was the en-

(25)

antiomer eat-(22) that remained in solution unchanged! Key steps in the further transformations were acid catalyzed dehydration to the tricycle (24)of the vinylsulfide obtained by zinc borohydride reduction (go%), followed by a Grignard reaction, deoxygenation, and dehydration to the final product (25). Chiral sulfoxides have proven to be very useful reagents in EPC syntheses, as the few examples in this overview have illustrated. For recent examples of conjugate addition to vinyl sulfoxides see ref. 20, 21. The availability via equilibration of sulfinylmethyl esters has removed a major obstacle to their broader application.

References [l] A useful list of acronyms in organic chemistry can be found in: G. H. Daub, A. C . Leon, I. R. Silverman, G. W . Daub, and S. B. Walker, Aldrichimica Acta 17, 13 (1984).

18

Stereodifferentiating Addition Reactions

[2] a) D. Seebach and E. Hungerbuhler, in R. Scheffold (Ed.): “Modern Synthetic Methods II”. Salle and Sauerlander, Frankfurt 1980. p. 93; b) D. Seebach, R. Imwinkelried, and T. Weber, ibid. Vol. IV, p. 125, Springer Verlag, Berlin 1986. [3] B. A. Trost, Chem. Rev. 78, 363 (1978). [4] G. Solladie‘,in J. D. Morrison: “Asymmetric Synthesis”, Vol. 2, p. 157, Academic Press 1983. [5] G. H. Posner, in J. D. Morrison (Ed.): “Asymmetric Synthesis”. Vol. 2. p. 225, Academic Press 1983. [6] G. Solladie‘, Synthesis 1981, 185. [7] B. A. Trost, T. N. Salzmann, and K. Hirois, J. Am. Chem. SOC.98, 4887 (1976). [8] R. Tang and K. Mislow, J. Am. Chem. SOC.92, 2100 (1970). [9] P. A. Grieco, R. Lis, R. E. Zelle, and J. Finn, J. Am. Chem. SOC.108, 5908 (1986). [lo] E. J. Corey, L. 0. Weigel, A. R. Chamberlin, and B. Lipshutz, J. Am. Chem. SOC.102, 1439 (1980). [ll] G. I. Tsuchihashi, S. Iriuchijma, and M. Ishibashi, Tetrahedron Lett. 1972, 4605. [12] R. R. Fraser, F. J. Schuber, and Y. Wi&eld, J. Am. Chem. SOC.94, 8795 (1972).

[13] C. Mioskowski and G. Solladie‘,Tetrahedron 36, 227 (19801 [14] For a review on chelation control see: M. Reetz, Angew. Chem. 96, 542 (1984); Angew. Chem. Int. Ed., 23, 556 (1984). [l5] a) G. Solladik, G. Demailly, and C. Greck, Tetrahedron Lett. 26, 435 (1985); b) H. Kosugi, M. Kitaoka, A. Takahashi, and H. Uda, J. Chem. SOC.Chem. Commun. 1986,1268; c) y.C. Carreiio, J. L. Garcia Ruano, A. M. Martin, C. Pedregal, J. H. Rodriguez, A. Rubino, J. Sanchez, and G. Solladik, J . Org. Chem. 55, 2120 (1990). [16] M. Mikolajczyk, S. Grzejszak, and A. Zaorski, J. Org. Chem. 40, 1979 (1975). [17] a) G. SolladiP, Chimica Scripta 25, 149 (1985); b) G. Solladie‘ and G. Moine, J . Am. Chem. SOC. 106, 6097 (1984). [18] D. H. Hua, J. Am. Chem. SOC.108, 3835 (1986). [19] S. Takahashi, M. Takeuchi, M . Arai, H. Seto, and N. Otake, J. Antibiot. 1983, 226. [20] G. H. Posner and T. G. Hamill, J . Org. Chem. 53, 6031 (1988). [21] K. Takaki, T. Maeda, and M. Ishikawa, J. Org. Chem. 54, 58 (1989). %

,

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Chiral Cyclic Acetals in Synthesis

In addition to their well-established role as protective groups for carbonyl compounds, cyclic acetals have also served increasingly in recent years as valuable synthetic intermediates. This is particularly true for enantiomerically pure cyclic acetals involved in asymmetric syntheses. Because of the rigid stereochemistry characterizing the heterocyclic acetal ring, stereoselectivity is not restricted only to the ring, but may under some conditions apply to reactions at distant sites, or to the acetal center itself. It is the latter case that appears to be most useful and interesting, since Lewis acid-catalyzed substitution at the acetal function permits C-C bond formation with a variety of carbon nucleophiles. Prerequisite to the general application of acetals in synthetic sequences is that they can be easily prepared under mild conditions. In those cases where classical acetal syntheses fail (i.e., acid-catalyzed reaction of aldehydes and ketones with dihydroxy compounds, or transacetalization), as with sterically hindered ketones or labile systems, acetals can ofR

-CHO

88.94% do

I

4

ten be prepared by the method of Noyori [l], in which a bistrimethylsilyl derivative of the dihydroxy compound is treated with the carbony1 component in the presence of the catalyst trimethylsilyl triflate.

Acetals as Temporary Chiral Auxiliaries It has long been known that stereocontrol can often be achieved in reactions involving cyclic acetals derived from chiral diols with C2 symmetry, since those are capable of differentiating between the re- and si-faces of a neighboring prochiral group. A good example is the asymmetric formation of cyclopropanes from a$-unsaturated carbonyl compounds via the Simmons-Smith reaction, in which acetals derived from diethyl tartrate provide both acyclic [2] [e.g. ( I ) -+(4)] and cyclic systems [3] with high diastereoselectivity. The directing effect of substituents attached to the chiral dioxolane skeleton caused by coordination with Grignard reagents can also be exploited to induce their stereospecific reaction with both open-chain and cyclic a-ketoacetals [e.g. (5) + (61[4].

20

Stereodifferentiating Addition Reactions

Terashima has utilized inexpensive tartaric acid derivatives to synthesize optically active anthracyclinone systems [S]. The key reaction is an asymmetric bromolactonization of an a$unsaturated ketone ketalized with tartramide, a reaction whose high regio- and diastereoselectivity is not limited to the model system (7). A further example of the adroit use of ketals based on tartaric acid is the bromination of aryl alkyl ketones to optically active a-bromo derivatives (10) via ketal (9),a process that is carried out on the industrial scale [6].

(1 5)

( 1 6)

on chiral columns [12] to enantiomerically pure parent compounds such as (11) (R = H) 1 and (1.9, so nothing should stand now in the H3C0 way of even broader application of these and 0, o , O I z 0. similar systems [13]. Seebach’s asymmetric syntheses of u-amino acids using chiral N,N-acetal 0 ‘C OCH, OCH, intermediates (15)are also dealt with in another chapter [14]. It was Seebach again who showed (7) (8) that not only five-membered, but also six-membered ring acetals can be valuable, including system (16), accessible from optically active 3Ar ’ 86% de ~ ~ ’ ~ hydroxybutyric x acid [7,15]. The powerful di’Br recting effect of the stereogenic acetal center in (16)is found not only in Michael additions and catalytic hydrogenations but also in [2 + 21 cyAnother possibility for diastereoselective recloadditions to the double bond. The imporactions at acetals takes advantage of a stereotance of chiral dioxinones for asymmetric regenic acetal center as the control element. Reactions has also been recognized by other recognizing that pivaldehyde and optically active search groups, as in the case of spirocyclic a-hydroxy and a-amino acids can be used to systems such as (17) and (18) [16,17]. Syntheses construct diastereomerically pure acetal-like starting from natural (-)-menthone always systems such as (11)Seebach developed a series lead to mixtures of (17) and (18), but this fact of procedures that have transformed these hetcan be exploited in a rather clever way. The erocycles into extraordinarily versatile chiral two isomers are readily separated, and since intermediates [7,8,9]. Thus, he was able to show steric factors assure that attack at the C=C that the enolate of (11)reacts with electrophiles double bond will be subject to similar effects in almost exclusively on the face opposite to the both cases, compounds derived from each of the sterically demanding tert-butyl group. This reaction principle, which also applies to the exo- enantiomeric series are accessible from a single cyclic enolates derived from (13), is discussed chiral auxiliary. Attack from the front is favored in reactions with nucleophiles and on catalytic elsewhere in this volume [lo]. In the meantime, Seebach has also developed hydrogenation, presumably due to effective simple routes involving classical resolution shielding of the back side by the isopropyl methods [l 13 or chromatographic separation group. However, in the case of [ 2 + 21 cycload-

w,i’

fk

Chiral Cyclic Acetals

ditions it is attack from the rear that is observed, probably because the reaction proceeds from a different conformation. The shortest synthesis to date of the optically active form of grandisol, reported by Demuth [16], is a beautiful application of this reaction. The crucial intermediate is (20), available with high diastereoselectivity, and a de Mayo reaction serves as the key step.

--_

employed as efficient chiral glycolate enolates. Conveniently enough, the expensive chiral auxiliary is readily recovered [18].

Acetals as Electrophilic Reactants A quite different aspect of the synthetic potential of chiral acetals is illustrated by Johnson's biomimetic cationic cyclization of the optically active acetal (25) [19]: stereochemical control of a C -C bond-forming reaction involving Lewis acid-catalyzed opening of an acetal ring with a nucleophile. The detour via a chiral acetal thus allows enantioselective addition of nucleophiles to aldehydes and ketones [(27)+ + (29)].The diverse nature of the possible reaction partners is impressive: alkylsilanes, silylacetylenes, silyl cyanides, a-silylketones, silylenol ethers, silyl ethers, silylketene acetals, alkyl Grignard reagents and alkyllithiums, alkyltrihalotitaniums, and dialkylcuprates. This strategy has been extensively utilized in the preparation of optically active alcohols [7,20], whereby a series of chiral dihydroxy compounds has been tested [e.g. (30) to (35)]. One general difficulty appears to be the final romoval of the chiral auxiliary, a process that usually requires several steps. Since the chiral auxiliary is destroyed in the process, the utility of SnCi,

Dioxolanones (23) and (24) are further examples of the novel principle of stereofacial differentiation by spirocyclic acetals. These compounds are readily prepared from 8-phenylmenthone by the Noyori method, and can be

21

k!,

,

85% dc

OH

(26)

(25)

R

H

'r( ).:::::::::::::::I::: 0

R H

x

Nu

OH

22

Stereodifferentiating Addition Reactions

H b O H

xo

HOMOH

\\\‘

Ph

Lewis acid

0

implies that it proceeds through the transoidal conformation (41). Both organoaluminum [21] and organocopper [22] reagents have been reported to serve as nucleophiles. In contrast to saturated aldehydes, @unsaturated systems are said to be amenable to the use of acetals of tartramide (32) as well [23].

Al’

the reaction is heavily dependent upon its availability and cost. Six-membered rings have been shown to provide better selectivity than fivemembered rings. The high diastereoselectivity often observed in the case of 1,3-dioxanes can be attributed to specific coordination of the Lewis acid with the acetal oxygen on the sterically less hindered face, opposite to the axial methyl group [cf. (36)]. This hypothesis is supported by the different stereochemical course of reduction with aluminum hydrides, since hydride evidently attacks intramolecularly from the same face [cf. (37)]. A fixed conformation for the heterocycle is of course a prerequisite for high selectivity. This is always the case for aldehydes, since the hydrogen adopts an axial position. With ketals it is necessary that the substituents R’ and R2 be sufficiently different in size, as is true, for instance, in alkynyl ketones, because the axial position is occupied by the smaller alkyne group. The previously described complexing effect then permits selective ring opening to either enantiomer. Thus (38) can be made to yield selectively either (39) or

Lewis acid

Another clever utilization of spiroketals, this time with chiral induction from the carbonyl component, has been developed by Oku for the enantioselective differentiation of prochiral diols [24]. For example, if 1-menthone is acetalized with the bistrimethylsilyl ether of a 2substituted 1,3-propandiol, then it is exclusively the thermodynamically more stable spiroketal (43) that is formed. Ketal cleavage with the trimethylsilylenol ether of acetophenone in the presence of titanium chloride leads to selective

(40).

It is worth pointing out that acetals of a$unsaturated aldehydes also undergo remarkably diastereoselective reactions in most cases, usually by nearly exclusive anti-SN2‘ attack. The reaction leads to (E)-enol ethers (42),which

(43&~0H

Chiral Cyclic Acetals

opening of the equatorial C - 0 bond with retention of configuration, evidently as a result of better coordination of the Lewis acid with the equatorial oxygen function. The enantiomerically pure 2-substituted 1,3-propandiol derivative can be released under basic conditions after protection or appropriate functionalization. Such a selective spiroketal cleavage can also provide access to other prochiral diols [25] and it has been employed for the resolution of racemic diols as well [26]. A new aspect to the value of acetals was revealed by an investigation of the nucleophilic ring-opening reactions of acetal-like derivatives of hydroxycarboxylic acids such as (34) and (35). The two reacting C - 0 bonds are then no longer simply diastereotopic to each other: they also differ constitutionally. The superior leaving-group properties of a carboxylate as compared with a hydroxyl function simplifies the reaction with the nucleophile, so the transformation depends less critically upon the reaction conditions than in the case of acetals based on diols (30) to (32). 3-Hydroxybutyric acid (35), a reagent introduced by Seebach [7,28], has been found to be even more satisfactory than the system (34) originally utilized by Kellog [27]. Acetal formation with aldehydes leads predominantly to the thermodynamically more stable cis systems ( 4 4 , which can be opened to (46) with a host of nucleophiles in the presence of Lewis acids. Astonishingly, high diastereoselectivities are also observed if the starting material is the crude cis/trans mixture isolated directly from the acetalization reaction. The optically active alcohol can be released from (46)quite easily using either lithium diisopropylamide or potassium tert-butoxide, so that according to Schreiber [29] and Seebach [28] this method repre-

23

sents an alternative to the established methods for preparing enantiomerically pure alcohols. One advantage of this dioxanone method over the previously deseribed acetal methods based on diols (30)to (33)is that (R)-and (S)-hydroxybutyric acids are easily obtained even though they are still expensive. Moreover, there are no delicate reactions to perform and the chiral auxiliary can be removed by means of a strong base without prior oxidation.

An interesting extension in the field of acetallike derivatives has recently been reported [30]: dioxolanones of type (47) from a#-unsaturated aldehydes can be opened to allylnickel complexes (48) with Ni(CODh, and these can in turn be converted to (49) by reaction with trimethylsilyl chloride. On irradiation, (49) reacts with alkylating agents to yield enol ethers (50), which may be regarded as a new type of C3 component for use in enantioselective reactions. Other applications of these systems may be anticipated in the near future, including Lewis acid or palladium-catalyzed additions to (47) and alternative reactions of (48).

References R

Nu (45)

(46)

[l] R. Noyori, T. Tsumoda, and M . Suzuki, Tetrahedron Lett. 1980,1357. [2] I. Arai, A. Mori, and H . Yamamoto, J. Am. Chem. SOC. 107, 8254 (1985).

24

Stereodifferentiating Addition Reactions

[3] E. A. Mash and K. A. Nelson, J. Am. Chem. SOC. 107, 8256 (1985); Tetrahedron Lett. 27, 1441 (1986). [4] Y. Tamura, H. Kondo, H. Annoura, R. Takeuchi, and F. Fujioka, Tetrahedron Lett. 27, 81, 2117 (1986); M. P. Heitz, F. Gellibert, and C. Mioskowski, Tetrahedron Lett. 27, 3859 (1986). [5] M. Suzuki, Y. Kimura. and S. Terashima, Bull. Chem. SOC.Jap. 59, 3559 (1986) and ref. cited. [6] G. Castaldi, S. Cavicchioli, C. Giordano, and F. Uggeri, Angew. Chem. 98, 273, Int. Ed. Engl. 25, 259 (1986); G. Castaldi and C. Giordano, Synthesis 1987, 1039. [7] D. Seebach and R. Scheffold (Ed.): “Modern Synthetic Methods 1986”. Springer Verlag, Heidelberg. [8] D. Seebach, S. Roggo, and J. Zimmermann in W. Bartmann and K . B. Sharpless (Eds.): “Stereochemistry of Organic and Bioorganic Transformations”. VCH Verlagsgesellschaft, Weinheim 1987. [9] D. Seebach, G. Stucky, and P. Renaud, Chimia 42, 176 (1988) and ref. cited. [lo] This book, page 9ff. [ll] D. Seebach and R. Fitzi, Angew. Chem. 98,363, Angew. Chem. Int. Ed. Engl. 25, 345 (1986). [12] D. Seebach, S. G. Miiller, U. Gysel, and J. Zimmermann, Helv. Chim. Acta 71, 1303 (1988). [13] D. Seebach, G. Stucky, and P. Renaud, Chimia 42, 176 (1988). [14] This book, page 300ff. [l5] D. Seebach and J. Zimmermann, Helv. Chim. Acta 69, 1147 (1986). [16] M. Demuth, A. Palmer, H.-D. Sluma, A. K. Dey, C. Kriiger, and Y.-H. Tsay, Angew. Chem. 98,

[17] [l8] [19] [20] [21] [22] [23] [24] [25] [26]

[27] [28] [29] [30]

1093, Angew. Chem. Int. Ed. Engl. 25, 1117 (1986). M. Sato, K. Takayama, T. Furuya, N. Znukai, and C. Kaneko, Chem. Pharm. Bull. 35, 3971 (1987). W.H. Pearson and M.-C. Cheng, J. Org. Chem. 52, 3178 (1987) and ref. cited. W. S. Johnson, Angew. Chem. 88, 33, Angew. Chem. Int. Ed. Engl. 15 (1976). Z. R. Silverman, C. Edington, J. D. Elliott, and W. S. Johnson, J. Org. Chem. 52,180 (1987) and ref. cited. A. Mori, K. Zshihara, I. Arai and H. Yamamoto, Tetrahedron 43, 755 (1987) and ref. cited. A. Alexakis, P. Mangency, A. Ghribi, J. Marek, R. Sedrani, C. Guier, and J. Normant, Pure Appl. Chem. 60,49 (1988). K. Maruoka, S. Nakai, H. Sakurai. and H. Yamamoto, Synthesis 1986, 130 and ref. cited. T. Harada, T. Hayashiya, Z. Wada, N. Zwa-ake, and A. Oku, J . Am. Chem. SOC.109,527 (1987). T. Harada, K. Sakomoto, Y. Zkemura, and A. Oku, Tetrahedron Lett. 29, 3097 (1988). T. Harada, H. Kurokawa, and A. Oku, Tetrahedron Lett. 28, 4843, 4847 (1987); T. Harada, K. Sakamoto, Y. Ikemura, and A. Oku, Tetrahedron Lett. 29, 3097 (1988). S. H. Mashraqui and R. M . Kellog, J. Org. Chem. 49, 2513 (1984). D. Seebach, R. Zmwinkelried, and G. Stucky, Helv. Chim. Acta 70, 448 (1987) and ref. cited. S. L. Schreiber and J. Reagan, Tetrahedron Lett. 27, 2945 (1986). D. J. Krysan and P. B. Mackenzie, J. Am. Chem. SOC.110, 6273 (1988).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Syntheses with Aliphatic Nitro Compounds

There are two classic reagents that provide a carbanionic center immediately adjacent to a nitrogen atom: the cyanide anion and a deprotonated nitroalkane (f). It is the latter species that will be discussed in this chapter with respect to synthetic applications. Nitro compounds that have been deprotonated and subsequently treated with an electrophile (a) may be reduced to amines (b), or they may be converted into carbonyl compounds by a Nef reaction (c) [l]. R-CH,-NO,

( 1)

Moreover, the yields decrease with an increase in the number of substituents at the carbon atoms to be connected [2].

According to Matsumoto [3], a certain amount of improvement is possible if the reaction is carried out in the presence of tetrabutylammonium fluoride at high pressure. For instance, this modification permits the heretofore unknown addition of nitroethane to 2methylcyclohexanone, affording the nitro alcohol in 40% yields. CH3-CH,-N0,

+

&H3

0

R-CH-NH, I

E

c R-CH-NO, @) I

E

--+ (C)

R-C

//

I

E

- OCH3 9 kbar

Provided that C-electrophiles are used, these reactions open the possibility of carbon-carbon bond formation. The scope of the process turns out to be rather limited, however, because of the intervention of 0-rather than C-alkylation, and also because of low reactivity and insufficient stereoselectivity.Thus, in the reversible nitro aldol addition ("Henry reaction") (d), reasonable yields are obtained only when aldehydes are treated with nitromethane.

.NO, HO CH-CH3

30°C

4d n-BuNF

Double deprotonation of nitroalkanes causes a dramatic enhancement in nucleophilicity. The first representatives of the dilithiated species (3) were generated by Seebach and Lehr [2], [4]. Whereas the acidity of nitroalkanes (measured in aprotic solvents) lies between 15 and 18 pK, units, nitronate (2) with one remaining proton

26

Stereodifferentiating Addition Reactions

still has about the same acidity as diisopropylamine. Reagent (3) can be prepared by rapid addition of butyllithium to a solution of the nitroalkane (1)in tetrahydrofuran and HMPA. As in similar cases, the carcinogenic hexamethylphosphorus triamide can be replaced by the urea derivative DMPU [S]. -H’

R-CH,NO,

alcohol (13)is the desired product, then the epimeric mixture of silylated carbinols (10) is first metallated and subsequently reprotonated. This procedure leads to a diastereomeric ratio of 95:s [6].

LiKR N0,Li

R’-CHO

N0,Li

(1)

R-c

I

H-cI -R

R-c H-C-R I I NO, R

NO, R

(3)

0

DMPU =

r

1..

(6)

H,c,~K~,cH,

U

The irreversible addition of (3) to ketones produces nitro alcohols in yields that are distinctly superior to those from the Henry reaction, especially in cases with sterically demanding substituents R. The initially formed alkoxides (4,which are stable in solution, may either be protonated to give (5), or they may be converted immediately into the protected alcohols (6). In contrast to the Henry addition, reactions with doubly deprotonated nitroalkanes (3)proceed with a considerable degree of diastereoselection. Protonation of the adducts (7) leads mainly to the syn-isomers (9),the highest selectivities being obtained with aromatic aldehydes (94:6, for instance, in the case of p-methoxybenzaldehyde). If, on the other hand, the anti-

Both results can be interpreted as follows: due to mutual repulsion of the negative centers in the nitronate (7), the antiperiplanar conformation (8)should be favored. Approach of acid from the less hindered face, as indicated in formula (8), leads primarily to the formation of isomer (9).In the silylether (1I ) , however, a conformation corresponding to “Cram’s cyclic model” seems to be preferred. Approach of a proton from the less hindered side [as outlined in formula (12)] provides a pausible explanation for the favored generation of nitro alcohol (13).Alternatively, anti-products (13)can be obtained in a diastereoselective way by fluoridecatalyzed addition of silylnitronates (14) to al-

Aliphatic Nitro Compounds

dehydes. The reduction of nitro compounds (13) with Raney nickel affords amines (IS),permitting epimerization to be avoided completely so long as neutral conditions are carefully maintained.

-

HR)'j

R'CHO

Fe

+/sio,N?oe 114)

NO L O : - +

f 16)

The addition of nucleophilic reagents to nitroolefins has also been a subject of intensive investigation by Seebach's research group [l b]. Among other results nitropropenyl pivalate (16) was found to be a useful "multiple-coupling reagent" [7]. This opens the possibility of successive introduction of two different nucleophiles Nu' and Nu2, because the first addition is followed immediately by elimination of the pivalate anion, with simultaneous regeneration of a nitroolefin.

The sequence may be performed as a one-pot reaction, as has been demonstrated in the case of y-nitrocarboxylic ester (f 7 4 but higher overall yields are obtained if intermediates such as (f 7b) are actually isolated. The primary adducts may also serve as dienophiles in Diels-Alder reactions.

YO2

6 6%

71%

27

28

Stereodifferentiating Addition Reactions 2 HzCO

+

NOzNa I1

CHZ

N0,Na H&OH.

I

CH~OH

2 CH,OH

95% H@/+oM~

75%

95%

EtzO

45% (16)

Reagent (16) is readily available from inexpensive chemicals in four simple steps, and the reaction may be run on a 40 to 200 g scale without any problems.

Hoi’r

NO2

NO2

80-90%

ee>95%

1) Piv20/H @

2) MeOH/H 3) DCCiCuCl

@

’ pivo40

Piv = Me3CC0

(18) 67%

(I9)

More recently, chiral “multiple-coupling reagents” have been prepared in enantiomerically pure form by enantioselective saponification with porcine-liver esterase (PLE) of open-chain and cyclic diacetates of meso-2-nitro-1,3-propanediols [S]. The method is illustrated by the synthesis of the nitroallylic pivalate (18). Reinvestigating the well-known [9] addition of enamines to nitroalkenes, Seebach and coworkers found an interesting example of a stereoconvergent carbon-carbon bond formation [lo]. Both Z- and E-nitrostyrene (19) and (20) afford the enamine (21) in over 90% diastereomeric purity upon reaction with morpholinocyclohexene. The following explanation is proposed by the authors, and it seems rather plausible: with Z-nitroolefin (19) as starting material the first step might be an isomerization to the thermodynamically more stable E-alkene (20),and this has in fact been proven by NMR spectroscopy to be an intermediate. Betainelike species could be responsible for such a Z/E-isomerization. The conversion of E-nitroolefin (20) into the major product (21) might be rationalized by postulating a favored gauche conformation (22) for the reactive n-systems in the transition state. Hydrolysis of enamine (21) finally affords nitro ketone (23).

\ fO’l

Aliphatic Nitro Compounds /O\

The chiral enamine (24) provides the opportunity for an effective enantioselective Michael addition to nitrostyrenes [ll]. Thus, ketone (25) is obtained as a single diastereomer with an ee >90%. Q&CHzOCH3

29

tion [12 - 14). For example, nitro ketone (26) reacts with sodium hydride to afford the lactone (27) in 91% yield. The nitro group can be subsequently removed by reduction with tributyltin hydride [14]. In a similar way, nitro compound (29) leads to the twelve-membered ring (30)[12]. The synthesis starts with 2-nitrocyclooctanone, which is first converted into (29) by Michael addition to acrolein. This is subsequently treated with the titanium reagent (28), which adds in a chemoselective manner exclusively to the aldehyde group (the keto function is not attacked).

2) HzO/CzHsOH 1)C.Ha-OZ+

(24)

(2.5)

3 (29) 90%

The ability of the nitro group to stabilize a carbanion can be exploited in the synthesis of macrocyclic lactones and lactams, a process that involves an elegant ring-expansion reac6070

(30) 90%

During the reductive amination of ketoaldehyde (31), the ring-expanded product (32) forms spontaneously in 41 % yield [13].

NH3/NaBHaCN

I

B",S"H

2 6%

30

Stereodifferentiating Addition Reactions

1-Deoxy-1-nitroaldoses have been studied intensively by Vasella and coworkers [lS], [16], who found the ozonolysis of N-glycosylnitrones to be well suited as the key step in an effective synthesis of those carbohydrate derivatives. The starting material is an aldoxime, such as the mannose derivative (33). Reaction of (33) with aromatic aldehydes involves the cyclic isomer (34, and it leads to the formation of crystalline and sublimable nitrones (35).Subsequent ozonolysis gives the 0-protected nitro mannose (36) in an overall yield of 70-76% (relative to (33))~ 1 5 1 .

(331

addition of nitroribose derivative (37) to vinylphosphonate (38)affords a mixture of anomers, reduction of which gives primarily diol (404 along with small amounts of (4%)(22:l). The major product (404 is deprotected (trityl group), cleaved with periodate, and then silylated to produce a mixture of silyl glycosides (41) and (42). The two compounds are separated, and each is then deprotonated with butyllithium and quenched with chloroformate, giving a 1 : l diastereomeric mixture. Both mixtures lead to the same acetonide (45)on desilylation and intramolecular Wittig-Horner reaction. Finally, the deprotection of (45) affords methyl shikimate (46). Recently, nitroalkenes have been found to be suitable for use as heterodienes in intramolecular [4+ 21 cycloadditions [17]. Thus, treatment of nitrodiene E,E-(47u) with SnC14in toluene gives almost exclusively trans-nitronate (48a), whereas the cis-isomer (4%) is obtained from E,Z-diene (47b)with equal selectivity. The

OJCH3

The nitro group may also be utilized in the preparation of homologous sugars. This is effectively demonstrated in the synthesis of methyl shikimate (46)by Mirza and Vasella [16], outlined in Scheme 1. The base-catalyzed

59%

(49) 85%

Aliphatic Nitro Compounds

31

Scheme 1 Synthesis of methyl shikimate by Mirza and Vasella [16].

p4

(37)

+\sio

(39) 07%

Y3-,o

+ +\sio

WOW2

/

a 0 O

X

O X 0

I

(41) 69%

'

Y2-
X

C02CH,

O

L

P(OW2

+>io

I

1) n-BuLi 2) CICOzCH3

o

"1

0

X

R2

0

(40a) : R1 = OH, R2 = H (40b) : R' = H, R2 = OH

(42) 10%

1) n-BuLi 2) CiCOZCH3

+\sio

WOW2

O

-

0 P(OW2

97%; (40a) :(4Ob) = 22 : 1

CO,CH,

l

o

P(OW2

O X 0

(43) 94%

(44) 95%

PgNF

J,EW~NF

Mwe

NaOMe &%

6 - 6 COpCH,

COpCH,

HO"

0''

+o

~

OH

(45)

conversion of nitronates (47a, b) into y-lactones (49) underscores the utility of the method. This short review on the versatility of aliphatic nitro compounds can be appropiately concluded with a reference to a very simple procedure for their preparation: Corey and coworkers [18] found that nitroalkanes can be

OH

OH

(46) 97%

prepared in a one-pot reduction via phosphinimines (50) starting with azides. RN, 03

(C&W

- N2

+ R-NO,

RN=P(C,H,), (50)

+

(C,H,),PO

32

Stereodfferentiating Addition Reactions

References c11 a) Houben- Weyl-Miiller: Methoden der Organischen Chemie, Vol. X/I, Thieme, Stuttgart 1971, p. 130. More recent reviews on the chemistry of nitroalkanes: b) D. Seebach, R. Imwinkelried, and T. Weber, in: Modern Synthetic Methods 1986, R. Scheffold (Ed.), Springer, Berlin-Heidelberg 1986, p. 125. c) A. G. H. Barrett and G. G. Grabowski, Chem. Rev. 86, 751 (1986). D. Seebach and F. Lehr, Angew. Chem. 88, 540 (1976); Angew. Chem. Int. Ed. Engl. 15, 505 (1976). c31 K. Matsumoto, Angew. Chem. 96, 599 (1984); Angew. Chem. Int. Ed. Engl. 23, 617 (1984). c41 D. Seebach, E. W.Colvin, E. Lehr, and T. Weller, Chimia 33, 1 (1979) and ref. cited therein. cf. Nachr. Chem. Tech. Lab. 33, 396 (1985). D. Seebach, A. K. Beck, T. Mukhopadhyay, and E. Thomas, Helv. Chim. Acta. 65, 1101 (1982). D. Seebach and P. Knochel, Helv. Chim. Acta 67, 261 (1984). M. Eberle, M . Egli, and D. Seebach, Helv. Chim. Acta 71, 1 (1988).

[9] M. E. Kuehne and L. Foley, J. Org. Chem. 30, 4280 (1965); A. Risaliti, M. Forchiassin. and E. Valentin, Tetrahedron Lett. 1966, 6331. [lo] D. Seebach, A. K. Beck, J. Golihski, J. N . Hay, and T. Laube, Helv. Chim. Acta 68, 162 (1985); for a directed synthesis of the epimer of (21), see: D. Seebach and M . Brook, Helv. Chim. Acta 68, 319 (1985). [ll] S. J. Blarer, W. B. Schweizer, and D. Seebach, Helv. Chim. Acta 65, 1637 (1982). [12] K. Kostova and M. Hesse, Helv. Chim. Acta 67, 1713 (1984) and ref. cited therein. [I31 R. Wiilchli,S. Bienz, and M. Hesse, Helv. Chim. Acta 68, 484 (1985). [14] N. Ono, H. Miyake, and A. Kaji, J. Org. Chem. 49, 4997 (1984). [15] B. Aebischer and A. Vasella, Helv. Chim. Acta 66, 789 (1983). [16] S. Mirza and A. Vasella, Helv. Chim. Acta 67, 1562 (1984). [17] S. E. Denmark, M . S. Dappen, and C. J. Cramer, J . Am. Chem. SOC. 108, 1306 (1986). [I81 E. J. Corey, B. Samuelsson, and F. A. Luzzio, J. Am. Chem. SOC.106, 3682 (1984).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Boron: Reagents for Stereoselective Syntheses

Diborane, BzH6,once a chemical curiosity, has developed into an extremely useful reagent, especially since chemists have learned to apply it in its various modified fbrms. Undoubtedly, the pioneer work of H. C . Brown and his coworkers [l], documented in vast number of publications, contributed in an essential way to the success of these versatile reagents. In recent years, organoboranes have been applied more and more in stereoselective syntheses, and their use is no longer restricted to reduction since it may also involve carbon-carbon bond formation. B-3-Pinanyl-9-borabicyclo[3.3.l]nonane (2), which can be prepared easily from (+)-a-pinene, opens an interesting possibility for enantioselective reduction of alkynyl ketones.

H3C H3C

CH3

(1)

Formula (3) presents a plausible transition state model for this hydride-transfer reaction,

one which explains the predominant formation of enantiomer (4). Depending upon the nature of the substituents R and R , (4) is formed in 77 to 99% ee (enantiomeric excess) [ 2 ] .

When (-)-a-pinene is chosen as starting material, the enantiomeric borane ent-(2) is obtained. This reagent was used by Midland and Graham to generate the alcohol (5) in 83% ee in the course of a synthesis of (-)-pestalotin, outlined in Scheme 1 [3]. To this end, alkynyl alcohol (5) is first hydrogenated to the corresponding alkene and then protected as the MEM ether. Subsequent degradation leads to the formation of aldehyde (6), which serves as a dienophile in a hetero Diels-Alder reaction with diene (7). Europium shift reagents like

34

Stereodifferentiating Addition Reactions

H

CH3

OH

1

(5)

CH3

ent-(2)

OCHQ

OH

OCH3

(8) 50%

1

0

EuoQ MEM = CH,OCH,CH,OCH,

OCH,

Eu(hfc)Q =

(9)

Eu(hfch are effective as catalysts in this method elaborated by Danishefsky and his group [4]. Thus, pestalotin (8) is the only diastereomer formed in the cycloaddition step. It can also be isolated in enantiomerically pure form by recrystallization. Oxidation affords ketone (9),a compound which, like pestalotin, is a fungal metabolite. The chiral boranes (2) and ent-(2) have also been applied successfully in reductions of aketo esters. Thus, tert-butyl pyruvate affords @)-lactate (10) in 97% ee, provided that the

(10) 9870

chiral auxiliary reagent, a-pinene, displays the corresponding degree of optical purity [ S ] . The reaction of allylboronates with aldehydes has been investigated in a detailed and intensive manner by R. W. Hoffmann and his group [6a]. This addition results in the formation of homoallylic alcohols (If), which might be considered as precursors to phydroxycarbonyl derivatives (12). It therefore

OH 0

OH H3CACOz-f

EU J3

L

-Bu

Rx -

(12) X = H, OH

-

1

N(CHzCH2OH)e

R

XA (11)

Boron Reagents

becomes evident that this reaction sequence is equivalent to the aldol addition [6b]. If crotylboronates (13) are used as nucleophiles, an unambiguous connection is observed between the configuration of the boronate ( E or Z) and the syn-anti ratio of the products (14a: 14b): Z-crotylboronate (134 leads primarily to syn-alcohol (144, whereas E-alkene (13b) gives mainly the anti-diastereomer (14b). According to a widely accepted mechanism, this result is to be explained by assuming a sixmembered ring transition state [(I54 or (fSb), respectively], in which the aldehyde substituent R prefers the equatorial position [7].

35

The reaction can also be applied to y-alkoxyallylboronates without serious loss in diastereoselectivity. It seems especially advantageous that, in this case, facile routes have been developed for the preparation of both Z- and Eboronates (id). The metallation of allylether (17)provides Z-reagent (18), which is thermodynamically more stable than the corresponding (E)-isomer. Conversion of the former into the allylboronate (164 is accomplished by a two-step procedure via the diaminoborane.

IRCHO Isomerization from the 2- to the E-configuration is avoided, however, with the allylpotassium derivative (20). Thus, starting with reductive metallation of sulfide (19) it is possible to generate E-alkoxyallylboronate (1db).

f

t

H3C

# (136)

When boronate (164 is allowed to react with aldehydes, the glycol derivative (214 results, whereas the corresponding reaction of isomer (16b)leads to the formation of (21b).Chemical yields are in the range of 75-95%, and the diastereomeric purity exceeds 90% [8].

36

Stereodijjferentiating Addition Reactions

OCH,

(2lb)

C .i the other hand, a stereoconvergent reaction occurs when boron enolates (224 or (22b) are added to aldehydes. Both E- and Zisomers lead to the formation of syn-P-hydroxyketone once the initially formed adduct has been cleaved with triethanolamine [9].

More recently, the tartrate-derived allylboronate (234 was found to react with aldehydes in 71 -87% ee [12]. Esterification of the propadienylboronic acid (24) with tartaric acid yields an even more effective transmitter of chirality: homopropargyl alcohols are obtained in 92-99% ee, with chemical yields between 78 and 90% [13]. C0,-i-Pr

H3C

CH3

RCHO

OH

H,C=C=CH-B(OH),

It would seem to be a creative idea to incorporate chiral substituents into allylboronates, since modified in this way they should then be capable of differentiating between the enantiotopic faces of an aldehyde. This could in turn open an enantioselective route to the formation of homoallylic alcohols. Early studies involving camphor-derived allylboronates (23a) [lo] and crotylboronate (2%) [l 11 were rather encouraging: enantiomeric purities of the products ranged from 45 to 86% ee.

RCHO 7 HOVCOpI-Pr R& -

The research groups of Evans and Masamune developed various chiral boron enolates, including (2.5~) and (25b),which have proven to be very useful chiral reagents for aldol additions. Thus, the adducts (26)and (27)are formed as almost pure diastereomers [14]. In a similar way, P-hydroxythioesters (28b) are obtained in 87-94% ee when the chiral boron enolate (28a) is added to aldehydes [l5].

Boron Reagents

37

Matteson and coworkers reported on an elegant transfer of chirality within a boronate [17]. The combination of dichloromethyllithium and (31), as well as that of dichloromethylboronate (32) and butyllithium, leads to the formation of the same lithium complex (33),as a consequence of the C2 symmetry of the 2,3butanediol moiety. Addition of zinc chloride induces migration of the butyl substituent to give largely the diastereomer (34). Subsequent hydrolysis affords the acid (35) in 96% ee, and butanediol can be recovered.

Rfi+ H

/o-B3

HC , =C

-

\

(33)

OH 0

RCHO

R

(284

(28b)

Transfer of the allyl group from the chiral borane (29) to aldehydes occurs with excellent stereoselectivity. Brown and Jadhav [16] succeeded in synthesizing (S)-artemisia alcohol (30) from 3-methylbutenal in 85% chemical yield and an enantiomeric purity of 96% ee. The corresponding enantiomeric product (R)-(30) is also available via the reagent ent-(29). The two enantiomers of the terpene (30)have been found to occur in different plants.

(@T1) A

2

(29)

P

O

2) NPOWHiOa

(34)

(35)

R = n-Bu

Hoffmann and coworkers [18] have been able to demonstrate that a-chiral allylboronates and crotylboronates are suited for stereoselective addition to aldehydes. Thus, the butanediol-derived boronate (36),available again from (32) in >90% diastereomeric purity, is first converted into the pinacol-derived u-chloroboronate (37). When the latter is allowed to react with aldehydes, the diastereomeric homoallyl alcohols (39a) and (39b) are formed in a ratio of 95:5 (R = C,H,). The relationship between the configuration of the double bond in (37) and the carbinol carbon atom of the prod-

38

Stereodifferentiating Addition Reactions

uct [i.e., Z c-) (R)and E c-) (S)] is reasonable provided one assumes that both major and minor product arise via the same type of transition state [(38a) and (38b),respectively].

H,C-B,~ CI

CH:, CI

92-96~~ ee

(40)

(40)

Cl

OCH, (47)

96-98% ee

8842% ee 1RCHO

OH

R

m CH, OCH,

(42)

h/# 51 (37)

88.94%

ee

method [20], gives a product whose enantiomeric purity reaches 99.5% ee [6a]. Obviously, both types of chiral information in the reagent (43) contribute in a cooperative manner to this high degree of stereoselectivity. 1) CHBLi 2) ZnClp

(43)

1

PhCHO

OH

P

-

h

,v

CH,

CH,

Still higher selectivities are achieved in the addition of a-chlorocrotylboronate (40) to aldehydes [19]. The substitution of the chloro substituent by a methoxy group to give (41) is accompanied by a slight loss of optical purity. Even so enolethers (42) are obtained in 88 - 94% ee [6a]. Addition to benzaldehyde of the Z-crotylboronate (43),available according to Mattesons

References [l] H. C. Brown, Angew. Chem. 92, 675 (1980) and ref. cited therein. [2] M. M. Midland, D. C. McDoweIl, R. L. Hatch, and A. Tramontano, J. Am. Chem. SOC. 102,867 (1980). [3] M. M. Midland and R . S. Graham, J. Am. Chem. SOC. 106, 4294 (1984). [4] M , Bednarski, C. Maring, and S. Danishefsky, Tetrahedron Lett. 24, 3451 (1983).

Boron Reagents

[5] H. C. Brown, G. G. Pai, and P. K. Jadhav, J. Am. Chem. SOC.106, 1531 (1984). [6] a) R. W. Hoffmann, Pure Appl. Chem. 60, 123 (1988) and references cited therein. b) For a discussion of this alternative to the aldol reaction see: M. Braun, Angew. Chem. 99,24 (1987), Angew. Chem. Int. Ed. Engl. 26, 24 (1987). [7] R. W.Hoffmann and H.-J. Zeip, J. Org. Chem. 46, 1309 (1981). [8] R. W. Hoffmann and B. Kemper, Tetrahedron Lett. 23, 845 (1982); Tetrahedron Lett. 22, 5263 (1981). [9] R. W. Hoffmann and K. Ditrich, Tetrahedron Lett. 25, 1781 (1984); vgl. R. W. Hoffmann and S. Froech, Tetrahedron Lett. 26, 1643 (1985). [lo] R. W. Hoffmann, W. Ladner, K. Steinbach, W. Massa, R. Schmidt, and G. Snatzke, Chem. Ber. 114, 2786 (1981). [l 11 R. W.Hoffmann and T. Herold, Chem. Ber. 114, 375 (1981). [12] R. W. Roush, A. E. Walts, and L. K. Hoong, J. Am. Chem. SOC.107, 8186 (1985).

39

[13] N. Ikeda, I. Arai, and H. Yamamoto, J. Am. Chem. SOC.108, 483 (1986); cf. also: N . Zkeda, K. Omori, and H. Yamamoto,Tetrahedron Lett. 27, 1175 (1986). [14] S. Masamune, W. Choy, J. S. Petersen, and L. R. Sita, Angew. Chem. 97, 1 (1985), Angew. Chem. Int. Ed. Engl. 24, 1 (1985) and ref. cited therein. [l5] S. T. Masamune, T. Sato, B. M. Kim,and T. A. Wollmann,J. Am. Chem. SOC.108, 8279 (1986). [16] H. C. Brown and P. K. Jadhav, Tetrahedron Lett. 25, 1215 (1984). [17] K. M. Sadhu, D. S. Matteson, G. D. Hurst, and J. M . Kurosky, Organometallics 3, 804 (1984). [18] R. W. Hoffmann and B. Landmann, Angew. Chem. 96, 427 (1984); Angew. Chem. Int. Ed. Engl. 23, 437 (1984). [19] R. W.Hoffmannand S. Dreseley, Angew. Chem. 98,186 (1986); Angew. Chem. Int. Ed. Engl. 25, 189 (1986). [20] K. M. Sadhu, D. S. Matteson, G. D. Hurst, and J. M. Kurosky, Organometallics 3, 804 (1984).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

a-Hydroxylation of Carbonyl Compounds

The a-hydroxy carbonyl moiety (2) is an important structural feature of many natural products. This is why its preparation from carbonyl compounds (1)has received much attention in recent years. Analysis of the transformation ( I ) + (2) reveals the challenge: target (2) is usually obtained by combination of a donor synthon (3) and an acceptor synthon (4), which requires a reversal of polarity ("Umpolung") of the donor characteristics of the oxygen centers in (4). Therefore, it was necessary that efficient electrophilic oxygen transfer reagents be developed.

R 4

these methods are restricted to carboxylic acid derivatives or highly substituted ketones. The Vedejs reagent Moos . Py . HMPT a complex easily prepared from molybdenum peroxide, pyridine, and hexamethyl phosphoric acid triamide - is much more generally applicable. The a-hydroxylation of camphor shown in the sequence (5)+ (6)-+ (7) is just one example of many [l]. Nevertheless, this reagent has disadvantages, not the least being the involvement of the toxic and carcinogenic HMPT.

+ R h Ro' H

R'

Several methods make direct use of dioxygen 77% or its derivatives. The reaction of lithium enoOH lates - the most commonly employed equivalents for (3) - with triplet oxygen gives a(7) hydroxy peroxides, which can be reduced by phosphites to afford the desired a-hydroxy carNew oxygen transfer reagents have been debonyl compounds. Bis(trimethylsily1)peroxide veloped by Davis. All of them are characterized or dibenzyl peroxydicarbonate have also been by a 2-sulfonyloxaziridine moiety as the reacutilized as oxygen transfer reagents. However, tive site. The potassium enolate of ethyl phen-

a-Hydroxylation of Carbonyl Compounds

41

Fig. 1 a-Hydroxylations employing 2-phenylsulfonyloxaziridine(9).

ylacetate (8) is oxidized by (9) to provide the corresponding a-hydroxyester (10) in good yield (Figure l), whereas the yield is only 58% with the Vedejs reagent [2]. One drawback of all Davis procedures is the more tedious workup, including separation of the resulting imine, e.g. (ii), from the a-hydroxy carbonyl compound. On the other hand, bulky reagents such as (9) display much higher stereoselectivity, as shown in the case (12) + (13), where Moos . Py . HMPT affords only a 3: 1 mixture of (13) and (14) [2]. The more efficient approaches to asymmetric a-hydroxylations involve chiral enolates bearing auxiliaries that have already proven their reliability in many other reactions (e.g., asymmetric alkylations). The hydroxylation of camphor-derived ester enolates with the Vedejs reagent has been thoroughly investigated, and it has been shown that optimization permits enantiomeric excesses (ee)of up to 98% [3]. Oxidation of Evans’ chiral imide enolates with Davis’ reagent (9) provides a-hydroxy carboxylic acid derivatives in very good diastereomeric excess. This process is highly predictable, and it is possible to prepare both enantiomers of a target molecule since auxiliaries of opposite induction are also available [4]. Application of

OH

CO,H

L

12 (R)-HETE

this method to the synthesis of 12(R)-HETE was recently reported [5]. The chiral amide (15) has been studied by Davis and coworkers (Figure 2). Interestingly, the lithium enolate generated by deprotonation with LDA gave (16) with an S-configurated Catom, while the dianion with sodium as the counterion affords primarily the diastereomer (18). The carboxylic acids (17) and (19) were obtained from these intermediates in high optical purity following hydrolysis. The authors postulate that the dilithio intermediate (20) is conformationally locked by the lithium cation, so that the attack of (9) occurs from the front

42

Stereodfferentiating Addition Reactions 1) 3 LDA

I

2) (9)

G F C 6 H 5 -\

O

OH

-\

O

OH

(16), 05%

(17), e.e.95%

( l a ) , 07% d.e. 93%

(19), e.e.93%

d.e. 95%

J CNFC6Hs

j o

Na

0 .Li

Li

(20)

@

(27)

Fig. 2 Asymmetric a-hydroxylations of a chiral enolate with oxaziridine (9).

side. In contrast, the less covalent nature of the sodium-oxygen bond might lead to species (21), in which the electrophile (9) prefers the back side approach [6]. Despite mechanistic ambiguities, asymmetric oxidations with (9)were used in other examples with great success. Thus, the enolate derived from (L)-pyroglutamate was transformed into the optically active hydroxypyrrolidone intermediate (22) required for synthesis of (-)-bulgecinine (23) [7]. Even the otherwise difficult preparation of a-hydroxylated aldehydes is possible with (9). The SAMP/RAMP-hydrazone method developed by Enders solves this problem and provides good selectivities [S]. HO

HO,

OQCO0Bzl

Boc (22)

++

HO"'

Q C O O H H (23)

The second strategy employs achiral enolates and optically active oxaziridines. The first reagent examined was compound (24). Later, Davis introduced the more efficient derivatives (+)-(25)and ( 4 4 2 5 ) [9].

OCH, (24)

Kjellrnanianone

43

a-Hydroxylation of Carbonyl Compounds

The hydroxylation of a ketoester enolate with reagent (24)in 37% ee was the crucial step in the synthesis of the antibiotic (+)-kjellmanianone [lo]. Other carbonyl compounds are oxidized by (+)-(25)in up to 95% ee, but the steIeoselectivities are highly dependent on the substrate and the reaction conditions [ll, 12, 131. The best result was achieved with deoxybenzoin (26). Its sodium enolate reacted with (+)-(25)to give (9-benzoin (27). After recrystallization the optical purity was 98%. Intermediate (27) can be reduced to erythro-a,P-diphenyl-P-hydroxyethanol (29) or to the corresponding amine (28) [14]. Both compounds are valuable auxiliaries for other asymmetric reactions.

H,N

H

P+Ph

h

I+

(9)

)-(251

f- )-W HMPT/ (+)-(25) HMPT/ (-)-(25)

% de 55

48 88 89 91

configuration

(S) (S)

6) 6)

(S)

Fig. 3 Double asymmetric induction observed for the enolate of (30) and oxaziridines (9),(+)-(25), or (-)-

(25).

idation of the latter is possible with m-chloroperbenzoic acid [161, hypervalent iodo compounds [17], or lead tetraacetate [18], and even asymmetric variations [191 have been successfully performed. In conclusion, the conversion (1) + (2) is possible in a variety of ways and frequently with quite satisfying results.

References

HO H P

H OH

oxaziridine

v

H OH

The principle of double asymmetric induction was also tested with the oxaziridine (25). Figure 3 displays the most important results obtained with the lithium enolate of amide (30). In all cases, (31) was generated in the ( S ) configuration, which demonstrates that the stereodirecting effect of the amide is much stronger than that of the oxidizing reagents. Interestingly, addition of HMPT leads to a diastereomeric excess of approximately 90% regardless of whether (+)-(25)or (-)-(25) is used [l5]. Finally, it should be mentioned that ahydroxylotion of carbonyl compounds may also be krfermed with enols as reactive intermediates or silyl enol ethers as substrates. Ox-

[I] E. Vedejs and S. Lursen, Org. Synth. 64, 127 (1985). [2] F. A. Davis, L. C.Vishwakarma, J. M . Billmers, and J. Finn, J. Org. Chem. 49, 3241 (1984). [3] R. Gamboni and C . Tamm, Helv. Chim. Acta 69, 615 (1986). [4] D . A. Evans, M. M. Morrissey, and R. L. Dorow. J. Am. Chem. SOC. 107,4346 (1985). [5] S. W.Djuric, J. M. Miyashiro, and T. D. Penning, Tetrahedron Lett. 29, 3459 (1988). [6] F. A. Davis and L. C . Vishwakarma, Tetrahedron Lett. 26, 3529 (1985). [7] T. Ohta, A. Hosoi, and S. Nozoe, Tetrahedron Lett. 29, 329 (1988). [8] D. Enders and V. Bhushan, Tetrahedron Lett. 29, 2437 (1988). [9] For efficient synthesis of (-)-(25) and (+)-(25) see: F. A. Davis, J. C . Towson, M. C . Weismiller, S . Lal, and P. J. Carroll, J. Am. Chem. SOC.110, 8477 (1988). [lo] D. Boschelli, A. B. Smith ZZZ,0. D. Stringer, R. H. Jenkins Jr., and F. A. Davis, Tetrahedron Lett. 22, 4385 (1981).

44

Stereodifferentiating Addition Reactions

[ll] F. A. Davis. M. S. Haque. T.G. Ulatowski, and J. C. Towson, J. Org. Chem. 51, 2402 (1986). [12] F. A. Davis and M. S. Haque, J. Org. Chem. 51, 4083 (1986). [13] F. A. Davis, A. C. Sheppard, and G. S. Lal, Tetrahedron Lett. 30,779 (1989). [14] F. A. Davis, M. S. Hague, and R. M . Przeslawski, J. Org. Chem. 54, 2021 (1987). [l5] F. A. Davis, T. G. Ulatowski, and M. S. Haque, J . Org. Chem. 52, 5288 (1987). [16] G. M . Rubottom, J. M . Gruber, H. D. Juve Jr., and D. A. Charleson, Org. Synth. 64,118 (1985).

See also: B. B. h h r a y and D. Enders, Helv. Chim. Acta 72, 980 (1989). [17] R. M. Moriarty, M. P. Duncan, and 0. Prakash, J. Chem. SOC.,Perkin Trans. I 1987, 1781. - R. M. Moriarty and 0. Prakash, Acc. Chem. Res. 19, 244 (1986). [18] G. M. Rubottom, J. M. Gruber, R. Marrero, H. D. Juve Jr., and C. W. Kim, J. Org. Chem. 48, 4940 (1983). [19] W.Oppolzer and P. Dudfield, Helv. Chim. Acta 68, 216 (1985).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Electrophilic Aminations

Amines (3) are usually prepared by attack of a nucleophilic nitrogen atom from a species like ( I ) on an electrophilic carbon atom, as in (2). A new C-N bond is formed by displacement of the leaving group on carbon to afford (3). R,N:--c-x

I/,

I

+R,N-C- II + x@

However, the general applicability of nucleophilic substitution of alkyl halides by amines is severely restricted by structural parameters associated with ( I ) and (2). For this reason, the reverse process - a carbon nucleophile (5) replacing a leaving group “X” on electrophilic nitrogen, as in (4) - is receiving increasing attention.

carbon nucleophile (5). The spectrum of possibilities extends from the relatively hard lithium alkyls or lithium aryls to the soft heteroatomstabilized carbanions. Even silyl enolethers can be aminated with Lewis acid catalysis by a Mukaiyama-type reaction. The amination of ester enolates was obviously developed with a very short amino acid synthesis in mind. Electrophilic reactions at nitrogen have been known for some time [2], but until recently the procedure had little preparative significances. Synthetic applications began to appear only as new types of electrophilic amination reagents were developed.

Hydroxylamine Derivatives

In the development of reagents of type (4), one obvious step was to replace the hydroxy s\ - 1 I 8 X-NR, :C+ R2N-C- + X group in hydroxylamine by a better leaving I I ’group.Early candidates, such as the rather dangerous chloroamine (6)and the almost insoluble hydroxylamine-0-sulfonic acid (7) [2c], This reaction is related to the cr-hydroxyla- were soon superceded by such derivatives as 0tion of carbonyl compounds, discussed elseH,NCl H2NOSOJH where (p. 40ff.) in this volume. The synthetic potential of this type of “Umpolung” (polarity (6) (7) reversal) process has been substantially expanded by the development of new metalation techniques [l]. A wealth of new electrophilic H amination reagents is now available, removing almost all the restrictions on the nature of the

46

Stereodgferentiating Addition Reactions

2,4-dinitrophenylhydroxylamine (8) [3] or by 0-mesitylenesulfonyl hydroxylamine (9) [4]. A variety of stabilized carbanions (including the anion of acetoacetic ester) can be aminated by reagents (8) and (9) in good yield, but the yield falls drastically in the case of less stabilized carbanions [2]. The use of increasingly basic nucleophiles leads to problems associated with deprotonation of the aminating reagent; i.e., a deprotonated amine can react with another molecule of H2N-X to form an N-N bond and, ultimately, a diimide: Scheme 1 B:-

+ HZN-X + BH + HN--X

HN--X

+

H2N-X

+ HZNN-X -+ HN=NH

This problem cannot arise with NN-dialkylated reagents such as dimethyl-0-mesitylenesulfonylhydroxylamine (II), and a number of organometallic reagents as well as such stabilized carbanions as that from cyanoacetic ester (10)have been dimethylaminated in good yields

two equivalents of the precious organometallics were always required to obtain good yields of amines. An important mechanistic implication is hidden in this experimental observation, a fact exploited by Beak and Kokko [7] in their development of a practical synthesis of primary amines. The desired products (characterized as their benzamides) could be isolated in good yields if methoxyamine was first treated with one equivalent of methyllithium and then reacted with the organometallic reagent: RLi

+ R’ONH2/MeLi + RNH2

The examples listed in Table 1 show that clean reactions are observed with primary, secondary, and tertiary aliphatic as well as aromatic lithium compounds. Grignard reagents give lower yields ~ 7 1 . Table 1. Selected examples of the reaction of R M and (MeLi H 2 N O M e ) according to Beak and Kokko +

17 1

1 ’ I ’

yield (Yo)

RM

Amide

-Li

-NHCOPh

77

+Li

+NHCOPh

80

-MgBr

-NHCOPh

16

to afford (12)[S] (Scheme 2).

Scheme 2

Ph. ,CHC02Et NC

-

,OM8

Ph.

,CC02Et NC I

How can side reactions caused by deprotonation be avoided in the preparation of primary and secondary amines? One possibility might be to reduce the leaving-group activity of the substituent: replacing sulfonate by a methoxy group, for example. In fact, amination of organometallic reagents was observed as early as 1946 by Brown and Jones [6]. Interestingly,

6

L

i

.OM0 6 N H C O P h

96

In addition to the NH,’ equivalent (H2NOMe/MeLi), the secondary amine synthon RNH+ (RNHOMe/MeLi) also reacts in good yield with lithium compounds [8]. Furthermore, no problem is associated with intramolecular reactions starting from (13)to afford the dihydroindole (14) [8] (Scheme 3). Why are the lithiated “nitrenoids” LiRNOR’ more electrophilic than the corresponding

Electrophilic Aminations

41

Scheme 3

alkoxy amines? The amination method of Beak and Kokko involves two negatively charged species that ought to repel each other. Beak et al. [9] suggest that the dimer (15) is the reactive species, and MNDO calculations carried out by Boche and Wagner [lo] reveal that the N - 0 bonds of the lithiated hydroxylamine and the corresponding MeLi adduct are considerably longer (1.6093 A) than in the corresponding nonlithiated species (1.437 A). Li/

R. ’..Li

“H/I

OR

(15)

0

I f 1,4374 N

H’

\H

R.

H

Li::::.$-

(R-CrC)$hLi2

+

(16)

+R-C=C-NMe2

How does the yield in amination change if the N-methyl groups in (16) are replaced by hydrogens, as in (la)? The examples of Table 2 show that aryl and alkyl lithium and magnesium compounds can still be aminated, although the yields are lower than for the corresponding compounds (16) or (17)[13]. A satisfactory yield is obtained with more stabilized carbanions, as shown by the amination (60%) of benzyldiethylphosphonoacetate [14].

MNDO-calculations[’ol:

H\

Of special preparative interest is the dimethylamination of alkynyl cuprates to afford good yields of alkynyl amines [12]. This reaction has recently been extended to the preparation of imino alkynes [12b] via iminoalkylation, using imino tosylates and ethinyl cuprates.

1,6093

‘”,H

These calculations also reveal that LiNH is stabilized relative to the NH + cation. Separation of the carbenoid LiRN-OR into the ion pair LiRN+ OR- is thus energetically favored, a finding that is in agreement with the high electrophilicity of Beak‘s reagents. The even more effective reagents 0-(diphenylphosphiny1)-N,N-dimethylhydroxylamine (16) and the corresponding phosphoryl compound (17)were obtained by replacing the sulfonyl groups by phosphoryl groups [lla]. Amination reagents of type (16)with various alkyl residues on the nitrogen can be prepared by reaction of primary and secondary amines with bis-(diphenylphosphiny1)-peroxide [l 1b]. +

Table 2. Reactions of R M with (18) according to Boche et 01. [13]. RM

Amine

yield (%)

PhMgCl

PhNH2

35

PhCH2U

PhCH2NH2

PhzC(Li)CN

PhzC(NH2)CN

30 67

A “double charge reversal” strategy is involved in the reaction of silylated cyanohydrin anions with the aminating reagent (16). Fifteen aromatic aldehydes have been converted in this way directly into carboxylic acid amides [lS]. An example is the conversion of 4-methoxybenzaldehyde (19)into cyanohydrin anion (20),

48

Stereodijjfuentiating Addition Reactions

followed by reaction with (16) to afford the benzamide (21) (Scheme 4) [15]. Scheme 4

enolate (24)with isoamyl nitrate affords a nitro ester in 71% yield, and this is hydrogenated with hydrogen-Pd/C to the amino ester (25) (Scheme 6). Scheme 6

\

(24)

If a new chiral center is to be created in the amination step, ephedrine-modified reagents of type (17)can be used to effect asymmetric induction [16], although other reagents were shown to give even better results (see below). Investigations into electrophilic aminations have made an important contribution to the study of aromatic amine carcinogenicity. It is now generally accepted that this carcinogenicity is itself a consequence of electrophilic amination. Reaction of the electrophilic amination reagent (22) with amines as nucleophiles to afford hydrazines (23) can be regarded as an in uitro model (Scheme 5). This procedure is also of preparative value, as shown by 26 reported examples [17]. Scheme 5

R’

Hahner and Seebach [18] have described an indirect method for the introduction of the NH2 group, another case in which an N - 0 bond is broken during the attack of a C-nucleophile. Thus, reaction of the sterically hindered ester

The l-amino-cyclopropanoic ester moiety constitutes an interesting substrate because the cyclopropane ring is readily opened by nucleophiles to give new products. However, the synthesis of amino acids via nitration is not universally applicable; it seems rather to be restricted to especially nucleophilic, strained ester enolates.

Azides as Electrophiles Azides have found manifold application as reagents for the synthon “(NH,)”.-Alkyl or aryl azides prepared with these reagents can be either reduced [I91 or hydrolyzed to primary amines. Cleavage of an N-N bond is thus the final step in the amination process. Activation of the azido group by leaving groups is in some ways analogous to the reactions of hydroxylamine derivatives discussed above. The work of Regitz [20] initially revealed that tosyl azide could act as a diazo transfer reagent, and only later were its properties as an azido transfer reagent investigated [21]. The reagent has found broader application in connection with the ortho-selective metalation of aromatic benzamides. The three step process metalation, conversion to an azide, and phase-transfer catalyzed borohydride reduction gives amines in quite

Electrophilic Aminations

satisfactory yields (43 - 71%, nine examples). Such a sequence is illustrated in Scheme 7 for the conversion of the amide (26) to the 2-amino derivative (27) [22]. Scheme 7

49

ride and sodium azide. Good yields are obtained even with sterically hindered Grignard reagents, as shown by the conversion of (31)to the amine (33) (Scheme 9); five additional examples were shown to give yields of 72-92%. Organolithium compounds decompose the reagent, however, so the observed yields in this case are correspondingly lower. scheme 9

The analogous trifluoromethanesulfonyl azide (29)seems to have properties rather similar to those of tosyl azide. The reagent is not isolated (explosive?),but is generated in situ in DMF solution from trifluoromethanesulfonyl chloride and sodium azide [23]. Doubly activated C-H acids react to give the monoazides in 50-60% yield. Thus, the C-H-active ethyl triethyl phosphonoacetate (28) could be aminated in this way to afford the a-amino ester (30)(Scheme 8). Scheme 8 n

1. F3CSOzNdNEt, (40%)

II

(EtO),P-CHC0,Et I

(30)

NHz

The reaction of trimethylsilyl azide with Grignard reagents has also been described, but strong acid is required for the subsequent hydrolysis to amines [24]. On the other hand, amines can be liberated under mild, neutral conditions from the (not yet completely characterized) intermediates obtained in the reaction of aromatic Grignard reagents with trimethylsilyl methyl azide (32) [25]. The apparently stable reagent (32)is in turn easily prepared from trimethylsilyl methyl chlo-

The favorable characteristics of the reagent (32)may be due to the a-carbanion stabilizing effect of silicon. A similar stabilization by sulfur may be applicable [26b] to the phenyl sulfide (35) utilized by Trost and Pearson [26a]. An illustrative example for the application of (35) is the amination step in the synthesis of the naphthalene skeleton of streptovaricine D, starting with the bromide (34) [26c] (Scheme 10). It is noteworthy that the linearly arranged azides are relatively insensitive to steric hindrance, a fact that should be considered in the process of choosing reagents for a specific amination. Scheme 10 1. Mg

71%

(34)

OCH3

50

Stereodifferentiating Addition Reactions

The amination species (32) and (35) were found to give better yields with Grignard reagents than with organo lithium compounds, but this behavior is reversed in the reaction with vinyl azides [27]. The vinyl azide (37) reacts initially to afford the isolable vinyltriazene (38). Depending upon the nature of the substituent R, hydrolysis with dilute hydrochloric acid can occur via either of the two routes a and b (Scheme 11). The amine RNHz is obtained if R is an aromatic substituent (route a), while (37) decomposes to a diazonium salt and an enamine if R is aliphatic (route b).

N-protected a-amino ketones are accessible by thermolysis of silylenol ethers (41)with azido formates (42).It is tentatively assumed that the reaction proceeds via d o x y aziridines (44), which rearrange to (45). This is followed by hydrolysis to the N-ethoxycarbonyl-a-aminoketones (43) [28] (Scheme 13). Similar products are obtained in the photolysis of (42) with enol acetates [29]. (See ref. 29a for the synthesis of optically active amino acids using various azides for the electrophilic amination of N-acyloxazolidones). Scheme 13

Scheme 11

R-Li

2

OSiMeJ

+

( >-

R-N=N-N

H

+

EtOCONj>-

p'

@

fi

1. 110%. 15h 2) S O o separation

R-Ukyl

The competing decomposition pathways have a marked influence on the synthetic applicability of the reaction, and vinyl azides such as (37) are used preferentially for the electrophilic amination of aromatic and heteroaromatic lithium compounds. The corresponding conversion of (39) to (40) is illustrated in Scheme 12; in seven further examples the observed yields were in the range of 45 - 70%. Scheme 12

(41) (tenfold excess)

Azo- and Diazo Compounds Sahakura and Tanaka [30] have employed silyl ketone acetals (46) derived from esters in a new synthesis of a-amino acids. In this case it is not the azide, but the stable tetrafluoroborate of an aromatic diazonium salt that serves as the N-electrophile (Scheme 14). An analogy to the familiar coupling reaction for preparing diazonium dyes is almost selfevident. The reaction conditions are mild (2 h, at 0 "C),and the stereoisomeric hydrazono esters (49, obtainable from monosubstituted ketone acetals, are easily hydrogenated to a-

Electrophilic Aminations Scheme 14

wOMe

Ph

P h N z BFT

>

amino esters. Disubstituted silyl ketene acetals yield a-azo esters without rearrangement, and these can also be hydrogenated to amino esters. If the azo group is substituted with electron acceptors, as in tert-butyl azodicarboxylate (49),a Michael-type addition should be possible in analogy to the behavior of the corresponding carbon compounds (fumarate esters). In fact,

such reactions have been known for a long time [31]. Four papers appeared almost simultaneously in 1986 describing the synthetic potential of azodicarboxylates as electrophilic amination reagents for the synthesis of a-amino and ahydrazino esters. In all cases, chiral auxiliaries made it possible to achieve asymmetric inductions with > 90% de. The diastereomeric products (50) can be purified by crystallization or chromatography, and essentially enantiomerically pure a-amino and a-hydrazino esters result upon removal of the chiral auxiliaries. The reactions investigated by Gennari et al. [32], Evans et al. [33], Vederas et al. [34], and Oppolzer et al. [35] all follow a similar pattern. The major differences lie in the nature of the chiral esterenolates [(Sl) and (52)] or silylenol ethers [(48) and (53)] used to achieve asymmetric induction. Aspects of the chiral induc-

Scheme 15 0

I0I

1. t-BuOC-N-N-COt-Bu

(49)

(45-70% 78-91%de)

(48)

R H

> Ra0')+N-NHC02I

t- Bu

ref. 32)

C02t-Bu

(501 R' = chiral

auxiliary

ref. 33)

ref. 34)

ref. 35) (65-85% 91 -96%da) (on one case 64% de)

51

52

Stereodifferentiating Addition Reactions

tion effected by (51)and (52)are discussed further in this book @. 300ff.); see ref. 36 for a related synthesis of P-hydroxy amino acids.

Scheme 16. Seven examples using ArLi or ArMgBr, with yields in the range of 65 -95%, illustrate the synthetic utility of the procedure. (See ref. 37b,c for additional methods). Besides amines themselves, a-hydroxy amines have also come to play an important Miscellaneous role [38]. In the hope of discovering hydroxyFinally, it is worth mentioning two innova- amination reactions similar to those effected by tive contributions that do not fit into the pre- the Sharpless reagent osmium tetroxide/chloceding classification scheme for electrophilic roamine T [38a], Dyong et al. [39] investigated aminations. Any student of chemistry knows the reaction of enamines (58)with chloroamine that nucleophiles are expected to add at the T. The cl-dialkylaminoaldehydes (60)were proelectropositive carbon atom of a C = N double duced in a reaction that was surprisingly clean bond. Nevertheless, we shall see that this is not (Scheme 17, eight examples, 50 - 84%). It could always the case [37a]! The stabilized tetra- also be demonstrated that migration of the niphenylcyclopentadienylanion (56)forms by ad- trogen occurred intramolecularly via the aziridition of Are to nitrogen of the tosylate (55), dinium ion (59). which is derived from the tetraphenylcyclopentadiene oxime (54). It may be that the electron- Scheme 17 withdrawing tosyl group helps in establishing the observed mode of addition. Elimination of the tosyl group affords the imine (57),and treatment with hydroxylamine yields a mixture of the amine ArNHz together with starting material (54, as shown in the cyclic reaction R’ NR2 C--CH-NKTs

Scheme 16

R2/

H20

- HCI

- TaNH,

>

\I C-CHO R2/

(59)

References

Ph

N

TsO

/ \

Ar

(56)

[l] Review of metalations: P. Beak and V. Snieckus, Acc. Chem. Res. 18, 306 (1982). VSnieckus, J. Heterocycl. Chem. 7, 95 (1984). [2] Reviews: a) T. Sheradsky in S. Patai (Ed.): “The chemistry of amino, nitroso and nitro compounds and their derivatives”. John Wiley, New York 1982. p. 395; b) Y. Tamura, J. Minomikawa, and H . Zkeda, Synthesis 1977, 1; c) Hydroxylamine-0-sulfonic acid: R. G. Wallace, Aldrichim. Acta f3,3 (1980); d) E. Erdik and M . Ay, Chem. Rev. 89, 1947 (1989). [3] T. Sheradsky, G. Salemnick, and Z . Nir, Tetrahedron 28,2833 (1972). [4] Y. Tamura, J. Minarnikawa, K. Sumoto, S. Fujii? and M . Zkeda, J. Org. Chem. 38, 1239 (1973).

Electrophilic Aminations [5] G. Boche, N. Mayer, M . Bernheim, and K. Wagner, Angew. Chem. 90, 733 (1978); Angew. Chem. Int. Ed. Engl. 17, 687 (1978). [6] R. Brown and W. E. Jones, J . Chem. SOC.1946, 781. [7] P. Beak and B. J. Kokko,J. Org. Chem. 47,2822 (1982). [S] B. J. Kokko and P. Beak, Tetrahedron Lett. 24, 561 (1983). [9] P. Beak, A. Basha, and B. J. Kokko, J. Am. Chem. SOC.106, 1511 (1984). [lo] G. Boche and H . 4 . Wagner, J. Chem. SOC. Chem. Commun. 1984, 1591. [ I l l a) M . Bernheim and G. Boche, Angew. Chem. 92,1043 (1980); Angew. Chem. Int. Ed. Engl. 19, 1010 (1980); Tetrahedron Lett. 23, 3255 (1982); b) G. Boche and R. H. Sommerlade, Tetrahedron 42, 2703 (1986). [12] a) G. Boche, M. Bernheim, and M. NieJner, Angew. Chem. Suppl. 1983,34; b)E.-U. Wurthwein: “N-Methylene-inamine”, presented at the Chemiedozententagung, Bielefeld, March, 1989. [13] G. Boche, M. Bernheim, and W. Schrott, Tetrahedron Lett. 23, 5399 (1982). [14] E. W. Colvin, G. W. Kirby, and A. C. Wilson, Tetrahedron Lett. 23, 3835 (1982). [l5] G. Boche, F. Bosold, and M . NieJner, Tetrahedron Lett. 23, 3255 (1982). [16] G. Boche and W . Schrott, Tetrahedron Lett. 23, 5403 (1982). [17] a) G. Boche, R. Sommerlade, and F. Bosold, Angew. Chem. 98, 563 (1986); Angew. Chem. Int. Ed. Engl. 25, 562 (1986); b) R. H. Sommerlade, Dissertation, Univ. Marburg 1987. [18] R. Huner and D. Seebach, Chimia39,356 (1985). 1191 Reduction of azides: a) Triphenylphosphane: M. Vaultier, N. Knouzi, and R. Carrie‘, Tetrahedron Lett. 24, 763 (1983) and ref. cited; b) NaBH4: F. Rolla, J. Org. Chem. 47,4327 (1982); c) catalytic hydrogenations see ref. [23]. 1201 M. Regitz, Synthesis 1972, 351. [21] a) S. J. Weininger, S. Kohen, S. Mataka, G. Koga, and J.-P. Anselme, J. Org. Chem. 39,1591 (1975) and ref. cited; b) Sulfonyl azides: P. A. S. Smith, C. D. Rowe, and L. B. Brunner, J. Org. Chem. 34, 3430 (1969). [22] J. N. Reed and V. Snieckus, Tetrahedron Lett. 24, 3795 (1983).

53

[23] G. H. Hakimelahi and G. Just, Synth. Commun. 10, 429 (1980). [24] N . Wiberg and W.-C. Joo, J. Organomet. Chem. 22, 333 (1970). [25] K. Nishiyama and N. Tanaka, J. Chem. SOC. Chem. Commun. 1983, 1322. [26] a) B. M. Trost and W.H. Pearson, J. Am. Chem. SOC.103,2483 (1981); b) J. Am. Chem. SOC.105, 1054 (1983). c) Tetrahedron Lett. 24,269 (1983). [27] A. Hassner, P. Munger, and B. A. Belinka, Jr., Tetrahedron Lett. 23, 699 (1982). [28] S. Lociuro, L. Pellacani, and P. A. Tardella, Tetrahedron Lett. 24, 593 (1983). [29] J. F. W . Keana, S. B. Keana, and D. Beetham, J. Org. Chem. 32, 3057 (1967). [29a] D. A. Evans and T. C. Britton, J. Am. Chem. SOC.109, 6881 (1987). 1301 T. Sakakura and M. Tanaka, J. Chem. SOC. Chem. Commun. 1985, 1309. [31] Cf. E. Fahr and H.Lind, Angew. Chem. 78,376 (1966); Angew. Chem. Int. Ed. Engl. 5, 372 (1966). [32] C. Gennari, L. Colombo, and G. Bertolini, J . Am. Chem. SOC.108, 6394 (1986). [33] a) D. A. Evans, T. C. Britton, R. L. Dorow. and J. F. Dellaria, J. Am. Chem. SOC. 108, 6395 (1986); b) D. E. Evans, T. C. Britton, R. L. Dorow, and J. F. Dellaria Jr., Tetrahedron 44,5525 (1988). 1341 L. A. Trimble and J. C. Vederas, J. Am. Chem. SOC.108, 6397 (1986). [35] a) W . Oppolzer and R. Moretti, Helv. Chim. Acta 69, 1923 (1986); b) W. Oppolzer and R. Moretti, Tetrahedron 44, 5541 (1988). [36] G. Guanti, L. Banfi, and E. Narisano, Tetrahedron 44, 5553 (1988). [37] a) R. A. Hagopian, M. J. Therien, and J. R. Murdoch, J. Am. Chem. SOC.106, 5753 (1984); b) Diarylamines from ArLi and LiCuXNRAr: M. Zwao, J. N . Reed, and V.Snieckus, J. Am. Chem. SOC.104, 5531 (1982); c) oxidative amination with organocopper compounds: H . Yamamoto and K. Maruoka, J. Org. Chem. 45,2739 (1980). [38] a) E. Herranz and K. B. Sharpless, J. Org. Chem. 43,2544 (1978); b) alternative cis-oxaminations: B. M. Trost and A. R. Sudhakar, J . Am. Chem. SOC.109, 3792 (1987) and ref. cited. [39] L. Dyong and Q. Lam-Chi, Angew. Chem. 91, 997, Angew. Chem. Int. Ed. Engl. 18,933 (1979).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Asymmetric Induction in Diels-Alder React ions

In 1988 the Diels-Alder reaction celebrated its sixtieth birthday[l]. This article covers recent results on asymmetric induction in Diels-Alder chemistry. Up to four new chiral centers are formed in the course of this cycloaddition [la]. Control over the asymmetric induction accompanying the formation of these centers is currently an area of very active research. Welzel [2] has introduced the topic in a systematic way and also reviewed the historical background. This second and independent report reviews some of the more recent results in this rapidly developing area, ones that are of particular practical importance. The literature to the end of 1983 [3-61 or mid 1988 [6a] is covered by various reviews. A detailed description in the case of enoates up to the end of 1985 is given by Helmchen [7], and camphor derivatives as chiral auxiliaries are reviewed by Oppolzer ~74. Many recent papers seem to reflect an increasing interest in practical applications. Earlier papers addressed the more fundamental development of reaction models and attempted to assess the degree of asymmetric induction as a function of various reaction parameters. However, a table with experiments giving high ee values (see ref. [2] for the definition of ee and de) is not sufficient for preparative purposes. Equally important (along with high chemical yields) are satisfactory answers to the following questions:

What is the endolexo ratio of the products (apart from the ratio of regioisomers in reactions of non-symmetrically substituted reaction components)? How great is the tendency of diene and dienophile to polymerize in the presence of Lewis acids? How large must the excess of the nonchiral component be? Are both enantiomers of the chiral auxiliary available? Can the chiral auxiliaries be recovered or removed without the racemization of product that often accompanies ester cleavage? How easily can the educts be upgraded to 100% purity either by chromatography or, even better, by recrystallization of intermediates or final products?

Chiral Dienophiles The overwhelming majority of the reported investigations deal with chirally modified enoates. For instance, the Lewis acid-catalyzed DielsAlder reactions of acrylates derived from of menthol or camphor (studied by Helmchen and Oppolzer) afford extraordinarily high de values [2 - 71. Of decisive importance for the degree of asymmetric induction is not only the effective shielding of one of the diastereotopic faces of the chiral enoate but also the existence of a single reactive conformation. Lewis acid cata-

55

Asymmetric Induction in Diels-Alder Reactions

lysis not only accelerates the reaction, it also gives better endolexo ratios. The role of Lewis acid in a Diels-Alder reaction may be to ensure fixation of the s-trans (or antiperiplanar) conformation (f) of the ester (exceptions confirm the rule: see below). An s-cis (or synperiplanar) conformation may well prevail in the uncatalyzed reaction, a conclusion supported by the recent calculations of Houk et al. [8]. Attack from the same side on the two different conformations obviously leads to products of opposite configuration.

and ent- (4) derived from camphor, both of which are now commercially available. The crotonic imide prepared from (4) is believed to form chelate complexes (5)upon addition of titanium tetrachloride (Scheme 2). Scheme 2

'.

Y

Acrylate (3), derived from camphor, permitted the synthesis of both (-)-norbornenone and (-)-p-santalene [9]. It afforded both good endolexo selectivity (19: 2 to 41 : 1) and excellent de values: in the 98.0 to 99.2% range (Scheme 1). Scheme 1

(-) - Norbornenon (-> - @ - Santalen (3)

However, esters of type (3) suffer from two disadvantages: the strong Lewis acid Tic& leads to decomposition (by ether cleavage) of many substrates, and reaction rates with substituted acrylic esters are so low that polymerization of the diene is observed. The Oppolzer group [lo] undertook a search for chiral auxiliaries that would increase the dienophilicity of the crotonic ester as a result of bonding to strong electron acceptors. This led to development of the crystalline sultams (4)

CI

NaH

1. MCPBA 2. Swern-Oxid. 4. Oxid. 56%

&

1. MCPBA 2. NaOCH3

CH2(0Me)2 (7)

H

c

ox

3 Mitsunobumverston Ill]

58%

~

'

1~ Formylation M ~

2. BF3 * OEt, 3. NaOCH3 54%

The s-cis form presumably predominates here due to steric hindrance of the s-trans conformation. As indicated in (9, addition of cyclopentadiene occurs with 98% endo- and 94%

56

Stereodifferentiating Addition Reactions

a-selectivity to afford the adduct in 57% yield as an analytically pure, crystalline material. The chiral auxiliary is eliminated and recovered by mild alanate reduction. The efficiency of the methodology is illustrated by the transformation of chiral alcohol (6)into 0-methyl loganine (9) via the intermediates (7) and (8) [lOc]. High diastereomeric excesses are also obtained in 1P-additions [12a], enolate alkylations [12a], acetoxylations [12b], halogenations [12c], and hydrogenations [12d] using (4) as chiral auxiliary (see ref. [7a] for a review). A similar increase in dienophilicity and conformational fixation by chelate formation as in (11) is observed for the N-crotyloxyoxazolidones (10) introduced by Evans et al. [13] (Scheme 3). A C = C/C = 0-syn planar conformation prevails in these compounds. Optimal stereodifferentiation is obtained with the (S)benzyl substituted oxazolidone (lo), which affords the adduct (12) in 88% de. Numerous other novel examples with even greater selectivities are described in the full paper [13a]. (See ref. [13b] for the Diels-Alder reaction of an

achiral acryloyloxazolidinone mediated by chiral Lewis acids.) Helmchen et al. [7, 141 consider not only the steric congestion of the substituents RL and R M in the models ( I ) and (2) but also their shape (convex, concave [2a]) and polarity. The polar effect is particularly significant in acrylates of lactic acid, in which the diastereomeric ratio is strongly dependent on the polarity of the solvent (&-value [ls]). All four possible adducts are formed in the reaction of acrylate (13) with cyclopentadiene in toluene. The picture changes with reaction of the fumarate (14), which has two chiral lactic acid residues [16]. (For the use of dimethylfumarate see [16a].) Here only the endo-adduct (15) is observed as a result of Re attack, with 88% (toluene, O T ) and 96% (C6HI2/CCl4,-40°C) de (Scheme 4). Scheme 4 C0,Et

Me

3

40qi \ H

Re

(13)

Scheme 3

0

Toluene 0 %

endo (de Re): 66(46) ex0 (de Re): 34(60) O

0

C0,Et

Toluene 0 OC

CeH12/CC14,

H

-

: aax de 40% 96% de

I (15) 'OZEt

o:16)

1. LiOH

2. KJ/J,

(95%

0

Asymmetric Induction in Diels-Alder Reactions

The lactate esters can be saponified without racemization, and iodolactonization yields the crystalline iodolactone (16) [7]. A de value of 96% is a remarkable result for a non-catalyzed Diels-Alder reaction. Similar cooperative effects are cited by Tolbert and Ali [17] as arguments in favor of a synchronous mechanism for noncatalyzed Diels-Alder reactions. Lactic acid has been used in yet another way in an asymmetric Diels-Alder reaction: starting from the concept of “captodative” olefins in normal and inverse Diels-Alder reactions [17a] Mattay et al. [17b] prepared the exomethylene pseudolactone (16b) (Scheme 4a). Scheme 4a

(59%)

1

57

i-Bu,AlCI afforded de values of up to 94-99%. The decisive influence of the Lewis acid was also demonstrated in the reaction of acrylates of lactic acid with cyclopentadiene in the presence of various Lewis acids [7, 141. An s-cis conformation was established by X-ray analysis [20] for the titanium complex (13, thus providing a reliable basis for the discussion of transition states. Tic4 catalysis leads to a major product that must be derived from Si attack (70% de for the endo product), while catalysts with less tendency to undergo sixfold coordination (e.g. AlEtCl,) give products with the reverse configuration (34% de). The non-chelated structure (18) is presumed to be the reactive complex in this case. Interestingly, the Re side of (17)is shielded not by the ester group but by the chlorine atoms of the Lewis acid.

/i\

The chiral dienophile (16b) was synthesized in 59% yield from Seebach’s [17c] lactic acid cis-acetal (f 6u) by bromination and elimination (Scheme 4a). The uncatalyzed reaction of (16b) with cyclopentadiene at room temperature showed a remarkable degree of n-face selectivity. The major product was (16c), and only 4% of the exo-isomer could be detected. Conversion of the endolexo mixture to an optically active norbornenone confirmed the overall selectivity of about 95%. Interestingly, catalysis with Lewis acids such as TiCl,(i-PrO), increased the endolexo selectivity, but decreased the n-face selectivity to an impractical level. The pioneering work of Walborsky et al. [18] has been extended by Yamamoto et al. [19] in an investigation of the reaction of dimethyl fumarates with a new type of aluminium catalyst. In contrast to the previously employed Tic&catalyst, with a maximum de of 78%, the new aluminum catalysts AIC13, Et2AICl, and

Simple acrylates of (S)-proline benzyl ester, such as (I&), were recently utilized for asymmetric Diels-Alder reactions by Waldmann [20a] (Scheme 4b). Scheme 46

TiGI.+ - 10°C _t_j 53 Yo

(186) 95.5% de

58

Stereodfferentiating Addition Reactions

An excellent diastereomeric excess of 95.5% was obtained in a titanium tetrachloride-catalyzed reaction at - 10°C. The major endo-product (1%) was accompanied by 6% of the exoisomer. A reversal of x-face selectivity was observed upon replacing Tic& with ZnC12, BF3, or EtAlCl,. The latter Lewis acids are limited to tetracoordination, and a change from the scis- to the s-trans-conformation of the acrylate in the transition state was held to be responsible for the observed effect. It is important from a practical point of view that products such as (18b)can be purified by crystallization, and that the chiral auxiliary can be removed and recovered either by hydrogenation or by methylation with trimethyloxonium tetrafluoroborate (Meerwein's reagent) without racemization of the product. In addition to lactates, which have been shown useful in the synthesis of the natural product (-)-a-bisabolol [14], recent investigations have been directed toward acrylates (19) of the cyclic compound D-pantolactone [21] (Scheme 5). The major products (29) are obtained in high yield, and they are easily purified by crystallization to an essentially homogeneous state.

malonate (214, investigated by Katagiri [21a]. This chiral dienophile affords the adduct (21b) as a 3: 1 endolexo mixture following TiC1,-catalyzed cycloaddition (Scheme 5a). The mixture (21b) was subsequently converted to the carbocyclic analogue of a C-nucleoside, in which the difference between the endo and exo products disappears. The enantiomeric excess was > 90%, a noteworthy example of selectivity. Scheme 50

The high degree of asymmetric induction observed in the reaction of boric acid complexes Scheme 5 (22) of juglone may also be due to the abovementioned cooperative effect. In contrast to the 0.3 eq. TiCI, 0-methyl mandelate ester of Trost [22], relsopren garded as a model case of "x-stacking" (com0 0 ooc, 73% pare ref. [2a]), Kelly et al. [23] and Yamamoto 0 et al. [24] transformed the dienophile into the chiral partner. This was accomplished, as shown in Scheme 6, by complexation with the chiral ligands (24) and (25), which display C2 0 0 symmetry. 0 Reaction of acetoxybutadiene (R = Ac) and 0 0 the diphenylbinaphthyl ligand (24)led to de va(21) (20) lues of 98% [23]. Tartaric acid amides are more 97 : 3 easily accessible, but the corresponding de valMenthyl esters, initially studied by Wal- ues are somewhat lower, typically about 80%; borksi [18], have again received attention in in the best case a value of 92% was achieved, the form of di-1-menthyl(acetoxymethy1ene)- with (25) as ligand and R = Si Et, [24].

-

?pP

q4y"443""3

Asymmetric Induction in Diels-Alder Reactions Scheme 6

Scheme 7 cF3

1. HCEC-C02Men, NEt3 2. MCPBA

SH

3. Crystalliiation

(26)

\0' . 0'

(20%)

1. QOCH,

0 ' R = 98% d e R = SiES 92% d e

2. OsO,, Me3N0 A

F 3 C T

)(::: C-co2Men 3.

4-

Ph

59

OH OH

Ph

.q

He

(27)

0

OH

ONH - m -To1

~ O N -Hm -TO[

(24)

(25)

The menthylsulfinate (27) bearing two chiral groups also affords the remarkable de value of 96% upon reaction with methoxyfurane [25] (Scheme 7). The menthyl group perhaps has only a minor influence on chiral induction during the cycloaddition, but it is necessary for separating the diastereomeric 1 :1 adducts of thiol (26) with the menthylprolinol ester (27). The adduct is subsequently converted into the glyoxylase inhibitor (29) via cis-hydroxylation and acetal formation. Recently, Koizumi et al. [25a] used a chiral derivative of (27) without the trifluoromethyl group in the synthesis of (+)-methyl 5-epi-shikimate. Substrate (27)is just one example from a long series of attempts to use chiral sulfinyl dienophiles in asymmetric Diels-Alder reactions (for dienyl sulfoxides see ref. [26]). Enantiomerically pure alkenyl sulfoxides are becoming easier and easier to prepare (see ref. [27]), but unfortunately the chirality of the chiral auxiliary disappears upon elimination, as seen in the synthesis of (29). Not only chiral acrylates but also vinyl ethers such as (30) can be reacted with electron-defi-

(28) SOAr 0

OH

0

(29)

cient dienes such as (31) to form adducts (32) with high selectivity [28]. Only a modest 5% de is observed with the normally very effective 8-phenylmenthyl group (Corey alcohol) in this particular Diels-Alder reaction, with its inverse electron demand. However, 84% de is obtained with isopropylphenylcarbinol, which is available in both enantiomers. Vinyl ethers such as (30) can be prepared by Hg2+-catalyzed transetherification starting with n-butyl vinyl ether and the corresponding chiral alcohol (Scheme 8). Such products are also easily cleaved by treatment with trifluoro acetic acid. As in the chiral enones of Masamune [29] (see ref. [2a]) the chiral center of (30) has moved one bondlength closer as compared to the acrylates described previously. Nevertheless, the high de values observed in the non-catalyzed Diels-Alder reaction of (31) to (32) are surprising con-

60

Stereodgferentiating Addition Reactions

Scheme 8

+ (S)-(-)-Ph(i-Pr)CHOH

55% 7

ti

0

n

Ph H

(30)

25-6OoC

94%

COZMe

To&o

OR*

(32)84% de

Y-> ,O,Q

OAc OAc

(33)

sidering the conformational flexibility of the ether bond in (30) (Scheme 8). The adduct (32) can be further transformed into the shikimic acid derivative (33) [30]. A question is often raised about the distance between the chiral center and the reaction center, but this question does not really address the core of the problem. The energy difference between diastereomeric transition states is determined by the relative accessibility of the reaction center, which in turn depends upon the conformation of the entire system. An illustrative example of this point is the intramolecular hetero Diels-Alder reaction investigated by Tietze et al. [31]. Here it is the unusual boat conformation of a seven-membered oxazepanedione that determines the stereochemical outcome of the reaction. (See ref. [32-341 for further hetero Diels-Alder reactions.)

Chiral Dienes Few systematic investigations have been conducted into the reactions of chiral dienophiles. Predictions are much more difficult in this case because of the high - conformational flexibility of the systems, particularly in the absence of

strong n-n-interactions ("n-stacking model") between neighboring aromatic systems. However, research in this area is continuing, as demonstrated by examples drawn from three groups employing different chiral auxiliaries. Charlton's group has extended the early investigations of Ito et al. [35], in which chiral ortho-quinodimethides were reacted with dienophiles. The intramolecular modification of this reaction has led to a variety of natural product syntheses [36]. Thus, thermal SO2 elimination from the chiral sulfone (34) affords the reactive ortho-quinodimethide (34, which with methyl acrylate yields the adduct (36) (Scheme 9). This reaction, conducted at 150"C, produces a diastereomeric excess of only 47%. Nevertheless, the reaction did serve as the basis for an enantioselective synthesis of the lignan isolariciresinol [37]. The author rules out an explanation involving n-stacking on the basis of models. Scheme 9

943

[d1 (34)

0-R*

\

(35)

-0

w OMe \

(36)

Numerous investigations have been conducted into the use of inexpensive carbohydrates as chiral auxiliaries in asymmetric DielsAlder reactions (see ref. [3 - 71). Very often, the more or less modified sugar residues are thereby incorporated into the target molecule, as illustrated by two recent examples from Franck [38] and Grieco [39]. Unfortunately, the sugar moiety can prove a nuisance if it is merely intended to serve as a chiral auxiliary, because it

Asymmetric Induction in Diels-Alder Reactions

is not easily removed. Periodate glycol cleavage is the most commonly invoked solution, but this oxidative approach is relatively drastic and is not applicable to every substrate. An elegant alternative was invoked by Lubineau and Queneau [40], who used enzymatic methods to cleave the glucose residues from products (39) and (40). Incidentally, this is not the only step that was conducted in aqueous medium: the cycloaddition itself was also carried out in water. The experiment was based on the remarkable observation of Breslow [41] that the rate and selectivity of a cycloaddition can be significantly increased by carrying out the reaction in water rather than an organic solvent. The effect is attributed to the aggregation of organic molecules in the polar solvent water, which should have a positive effect on any reaction with a negative activation volume (see ref. 2b, 41a, cf. this book, p. 71ff.). In fact, the temperature of the reaction between (38)and acrolein can be decreased from 80 to 20°C and the reaction time shortened from 168 h to 3 h relative to reaction of the acetylated analogues in toluene (Scheme 10). Moreover, only endo adducts were isolated, whereas the product of reaction Scheme 10 (OAC

61

in organic solvent contained 7 to 16% of the exo adduct. Only the diastereoisomeric ratio of (39)to (40) left something to be desired (73: 27). Further investigations into this phenomenon are certainly warranted, particularly given the relatively easy preparation of the starting material from acetobromoglucose (37). Intermolecular Diels-Alder reaction of methyl propiolate with the siloxy diene (41) derived from threonine is the key step in the synthesis of an epimer of the antibiotic actinobolin [42]. In this case the amino acid unit is retained in the end product just as it is in many syntheses of cytocalasin [3 - 61 (Scheme 11). However, the two isomers (42u/42b)are formed with only a moderate selectivity of 3: 1. (See ref. [42a] for the use in ha-Diels-Alder reactions of Schiff bases derived from reaction of amino acids with formaldehyde and ref. [42b] for chiral vinylketene acetals as dienes in the Diels-Alder reaction).

1. m

N

a (DMSO)

2. PhJP=CHz (THF)

3. MeOH/NEtJHzO

OH

___j 2OoC, 3 h

Chiral catalysts Relatively few papers have been published on catalyzed asymmetric Diels-Alder reactions since the sensational report by Koga et al. [43] regarding the reaction of methacrolein with cyclopentadiene using menthyloxyaluminum di-

62

Stereodgferentiating Addition Reactions

chloride as catalyst (43) (69% ee; 55% was reported in a repetition of the work by Oppolzer's group [ S ] ) . Nevertheless, a study involving systematic variation of the chiral alcohol component has led to greater insight into the relationship between the chiral source and the absolute configuration of the resulting Diels-Alder adduct [43a].

&

been shown to be very powerful catalysts for asymmetric Diels-Alder reactions. The catalyst (47b), of yet unknown structure, is prepared from diborane and the chiral tartaric acid derivative (474 (Scheme 12a). Scheme 12a OMeO

COOH

OAICI,

OH

BL,'

- 78OC. CH2C12

(476)

(474

The attractive possibilities inherent in catalytic processes continue to stimulate interesting new experiments in this difficult field. For instance, Bir and Kaufmann [44] report the use of isocamphenyl haloborane (46) as chiral catalyst in the reaction of cyclopentadiene with methylacrolein to afford (44) and (45) (Scheme 12). The endo-isomer (44) is the major product (endo selectivity 99%), and ee values of up to 48.2% are obtained if dimethylsulfide is added as ligand. Good results can also be achieved with the catalyst derived from P-binaphthyl (47) C451. Scheme 12

CH3 (47c) 97% ee

Perhaps the best asymmetric inductions ever observed in catalytic Diels-Alder reactions are those from reaction of methacrolein with 1,2dimethylbutadiene, which afford (47c) in 97% ee. Eight further examples with ee values in the range of 80-97% (one exception) confirm the effectiveness of this new chiral catalyst. The hetero cycloaddition of the chiral diene (48)to aldehydes in the presence of Eu(hfch as chiral catalyst afforded products like (49) in diastereomeric excesses of up to 95% [46] (Scheme 13). Scheme 13

bCozMe &. +

(46)

Eu(hfc)3 PhCHO

(45) endo

(44) exo

&BX*

&COzMe

(SMe),

a &

z,'BCI

'

Me

-

D

Ph (47)

/

Very recently, chiral acyloxyboranes investigated by the group of Yamamoto [44a] have

0

Zi\

(49)

(Isomers 25 : 1)

78oc+-

20%

>

Asymmetric Induction in Diels-Alder Reactions

Danishefsky does not attribute this remarkable selectivity to the usual additive effect found in double diastereoselection [47], because substrate and catalyst exhibited opposite selectivity in other experiments. At the moment it is not possible to say with certainty what special interactions are operative in this reaction, nor whether the cycloaddition can still be classified as a Diels-Alder addition. Even so, two recent applications - in the total syntheses of the avermectine A, aglycone [47a] and of zincophorine [47b] - demonstrate the usefulness of the method. A comparison has recently been published [47c] of the menthyloxyaluminum catalyst (43)with lantanide-derived chiral catalysts. A Diels-Alder reaction in the classical sense probably is operating in the reaction of the achiral dienophile (50) with cyclopentadiene to give adduct (52) in the presence of the chiral titanium catalyst (51) (Scheme 14) [48a]. Scheme 14 0

(50)

u

Retro-Diels-Alder Reactions In only a few cases has the retro Diels-Alder reaction been used in the synthesis of enantiomerically pure building blocks [49]. One recent example may suffice to illustrate the principle [SO]. Thus, dienophiles add with high yields and excellent regio- and stereoselectivity from the P-side of the dehydroestrone-related diene (53)to afford adduct (54) (Scheme 15). Cuprate addition, reduction, and acetylation, followed by thermal retro-diene reaction (200- 220°C), leads to the ally1 acetate (55) with 98% ee. Scheme 15 Ph

(53) 1. [CuMe2]Li 2. Red.

0

63

(54) OAc

H

(55)

92% de for endo

References Ph Ph

U

(52) endo : exo = 9 : 1

Initially, a two-fold excess of the catalyst was required to achieve a selectivity of 92% ee. A truly catalytic process resulted upon addition of molecular sieves (4 A), permitting the amount of catalyst to be reduced to 10 mol% without loss of selectivity. Seebach et al. have also employed similar catalysts in independent investigations [48c].

[I] 0.Diels and K. Alder, Liebigs Ann. Chem. 460, 98 (1928). [la] D . Craig, Chem. Soc. Rev. 1987, 187. [2] a) P . Welzel, Nachr. Chem. Tech. Lab. 31, 979 (1983); b) examples of high-pressure reactions: ibid. 31, 184 (1983). [3] L. A. Paquette in J. D . Morrison: “Asymmetric Synthesis”, Vol. 3B. Academic Press, New York 1984, p. 455. [4] H. Wurzinger, Kontakte (Darmstadt) 1984 (2), 3. [S] W. Oppolzer, Angew. Chem. Int. Ed. Engl. 23, 876 (1984). [6] M . Nogrudi: “Stereoselective Synthesis”, VCH Verlagsgesellschaft, Weinheim 1987, p. 267. a) M . J. Tuschner, Asymmetric Diels-Alder Reactions in Organic Synthesis: Theorie & Applications (T. Hudlicky, Ed.) JAI Press, London 1989.

64

Stereodifferentiating Addition Reactions

[7] This area is covered by: G. Helmchen in R. Scheffold (Ed.): “Modern Synthetic Methodes 4”, Springer-Verlag, Berlin 1986, p. 261. a) W . Oppolzer, Tetrahedron 43, 1969 (1987). [8] D. P. Curran, B. H. Kim, H. P. Piuaseana, R. J. Loncharich, and K. N. Houk, J. Org. Chem. 52, 2137 (1987). [9] W. Oppolzer, C. Chapuis, D. Dupuis, and M. Guo, Helv. Chim. Acta 68, 2100 (1985). [lo] a) W . Oppolzer and D. Dupuis, Tetrahedron Lett. 26, 5437 (1985); b) W. Oppolzer, C. Chapuis, and G. Bernardinelli, Helv. Chim. Acta 67, 1397 (1984); c) M . Vanderwalle, J. van Eycken, W. Oppolzer, and C. Vullioud, Tetrahedron 42, 4035 (1986). [ll] 0. Mitsunobu, Synthesis 1981, 1. [12] a) W. Oppolzer. P. Dudfield, T. Stevenson, and T. Godel, Helv. Chim. Acta 68,212 (1985);b) W. Oppolzer and P. Dudfield, Helv. Chim. Acta. 68, 216 (1985);c) W.Oppolzer and P. Dudfield, Tetrahedron Lett. 26, 5037 (1985); d) W. Oppolzer, R. J. Mills and M. Reglier, Tetrahedron Lett. 27, 183 (1986). [13] D. A. Evans, K. T.Chapman, and J. Bisaha. J. Am. Chem. SOC.106, 4261 (1984). [13] a) D. A. Evans, K. T. Chapman, and J. Bisaha, J. Am. Chem. SOC.110,1238 (1988); b) C. Chapuis and J. Jurczak, Helv. Chim. Acta 70, 436 (1987). [14] a) T. Poll, G. Helmchen, and B. Bauer, Tetrahedron Lett. 25,2191 (1984); b) G. Helmchen in J. Streith, H. Prinzbach, and G. Schill (Eds.): “Organic Synthesis, an Interdisciplinary Challenge’’, Blackwell Scientific Publications, Oxford 1985, p. 167. [l5] C. Reichardt, “Solvents and Solvent Effects in Organic Chemistry” 2nd Ed., VCH Verlagsgesellschaft, Weinheim 1988. [16] a) G. Helmchen, H. Hartmann, and T. Poll, unpublished; b) C. H. Heathcock, B. R. Davies, and C. R. Hadley, J. Med. Chem. 32, 197 (1989). [17] M. Tolbert and M. B. Ali, J . Am. Chem. SOC. 107, 4589 (1985) and ref. cited. a) J. Mertes and J. Mattay, Helv. Chim. Acta 71, 742 (1988); b) J. Mattay, J. Mertes, and G. Maas, Chem. Ber. 122, 327 (1988); c) D. Seebach, R. NaeJ and G. Calderari, Tetrahedron 40, 1313 (1984). [18] H. M . Walborsky, L. Barash, and T. C. Davis, J . Org. Chem. 26,4778 (1961) and Tetrahedron 19, 2333 (1963). [19] H. Yamamoto,K. Maruoka, K. Furuta, N. Ikeda, and A. Mori in W.Bartmann and K. B. Sharpless (Eds.): “Stereochemistry of Organic and Bioorganic Transformations”, VCH Verlagsgesellschaft Weinheim 1987, p. 13.

[20] T. Poll, J. 0. Metter, and G. Helmchen, Angew. Chem. 97, 116 (1985); Angew. Chem., Int. Ed. Engl. 24, 112 (1985); a) H. Waldmann, J. Org. Chem. 53, 6133 (1 988). [21] T. Poll, A. Sobczak, H. Hartmann, and G. Helmchen, Tetrahedron Lett. 26, 3095 (1985); a) N. Katagiri, T. Haneda, E. Hayasaka, N. Watanabe, and C. Kaneko, J. Org. Chem. 53, 226 (1988). [22] B. M. Trost, D. O’Krongly, and J. C. Belletire, J. Am. Chem. SOC.102, 7595 (1980). [23] T. R. Kelly, A. Whiting, and N. S. Chandrakumar, ibid. 108. 3510 (1986). [24] K. Maruoka, M. Sakurai, J. Fujiwara, and H. Yamamoto,Tetrahedron Lett. 27, 4895 (1986). [25] H. Takayama, K. Hayashi, and T. Koizumi, Tetrahedron Lett. 27, 5509 (1986) and ref. cited;,a) T. Takahashi, A. Iyobe, Y.Arai, and T. Koizumi, Synthesis 1989, 189. [26] G. H. Posner and W. Harrison, J. Chem. SOC. Chem. Commun. 1985, 1786. [27] H. Kosugi, M. Kitaoka, K. Tagami, A. Takahashi, and H. Uda, J. Org. Chem. 52, 1078 (1987). [28] G. Posner and D. G. Wettlaufer, Tetrahedron Lett. 27, 667 (1986). [29] W. Choy, L. A. Reed, III, and S. Masamune, J. Org. Chem. 48, 1139 (1983). [30] G. H. Posner and D. G. Wettlaufer, J. Am. Chem. SOC. 108, 7373 (1986). [31] L. F. Tietze, S. Brand, T. Pfeiffer. J. Antel, K. Harms, and G. M. Sheldrick, J. Am. Chem. SOC. 109, 921 (1987). [32] S. W.Remiszewski,J. Yang, and S. M. Weinreb, Tetrahedron Lett. 27, 1853 (1986). [33] J. K . Whitsell, D. James, and J. F. Carpenter, J . Chem. SOC.Chem. Commun. 1985, 1449. [34] P. Herczegh, M: ZsPly, and R. Bognar, Tetrahedron Lett. 27, 1509 (1986). [35] Y.Ito, Y.Amino,N. Nakatsuka, and T. Saegusa, J. Am. Chem. SOC.105, 1586 (1983). [36] a) J. L. Charlton, Tetrahedron Lett. 26, 3413 (1985); b) Can. J. Chem. 64, 720 (1986). [37] J. L. Charlton and M. M. Alauddin, J. Org. Chem. 51, 3490 (1986). [38] R. W .Franck, V,Bhat, and C. S. Subramaniam, J. Am. Chem. SOC.108, 2455 (1986). [39] P. A. Grieco, R. Lis, R. E. Zelle, and J. Finn, J . Am. Chem. SOC.108, 5908 (1986). [40] A. Lubineau and Y. Queneau, J. Org. Chem. 52, 1001 (1987). [41] C. D. Rideout and R. Breslow, J. Am. Chem. SOC.102, 7816 (1980); a) S. Colonna, A. Manfredi, and R. Annunziata, Tetrahedron Lett. 29, 3347 (1988).

Asymmetric Induction in Diels-Alder Reactions [42] A. P. Kozikowski and T. R. Nieduzak, Tetrahedron Lett. 27, 819 (1986); a) H. Waldmann, Angew. Chem. 100, 307 (1988); Angew. Chem. Int. Ed. Engl. 27, 274 (1988); b) J. P. Konopelski and M. A. Boehler, J. Am. Chem. SOC. iff, 4515 (1989). [43] S. Hashimoto, N. Komeshima and K. Koga, J. Chem. SOC. Chem. Commun. 1979, 437; a) H. Takemura, N. Komeshima, I. Takahashi, S. Hashimoto, N . Ikota, K. Tomioka, and K. Koga, Tetrahedron Lett. 28, 5687 (1987). [44] G. Bir and D. Kaufmann, Tetrahedron Lett. submitted 1989; a) K. Furuta, S. Shimizu, Y. Miwa, and H . Yamamoto,J. Am. Chem. SOC.f f f , 1481 (1989). [45] D. Kaufmann and R. Boese, Angew. Chem. 102, 568 (1990); Angew. Chem. Int. Ed. Engl. 29,545 (1990). [46] M. Bednarski and S. Danishefsky, J. Am. Chem. SOC. 108, 7060 (1986). [47] S. Masamune, W. Choy. J. S. Petersen, and L. R. Sita, Angew. Chem. 97, 1, Int. Ed. Engl. 24, 1 (1985); a) S. J. Danishefsky, D. M . Armistead,

65

F. E. Wincott, H. G. Selnick, and R. Hungate, J. Am. Chem. SOC. 109, 8117 (1987); b) S . J. Danishefsky, H. G. Selnick, R. E. Zelle, and M. P. DeNinno, J. Am. Chem. SOC. 110, 4368 (1988); c) M . QuimpPre and K. Jankowski, J. Chem. SOC., Chem. Commun. 1987, 676. [48] a) K. Narasaka, M. Inoue, and N. Okada, Chem. Lett. 1986, 1109; b) K. Narasaka, M . Inoue, and T. Yamada, Chem. Lett. 1986, 1967; c) D. Seebach, S. Roggo, R. Imwinkelried, A. K. Beck, and A. Wonnacott, Helv. Chim. Acta., in preparation. [49] a) P . Magnus and P. M. Cains, J. Am. Chem. SOC. 108, 217 (1986); b) G. Helmchen, K. Ihrig and H. Schindler,Tetrahedron Lett. 28,183(1987); c) A. J. H. Klunder, W. B. Huizinga, P. J. M . Sessink, and B. Zwangenberg, Tetrahedron Lett. 28,357 (1987). [SO] a) D. Schomburg, M . Thielmann, and E. Winterfeldt, Tetrahedron Lett. 27, 5833 (1986); b) K. Matcheoa, M. Beckmann, D. Schomburg, and E. Winterfeldt, Synthesis 1989, 814.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Chiral Lewis Acids

Chiral Lewis acids are employed in organic synthesis in a series of important C - C-connections. These include Diels-Alder and ene reactions, Michael and aldol additions, and above all the addition of ally1 and enol silanes and trimethylsilyl cyanide to aldehydes. The primary role of the Lewis acid is to activate a carbonyl function by complex formation. In principle, however, it should also be possible to introduce chiral Lewis acids as a way of obtaining complexes suitable for asymmetric syntheses. The challenge is enticing, since this would eliminate the need to first introduce a chiral function into one of the reactants and then remove it later, and it also suggests the fascinating possibility of carrying out such a process catalytically. Until recently this field was practically unexplored, only a few examples being known in the case of Diels-Alder reactions. It must be admitted that the first experiments were not very encouraging: Diels-Alder reactions with a menthyl ethyl ether-BF3 complex achieved an ee of only 3% [l]. More promising was the report by Koga [2] in 1979 that catalysis of the reaction of methacrolein (2) with cyclopentadiene (1) in toluene at -78°C by the chiral Lewis acids (4) or (5) yields mainly the em-adduct (3) with up to 72% ee. Later investigations, including ones with other reactants, also demonstrated [3, 41 that the effectiveness of the optically active Lewis acid (which can be very difficult to purify) is highly dependent

0 \

+

KcHo Cat’\

n (4)

bH (5)

upon experimental techniques used in its preparation. A general problem that makes efficient induction unlikely is the excessive conformational flexibility associated with complexes between simple unsaturated aldehydes or ketones and systems such as (4) and (5). Apparently the mobility of the Al-0-terpene bond in the catalyst is less important than the weak fixation of the complex with the C = 0 function. This is demonstrated by an observation of Reetz [5], who noted that reaction of ( I ) and (2) in the presence of the less mobile chiral titanium complex (6) actually produced worse results: only 16% ee of the exo-product, and an absolute configuration opposite to that of (3).

Chiral Lewis Acids

Another early example of the application of chiral Lewis acids in cycloaddition is due to Danishefsky [6], who found that the preparatively important addition of aldehydes to electron-rich dienes [7] can be catalyzed by the lanthanide chelate complexes employed as NMR shift reagents. Chiral complexes like the commercially available Eu(hfch made it possible to perform asymmetric induction in the hetero Diels-Alder reaction between aldehydes and systems such as (8)with an ee of up to 58%. In a recent investigation [8] Danishefsky reported that the selectivity can be increased further by “double diastereoselection” [9], in the course of which a remarkable phenomenon is observed: reaction of ‘aldehydes with chiral menthoxydienes, e.g. (ii),in the presence of chiral europium complex catalysts gives maximum diastereoselectivity in the “mismatched” case! The diastereoisomeric adducts (12) and (13) form in a ratio of 97:3, while with the chiral catalyst Eu(fodh the ratio is 45: 55. The reason for this apparent specific interaction between the dissymmetric elements of catalyst and chiral auxiliary remains unclear.

OMenth Me3Si0 Acof

( 1 1)

+

0

I . Cat.’

lph 2. Et3N. MeOH

(94

Yamamoto has very recently introduced highly effective chiral catalysts for the hetero Diels-Alder reaction of aldehydes with “Danishefsky dienes”, exploitingthe axial chirality

67

of 2,2‘-binaphthol derivatives [lo]. As demonstrated in a series of examples, aldehydes react with various siloxydienes in high enantioselectivity (up to 97% ee) at -20°C in toluene in the presence of ( 7 ) (with R = SiAr3 and Ar = Ph or 3,5-xylyl). However, such high selectivity was only achieved with sterically demanding 3,3’-substituted binaphthol derivatives, for which a new synthesis was developed starting from 3,3’-dibromobinaphthol. Aluminum systems ( 7 ) bearing smaller substituents R (e.g., H, Me, Ph, or SiMe3)and SiMe-t-Bu in the 3,3‘positions often provided acceptable yields only in stoichoimetric quantity, and then usually with drastically reduced selectivity.

(b): X =

-N

-v

Binaphthol-modified Lewis acids have also been employed successfully for normal DielsAlder reactions, as in model investigations of the reaction of acrylate esters or crotonamides with cyclopentadiene. Seebach tested in the former case various chiral alkoxytitanium(1V) complexes (22),prepared with various optically active 1,2- and 1,4-diols such as 2,2‘-binaphthol (184, diethyl tartrate, and systems (19a) derived from tartaric acid. He observed that the highest enantioselectivity was obtained with 2,2’-binaphthol(50% ee) and the dioxolane (18b)(up to 46% ee) [ll]. Nagasaka has investigated the asymmetric Diels-Alder reaction of cyclopentadiene with

68

Stereodijferentiating Addition Reactions

(188): R = H (18b): R = W e 3 (18c): R = Ph

(198): R1 = R2 = CH3 (19b): R' = H. R2 = t-Bu ( 1 9 ~ ) :R1 = CH., R2 = Ph

N z

(208): X = OCH2Ph (20b): X =

q

OH

(21)

crotonamide (164 in the presence of the alkoxytitanium complex (22),which incorporates the diol (19c) as a chiral ligand [12]. Chapuis and Jurczak in a concurrent wide-ranging study [13] tested the effects of various Lewis acids on the same reaction, this time with (16b)as dienophile. Chiral complexes of type (21) or (23) were prepared in situ by reaction of Tic& or EtAlC1, with optically active ligands such as (184 (18b),( 2 0 4 (20b),(21),and others. In general, it was found that the titanium compounds yielded better results than the aluminum com-

pounds, with respect to both the endolexo ratio and the extent of enantiotopic face differentiation. Even a ligand as simple as (S,S)-lP-dibenzyloxy-2,3-butandiol (20a) proved highly eficient (98% ee), but only when employed in at least equimolar quantity. Nagasaka [I41 later overcame this limitation by finding that catalytic amounts of Lewis acids would suffice if the reaction were carried out in the presence of powdered molecular sieves (91% ee) - conditions similar to those employed in the catalytic version of the Sharpless epoxidation [lS]! The high optical yields on reaction with crotonamides (164 and (16b) are also attributable to the fact that the dienophile experiences reduced conformational mobility on account of chelate formation with the Lewis acid, a circumstance that generally results in improved asymmetric induction. This last factor, coupled with the advantages of a bidentate ligand with C1 symmetry, also contributes to an elegant approach to (28), a compound frequently employed as an intermediate in the synthesis of tetracycline systems [16]. Thus, Kelly found that the Diels-Alder reaction of juglone (26) with acetoxybutadiene (27) in the presence of a Lewis acid (25) prepared from BH3, acetic acid, and 3,3'-diphenylbinaphthol yielded the adduct (28) with over 98% ee. It is likely that this reaction proceeds via a spirocyclic borate complex, shielding one face of the double bond in juglone efficiently from attack by the diene.

$)+y2& \

OH 0

OAc

OH 0

6Ac

Apart from the examples described for the Diels-Alder reaction there are at present few

Chiral Lewis Acids

other reports of successful applications of chiral Lewis acids. An enantioselective cyclization of unsaturated aldehydes [e.g. (29)-+ (30)] with a Lewis acid prepared from dimethylzinc and optically pure 2,2'-binaphthol has been described by Yamamoto [17], but here it was necessary to employ three equivalents of Lewis acid in order to achieve acceptable turnovers and optical yields of 88% ee.

69

using (37) and a Hiinig base, a reaction in which the ketone is evidently transformed in situ into the chiral boron enolate. The ee values observed varied between 32 and 92% in the five examples investigated. The disadvantage is that here again it has been necessary to employ equimolar quantities of Lewis acid. A catalytic reaction has so far been achieved only in the addition of Me3SiCN to aldehydes, and even then the ee was only 16%. n

Interesting possibilities should also be associated with aldol reactions. In one model study, Watanabe found [l8] that the addition of acetone to p-nitrobenzaldehyde can be catalyzed by metal salt complexes incorporating esters of a-amino acids as chiral ligands. The best results were apparently achieved with a Zn(I1)(TyrOEt), complex, although the exact extent of the asymmetric induction was not reported. 0

2 L-TyrOEt

OH

0

Chiral Lewis acid species catalyze the addition to aldehydes of silylated C-nucleophiles such as silylenol ethers, allylsilanes or trimethylsilyl cyanide, thereby producing enantioselective C-C coupling. Reetz [ S ] was able to report that an equimolar quantity of the titanium compound (6)in fact produces a selectivity of more than 80% ee in the addition of (34) to the aldehyde (35). In a subsequent investigation [19] Reetz introduced a new optically active Lewis acid, the boron compound (37). When equimolar quantities of this material were employed, addition of (34)to (35)occurred with 90% ee. Furthermore, it was also possible to realize direct enantioselective aldol addition

(35)

Most reactions involving chiral Lewis acids must be regarded as still in the development stage, and further spectacular achievements [20] are likely in the continuing search for more efficient systems, particularly with respect to true catalytic processes.

References [l] M. M. Guseinov, I. M. Akhmedov, and E. G. Mamedow, Azerb. Khim. Zh. 1976, 46 (C. A. 1976, 85, 1769252). [2] S. Hashimoto, N . Komeshima, and K . Koga, J. Chem. SOC. Chem. Commun. 1979,437. [3] C. J. Northcott and Z . Valenta, Can. J. Chem. 65, 1917 (1987). [4] M. Quimpere and K. Jankowski, J. Chem. SOC. Chem. Commun. 1987, 676. [5] M. T. Reetz, S.-H. Kyung, C . Bolm, and T. Zierke, Chem. Ind. 1986, 824. [6] N. Bednarski, C . Maring, and S. Danishefsky, Tetrahedron Lett. 1983,3451; M. Bednarski and S. Danishefsky, J. Am. Chem. SOC. 105, 3716 (1 983). [7] Review: S. J. Danishefsky and M . P . DeNinno, Angew. Chemie 99, 15 (1987); Angew. Chem.

70

[S] [9] [lo] [ll] [12] [I31 [14]

Stereodifferentiating Addition Reactions Int. Ed. Engl. 26, 15 (1987); S. J.Danishefsky, Aldrichimica Acta 19, 59 (1986). M. Bednarski and S. Danishefsky, J. Am. Chem. SOC.108, 7060 (1986). S. Masamune, W. Choy, J. S. Petersen, and L. R. Sita, Angew. Chem. 97, 1 (1985); Angew. Chem. Int. Ed. Engl. 24, 1 (1985). K. Maruoka, T. Itoh, T. Shirasaka, and H. Yamamoto, J. Am. Chem. SOC.110, 310 (1988). D. Seebach, A. K. Beck, R. Imwinkelried, S. Roggo, and A. Wonnacott, Helv. Chim. Acta 70, 954 (1987). K. Navasaka, M. Inoue, and N. Okada, Chem. Lett. 1986, 1109. C. Chapuis and J. Jurczak, Helv. Chim. Acta 70, 436 (1987). K. Navasaka, M. Inoue, and T. Yamada, Chem. Lett. 1986, 1967; K. Navasaka, M. Inoue, T. Yamada, J. Sugimori, and N . Zwasaka, Chem. Lett. 1987, 2409.

[15] R. M. Hanson and K. B. Sharpless, J . Org. Chem. 51, 1922 (1986). [16] T. R. Kelly, A. Whiting,and N.S. Chandrakumar, J. Am. Chem. SOC.108, 3510 (1986). [17] S. Sakane, K. Maruoka, and H. Yamamoto,Tetrahedron 42,2203 (1986). [18] K. Watanabe, Y. Yamada, and K. Goto, Bull. Chem. SOC.Japan 58, 1401 (1985). [19] M. T. Reetz, F. Kunisch, and P. Heitmann, Tetrahedron Lett. 1986, 4721; review: M . T. Reetz, Pure Appl. Chem. 60, 1607 (1988). [20] Most recent advances: E. J. Corey, R. Zmwinkelried, S. Pikul, and Y.B. Xiang, J. Am. Chem. SOC.111, 5493 (1989); E. J. Corey, C.-M. Yu, and S. S. Kim, ibid. 111, 5495 (1989). Recent reviews: D. A. Evans, Science 240, 420 (1988); H . Brunner, Synthesis 1988, 645.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

C - C Bond-Forming Reactions in Aqueous Medium

For synthetic chemists, water often appears as a natural enemy to be kept away from the reaction mixture until workup. Nevertheless, in recent years reports have appeared in increasing number describing the delibrate use of water as a solvent for various C -C bond-forming reactions. In 1980, Rideout and Breslow [l] reported a rate increase by a factor of more than 700 when the Diels-Alder reaction of cyclopentadiene ( I ) with methyl vinyl ketone (2) at 20°C is performed in water instead of hydrocarbons, as the solvent. Simultaneously, the endolexo ratio of (3):(4)rises from 4 to approximately 21

PI.

0

+

+o

philes [l, 21. Further acceleration of the reaction is achieved by addition of lithium chloride, whereas guanidinium chloride slightly retards the reaction. Breslow explains his results on the basis of hydrophobic interactions that induce a favourable aggregation of the apolar components ( I ) and (2) in the polar water [3]. Owing to the high cohesive force of water, pressure is exerted on the molecules, which are then entrapped in “holes” within the solvent. This effect would significantly accelerate the cycloaddition, and the more compact transition state should lead to a strong preference for the endo product (3). On the other hand, Grieco [4] believes that formation of micelles is responsible for the observed rate increase [S]. His group has concentrated on more complex starting materials for cycloaddition, appropriate for natural product syntheses. Figure 1 depicts several examples in which dramatic accelerations and/or changes in selectivity occur. Sodium salts of various unsaturated carbocyclic acids proved to be particularly useful and reactive dienes [6,7]. However, in some cases primarily cis-configurated cycloadducts isomerized to the more stable trans-isomers in aqueous medium. Grieco and coworkers [S] also performed hetero-Diels-Alder reactions, making use of the facile formation of iminium ions in water. As shown in equation (l), an amine hydrochloride is treated with aqueous formaldehyde solution in the presence of a diene. Iminium ion (5) gen-

h0+& (3)

(4)

Similar effects were observed for 9-hydroxymethylanthracene as diene, and acrylonitrile, alkyl acrylates, or dimethyl maleate as dieno-

72

me

Stereodqferentiating Addition Reactions

0 R = Me R = Na

O H

Solvent: toluene

H2O

25OC, 7d 25OC, I h

traces 77% (after esterification with CH,N,)

CO,R /CO,R

MeO$

R = Et R = Na

Me0

0

R = Me R = Na

Solvent: toluene

H,O

OMe Solvent: benzene H2O

H 25OC, 7d 25OC, 2h

no reaction 94% (R = H)

0 80°C, 12h 25OC, IOmin

OMe

63% 93% (R = H)

L C H O

'"OMe

"OMe Solvent: toluene "20

25OC, 7d 25OC, 17h

46% 14u : 14p = 0.7 : 1 85% 1 4 ;~14p = 2 1

Fig. 1 Diels-Alder reactions in water according to Grieco et al. [ 4 , 6, 71.

erated under these Mannich conditions adds smoothly to cyclopentadiene to provide a quantitative yield of a bicyclic heterocycle. Other examples shown in Figure 2 require little further explanation, though they reflect the wide scope as well as the stereoselectivity and regioselectivity of this method. Of course, intramolecular variants are also conceivable. Asymmetric syntheses have recently been re-

ported using esters of a-amino acids as starting materials [9]. Grieco et al. [lo] also demonstrated in situ generation and trapping of C-acyl N-alkyliminium ions. A mixture of cyclopentadiene, benzylamine hydrochloride, and phenyl glyoxal in water furnishes the diastereomeric bicyclic compounds (7) and (8) in 88% yield, via (6) as the reactive intermediate. The same protocol also

C - C Bond-Forming Reactions

73

Fig. 2 Aza Diels-Alder reaction of iminium ions [8].

Fig, 3 Synthesis of piperidine derivatives in aqueous mediuin starting from ally1 silanes and benzyl ammonium trifuoroacetate [ill. I

74

Stereodifferentiating Addition Reactions Ph

@

vNH3ClB

-t H2C0

d5

N-Ph

h0

i hP, ,N3H @

parently faster than the protodesilylation normally observed with these reagents in acidic medium. Generation of iminium ions (9) and (10) is followed by inter- and intramolecular addition to the corresponding C -C double bond. The final carbenium ion captures a nucleophile (HO-) to give a 4-hydroxypiperidine derivative. Figure 3 illustrates the scope and elegance of this reaction cascade.

HpC=O

L“

(9)

C P

Ph

R I

6 e02CCF3

works with methylamine hydrochloride or ammonium chloride, affording the corresponding acyliminium ions, which add smoothly to cyclopentadiene. The examples presented so far involve reagents that are fairly insensitive to hydrolysis. Surprisingly, Grieco and coworkers [l 11 were also able to work under Mannich conditions with ally1 silanes. Aminomethylation followed by cyclization to piperidine derivatives is ap-

R

”$

I

OH

The stereoselectivity found in an aldol addition [12] tends to support the mechanistic picture described above involving high pressure generated by hydrophobic forces in water. Under Mukaiyama’s conditions, l-trimethylsiloxycyclohexene and benzaldehyde react to yield a 25:75 synlanti mixture of the two aldol adducts (1f ) (Figure 4).No transformation whatsoever is observed at atmospheric pressure without a Lewis acid, but ( i f ) is obtained in 90% yield under a pressure of 10 kbar. Interestingly, the diastereomeric ratio is this time reversed; the more compact transition state (AV* being more negative) leads to s y n - ( f f ) . Indeed, similar synlanti ratios are recorded if the reaction is run at room temperature in wa-

C - C Bond-Forming Reactions

75

Fia. 4 Diastereoselectivity of an aldol addition performed under different reaction conditions [i2].

Fig. 5 Preparation of homoallylic alcohols using zinc in saturated aqueous ammonium chloride solutionlTHF ( 5 : i) according to Luche et al. [13, 141 and Benezra et al. [15].

ter or in a mixture of water and tetrahydro- addition of siloxycyclohexene has been found furan. The moderate yields in this case are due for a,p-unsaturated ketones, while normal keto hydrolysis of the silyl enol ether. Smooth 1,4- tones do not react under these conditions. Fur-

76

Stereodifferentiating Addition Reactions

ther examples will be required to firmly establish the synthetic value of this variant of the aldol addition. In any case, the mild and experimentally simple procedure is noteworthy. Allyl silanes and silyl enol ethers are not organometallic compounds in the strictest sense, and they might be expected to have a certain chance for survival in water (as demonstrated here), but the successful generation and transformation of allylic zinc and tin reagents in aqueous medium is really remarkable. Luche et al. [I31 report almost quantitative formation of homoallylic alcohols from the reaction of aldehydes or ketones, allylic halides, and zinc dust when the reaction is carried out in a mixture of saturated aqueous ammonium chloride and tetrahydrofuran. This Barbier reaction occurs only with allylic halides; it is accompanied by an allyl shift, and is aldehyde selective, as shown in competition experiments [14]. An efficient synthesis of a-methylene y-lactones has also been carried out using this method [IS] (Figure 5). Similar results are obtained with tin powder, in water/THF under ultrasonic treatment [14]. In the meantime it has become clear that free allyl metal compounds are not formed under these conditions. Instead the authors consider a radical reaction in the proximity of the metal surface [161. Some of the synthetic methods described here may be classified as biomimetic, as it is wellknown that nature makes use of both hydrophobic interactions and Mannich reactions. The collection of aqueous C -C bond-forming reactions presented here suggests that similar dramatic solvent effects can be expected with other reactions.

References [l] D. C . Rideout and R. Breslow, J. Am. Chem. SOC.102, 7816 (1980). [2] R. Breslow, U.Maitra, and D. C . Rideout, Tetrahedron Lett. 24, 1901 (1983).

[3] R. Breslow and U. Maitra, Tetrahedron Lett. 25, 1239 (1984); R. Breslow and T. Guo, J. Am. Chem. SOC.110, 5613 (1988). [4] P. A. Grieco, P. Garner, and Z . He, Tetrahedron Lett. 24, 1897 (1983). [5] See also: R. Braun, F. Schuster, and J. Sauer, Tetrahedron Lett. 27, 1285 (1986). [6] P . A. Grieco, K. Yoshida, and P. Garner, J. Org. Chem. 48,3137 (1983). See also: A . G. Griesbeck, Tetrahedron Lett. 29, 3477 (1988). [7] P. A. Grieco, K. Yoshida, and Z . He, Tetrahedron Lett. 25, 5715 (1984). For a formal synthesis of the Znhoffen-Lythgoe diol see: E. Brandes, P. A. Grieco, and P. Garner, J. Chem. SOC.,Chem. Commun., 1988, 500. Application of dienyl ammonium chlorides: P. A. Grieco, P. Galatsis, and R. F. Spohn, Tetrahedron 42, 2847 (1986). [8] S. D. Larsen and P. A . Grieco, J. Am. Chem. SOC.107, 1768 (1985). For applications of the intramolecular reaction in alkaloid synthesis see: P. A. Grieco and D. T. Parker, J . Org. Chem. 53, 3325, 3658 (1988), P. A. Grieco and S. D. Larsen, J. Org. Chem. 51, 3553 (1986). Iminium ions derived from aryl amines and aldehydes function as heterodienes to provide novel tetrahydroquinolines: P. A. Grieco and A. Bahsas, Tetrahedron Lett. 29, 5855 (1988). [9] P. A. Grieco and A . Bahsas, J. Org. Chem. 52, 5749 (1987). H. Waldmann, Angew. Chem. 100, 307 (1988); Angew. Chem. Int. Ed. Engl. 27,274 (1988); Liebigs Ann. Chem. 1989, 231. [lo] P. A. Grieco, S. D. Larsen, and W. F. Fobare, Tetrahedron Lett. 27, 1975 (1986). [ll] S. D. Larsen, P. A. Grieco, and W.F. Fobare, J. Am. Chem. SOC.108, 3512 (1986). P. A. Grieco and W. F. Fobare, Tetrahedron Lett. 27, 5067 (1986). Allyl stannanes do not form piperidines under these conditions, bishomoallyl amines being formed instead P. A. Grieco and A. Bahsas, J. Org. Chem. 52, 1378 (1987). [12] A. Lubineau and E. Meyer, Tetrahedron 44, 6065 (1988). [13] C. Petrier and J.-L. Luche, J. Org. Chem. 50, 910 (1985). [14] C . Petrier, J. Einhorn, and J.-L. Luche, Tetrahedron Lett. 26, 1449 (1985). C . Einhorn and J.L. Luche, J . Organomet. Chem. 322, 177 (1987). For the diastereoselectivity of this reaction also see: T. Kunz and H . 4 . Reissig, Liebigs Ann. Chem. 1989, 891. [l5] H . Mattes and C. Benezra, Tetrahedron Lett. 26, 5697 (1985). [16] J.-L. Luche, C . Allauena, C . Petrier. and C. Dupuy, Tetrahedron Lett. 29, 5373 (1988).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Natural Product Synthesis via 1,3-Dipolar Cycloadditions

Even though its origins can be traced back to the 19th century, the potential of 1,3-dipolar cycloaddition was not been really recognized until 1960 when R. Huisgen and his group started to elucidate the full scope of the reaction [l]. This monumental investigation extended over more than twenty years, and it provided detailed information about a wide variety of 1,3-dipolesand the mechanism of their addition to unsaturated systems. The main results may be summarized as follows [2]: 0 1,3-Dipoles fall into two classes: heteroallyl anions (type A), and heteropropargyl-allenyl anions (type B). The heterosubstitution in both classes must be chosen such that the overall species is neutral, although mesoionic resonance structures are required in most cases for correct formulation. 0 Many 1,3-dipoles are unstable. Exceptions include nitrones, diazoalkanes, aides, and suitably substituted nitrile oxides, which may be isolated prior to the cycloaddition. The unstable 1,3-dipoles must be generated in the presence of the dipolarophile. The orientation phenomena which occur in the case of unsymmetrical 1,3-dipoles and dipolarophiles may be described in terms of the HOMO- and LUMO-orbital coefficients at the reactive sites in both components [3]. Steric effects also play an important role. 0 Stereochemically, 1,3-dipolar additions are related to the Diels Alder reaction. Thus, addition proceeds suprafacially with respect to

the dipolarophile. The endo-exo selectivity is less pronounced in the case of 1,3-dipolar addition. 1,3-Dipolar cycloadditions were long ignored in natural product synthesis, perhaps because the primary heterocyclic adducts fail to show an obvious resemblance to natural product structures. Only after reactions had been devised to effect ring cleavage did intermediates emerge that were more suitable for conversion into traditional natural product target molecules. Of all the 1,3-dipoles, nitrones, nitrile oxides, and azomethine ylides have proven to be the most valuable in this respect, as demonstrated by the following sections. x//y\:

A Ally1 anion type

x=y-z

0

++

0

x=y=z

B

Propargyl-allenyl anion type

Intermolecular Nitrone-OlefinAddition C41 The regiochemistry for addition of ( I ) to (2) is straightforward in the case of monosubstituted olefins ((2),R4 = H), which give (3) in high selectivity over (4). 1,2-Disubstituted olefins form (3)/(4)-mixtures. An exception is acrylic esters, which furnish (3) (R4 = C02R) almost exclu-

78

Stereodijjferentiating Addition Reactions

9,

4"

Me

H Me

(8)

sively. Additionally, high facial selectivity (endo with respect to the allylanion system, exo with respect to the ring) is exhibited by cyclic nitrones like (7), which adds propene to give (8). As noted earlier, the primary isoxazolidines (3)/(4)serve mainly as synthetic intermediates, which are then hydrogenated to give the y-aminoalcohols (5)/(6).Thus, (8)is converted into the alkoloid sedridine (9) [S]. In this example, the cycloaddition process permits perfect control over the dificult 1,3-~tereorelationship. y-Aminoalcohol substructures are found in many of the amino sugars present in physiologically active glycosides. For instance, the glycosidic form of (10) is part of the anthracyclinone antibiotics carbinomycin, daunomycin, and adriamycin. Retrosynthetically, (10)may be derived from the nitrone olefin adduct (11)[ 6 ] , which was obtained in the desired stereo- and regiochemistry from nitrone (12)and ethyl vinyl ether. (12)was in turn prepared from ester (13) by routine operations. (11)was converted into (14), a known derivative of (10).

(?)-Sedridine

(9)3)

OH

n

OH Daunosamine (10)

1. DlBAL

(13)

2. BnNHOHI Et20/0"C

'

(1 1)

+

(12)

(do") 35OC/72 h

1. HdPd(OH)2 HCI/MeOH

(11)

.N H A c

Me ' OAc

B n = CH,Ph

(7 41

'

1,3-Dipolar Cycloadditions

Intramolecular Nitrone-OlefinAddition C71 Just as with the Diels Alder reaction, the intramolecular version of 1,3-dipolar cycloaddition lOl0

C-AlkenylNitrone (15)

n

N-AlkenylNitrone (16)

has many advantages over corresponding intermolecular reactions. For instance, entropy factors lower the activation barrier of the reaction, permitting the use of non-activated dipolarophiles. Additionally, regio- and stereoproblems are greatly simplified in an intramolecular addition if the tether connecting olefin and dipole is relatively short, generally consisting of 4 or 5 bonds. Two types of such unsaturated nitrones may be distinguished: the Calkenyl type (15) and the N-alkenyl type (16). (15) is by far the more common case, for which

cis-fused

R3

79

H

R3.m C H 2 I n

R2

adduct trans-fused

80

Stereodqfeerentiating Addition Reactions

Scheme 1 L-Acosamine and L-daunosamine according to Wovkulich ( 8 a l .

M i

$ I

I

OH 'NH,

L- Acosamine (22)

"'3

(24)

Me

O,@ NR'

0

Me

I

2I e J $

2

Bo

(23)

0

Me,'

Me

OH

I \

i

0

0

0

C0,Me 1. Zn/HOAc

(29)

Me ' 3. DlBAL

e h

:

NI X p h

: %

C0,Me

(37)

(32)

OH

Li/NH3

Me'

NHC0,CH3 OH

OH

(33)

OH

, OH

*

NHC0,CH3

(35)

(34)

L- Acosamine-a-methylglycoside

1. MsCl

Me'

.NH,

Me'

, OH

.NH, (36)

L-Daunosaminea-methylglycoside

I,3-Dipolar Cycloadditions Scheme 2 (-)-Ptilocauline according to Roush [8b].

(-)-Ptilocauline (37)

(38)

00

I

HyfJ; ON-Bn

==3

===?

H (40)

'Me

&.; (47)

1 1 3.rnCPBA

58

-.'Me

>

2. BUl

'Me

Bu

1. LDAICI-PO(OE1)2

81

82

Stereodifferentiating Addition Reactions

altogether four transition states (I -IV) may be envisaged. I/II and III/IV represent the two regioisomeric possibilities. Thus, I/II are of the annulating type and lead to cis- and trans-fused bicyclic adducts (16/17),while III/IV result in transannulation, furnishing trans- and cis-l,3bridged bicyclic structures (19/20). It will be noted that I and I1 (and 111 and IV analogously) can be interconverted by simple rotation around the C-2/C-3-axis, constituting another formulation of the familiar endo-exo problem. The geometry for optimum orbital overlap, as shown in ( 2 4 , is most closely approximated in I; IV is the second best choice, and I1 and I11 can be disregarded. Hence, one may normally expect I to be the favored orientation. IV is of importance only in cases where R3 dictates this regiochemistry (e. g. for R3 = C02R).

erated by cyclization of the nitrone (40).The synthesis started from the optically active ketone (42), which was elaborated into (4f)and then furnished (45) via a stereocontrolled SakScheme 3 (+)-Chanoclavine according to Oppolzer

[91.

(531

Chanoclavine (52)

C02Me

1. MeflH/CH2=0

Base

2. Mel. KCN

(54)

Additions via Transition State I In Wovkulich's synthesis of L-acosamine (22), the aminoalcohol(23) and the isoxazolidine (24) were designated as intermediates [8a]. (24) is an obvious candidate for an intramolecular nitrone-olefin addition, as represented by formula (25),with a chiral R* group for asymmetric induction. In fact, (28) which was prepared from (27) via ( 2 4 , furnished an 82 :18 mixture of the cycloadducts (29) and (30), consistent with reaction via transition state I in its two mirrorimage forms. After separation of the diastereomers, (29) was transformed into the methyl glycoside (34). Inversion of the 4-OH in intermediate (33) led to diastereomer (36),if so desired. Roush's synthesis [8b] of the antibiotic (-)ptilocauline (37) entailed closure of a six-membered carbocycle. It is not so easy in (37) to detect the required y-aminoalcohol substructure, but (38) and (39) emerge from retrosynthetic analysis, and it then becomes apparent that (39), via the isoxazolidine, might be gen-

>

155)

,C02Me

HN

4 EtNiPr2

1. LAH

2.

3. (BOC)*O

(Epimerization at C-10)

1. Ph3P=C,

HN'I

(60)

2. CF3C0$ 3. DlBAL

,Me

C02Me

(52)

l,3-Dipolar Cycloadditions

urai allylation. The aldehyde (47) was prepared via reduction of the enol phosphate (46),and was condensed with benzylhydroxylamine to give (40) in situ. Cyclization led selectively to (48),which was then transformed into (49). Introduction of the guanidino substructure under thermodynamic control gave a mixture of the isomers (50), (54, and (37), in which the latter predominated.

Competition between Transition States I and IV Transition state IV should offer regiochemical advantages in the case of acrylic ester dipolarophiles, and this might counteract the natural preference for I. These considerations are illustrated by Oppolzer's synthesis of the alkaloid chanoclavine (52) [9], which features the ni-

Scheme 4 (*)-Cocaine according to Tufariello [lo].

+ MCPBA

ToH , fi 0

_/co2Me

00

C0,Me

83

C0,Me

H

HO

"2'"3

1. MsCl 2. DBN

3.

A

>

84

Stereodij-ferentiating Addition Reactions

Scheme 5 d-Biotin according to Baggiolini [ l l ] .

=====3 5

d-Biotin (71)

9: 1

(72)

(Z):

6

~-Cysteine

(E)

2. CICOfle

(76)

0

(77)

0

trone-olefin cyclization of (53)as the key step. the preferred transition state geometry but the (53)was prepared from indole (54) via (55)and role of IV may no longer be ignored. (56); remarkably, the nitrile function in (56) could be reduced to the aldehyde selectively using nickel under controlled conditions. In situ Addition via Transition State IV cyclization of (53)furnished a mixture of (57) (GI) and (58) ( G IV). (57) was converted into the The previous example makes it obvious that a target molecule via (59)and (60). Thus, I is still little extra push might result in a complete

I .3-Dipolar Cvcloadditions

switch from I to IV. In fact, the synthesis of cocaine by Tufariello [lo] employs a nitroneolefine cyclization ((63)+ (62))that proceeds via IV exclusively. The apparent explanation is that neither in I nor in IV is optimum orbital overlap attained; consequently, the regiopreference for IV prevails, dictated by the acrylic ester substitution pattern. The key intermediate (63) was prepared in an elegant sequence using intermolecular nitrone olefin additions ((66) + (67) and (68)-, (69))for constructing (69).Dehydration of the hydroxycarbonyl function produces an acrylic ester dipolarophile, which is then submitted to thermal nitrone olefin cycloreversion. (63)is thereby formed in situ, and it recyclizes selectively to (62). Further manipulation eventually generates (61).

85

by opening of the lactam and closing the desired cyclic urea structure. The superfluous 5OH is then removed reductively. (72) was derived from L-cysteine methyl ester, which was N-acylated to give (74). After reduction of the disulfide, a 10-endo-dig-cyclization [121 between the sulfur and the acetylene affords the vinyl sulfide (75),whose ester substituent is converted into the nitrone (72).

Nitrile Oxides

Nitrile oxides may be regarded as the dehydrogenated analogues of nitrones. Although they belong to the B-type of 1,3-dipoles, their behavior is in many respects similar to that of nitrones. Like nitrones, nitrile oxides are reasonably stable, particularly if they contain bulky aromatic substituents (e. g., mesitonitrile Application of a Medium-Ring oxide). However, many nitrile oxides undergo spontaneous dimerization to furoxans (80).It is Templatefor Inducing Transition State I with Asymmetric Induction therefore advisable to generate (79)in the presence of the appropriate dipolarophile by one of As pointed out earlier, transition state I may the in situ methods a-c. Method a, the dehyarise in two mirror image forms, which opens dration of a nitroalkane with phenylisocyanate the possibility of asymmetric induction. A novel in the presence of triethylamine [13], is by far strategy for taking advantage of this situation the most general, and it is compatible with a was devised by Baggiolini [11] in his synthesis variety of functional groups in both the nitrile of the vitamin d-biotin (71). The stereochemis- oxide and the dipolarophile. (79)adds to monotry at the chiral centers C-6, 7 and 8 is con- substituted alkynes and alkenes with high retrolled by performing the intramolecular ni- giocontrol to form isoxazoles (81) and isoxatrone olefin addition within a ten-membered zolines (82), respectively. Again, a number of ring template. This ensures the correct orien- ring-cleaving procedures are applicable, so that tation of the two components, and the template derivatives (82), (84), (85) and (86) may be obcan subsequently be destroyed. Specifically, (72) tained from the primary adducts [14]. was constructed to serve as the key intermediate, a molecule whose conformation permits unstrained access to the optimum transition Intermolecular Additions to state I, at the same time shielding the undesired Alkynes face of C-7 from the attack of C-6. This results in selective formation of the adduct (76) with In the context of a brilliant but as yet incomthe correct configurations at C-6, 7 and 8. Re- plete synthesis of cobyric acid (90),conversion duction of the N-0-bond and N-carboxyla- of the isoxazole (87) into the enaminoketone tion furnishes (77), which in turn leads to (78) (88) and subsequent cyclization to semicorrin

86

Stereodgferentiating Addition Reactions

4)cH3 /

H,C

CO,CH,

0 0-

MeOH ‘

H a / C H 3 0

(83)

,

(84)

CO,CH,

H,C $)cH3

0 0

OH NH

/

‘CH,

oxide component (92) was constructed via the Diels Alder adduct (loo),obtained from methacrolein and diene ester (99).Ozonolytic cleavage of (100)delivered lactone (101),which was converted into the oxime (102).NBS oxidation of (102) furnished (92) in situ. Although this route opened a relatively short access to the bottom half of (90)(i. e., to (91)),it provides racemic material only and has only the character of a model study so far [16b].

Intermolecular Additions to Alkenes

(89) was investigated as a possible model reIn the majority of the synthetic applications in action [lS]. Application of this concept to the actual tar- this category, a primary isoxazoline (83)is conget molecule (90) entails synthesis of isoxazole verted to the corresponding aminoalcohol (84), (91)as a subgoal. (91)was prepared by addition in close analogy to the nitrone adducts disof the nitrile oxide (92) to alkyne (93) in a re- cussed before. The principal difference is that giospecificmanner. The synthesis of (93)was in :the chiral center at the y-position in (84) arises turn based on Eschenmoser’s fragmentation of through reduction, usually with lithium alugp-epoxyhydrazones [16a]. Thus, (97)was pre- minumhydride, while in the nitrone case it pared from ketone (94)via (95)and (96)and, as stems from the cycloaddition itself. The prinenvisaged, it provided (98) on thermolysis. Ke- ciple of the nitrile oxide methodology is illustalization of the aldehyde led to (93).The nitrile trated by Jager’s synthesis of the aminosugar

1.3-Dipolar Cycloadditions

87

Scheme 6 Corrin synthesis according to R. V. Stevens [is. i6b]. CONH,

\

CH3 CH3

CONH,

w F 3 W 2

\I, H2NOC H 2

N

J'

o N 1'1cCN c 9 NX-

X ,CH3Y

\

~

H

_ 2 j Me0,C Me0,C

Me 191)

C0,Me

/ CH,

CH,

HOOC

' CONH,

(90)

Me0,C

J

C0,Me

(92)

Me

CN

Me

OCH,~

Me

EmH OH

(94)

(93)

(95)

CN

a 1. CH30H/HCI

,CO,Me ' o C H Me = O

1.0dMeOH

HO,C (99)

(100)

J Me (101)

(a) R = H (b) R = Me

H C0,Me

in situ

OR

3.NH20H

=====3

88

StereQdifferentiating Addition Reactions

D-lividosamine (f03) from the aminoalcohol (l04), and ultimately from isoxazoline (105).105 is the cycloadduct obtained from (106) and (107). The stereocontrol of the overall process proved to be quite low. Thus, (109) was produced alongside the desired product (105). Moreover, reduction of (105) furnished a 3 : 1mixture of (104) and its C-2-epimer. Fortunately, the unwanted diastereomers could be removed by chromatography, and (103) was thus obtained in pure form [17]. A y-aminoalcohol substructure is not readily detectable in the structural formula of the antibiotic milbemycin p3 (110). Only after retrosynthetic disconnection to the fragments (111) and (112) does a 1,3-diol structure emerge (in ( i l l ) )and , this can be traced back to the precursor isoxazoline (116). The actual synthesis starts with (119) which gives ( 118) after treatment with allylmagnesium bromide and ketalization. (118) is then combined with the nitrile

oxide (117) to furnish (116)as a mixture of diastereomers, which is converted into the crystalline aldehyde (114) by reduction, Hofmann elimination, and deketalization. After recrystallization, ( 114) is transformed into (120)and submitted to an Ireland Claisen rearrangement to form the carboxylic acid (121).Reduction to the aldehyde and phosphine-oxide modified Wittig condensation with (112),leaves only a few simple steps to the target molecule (110) [18]. Synthetically useful transformations have been reported for the adducts of carbethoxyformonitrile oxide (123)and the olefins (Z)-and (E)-(122).On heating with alkali, the primary isoxazolines (124) and (126) are converted stereoselectively into the hydroxynitriles synand anti-(125) [19]. On the other hand, isoxazoline (127) furnishes the dihydroxyketone (128) after hydrolysis of the THP-group and reductive ring cleavage. (128)can be converted into the hydroxyacid syn-(129) by glycol cleav-

Scheme 7 D-Lividosamine according to Jager [17].

(103) ( o-Lividosamine)

2,4

:

1

Separation by LPLC

(105)

(104)

-+ -+

( + 22% C-2-Epimer)

(103)

89

1,3-Dipolar Cycloadditions

flZ according to A . B. Smith III 1181

$

Scheme 8 (k)-Milbernycin

0,

Me

& 0

Me

====3

O,\

\ /

OTBDMS

(111)

PPh,

OH

Milbemycin

p3

(112)

(110)

3

OMe

0

==3

====3 HQ

*

\

OBn

OBn

Me0

-

Me0

OY?? H

Bn = C,H,-CH,TBDMS = SitBuMe,

(17 7)

(116)

(118)

+ (117)

(116)

epimeric mixt.

0

1. LAH

(114) (crystallization)

3. Me1 4. TsOH

(1 19)

f114)

0 2. E C Z

CI

O”\

NH, OBn

4 steps

TMSCI

Et

OBn (120)

separation of diastereomers

OBn

(727)

(110)

90

Stereodqferentiating Addition Reactions

Scheme 9 8-Hydroxynitriles. -carboxylic acids, and -ketones from olefins and nitrile oxides [19, 201.

R’ H

R’ H

~‘fi

Hpaney-Ni

R’

R‘

B(OH)3 H p J e O H

age. A more direct route to P-hydroxycarbonyl derivatives has been reported by Curran, who cleaved the adducts (131)/(133)under carefully controlled conditions to obtain syn- and anti(132) selectively [20]. An application of this methodology is illustrated by Kozikowski’s synthesis of racemic blastmycinone [21]. After changing the protecting group, adduct (135) is deprotonated and then butylated according to Jager [22] to give (136). Reductive ring opening leads to (137), which furnishes the y-lactone (138) after THPremoval and periodate cleavage. Epimerization at C-3 and acylation produces (139).

>

Intramolecular Additions to Olefins Just as in the nitrone olefin cyclizations, the transition states I to IV have to be considered; however, it appears here that, because of the rigid rod-like shape of the nitrile oxide, only type I really matters. Thus, in Confalone’s synthesis of (*)-biotin [23], the cyclization of (144) to (143) serves as the key step, controlling both regio- and stereochemistry in the manner desired. Racemic (144) is prepared in a conventional way via (146) and (147) starting with 3bromo-cyclooctene (145). The cycloadduct (143) on treatment with lithium alu-

f ,3-Dipolar Cycloadditions Scheme 10 ( f)-Blastmycinone according to Kozikowski [21].

r’w

OSiMe,tBu

THP- 0 - CH2- CH2- NO2

Me

I.

3. LDAIHMPA, n-Bul

0-N

(135) ( + 19% C-3-Epimer)

Me

NBU~F@

TxGz+

Me

BU

0

1. NaOMe (3-Epim.)

----T-+ I1

‘OH

Me

2. (Me2CH-CH2C@

O-C-CH2CH(Me)2

II

0 ( ?)-Blastmycinone

(139)

Scheme 11 (+)-Biotin according to Confalone [23].

-0

0

II

1. CH3-C-SH

Br

(145)

Ph-N=C=O EtQN

NEi3 2. OEi @

>-o

CH2=CH-N02

0.S

(147)

(146)

0

[(WI

+ (743)

LAH

II

(742)

1. MeO-CCI 2. DMSO/Ac,O

3. NH,OH ’ HCI Pyridine 4. PPA

(140)

1. Ba(OH)2 2, cc12

t;

>

(77)

93

92

Stereodifferentiating Addition Reactions

Scheme I 2 Ergoline synthesis according to Kozikowski (24bl.

===+ H (+)-Paliclavine

(148)

(149)

Br@ HO

Ye

*C02H

-+

(S)-P-Hydroxyisobutyric acid (150)

1.

0

(151)

+ (152)

------+ n -BuLi

THpo7M i o ' THpoTMe

a1. KOH

2. A N O p

2. DHP/H@

I

(153)

4y, Ph,P&OH Me

Me HO&OtBu

4 steps

I

Ts (154) (E/Z = 12 : 1)

Ts

Ph-N=C=O

Et3N

(79)

H

J

H

(757)

(758)

1,1 0-N

H

1

Me

AVHg

(148)

H

(160) ( + 25% Epimer)

minumhydride yields the aminoalcohol (142) A y-aminoalcohol fragment is characteristic selectively. The eight-membered carbocyclic of numerous ergoline derivaties, e. g. paliclavine ring is cleaved by a Beckmann reaction entail- (148). It is not surprising that intramolecular ing (141) and (140).After base-catalyzed open- nitrile oxide cycloadditions (INOC reactions) ing of the lactam ring, recyclization of the di- [24a] have been applied in the synthesis of such natural products. In fact, the cyclization of deamine with phosgene gives (71).

1.3-Dipolar Cyclondditions

rivatives like (149)proceeds regioselectively and, of course, suprafacially with respect to the double bond. If R* is chiral, asymmetric induction may also be effected at the vicinal sp*-position. These are the principles underlying Kozikowski's synthesis of (148) from the known indole aldehyde (153).Optical activity is introduced via the phosphonium salt (152),which is in turn derived from acid (150). The ylide from (152) is then condensed with (153) (E)-selectively, and the OH function is protected as the THP derivative to give (154). N-Detosylation and Michael addition of nitroethylene leads to (155) and, after dehydration with phenylisocya-

93

nate, to the key intermediate (156). Thermal cyclization affords a 1.1 : 1 mixture of the diastereomers (157)/(158),which are separated chromatographically. (158) is converted into (159), which gives (160) after N-methylation and reduction. Again, considerable amounts of the undesired diastereomer must be removed. N - 0-cleavage ultimately provides (148) [24b]

Azomethine YZide-Olefin Additions Azomethine ylides (161)represent an interesting class of 1,3-dipoles, because their cycloaddition

Scheme 13 (+)-a-Allokainic acid according to Kraus (2.51.

HOq

Br-CH2-C02Et

t CH, - CH,OBn s

5

$0

H a-Allokainic acid (768)

S 4

E

====+

H H0,C' O 2 C W N5 " M e

Ho+?

$

(169)

Me

+ En-0-CH2-CH2-CH

,

(172)

0

\\

II

CH-C-CH3

NEt$CH$N

>

(171)

(1 70)

0

C0,Me

II

l.H$pd

>

2. Jones-Ox.

C0,tBu (7 73)

(1 74)

3. C H p 2

4. Ph3P=CH2

CH

h ' ! ( : H 3

E~O,C

N

I

C0,tBu (175)

1.KOH 2. CF3C02H 3. NaOH

(168,

94

Stereodfferentiating Addition Reactions

reactions lead to the formation of two C-C bonds. However, azomethine ylides tend to be unstable unless incorporated into aromatic systems (“miinchnones” and “sydnones”) [l]. For instance, the iminium moiety in the parent system (161) (R’ = R3 = H, R2 = C02Me) undergoes spontaneous trimerization. A synthetically useful modification by Kraus [25] takes advantage of aromatic stabilization in the thiazole derivative (164, which adds electron deficient dipolarophiles to form the bicyclic compounds (165). Silica gel induced cyclization furnishes (166), which is degraded to the monocyclic compound (167) by reduction and hydrolysis. The overall sequence from (164) to (167) corresponds to a 1,3-dipolar cycloaddition of a nearly unsubstituted azomethine ylide (161) R’ = R2 = H, R3 = CO,Et), a reaction which could not be performed directly, and it provides easy access to substituted prolines such as a-allokainic acid (168), a natural product with good anthelmintic properties. Retrosynthetic application of Kraus’s methodology leads to (169), which can be prepared from (170). Thus, N-alkylation and deprotonation lead to the azomethine ylide (164). Addition of (164) to the dipolarophile (172) yields (173) regioselectively. Sulfur is expelled from (173) upon reduction, and subsequent hydrolysis and carboxylation affords (174). This is elabarated into (175) and (168) after epimerization at C-2. The cycloaddition apparently proceeds via the activated complex (176), which leads to a cisarrangement of the substituents at C-2 and CH,

H

0

- CH,

- OH

C-3 in the adduct. Presumably, non-bonding orbital interactions between the C(0)Me- moiety and the thiazole double bond stabilize (176) relative to the corresponding ,,exo“ orientation. Quite recently, an intramolecular azomethine ylide-olefin addition was used in the synthesis of a related target molecule (kainic acid) [26]. In conclusion, enormous progress has been made in the application of 1,3-dipolar cycloadditions to natural product synthesis [27]. Nevertheless, the scope of the methodology is still limited, especially compared with the overwelming potential of the related Diels Alder reaction [28]. The main reason for this deficiency is the instability of many 1,3-dipoles, which greatly restricts the range of available substitution patterns.

References [l] R. Huisgen, Angew. Chem. 75, 604, 702 (1963); Angew. Chem. Int. Ed. Engl. 2, 565,633 (1963).

R. Huisgen, J. Org. Chem. 41,403 (1976). Comprehensive review of 1,3-dipolar cycloadditions: A. Padwa, “1,3-Dipolar Cycloadditon Chemistry”, Vol. 1 and 2, Wiley, New York, 1984. 1,3-Dipolar Cycloaddition in Natural Product Synthesis: G. Desirnoni, G. Tacconi, A. Barco, and G. P. Pollini, “Natural Product Synthesis through Pericyclic Reactions”, ACS Monograph 180, American Chemical Society, Washington, D.C., 1983, p. 90-117. [2] R. Huisgen in “1,3-Dipolar Cycloaddition Chemistry“, A. Padwa (Ed.), Vol. 1, p. 1, Wiley, New York, 1984. [3] K. N. Houk, Top. Curr. Chem. 79, l(1979). [4] Reviews: J. J. Tufariello, Acc. Chem. Res. 12, 396 (1979);D . St. Clair Black, R. F. Crozier, and V.D . Davis, Synthesis, 1975, 205. [S] J. J. Tufariello and S. A. Ali, Tetrahedron Lett. 1978,4647. [6] P. deShong and J. M . Lenginus, J. Am. Chem. SOC. 105, 1686 (1983). [7] W. Oppolzer, Angew. Chem. 89, 10 (1977), Angew. Chem. Int. Ed. Engl. 16, 10 (1977). [Sa] P . M . Wovkulich and M . R. Uskokovic, J. Am. Chem. SOC.103, 3956 (1981). [Sb] W. R. Roush and A. E. Walts, J. Am. Chem. SOC.106, 721 (1984).

f,3-Dipolar Cycloadditions

95

lanthocin: S. F. Martin, M . S. Dappen, B. Dupre, [9] W . Oppolzer and J. I. Gayson, Helv. Chim. Acta and C. J. Murphy, J. Org. Chem. 52,3706 (1987). 63, 1706 (1980). [lo] J. J. Tufariello et al., J . am. Chem. SOC.fOf, [21] A. P. Kozikowski and A. K. Gosh, J. Org. Chem. 49, 2762 (1984). 2435 (1979). [ I l l E. G. Baggiolini, H. E. Lee, G. Pizzolato and M. [22] H. Grund and V. Jager, Liebigs Ann. Chem. 1980, 80. R. Uskokovic, J. Am. Chem. SOC. 104, 6460 (1982). [23] P. N. Confalone, E. D. Lollar, G . Pizzolato, and M. R. Uskokovic, J. Am. Chem. SOC.100, 6291 [12] J. E. Baldwin, J. Chem. SOC.,Chem. Commun. (1978). 1976, 734. [I31 T. Mukaiyama and T. Hoshimo, J. Am. Chem. [24a] A. P. Kozikowski,K. Hiraga, J. P. Springer, B. C. Wang, and Z.-B. Xu, J. Am. Chem. SOC.106, 82, 5339 (1960). 1845 (1984). [14] Reviews: V. Jager. I. Muller, R. Schohe, M. Frey, R. Erler, B. Hayele, and D. Schroder, Lect. Het- [24b] A. P . Kozikowski and Y.-Y.Chen, Tetrahedron 40, 2345 (1984). Recent example of INOC: A. erocycl. Chem. 8, 79 (1985). A. P. Kozikowski, P. Kozikowski and C.-S. Li, J. Org. Chem. 52, Acc. Chem. Res. f 7, 410 (1984). 3541 (1987); P . N. Confalone and S. S. KO,Tet[IS] R. V. Stevens, J. M. Fitzpatrick, P. B. Germerahedron Lett. 25, 947 (1984); M. Asaoka et al., raad, B. L. Harrison, and R. Lapalme, J. Am. Chem. Lett. 1982, 215. Chem. SOC. 98, 6313 (1976). [16a] D. Felix, R. K. Muller, U.Horn, R. Joos, J. [25] G. A. Kraus and J. 0. Nagy, Tetrahedron Lett. 22, 2727 (1981), 24, 3427 (1983). Schreiber, and A. Eschenmoser, Helv. Chim. [26] S. Takano, Y. Twabuchi, and K. Ogasawara, J . Acta 55, 1276 (1972). Chem. SOC.,Chem. Commun. 1988, 1204, and [16b] R. V. Stevens, R. E. Cherpeck, B. L. Harrison, cited lit. J. Lai, and R. Lapalme, J. Am. Chem. SOC.98 [27] Most recent applications of nitrone olefin cy6317 (1976). clization: N. A. LeBel and N. Balasubramanian, [17] V. Juger and R. Schohe, Tetrahedron 40, 2199 J. Am. Chem. SOC.f f l ,3363 (1989); of nitrile (1984). oxide-olefin addition: M . de Amici, C. De Mich[IS] A. B. Smith ZZZ et al., J. Am. Chem. SOC.104, eli, A. Ortisi, G. Gatti, R. Gandolfi and L. Toma, 4015 (1982). J. Org. Chem. 54, 793 (1989). [19] A. P. Kozikowski and M. Adamczyk, J. Org. [28] Cf. this book, p. 54ff. Chem. 48, 366 (1983). [20] D. P. Curran. J . Am. Chem. SOC.f 0 5 , 5826 (1983).Application to the synthesis of (+)-phyl-

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

[4 + I 1 and [3 + 21 Cycloadditions in the Synthesis of Cyclopentanoids

The Pauson-Khand reaction discussed in this book, [l] can be regarded formally as a [ 2 + 2 + 11 cycloaddition. Several [4 11 and [3 + 21 cycloadditions that also lead to fivemembered carbocyclic rings are the subject of this chapter.

+

+

14 11 Cycloaddition The zirconium-catalyzed cyclization of enynes such as (f), discovered by Negishi et al. [2], is related to the Pauson-Khand alkene-alkyne addition reaction. Both procedures are accompanied by CO insertion. Dichlorodicyclopentadienyl zirconium(I1) [CI2Zr(II)Cp2]is the reagent of choice for this cyclization. Zirconium becomes incorporated into the ring system of

$Me3

(3)

intermediate (2), and it is subsequently exchanged for CO, which first replaces one of the ligands in the complex. Bicyclo[3.3.0]octenones such as (3)are particularly easy to construct by this method, and no isomerization of the exocyclic double bond is observed under the reaction conditions (Scheme 1). This CO insertion can be regarded as an example of migration of the residue R in (4) from the metal to the CO ligand, thus affording the adduct (5) (cf. Scheme 2). If the process is followed by a reductive elimination of ML,, then (6) is converted into (7). In the example of Scheme 1 this results in ring closure to (3). Scheme 2

Related insertions are in principle also possible with olefins, as shown by the palladiumcatalyzed double CO insertion to (9) starting from the vinyl iodide (8) (Scheme 3) [3]. The ester group in the side chain is a consequence of the presence of methanol, which also pre-

Cycloadditions in the Synthesis of Cyclopentanoids

vents the polymerization that readily occurs in other cases. An exo-cyclization is apparently much faster than the intramolecular Heck reaction [4] that might otherwise be anticipated.

yr

Scheme 3

CO; CIZPd(PPh.JZ, O ;H: :

>

90%

97

trolled insertion of other carbon fragments. Liebeskind [ 6 ] demonstrated for the first time that metal vinylidene complexes such as (15), prepared from terminal acetylenes, can undergo insertion to form the exocyclic cyclopentenediones (16) (Scheme 5). Cationic cobalt complexes such as (14) are accessible from cyclobutenediones (13). Benzoquinones appear as side products, but in low yield. Scheme 5

8 O Z C H 3

CO insertion is facilitated by a quarternary center at C-3 in the analogous reaction of 1,4dienes, as illustrated by the synthesis of ct-cuparenone by Eilbracht et al. [S] (Scheme 4). Diene (10) can be cyclized in good yield to the cyclopentenone (11)provided COz(CO)8is used as catalyst and high CO pressures are employed (140 bar). Iron carbonyls can be used instead but they produce lower yields. A methylation step completes the synthesis of ct-cuparenone (12).

66%

d 0

Scheme 4 Me

13 + 21 Cycloadditions

Me

nMe

\v

NaNHz. CH& 56%

These few examples suffice to show that transition metal catalyzed CO insertion has developed into a relatively common synthetic method. Much less is known about the con-

The efficiency and selectivity of the Diels-Alder reaction for the construction of six-membered rings certainly encouraged the development of similarly effective general cycloadditions for the synthesis of five-membered carbocycles. A suitable synthon was discovered in the form at trimethylenemethane (17),which can be represented as the 1,3 diradical(17a) or as the zwitterion (17b). This substance has enjoyed broad application within a rather short period at time, as revealed by two recent reviews by Trost [7] and Binger and Buch [ S ] .

98

Stereodifferentiating Addition Reactions

Chart 1

The diradical (17 4 can be generated from methylenecyclopropane (19) in a palladium-catalyzed reaction, permitting subsequent reaction with u,&unsaturated carbonyl compounds such as cyclopentenone to form the adduct (18) (Scheme 6).

The diradical nature of the reaction is also evident in the elimination of nitrogen from azo compound (24) to form the intermediate (25) (Scheme 8). Little's research group [113 prepared the triquinane (26) in 91% yield by intramolecular trapping of the diradical. However, intermolecular reactions of this type are much less selective. Scheme 8 SiR,

Scheme 6

*m CO Me H i 2

(26)

6SiR3

+ Epirners

Both five- and seven-membered rings are formed if allene is the reactive substrate [9]. This example shows that the reaction is unsatisfactory for nonactivated olefins, because in these cases methylene cyclopropene, and the olefin compete for n-complex formation with Pd(0). On the other hand, the simultaneous binding of both donor and acceptor to the transition metal offers possibilities for asymmetric induction. In the example 'of Scheme 7, nickel-catalyzed reaction of methylenecyclopropane (19) with 8-phenylmethyl acrylate (22) leads to the cyclopentene ester (23) in 64% de [lo]. Scheme 7

The creation of zwitterionic trimethylene methane synthons was a special challenge. On the one hand, TMM iron carbonyl complexes were shown to be too unreactive [12]. On the other hand, a suitable 1,3 carbanion-carbocation cannot be allowed to undergo self-destruction prior to the desired addition reaction. Palladium complexes such as (29) [7] were eventually found to be ideal reagents. These shortlived reactive intermediates are generated from (27) via (28),and they are capable of adding to activated double bonds to give the products (30) (Scheme 9). In principle, any electron acceptor applicable in the Michael addition is a candidate for reaction with (29). Keto, ester, cyano, and sulfonyl groups have so far been tested. Even substituted acetylenes can be transformed into 4-methylene-1-cyclopentenes by Ni-catalyzed codimerization with methylenecyclopropane using either the procedure of Binger [13a] or that of

Cycloadditions in the Synthesis of Cyclopentanoids

which can be prepared from 2-(trimethylsily1)methacrolein (33)(Scheme 11).

Scheme 9 SiMe,

SiMe3 Pdl,

Scheme 11

+n PdL,

-

OAc

SiMe3

(35)

OAc

OAc

(29) Z

=

99

F M e 3

/ (33) 'L

cSiMe3

electron acceptors

Trost [13b]. (See ref. 13c for a convenient new approach to (acetoxymethyl)-3-trimethylsilyl propene (29.)The reaction is very flexible with respect not only to the acceptor but also to the donor. For instance, the silicon atom in (27)can be replaced by tin. In special cases, the negative charge can also be stabilized by electron acceptors, such as the cyano group in the TMM precursor (31). Scheme 10 provides an example: reaction of the TMM precursor (31) with benzalacetone affords (32) [14].

OAc

OAc

(37)

(38)

The vinyl compound (37) is particularly interesting. Two possible TMM intermediates (39) and (40) - might here be expected to undergo reaction with cyclopentenone. In fact, (41)is the only product isolated, and the cycloheptenes formally derived from a [5 21 addition are not observed [15] (Scheme 12).

+

Scheme 12

Scheme 10

However, it is necessary to accept in this case a subsequent isomerization of the double bond to the thermodynamically more stable position. Substituted TMM systems are characterized by a loss of symmetry, so problems of regiochemistry arise. Various derivatives are available for use in palladium catalyzed [3 + 21 cycloadditions [lS], including (34) to (38),all of

Our discussion of TMM reactions will be concluded with a look at a new carboxylating reaction based on the precursor (42)(see ref. 7, X for additional TMM reactions). A carboxy-

100

Stereodifferentiating Addition Reactions

late electrophile eliminated in one of the first reaction steps from (42) is capable of adding to the intermediate carbanion (4.3) to afford (44). The TMM derivative (45) is then generated by an elimination of the trimethylsilyl group similar to that observed in (31)[16]. The reaction of (45) with the exocyclic acceptor (46) to afford the spiro compound (47) is particularly interesting. The example in Scheme 13 shows not only the potential for preparing spirocyclic systems, but also the fact that P-methoxy groups are tolerated, groups that would certainly be eliminated under the conditions of the Michael reaction. Scheme 13

+

(SiMe3

mediates are probably involved in the reaction of u,P-unsaturated acylsilanes with allenylsilanes, as studied by Danheiser et al. [17]. Depending upon the reaction conditions and substrates, the process can be caused to yield either five- or six-membered ring products. The silyl group in unsaturated ketone (48) not only activates the titanium tetrachloride catalyzed attack of the allene (49),but also serves as a useful functional group in the products (54) and (55). Addition leads first to the p-silicon stabilized cation (50). This is followed by the well-known cationic 1,2 silicon shift to isomer ( 5 4 , which cyclizes to (53)and provides the five-membered ring (55) in the course of a rapid workup (Scheme 14). Scheme 14

&OCH3

OCH3

EIZ = 67/33 (47)

We now leave the subject of TMM reactions and turn to examples of [3 + 21 cycloadditions that occur via ionic intermediates (arguments exist for concerted as well as stepwise mechanisms in TMM reactions [7]). Cationic inter-

R: Me;

t - Butyldirnethyl

Cycloadditions in the Synthesis of Cyclopentanoids

If the reaction mixture is allowed to warm to (52)through another 1,2 silyl migration and permitting the isolation of six-membered products such as (54). Five-membered rings are formed exclusively in the presence of large residues R (e.g., tert-butyldimethylsilyl groups). This is a nice example of selectivity, in the sense that the mode of reaction is truly open to selection. The examples cited so far might leave the impression that cyclopentenone syntheses via anionic cyclization of 1,6dicarbonyl compounds are completely outdated. Not so! Progress in the development of ever more effective reagents has been made here as well. 3-Chloro2-diethylphosphoryloxy-1-propene(53,introduced by Welch et al. [19], facilitates one-pot anullation with CH-acids, a reaction that probably occurs via 1,Cdicarbonyl intermediates. The new reagent (57) is available in almost quantitative yield from dichloroacetone by means of a Perkow reaction [20] (Scheme 15). - 50 "C, (53)may rearrange to

101

Beak et al. [23] have introduced a further development in the addition of allylic anions to electron deficient double bonds, a reaction investigated intensively by Boche and Kaufmann [22]. Beak's allylic anion (59)is derived from a benzenesulfonyl amide. The sulfonyl group activates the P-hydrogens in the deprotonation step, thereby determining the regiochemical behavior of the ambident anion, and it also functions as a good leaving group in the overall anionic [3 21 addition-elimination sequence. Cyclopentene (61)is thus formed via the intermediate (60),and it can be isolated in 59% yield (Scheme 16).

+

Scheme 16 PhSOz R,N-C I1-(@

0

+

MeUC02Me

(59)

Scheme 15 0 II

O

(56)

T

'

1oooc: 99%

(Eto)3P

(Eto)zpoPI

(57)

5 0

0

LDA. Pd. NaOH 79%

O

(58)

a

The yield in the alkylation step of the cyclohexanone enolate is considerably increased by palladium catalysis, as already observed by Negishi [21]. Treatment with NaOH leads to the bicyclic compound (58) in 79% yield without isolation of any intermediates. It will be interesting to see if comparable yields can be obtained with more complex substrates. An initial positive sign appears in a recently published synthesis of cis-jasmone [19b].

A synthetic method can be regarded as especially effective if it permits several successive reaction steps to be conducted in a single operation. This double Michael addition followed by elimination is a case in point. Another impressive example is the combination of two consecutive Michael additions included in the synthesis of functionalized five-membered rings developed by Bunce et al. [24]. Both a Michael donor and an acceptor are incorporated in a single molecule in the unsaturated triester (62). It is characteristic of Michael additions (including this one) that an equilibrium is established

Stereodifferentiating Addition Reactions

102

between several adducts, with the thermodynamically most stable compound eventually predominating. The strained cyclopropane anion (64)probably reopens to permit reaction to be terminated by ring closure of the Michael adduct (63) to the five-membered ring (65), as shown in Scheme 17. The equilibrating reaction conditions ensure that a mixture of stereoisomers is isolated, although the trans-adduct greatly predominates.

Scheme 18 generally:

I5

+ OJ type:

Scheme 17

room temp. 10 min

'9

'7(

Me02C

C02Me

[Me Me& C02Me

R

>o

Me02C

C02Me

C02Me C02Me

cisltrans = 1/50.

(65)

A Michael reaction was combined with a carbene insertion in an investigation reported by Ochiai et al. [25]. Alkynyl iodonium salts function as novel Michael acceptors that react with "soft" stabilized carbanions by addition at the carbon-carbon triple bond, affording "iodine allenes" of type (67)(Scheme 18). Reductive elimination of iodobenzene then furnishes the carbene intermediate (68). If the carbene inserts into the C -H bond of the starting alkyne, what results is a [S 01 anullation [formulas (69) to ( 7 f ) l ;insertion into the side chain of the carbonyl compound generates a [3 +2] type of addition [formulas (72)to (74)]. Space limitations have permitted the discussion of only a few of the possible routes to fivemembered rings. This research area is devel-

+

[3

+ 21 type:

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Recent Applications of the Paterno-Buchi Reaction

Although the Diels-Alder reaction has proven to be a highly reliable synthetic method for the formation of six-membered rings, [2 + 21-cycloaddition to give cyclobutanes (1) and oxetanes (2) was long considered to be a curiosity of interest mainly to physical and mechanistic organic chemists. Only more recently have synthetic chemists become aware that light is a “clean ‘reagent’, whose intensity and energy content can be finely controlled” [11. Indeed, photochemical reactions are now used not only in large scale industrial processes, as in the chlorination of alkanes [2], but more and more in laboratory syntheses of complex natural products [3].

In 1909, Paterno and Chiefti first described a reaction that takes place between benzaldehyde and trimethylethylene in sunlight [S]. This publication was more or less ignored for many years until it was repeated by Buchi, who was able to establish the structure of the oxetane (34,which formed as the major product [ 6 ] .

“/\^.

Numerous subsequent mechanistic studies, clearly indicate that the carbonyl compound is first excited (usually by irradiation with UVlight) to the triplet state, and that addition of this species to the alkene gives a diradical (4). This in turn cyclizes to produce a four-membered ring [7]. The existence of an intermediate

R

”#

R

R

( 1)

a

R R

(2)

The purpose of this chapter is to present several recent applications of what is known as the “Paterno-Buchi reaction” [4], a photocycloaddition that occurs between alkenes and aldehydes or ketones. This reaction leads to the formation of oxetanes (2),which are proving more and more useful as synthetic intermediates.

74- - [;n]

R R

(4)

106

Stereodifferentiating Addition Reactions

of type (4) has been proven spectroscopically C81However, it was only after regio- and stereocontrol of this nonconcerted cycloaddition had been significantly improved that the Paterno-Buchi reaction became established as a useful method in synthetic organic chemistry. The unsaturated alcohol (9),an insect pheromone, can be prepared from cyclohexadiene and propanal. Only moderate stereocontrol is observed in the photocycloaddition, but the diastereomeric oxetanes (64 and (6b) are formed in a highly regioselective manner. It would appear plausible to suggest that the intermediate (5)is the most stable of the four possible diradicals, thus explaining the absence of other regioisomers in the product mixture. Hydrogenation and separation of the major product from the endo-isomer (preparative gas chroA>

[

-

hv

260 nm

0-O-I

(5)

matography on a 5 to 10 g scale) leads to the oxetane (3,which is converted into the aldehyde (8)(purity > 95%) by a rhodium-catalyzed cycloreversion. Finally, reduction with lithium aluminum hydride affords the natural product (9) [9]. The complete reaction sequence might be regarded as an alkene-carbonyl metathesis. Photocycloadditions between carbonyl compounds and enol ethers can usually be conducted in high chemical yield, but they are often plagued by low selectivities. Thus, photoreaction of acetone with ethyl vinyl ether affords a 3: 7 mixture of the isomeric products (IOU)and (IOb) [lOa]. Nevertheless, 2-alkoxyoxetanesare subject to alcoholysis, whereas 3-alkoxyoxetanes do not undergo ring opening under these conditions. As a consequence, the mixture of oxetanes (IOu)/(IOb) can be converted into the readily separable mixture of acetal(1I) and unchanged oxetane (IOb). Hydrolysis of the heterocyclic compound (IOU) to P-hydroxyaldehyde (12) illustrates that the combination of photocycloaddition followed by ring cleavage is equivalent to the aldol reaction [lob].

a,,,,, +a H

H

(60) 6 2 %

/

I

/

H

H

(6h) 1 5 %

1) W P t Q 2) GC separation

c;ll.,,,, A

(7) (80%)

( 9 ) 100%

0

H3CKCH3

+

I

‘OCzH,

I

h’

The Paterno-Biichi Reaction

Schreiber and coworkers [11] were able to demonstrate that both stereo- and regioselective Paterno-Buchi reactions are feasible provided furanes are used as the alkene components. Related preliminary studies were carried out earlier in the research groups of Schenk [12a], Sakurai [12b], and Zamojski [12c]. Thus, the photoaddition of aldehydes to furane (13), which reflects a symmetrical substitution pattern, gives primarily the exo-oriented “headto-head products” (14) with an isomeric excess advantage of 20: 1. Subsequent mild hydrolysis leads to the anti-aldols (15). The scope of this type of Paterno-Buchi reaction is further demonstrated by the hydroboration of oxetane (14, which affords (after oxidation with hydrogen

peroxide) the diol (f6) in 82% yield. Presumably, borane approaches the double bond preferentially from the convex face of the molecule to give the intermediate (174. The fact that hydrogenolysis of the acetal occurs with retention of configuration might be explained by ring cleavage of the oxetane moiety in (174 to give (17b), followed by an intramolecular hydride transfer that leads finally to (174. In Schreiber’s total synthesis of the mycotoxin asteltoxin (18) [13], stereoselective generation of an aldol by means of the PaternoBuchi reaction is again used as the key step. According to the retrosynthetic scheme, the coupling of the aldehyde (19)with a-pyrone (21) was expected to proceed via the formylbutadiene synthon (20).

H

i 18)

H3C

I

(19)

33

\

/

B,,

TJ

107

OCH3

Q

\CHO

+

u

(21) i

17a)

i 17h)

Photocycloaddition between 3,4-dimethylfuran and 3-benzyloxypropanal, performed on a 10 g scale, is the key step in the formation of the bicyclic intermediate (19)(cf. Scheme 1). Oxetane (22) is the result - again formed in a stereoselective manner. Oxidation with m-chloroperbenzoic acid followed by hydrolysis af-

108

Stereodifferentiating Addition Reactions

fords the aldehyde (23)as a single diastereomer. Its free carbonyl group is protected as the hydrazone (24),and the latent aldehyde functionality is subsequently liberated from the hemiacetal moiety in situ by treatment with an excess of ethylmagnesium bromide. The Grignard re-

agent adds to the aldehyde in this case in a chelate-controlled manner. Subsequent cleavage of the hydrazone is carried out in a solution of acetone, so the acetonide (25) forms immediately. Cleavage of the benzyl group, selenylation, and elimination provides the alkene (26),

Scheme 1 Synthesis of (k)-asteltoxin by Schreiber and Satake.

H

(23): X = 0 (24) : X = NN(CH3), (72%)

45% (2 steps)

(25) 55% (2 steps)

' I

(29) 77%

(26): X = CH, 79% (19): X = 0 92%

SOC6H5 (28) 88% mixture of epimers

1) CF3COSOCH3 Acfl, Lulidine 2) HgCI2 CaC03 CH3CN/H20 LiNR2

\CHO

60 %

I

H3C4 OCH3 C H 3 '

80%

H3C

.

CH3

The Paterno-Biichi Reaction

which in turn gives the bicyclic aldehyde (19) upon ozonolysis. The metallated sulfoxide (27)may be used as a synthetic equivalent of the formylbutadiene synthon (20). Its addition to the aldehyde (19) followed by [2, 31 sigmatropic rearrangement leads to an epimeric mixture (3: 1)of triene (28). Diastereomer (28),which is the major product, is isolated by chromatography and deprotected to give the bicyclic compound (29).Conversion of the sulfoxide moiety into an aldehyde group is accomplished by a Pummerer reaction. This synthesis of racemic asteltoxin (18)is completed by a coupling reaction with a-pyrone (24, tosylation of the less hindered hydroxyl group, and elimination [14]. “Asymmetric” Paterno-Buchi reactions should result from the incorporation of chiral auxiliary groups into either the carbonyl component or the alkene. This goal was first

109

achieved by Gotthardt and Lenz in a photocycloaddition of menthyl phenylglyoxylate (304 to tetramethylethylene or 1,l-dimethoxyethylene. Thus, the carboxylic esters (31) and (32) were obtained in 53% and 37% enantiomeric excess after saponification and treatment with diazomethane [lS]. Scharf and coworkers [16] reached even higher degrees of diastereoselectivity by employing the phenylglyoxylic esters of carbinols (33a,b) [17]. Reaction of these species with the same olefins resulted in diastereomer ratios as high as 98:2. However, the corresponding chemical yield (40%) and the observed regioselectivity (about 2.5 : 1) were only moderate. More recently, 8-phenylmenthylphenylglyoxylate (30b)was shown to be a reliable and highly selective carbonyl component for asymmetric Paterno-Buchi reactions [18]. It may be that the scope of this photocycloaddition will be further extended, through this is likely to require that it be investigated with the same enthusiasm applied to the “asymmetric DielsAlder reaction” [19].

References [l] G. Quinkert and H . Stark, Angew. Chem. 95,

[Z] [3] [4] [S] [6] [7] [S]

Ph

h0& 0

(306)

[9] [lo]

651 (1983); Angew. Chem. Int. Ed. Engl. 22,637 (1983). M. Fischer, Angew. Chem. 90,17 (1978); Angew. Chem. Int. Ed. Engl. 17, 16 (1978). S. Blechert, Nachr. Chem. Tech. Lab. 28, 883 (1980). G. Jones, II, Org. Photochem. 5, 1 (1981). E. Paterno and G. Chieffi, Gazz. Chim. Ital. 39, 341 (1909). G. Biichi, C. G. Inman, and E. S. Lipinsky, J. Am. Chem. SOC.76,4327 (1954). D. R. Arnold, Adv. Photochem. 5, 301 (1968). S. C. Freilich and K. S. Peters, J. Am. Chem. SOC.103, 6255 (1981). G. Jones, II, M. A. Acquadro, and M . A. Carmody, J . Chem. SOC.,Chem. Common. 1975, 206. a) S. H. Schroeter and C. M. Orlando, Jr., J. Org. Chem. 34, 1181 (1969); b) S. H. Schroeter, J . Org. Chem. 34, 1188 (1969).

110

Stereodifferentiating Addition Reactions

[ll] S. L. Schreiber, A. H. Hoveyda, and H.-J. W u , J. Am. Chem. SOC.105,660 (1983).For a review: see S. L. Schreiber, Science 227, 857 (1985). [12] a) G. 0. Schenck, W. Hartmann, and R. Steinrnetz, Chem. Ber. 96, 498 (1963); b) s. Toki, K. Shirna, and H . Sakurai, Bull. Chem. SOC.Jap. 38, 760 (1965); c) A. Zamojski and T. Kozluk, J. Org. Chem. 42, 1089 (1977). [13] S. L. Schreiber and K. Satake, J. Am. Chem. SOC. 106, 4186 (1984); J. Am. Chem. SOC.105, 6723 (1983). [141 Furan-aldehyde photocycloaddition is also the key step in a synthesis of the u-methylene-lactone avenaciolid; cf. S. L. Schreiber and A. H. Hoveyda, J. Am. Chem. SOC.106,7200(1984). For Paterno-Buck reactions with silyl- and stannyl-substituted furans see: S. L. Schreiber, D. Desmaele, and J. A. Porco, Jr., Tetrahedron Lett. 29, 6689 (1988).

[l5] H. Gotthardt and W. Lenz, Angew. Chem. 91, 926 (1979);Angew. Chem. Int. Ed. Engl. 18,868 (1979). [16] H . Koch, J. Runsik, and H.-D. Scharf, Tetrahedron Lett. 1983, 3217. [17] a) H. E. Ensley, C. A. Parnell and E. J. Corey, J. Org. Chem. 43, 1610 (1978); b) G. Helmchen and R. Schmierer. Angew. Chem. 93,208 (1981); Angew. Chem. Int. Ed. Engl. 20, 205 (1981); c) W. Oppolzer et al., Tetrahedron Lett. 1982, 4781. [IS] A. Nehrings, H.-D. Scharf; and J. Runsik, Angew. Chem. 97, 882 (1985), Angew. Chem. Int. Ed. Engl. 24, 877 (1985); R. Pelzer, P. Jiitten, and H.-D. ScharJ Chem. Ber. 122, 487 (1989). [19] Cf. e.g. P. Welzel,Nachr. Chem. Tech. Lab. 31, 979 (1983);H. Wurziger, Kontakte (Darmstadt) 1984 (2), 3.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Diastereoselective Claisen Rearrangements

-

The Claisen rearrangement of ally1 vinyl ethers is an important method for the preparation of y, &unsaturated carbonyl compounds [11: 0

4

The reaction can be described as a 3,3-sigmatropic rearrangement involving a well-coordinated, generally chair-like transition state. As with other sigmatropic processes, the Claisen rearrangement is characterized by high stereoselectivity, and it lends itself to exploitation in many ways for the stereocontrolled synthesis of acyclic systems [2, 31. Of particular interest here is the stereoselective generation of vicinal centers, the resulting relative configurations of the two chiral centers being a function of EJZ-configurations of the previous double bonds (internal asymmetric induction). The opportunity also exists for transmitting chirality along the allylic system (relative asymmetric induction).

Relative asymmetric induction can also occur if the Claisen system carries substituents with chiral centers. It is this particular potential for diastereoselective synthesis of acyclic compounds that is now under intensive investigation, as may be deduced from a number of recent publications devoted to the theme. Prerequisites for the optimal utilization of the Claisen rearrangement include, on the one hand, a suitable method for preparation of the required allyl vinyl ether system and, on the other hand, the mildest possible rearrangement conditions. Several variants on the Claisen reaction are relevant with respect to the second point. Comparison of the Claisen rearrangements of allylic ketene acetals [(fb) -+ (2b)], ketene-N,O-acetals [(fc) -+ (2c)], and ester enolates [(Id) -+ (2d)] makes it evident that rearrangement occurs more readily with strong electron donation from substituents in the 2-position. 8 : X = H

Claisen rearrangement of allylic ester enolates may even take place below room temperature, and the method has been developed to such an extent that it is the subject of a separate contribution (see the following chapter). Both preparative [4] and theoretical [ S ] investiga-

112

Stereodifferentiating Addition Reactions

tions have also dealt with the activating effects of electron releasing substituents at other positions on the allyl vinyl ether system. Another possibility for moderating the rather drastic conditions of the classical Claisen rearrangement is catalysis. Only a few years ago, attempts at applying catalysis to the Claisen rearrangement had met with limited success [6], but more recent publications appear to indicate a breakthrough [7]. Of special interest is an investigation by Nakai [7], dealing with the diastereocontrol in the rearrangement of cyclic enol ethers as a function of the catalyst. Starting from (3), the thermally favored antiproduct is obtained in the presence of 2,6-dimethylphenol (6). However, on catalysis with palladium complexes at room temperature primarily the syn-product (7) is formed. The authors suggest that the phenol-catalyzed reaction occurs via the normal chair transition state, while complex formation between palladium and the l,S-diene, which acts as a bidentate ligand, demands a boat transition state.

The classical route to allyl vinyl ethers consists of vinylation of allyl alcohols with simple vinyl ethers, ketals, or acetals [l]. Unfortunately, these methods are often ineffective in the case of more complex systems, and they do not allow control over the stereochemistry of the substituted enol ether double bond except in the case of cyclic enol ethers. Until recently, the only method of achieving such substituted compounds in a stereocontrolled manner was the route via ketene-N,O-acetals [S, 91. Their synthesis by addition of allyl alcohols to substituted ynamines even allows the directed synthesis of adducts with either the E or 2 geometry depending on the conditions employed

~91.

NEt,

(3)

d

(4)

4

(5)

So far, the apparently plausible route to allyl vinyl ethers involving olefination of allyl formates seems not to have been exploited [lo]. An alternative route, the nucleophilic addition of allyl alcohols to propiolate esters, does lead exclusivelyto the trans-configuration for the resulting enol ether system [ll, 121, but in this case the stereochemical information is lost after the rearrangement because of enolization of the unsaturated formylacetic acid derivative. On the other hand, a fascinating possibility is presented by the nucleophilic addition of allyl alcohols to allenes activated by electron-accepting groups such as the sulfonyl or phosphoryl function [13, 141. Readily accessible allenes of this type allow the facile synthesis of u,p-or P,y-unsaturated allyl vinyl ethers depending on the degree of substitution of the allene and the reaction conditions.

-

Diastereoselective Claisen Rearrangements ArS02

L-

* -

1

-7

ArSO,

/NuH

+

ArS02

(12)

Denmark worked out reaction conditions for sulfonylallenes which allow the preparation of either the conjugated or the non-conjugated system [13], with the latter normally being the more stable. In the case of terminal monofunctional allenesulfones, attack occurs preferentially from the least hindered side of the allene, leading to formation of the trans-adduct (9). Nu

The adducts of allyl alcohols with allene sulfones are of particular interest because they may be used in a carbanion-accelerated Claisen rearrangement [141. As Denmark observed, the carbanions produced by deprotonation of the adducts rearrange orders of magnitude faster than the corresponding uncharged systems, a further example of the accelerating effect of Kdonor groups in position 2. This permits even the facile synthesis of highly functionalized systems with vicinal quaternary centers. The anion is generated in situ by addition of the alkoxide ion to an allene sulfone, so the reaction can be carried out as a “one pot” process. The generation of an allyl anion intermediate results in remarkably high stereoselectivity, often exceeding that of the thermal rearrangement. Evidently, the barrier to rotation in the sulfonyl-stabilized allyl group is exceptionally

LiDMSO

DMSO

7 oy

O\

X = SO@r, PO(OR),

113

(13)

98

2

high, or else the E-configuration of the anion is strongly favored in the equilibrium. The highest selectivities and yields are achieved if the anion is generated with lithium dimsylate in DMSO and the reaction time is minimized by increasing the temperature to 50 “C.

Denmark has recently opened up new perspectives for the carbanion-accelerated Claisen rearrangement [l 51 by introducing a chiral modification into phosphoryl-activated allenes, thereby achieving asymmetric induction. It is possible to produce the diastereoisomeric adducts (14) and (15) by addition of allylic alcohols to allenylphosphoramidates (diastereo-

\

6eq. LiCL

0

114

Stereodgferentiating Addition Reactions

meric at phosphorus), which are in turn readily synthesized from optically active allylic alcohols. Although no stereoselection is observed on thermal reaction of these compounds, Claisen rearrangement of the anions generated with potassium dimsylate results in a considerable degree of asymmetric induction (ca. 90:10), but only in the presence of excess lithium chloride. The favored products are the diastereoisomers (16) and (f 7). Further development of this interesting concept promises valuable applications in the future. Another possibility for inducing- chirality during the Claisen rearrangement involves taking advantage of a more distant chiral center, an approach developed by Welch [16], who employed for this purpose the amidacetal modification of the reaction, incorporating an optically active amine component into the keteneN,O-acetal. Addition of an allylic alkoxide ,to the salt produced by alkylating the initial amide with methyl trifluoromethanesulfonate (18) yields a Claisen system, which immediately rearranges giving as the major product the amide (20).

F

OLi OOTfl

L

(23)

The aza-Claisen rearrangement of N-allylketene-N,O-acetals (23) provides a further example of the principle of asymmetric induction by means of a stereogenic system at the periphery of a Claisen system. As has been shown by Kurth [17], such systems can be produced by alkylation of oxazolines with allylic alkoxytosylates, followed by deprotonation. Using chiral oxazolines of the type (21), the aza-Claisen rearrangement yields four diastereoisomeric rearranged oxazolines, with (24) as the major product. Although the relative diastereoselection induced by the center of asymmetry is acceptable, the internal diastereoselection is low. This is a function of the configuration of the ketene-N,O-acetal double bond, and once again the tiresome problem of controlling the stereochemistry of vinyl double bonds cries out for a solution!

References [l] Reviews: S. J. Rhoads and R. N . Raulins, Org. React. 22, 1 (1975); G. B. Bennett, Synthesis 1977,589; F. E. Ziegler, Acc. Chem. Res. 10,227 (1977);F. E. Ziegler, Chem. Rev. 88, 1423 (1988). [2] Review: R. K. Hill in J. D. Morrison (Ed.):

Both internal and relative asymmetric induction are dependent upon the spatial requirements of the chiral moieties, and has so far proven greatest with R' = CH3 and R2 = CH2Ph, giving ratios of 15.5: 1 and 6.4: 1, respectively.

"Asymmetric Synthesis", Academic Press, New York 1984, Vol. 3, Chap. 8. [ 3 ] P . A. Bartlett, Tetrahedron 36, 2 (1980). [4] J. F. Normant, 0. Reboul, R. SauvLtre, H. Deshays, D. Masure and J. Villieras, Bull. SOC. Chim. Fr. 1974, 2072; J. T. Welch and J. S. Samartino, J. Org. Chem. 50,3663 (1985);J. Barluenga, F. Aznar, R. Liz and M . Bayod, J. Chem.

Dia.str1renselet.til.c Cloisen Rearrangements

SOC.Chem. Commun. 1984,1427;J. Org. Chem.

52, 5190 (1987); M. Koreeda and J. I. Luengo, J.

[5]

[6] [7]

[8]

Am. Chem. SOC.107,5572 (1985); R. M . Coates, B. D. Rogers, S. J. Hobbs, D. R. Peck and D. P. Curran, J. Am. Chem. SOC.109, 1160 (1987). J. J. Gajewski, Acc. Chem. Res. 13, 142 (1980); C. J. Burrows and B. K. Carpenter, J. Am. Chem. SOC.103, 6983, 6984 (1981); J. J. Gajewski and K. E. Gilbert, J. Org. Chem. 49, 11 (1984); J. J. Gajewski and J. Emrani, J. Am. Chem. SOC.106, 5733 (1984); M . J. S. Dewar and E. F. Healy, J. Am. Chem. SOC. 106, 7127 (1984). Review: L. E. Ooerman, Angew. Chem. 96, 565 (1984), Angew. Chem. Int. Ed. Engl. 23, 579 (1984); R. P. Lutz, Chem. Rev. 84, 205 (1984). K. Takei, I. Mori, K. Oshima and H. Nozaki, Bull. SOC.Chem. Jap. 57, 446 (1984); J. L. oan der Baan and F. Bickelhaupt, Tetrahedron Lett. 1986, 6267; K. Mikapi, K. Takahashi and T. Nakai, Tetrahedron Lett. 1987, 5879. W. Sucrow and W. Richter, Chem. Ber. 104, 3679 (1979).

115

[9] P. A. Bartlett and W. F. Hahne, J . Org. Chem. 44, 882 (1979). [lo] M . Suda, Chem. Lett. 1981,967. Cf. the TebbeGrubbs-olefination, p. 192ff. [11] M. P. Cresson, C. R. Acad. Sci. Ser. C. 276,1473 (1973). [I21 W. Sucrow and G. Riidecker, Chem. Ber. 121, 219 (1988). [13] S. E. Denmark, M. A. Harmata and K. S. White, J. Org. Chem. 52,4031 (1987). [14] S. E. Denmark and M. A. Harmata, J. Am. Chem. SOC.104,4972 (1982); J. Org. Chem. 48, 3369 (1983); Tetrahedron Lett. 1984, 1543; S. E. Denmark, M. A. Harmata and K. S. White, J. Am. Chem. SOC.i f f , 8878 (1989). [l5] S. E. Denmark and J. E. Marlin, J. Org. Chem. 52, 5745 (1987). [16] J. T. Welch and S. Eswarakrishnan, J. Am. Chem. SOC.109, 6716 (1987). [I71 M. J. Kurth and 0.H. W.Decker, J. Org. Chem. 51, 1377 (1986) and references cited.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Ester Enolate Claisen Rearrangements

Among the several variants of the Claisen rearrangement [l] it is the rearrangement of ally1 ester enolates or the related ketene acetals derived by silylation that has acquired the greatest importance, as is apparent from numerous applications reported in recent years. The attractivity of the method lies in the stereoselective formation of a new C -C bond at the expense of a readily accessible ester C - 0 bond. Because the reaction is intramolecular, even difficult C -C linkages may be achieved once the two partners have been coupled by a simple ester linkage. However, the crucial breakthrough was Ireland's discovery [2] that it is possible by proper choice of solvent to influence

erythro

M =

Li,

- SiF \

threo

the geometry of the enolates resulting from treatment with strong, non-nucleophilic bases such as lithium diisopropylamide, thus facilitating stereochemical control of the rearrangement. An enolate with the E-configuration is the major product in THF, while addition of HMPT effects an almost complete reversal of the isomer ratio. In order to avoid complications involving the reactive enolates, and to ensure retention of the stereochemistry it is better to use not the enolate itself, but rather the corresponding silylenol ether, obtained by reaction with chlorotrialkylsilanes (usually the stable tbutyldimethyl derivatives). These systems rearrange under relatively mild conditions, in many cases even at room temperature via a 3,3-sigmatropic reaction to the corresponding y, &unsaturated carboxylic acid derivatives. In general, rearrangement takes place with high selectivity, normally via a chair transition state. In systems involving geometric and steric constraints the reaction may occur partially or completely by way of a boat transition state. This is usually observed, for instance, when one of the double bonds of the Claisen system is part of a ring; in such cases there are often subtle influences associated with the geometry and substitution of the double bonds. Ireland reported a host of practical examples that demonstrate the potential of the ester enolate Claisen rearrangement [2 -91. Starting with enantiomerically pure furanoid or pyra-

Ester Enolate Claisen Rearrangements

noid glycal systems of type (6),which are readily accessible from carbohydrates, he was able to exploit the 1,3-chirality transfer in Claisen-type rearrangements to construct oxygen heterocycles with chiral side chains [3] such as those occuring as subunits in polyether antibiotics and macrolides.

Syntheses of lasalocid A [4], tirandamycin [S], segments of chlorothricolide [6] and monensin [7], nonactic acid [S], and the PrelogDjerassi lactone [9], convincingly demonstrate the effectiveness of what is frequently described as the Ireland-Claisen rearrangement for the stereocontrolled synthesis of highly functional, complex systems. Interesting possibilities are revealed when unsaturated lactones are subjected to the Claisen enolate rearrangement. Many years ago, Danishefsky demonstrated that carbocycles could be produced from lactones of type (9) by Claisen rearrangement of the related silylenol ethers [lo].

The resulting stereochemistry indicates that rearrangement of small-ring lactones occurs via a boat transition state, enforced by the fact that a chair transition state would be too strained. A further modification is based on lactones of type (12), where all six atoms involved in the rearrangement are incorporated in a ring. This reaction, known as the alicyclic Claisen rearrangement [ll], leads to contraction of the ring by four atoms.

117

Starting from (13) with double bonds in the Z-configuration, the product is the cis-substituted system (14);if one of the double bonds in (13) has an E-configuration, possible only with larger rings, then trans-substituted systems (14) will result. Many interesting applications of this versatile method have recently been reported [ll, 121. Funk has described a simple synthesis of cischrysanthemic acid from lactone (15) [13].

The method is also suitable for the synthesis of heterocycles, provided the chain bridging the Claisen system itself contains a hetero atom. A good illustration is the synthesis by Knight of (-)-kainic acid [14], where (20) - readily prepared by coupling the C, component (18) with (19), derived from L-aspartic acid - is converted in very few steps into the kainic skeleton

OSiMe3

I

TIPS = Triisopropylsilyl

OTIPS CO Et (22)

11 8

Stereodifferentiating Addition Reactions

(22) by ring contraction using a Claisen rearrangement. Another technique for influencing the geometry of enolate formation is available in the case of allylic acetates bearing chelate-forming substituents in the u-position. Several groups [lS] have demonstrated that this permits selective access to the diastereoisomeric series as a result of intramolecular c,oordination of the lithium enolate.

(23)

(24)

X = Oo , OR, N < , CH,CHR

I

00

0

0

A variation of this method is due to Kallmerten [16], in which asymmetric induction during rearrangement of glycolate esters was achieved by the provision of a chiral center outside the Claisen system. Reaction of (26) leads primarily to diastereomer (27),which can, for instance, be transformed readily into R-( -)-pantolactone. The utility of this method for the preparation of functionalized acyclic systems is obvious, and it is likely to provide the impetus for further investigations.

References c11 See preceding chapter in this book. c21 R. E. Ireland, R. H. Mueller, and A. K. Willard, J. Am. Chem. SOC.98,2868 (1976);R. E. Ireland and C. S. Wilcox,Tetrahedron Lett. 1977,2839, 3975. c31 R. E. Ireland, S. Thaisrivongs, N. Vanier, and C. S. Wilcox, J. Org. Chem. 45, 48 (1980). c41 R. E. Ireland, R. C. Anderson, R. Badoud, B. J. Fitzsimmons, G. J. McGarvey, S. Thaisrivongs, and C. S. Wilcox,J. Am. Chem. SOC.105, 1988 (1983). c51 R. E. Ireland, P. G. M. Wuts, and B. Ernst, J. Am. Chem. SOC.103, 3205 (1981). C6l R. E. Ireland and M . D. Varney, J. Org. Chem. 51, 635 (1986). c71 R. E. Ireland and D. W.Norbeck, J. Am. Chem. SOC. 107,3279 (1985);R. Ireland, D. W.Norbeck, G. S. Mandel, and N. S. Mandel, J. Am. Chem. SOC.107, 3285 (1985). C8l R. E. Ireland and J. P. Vevert, J. Org. Chem. 45, 4259 (1980); Can. J. Chem. 59, 572 (1981). c91 R. E. Ireland and J. P. Daub, J. Org. Chem. 46, 479 (1981). c101 S. Danishefsky, R. L. Funk, and J. F. Kervin, J. Am. Chem. SOC. 102,6889 (1980);S. Danishefsky and K. Tsuzuki, J. Am. Chem. SOC.102, 6891 (1980). c111 M . M. Abelman, R. L. Funk, and J. D. Munger, J. Am. Chem. SOC.104, 4030 (1982); Tetrahedron 42, 2831 (1986). c121 A. G. Cameron and D. W. Knight, J . Chem. SOC. Perkin Trans I 1986, 161; M. J. Begley, A. G. Cameron, and D. W. Knight, J. Chem. SOC. Chem. Commun. 1984, 827. c131 R. L. Funk and J. D. Munger, J . Org. Chem. 49, 4319 (1984); 50, 707 (1985). c141 J. Cooper, D. W.Knight, and P. T. Gallagher, J. Chem. SOC.Chem. Commun. 1987, 1220. c151 P. A. Bartlett and J. F. Barstow, J. Org. Chem. 47, 3933 (1982); P. A. Bartlett, D. J. Tanzella, and J. F. Barstow, J. Org. Chem. 47,3941 (1982); S. D. Burke, W. F. Fobare, and G.F. Pacofsky, J. Org. Chem. 48, 5221 (1983); M. J. Kurth and C.-M. Yu, Tetrahedron Lett. 1984, 5003; T. J. Gould, M. Balestra, M. D. Wittmann,J. A. Gary, L. T. Rossano, and J. Kallmerten, J. Org. Chem. 52, 3889 (1987) and ref. cited. C161 J. Kallmerten and T. J. Gould, J. Org. Chem. 51, 1153 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

B. Cyclization Reactions

Ring formation can be achieved by either cycloaddition (as discussed in the previous chapter) or by cyclization, which is the subject of this section. A cyclization is some type of intramolecular addition or substitution process and it can lead to c , c or C-heteroatom bond formation. The mechanism may be ionic (e.g. of the aldol type, as in the Weiss reaction or cationic as in the polyepoxide cyclization), but it

may also involve radicals or be catalyzed by transition metals (Pauson-Khand reaction). Literature: Asymmetric Synthesis; D. J.Morrison, Editor, Academic Press, N. y., 1984, VOl. 3. B. Giese, Radicals in Organic Synthesis; Pergamon Press, oxford 1986. C. Thebtaranouth and Y. Thebtaranouth, Tetrahedron 46, 1385 (1990).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

B. Synthesis of Individual Natural Products

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

The Weiss Reaction

The frequent and diverse appearance of multiply-annulated five-membered rings among natural products as well as in compounds of theoretical and esthetic interest has generated an astonishing amount of activity recently in the synthesis of cyclopentane derivatives [I]. We will not deal here with the many pathways leading to a specific target molecule, but rather with one particularly versatile type of reaction that can serve as an efficient starting point for many synthetic projects. In 1968, U. Weiss and J. M. Edwards first reported the reaction of 1,2-dicarbonyl compounds ( I ) with dimethyl 3-oxoglutarate (2) in weakly acidic aqueous medium [2]. Their onepot procedure provided bicyclo[3.3.0]-octanedione tetraesters (3)in poor to moderate yield, compounds that are smoothly transformed into symmetric diketones (4) by saponification and

decarboxylation. In the case where R = H, the corresponding dione (4) had already been prepared at the beginning of this century by essentially the same sequence, though with a multistep protocol [3]. Cyclic 1,Zdiketones can also serve as starting materials, providing a very short route to [3.3.x]propellanes in which x 2 3. Weiss, Cook, and coworkers [4] studied the mechanism and synthetic potential of this bisannulation, which results in compounds (4) from combination of the donor and acceptor synthons (5) and (6).

(4)

(5)

(6)

(5)

Figure 1 provides a plausible explanation for the course of this multi-step/one-pot reaction. The first five-membered ring is formed by inter-, followed by intramolecular aldol addition of (2) to (f), the active species being enols in acidic medium, and enolates of the corresponding P-ketoesters under basic conditions. Dehydration of (7) furnishes a highly reactive Michael acceptor (8), which is attacked by a second 3-oxoglutarate molecule (2). Bicyclic compound (3) is finally generated by another dehydration/Michael addition (intramolecular

122

Cyclization Reactions

l

4%

Michael II

oo *

E E

R

E

O ,

Fig. 1 Mechanism of the Weiss reaction [ 3 ] . (In reality all j-ketoester units are present in the enol form.)

H

O&O H

69%

H

(la)

(48) -0

O

a H

x," (Id)

O

77%

52%

(46)

(4d)

(1s)

(4s)

Fig. 2 Preparation of diones (4a) - ( 4 9 ) from reaction of ( l a ) to (19) with (2) jollowed by decarboxylation.

The Weiss Reaction

this time). The product appears in the thermodynamically far more stable form, that with a cis ring junction. The proposed mechanism is supported by the nature of some of the side products, which can be explained by alternative cyclizations of the intermediates. Isolation of 1:l adducts (8) is also possible in certain cases, provided that their subsequent conversion into (4) is retarded or prevented by large substituents R [5]. The intriguing dimerization product (9) from reaction of 1,2-cyclopentane dione and (2) via (8) [R,R = - (CH,), -1 has recently been isolated and characterized by Quast and coworkers [6]. Optimization of the reaction conditions has gradually led to greatly improved yields [4, 6, 71. Control of the pH (buffering at pH 6 or pH 8) has been found to be particularly important. Figure 2 contains a number of characteristic

examples of the Weiss reaction that permit the synthesis of several interesting molecules starting from the inexpensive 3-oxoglutarate (2) and various 1,2-dicarbonyl compounds ( I ) . Applications of this approach to natural product synthesis and the preparation of biologically active compounds will be mentioned only briefly here: carbaprostacyclins and sesquiterpenes such as gymnomitrol, isocomene, modhephene, and pentalene can be synthesized more or less readily from precursors such as (4a) to (4d). Bicyclo[3.3.0]octanediones (4) are also ideal starting materials for substances of R

RSO,H =

H

1:4

(7 3) 90%

I

:,C,

H

61%

CH30H

I~HOH

lB 92% H3.THF

H (15)

(74)

8

Ht,,,,

123

al I-cis[5.5.5.5]-Fenestrane

H

(14)

Fig. 3 [5.5.5.5]-Fenestrane synthesis tri~c~ordirig to Cook et al. [8, 91.

124

Cyclization Reactions

are normally highly sensitive to nucleophiles [4], since they tend to undergo retro Claisen reactions. This is why the anticipated route towards the target molecule (14) must be preceded by reduction of (12) with borane-tetrahydrofuran complex. The mixture of tetraalcohols (15 ) undergoes smooth dehydration in refluxing hexamethyl phosphoric acid triamide (HMPT) [lo]. The resulting tetraenes (13) and (14) obtained in a 1 :4 ratio - may then be hydrogenated to provide all-cis-[5.5.5.5]-fenestrane (16), also called staurane. Yields are good in all five of the steps, and (16) or its precursors are now available in gram quantities.

academic interest with the semibullvalenestructure, including (10) and others. Cook, Weiss, and their students have contributed some particularly nice applications. The functionalized diones (4f)and (49) (Fig. 2) allow ready access to a remarkable series of polycyclic compounds. The strategy is illustrated in detail by the synthesis of [5.5.5.5]fenestrane (Fig. 3) [8,9]. The cyclopentene ring in (49) is oxidatively cleaved to give dicarboxylic acid (1I ) , the latter being subsequently converted into tetraketone (12) by Claisen condensation under acidic conditions. Strained compounds containing P-diketone units such as (12)

(2 isomers)

Fig. 4 Polyquinanes and polyquirierirs drricrd frorn W K ~ products SS [ 4 , 9, 111.

H

1. KH

25 '% 2. neutralization

E

3. C H p 2

E

H

-58%

3. HCI, HOAc

A 90%

E = C0,tBu

"@

E

1. BHg ' THF 0 oc

2. HMPT ca. 240 '% 74%

(1 7) Tripuinacene

Fig. 5 Synthesis of triquinacene (17) [12, 131.

2N HCI THF

0 &o

t-25 OC 92%

HO%

The Wviss Reaction

Figure 4 illustrates further polycyclic systems that have been realized with the aid of the Weiss reaction. A final highlight is the synthesis of triquinacene (17) and specifically substituted derivatives thereof [lZ], included in Figure 5 without further comment. 1,lO-Dimethyl triquinacene and 1,lO-cyclohexanotriquinacene may also be prepared employing the same strategy [13]. The efficiency, flexibility, and rapidity of this route exceeds that of all other known pathways and is unlikely to be overshadowed by future methods [14].

References [l] Reviews: L. A. Paquette, Top. Curr. Chem. 79,

41 (1979) and 119, 1 (1984); M. Ramaiah, Synthesis 1984,529. L. A. Paquette and A. M. Doherty, Polyquinane Chemistry, Springer, Berlin 1987. [2] U.Weiss and J. M. Edwards, Tetrahedron Lett, 1968, 4885. [3] G. Vossen, Dissertation, Univ. Bonn 1910; G. Schroeter, Liebigs Ann. Chem. 426, 1 (1922).

125

[4] R. Mitschka, J. Oehldrich, K. Takahashi, J. M. Cook, U.Weiss,and J. V.Silverton, Tetrahedron 37,4521 (1981). S. H . Bertz, J. M. Cook, A. Gawish, and U. Weiss, Org. Synth. 64, 27 (1985). [5] G. Kubiak, J. M. Cook, and U. Weiss, Tetrahedron Lett. 26, 2163 (1985) and references cited. [6] H. Quast, H . Roschert, E.-M. Peters, K. Peters, and H . G. v. Schnering, Chem. Ber. 122. 523 (1989). [7] S. H . Bertz, G. Rihs, and R. B. Woodward, Tetrahedron 38, 63 (1982). [8] M. N. Deshpande, M. Jawdosiuk, G. Kubiak, M . Venkatachalam, U. Weiss. and J. M. Cook, J . Am. Chem. SOC.107,4786 (1985). [9] M . Venkatachalam, G. Kubiak, J. M. Cook, and U.Weiss, Tetrahedron Lett. 26, 4863 (1985). [lo] R. S. Monson, Tetrahedron Lett. 1971, 567. [ I l l M. Venkatachalam, M . Jawdosiuk, M. Deshpande, J. M. Cook, and U. Weiss, Tetrahedron Lett. 26, 2275 (1985). [I21 S. H. Bertz, G. Lannoye, and J. M . Cook, Tetrahedron Lett. 26, 4695 (1985). [I31 A. K. Gupta, G. S. Lannoye, G. Kubiak, J. Schkeryantz, S. Wehrli, and J. M. Cook, J. Am. Chem. SOC.fif, 2169 (1989). [141 For attempts to prepare dicyclopentapentalenes see: G. Lannoye and J. M. Cook, Tetrahedron Lett. 29, 171 (1988); G. Lannoye, K. Sambasivarao, S. Wehrli, and J. M. Cook, J . Org. Chem. 53, 2327 (1988).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Radical Reactions for Carbon-Carbon Bond Formation

Radical chemistry is commonplace in the industrial-scale polymerization of alkenes, but organic chemists interested mainly in the synthesis of monomeric species tend to be rather suspicious of free radicals because these intermediates are considered as a source of unselective and undesired reactions. Therefore, with very few exceptions (e.g., the Meerwein aryl coupling reaction), polar or “concerted” reactions are preferred in synthetic organic chemistry. Only recently have certain research groups been able to demonstrate in a convincing manner that radical chemistry can indeed result in the formation of carbon-carbon bonds in a chemoselective, regioselective, and even stereoselective way [l]. The addition of a radical R’ to a carboncarbon double bond leads in the first step (a) to the intermediate ( I ) . This intermediate can either react with a second molecule of the alkene (b),or it might release the saturated monomer (2), giving rise once again to the radical R’ (c). Given an appropriate relationship between the rate constants of the reactions (a), (b), R’

Dimers,.

,

+

la

. Polymers

and (c) [2], which presupposes a suitable pattern of substituents in both the radical and in the alkene, polymerization might be suppressed completely in favor of formation via (c) of the monomeric product (2). The easiest way to reach this goal, at first appeared to be the intramolecular addition of radicals to alkenes, a reaction investigated mainly in the laboratories of Julia and Beckwith [3]. The steps involved in this type of freeradical chain reaction may be illustrated by the cyclization of Sbromohexene with tri-n-butyltin hydride (Bu,SnH) in the presence of the initiator azo-bis-isobutyronitrile (AIBN). Tributylstannyl radical is formed in the initiation step, and this abstracts a halogen atom to generate the radical (3),which in turn cyclizes to give the five-membered ring (4) in a regioselectioe manner [4]. Finally, methylcyclopentane is produced by the abstraction of a hydrogen atom from Bu3SnH,which ensures propagation BusSnH

AIBN

uBr +

H,C=C<

R-CHz-6-

(2)

I

H

+ R’

Bu3Sn‘

(3)

-0 +

+ Bu3SnBr

Bu,Sn’-O’

BusSnH

-

(3)

(41 H 3 C a

+ Bu3Sn’

Radical Reactions for C-C Bond Formation

of the reaction chain. The isomeric product cyclohexane forms only in trace amounts. With respect to the synthesis of more complicated target molecules such as dihydroagarofuran (6u), a constituent of galbanum resin, the question of stereoselectivity inevitably arises. Thus, the Bu3SnH/AIBN-mediated cyclization of a-chloroether (5) leads to both (6u) and (6b), in a rather unselective manner (ratio: 47:20). However, this stereochemical problem has been overcome in the following manner: intramolecular radical reaction of the alkyne (7) gives a mixture of E- and 2-vinylsilanes (a), which upon desilylation affords (9). Finally, diastereoselective hydrogenation with diimide results in dihydroagarofuran (6a), contaminated with only about 5% of the undesired isomer (6b)[5].

127

Stork and coworkers [6] reported on a cyclization of a-bromoacetal (1I ) , itself available from the carbinol (fO), in which they obtained a mixture of methyl esters (134 and (1%)in the ratio 85: 15. The predominance of isomer (13a) is plausibly explained by assuming that hydrogen prefers to approach the radical (12) from the convex face.

/

BusSnHIAIBN

(5)

1 Bu.SnWAIBN

(130)

1

HN=NH 92%

(9) 9 2 %

c

@H3

\

SiMe3 ( 7)

(136)

If allylic alcohol (14) is used as starting material instead of the homoallylic alcohol (1f ) , stereoselectivity increases significantly. Thus, lactone (16)is the only diastereomer that arises from cyclization of a-bromoacetal(1.5) and subsequent oxidation [7]. Here again, Bu3SnH must have approached largely from the convex face of radical (17), the presumed intermediate. Stork and his group also investigated the cyclization of vinyl radicals [8]. Such intermediates can be generated either from vinylic halides, as in the case of (fa), or by the addition of radicals to alkynes, the approch taken in the synthesis of butenolide (21). A tandem reaction is initiated by treatment of a-bromoacetal (19)

128

Cyclization Reactions

Bu&H

AIBN

Jonesox.

F

CH3

(17)

with Bu3SnH/AIBN to afford a mixture of Eand Z-(20). Deprotection and oxidation, followed by double bond migration, then leads to the lactone (24.

CN

1

H, A7I/\

8

do(20) 7 5 %

H

(21) 50%

CN

The scope of radical cyclizations was considerably extended by the observation that radical traps other than hydrogen may also terminate the reaction sequence. Thus, Stork and Sher [9] were able to obtain nitrile (25) from reaction of bromoacetal(22) with tert-butylisocyanide.Obviously, the intermediate (23) is trapped in this case by tert-butylisocyanide to give the vinyl radical (24). Elimination of the tert-butyl radical finally leads to the nitrile (25).

In many cases, free-radicals are useful for carbon-carbon bond formation even in the presence of functional groups incompatible with polar (cationic or anionic) reagents. This significant advantage is illustrated in the following reaction sequence: the unsaturated ketone (23, itself available from diene (26) by acetoxymer-

Radical Reactions for C-C Bond Formation

curation, is transformed into the bicyclic product (28) using a reductive method for radical generation described by Giese [2]. The p-acetoxy radical (29a) appears to be a plausible intermediate [lo]. Any attempt to realize this conversion by means of a Michael addition via carbanion (29b)would inevitably fail because of spontaneous elimination of the acetate anion to give the starting material (26). 0

0

0

OAc

129

[ll]. In this case, the key intermediate (31)originates from cleavage of a carbon-sulfur bond in the lactam (30). Cyclization of the radical (3f) results in formation of a mixture of diastereomers (32a)/(32b),produced in a ratio of 9: 1. The major product (32a) is accessible in pure form (70% yield) by recrystallization. Final conversion of (324 into the target molecule (33) is accomplished by rather conventional steps. Recently, even an intermolecular free-radical reaction (cf. step (c) from the beginning of this chapter) has been shown to be a useful synthetic method. Thus, Giese et al. [lb, 23 found that free-radicals such as those generated by reduction of organomercurials [e. g., (34)] undergo smooth addition to acrylonitrile. The result is the mixture of diastereomers (35) [12a].

OAc

(296)

(2%)

Pyrrolizidine alkaloids are available through cyclization of a-acylamino radicals. This approach is demonstrated in a synthesis of isoretronecanol (33),described by Hart and Tsai C0,tBu

C0,tBu SC6H5

- “2 Bu&H

0

NBN

0

(30)

This metho has been applieL to the synthesis of the antibiotic malingolide (37) in racemic form, using the allylic alcohol (36) as starting material. The target molecule (37) again was obtained as a mixture of diastereomers [12b].

J

HgBr 45%

HO

+b (33)

dN

(37)

49%

130

Cyclization Reactions

The fact that intermolecular radical reactions can also occur in a stereospecific manner is demonstrated by a synthesis of the C-glycoside (39),starting from glucose bromide (38)and acrylonitrile [13]. This procedure is characterized by exclusive formation of the thermodynamically less favored a-anomer - a remarkable stereochemical result [14]. A

c AcO

O

q

7

,

H#CHCN

CHz-CHZ-CN

(39) 1 2 %

If the addition of an alkyl halide to an alkene via free-radicals is mediated by Bu,SnH, tri-nbutylstannyl halides are produced, but these may be reduced in situ with sodium borohydride [lS]. Thus, free-radical addition of this type may also be carried out with sodium borohydride in the presence of catalytic amounts of Bu3SnC1, a practical improvement illustrated by the following example: H2C = CH - CO $3

NaBH4 1.3 molar eq. n-Bu3SnCl 0.2 molar eq. hv

CHz-CHz-COzCH3

85%

Free-radicals are compatible with a wide range of functional groups. As a consequence, radical reactions may well come to fill a crucial gap in the repertory of methods applicable to the formation of carbon-carbon bonds.

References [I] Reviews: a) D . J. Hart, Science 223, 883 (1984). b) B. Giese, Angew. Chem. 97, 555 (1985), Angew. Chem. Int. Ed. Engl. 24, 553 (1985). c) D. P . Curran, Synthesis 1988, 417; d) B. Giese, Angew. Chem. 101,993 (1989);Angew. Chem. Int. Ed. Engl. 28, 969 (1989). [2] B. Giese, Angew. Chem. 95, 771 (1983);Angew. Chem. Int. Ed. Engl. 22, 753 (1983). [3] J.-M. Surzur in R. A. Abramovitch (Ed.): Reactive Intermediates. Plenum Press, New York London 1982, p. 121, and ref. cit. therein. [4] For a discussion of the regioselectivity see: ref. 3; A. L. J. Beckwith, C . J. Easton, T. Lawrence, and A. K. Serelis, Aust. J. Chem. 36, 545 (1983). [5] G. Biichi and H. Wiiest, J. Org. Chem. 44, 546 (1979). [6] G. Stork, R. Mook, Jr., S. A. Biller, and S. D. Rychnovsky, J. Am. Chem. SOC.105,3741 (1983). [7] G. Stork and M . Kahn, J. Am. Chem. SOC.107, 500 (1985). [S] G. Stork and N . H. Baine, J. Am. Chem. SOC. 104,2321 (1982);G. Stork and R. Mook, Jr., Am. Chem. SOC.105,3720 (1983);for the corresponding cyclization of allylic bromides see: G. Stork and M. E. Reynolds, J. Am. Chem. SOC.110, 6911 (1988). [9] G. Stork and P. M. Sher, J. Am. Chem. SOC.105, 6765 (1983). [lo] S. Danishefsky, S. Chackalamannil, and B.-J. Uang, J. Org. Chem. 47,2231 (1982). [Ill D. J. Hart and Y.-M. Tsai, J. Am. Chem. SOC. 106, 8209 (1984); the same strategy was recently applied in a synthesis of (-)-swainsonine: J. M . Dener, D . J. Hart, and S. Ramesh, J. Org. Chem. 53, 6022 (1988). [12] a) B. Giese and K. Heuck, Chem. Ber. 112, 3759 (1979);b) A. P . Kozikowski, T. R. Nieduzak, and J. Scripko, Organometallics 1, 675 (1982). [13] B. Giese and J. Dupuis, Angew. Chem. 95, 633 (1983); Angew. Chem. Int. Ed. Engl. 22, 622 (1983).R. M . Adlington, J. E. Baldwin, A. Basak, and R. P . Kozyrod, J. Chem. SOC.Chem. Commun. 1983,944. [I41 For discussion of the stereochemistry and for ESR spectroscopic investigations see: J. Dupuis, B. Giese, D. Riiegge, H. Fischer, H.-G. Korth, and R. Sustmann, Angew. Chem. 96,887 (1984); Angew. Chem. Int. Ed. Engl. 23, 896 (1984). [l5] B. Giese, J. A. Gonzalez-Gdmez, and T. Witzel, Angew. Chem. 96,51 (1984);Angew. Chem. Int. Ed. Engl. 23, 69 (1984).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Cyclization of Allyl- and Vinylsilanes

A wide variety of silicon reagents is used in modern preparative chemistry [l]. Together with boron compounds [2], these provide an excellent supplement to classical carbanion chemistry, because they permit the formation of C-C bonds under weakly acidic or even neutral reaction conditions. This article is restricted to a description of those reactions in which a carbon residue is transferred intramolecularly to an electrophile, with accompanying cleavage of a silicon-carbon bond. Allyl- and propargyl- as well as vinyl- and ethynylsilanes serve as terminators in this type of reaction. Before describing such intramolecular reactions in more detail it will be useful to review some basic principles of silicon chemistry, illustrated by a few intermolecular examples. The Si - C bond is strongly polarized due to the high electronegativity of carbon (2.35) compared to silicon (1.64) [3]. As a consequence, three remarkable properties can be observed in silicon-carbon componds: The silicon atom is easily attacked by nucleophiles; negative charges in the u-position are stabilized, partly as a result of interaction of the empty silicon 3d orbitals with 2p orbitals from the neighboring carbon atom; positive charges in the P-position are also stabilized @-effect). Comparisons always involve a certain amount of ambiguity, but many of the properties noted (e.g., vulnerability to attack by nu-

cleophiles and electrophiles [4]) can be appreciated by imagining the SIR3 residue to be replaced by a carbonyl group, as shown in Chart 1. Chart I

The surprisingly facile elimination of hydrogen chloride from P-chlorosilanes [5] is a typical example. Other properties manifest themselves under specific sets of reaction conditions. Thus, treatment with fluoride ion generates a carbanionic species (analogy: base-catalyzed carbonyl reactions). This opens the way to a completely novel preparation of ylides from a-silyl onium salts under neutral conditions [6]. On the other hand, electrophiles activated by treatment with Lewis acids can be caused to attack the a-carbon of silanes (analogy: proton-catalyzed carbony1 reactions). This places a positive charge in the P-position of the vinylsilane prior to the departure (assisted by a nucleophile) of silicon. The positive charge resulting from addition of the electrophile is stabilized by interaction with an orbital of the C-Si bond, a stabilization made possible by rotation of the bond as shown in Chart 2. Such regio- and stereoselec-

132

Cyclization Reactions

tive substitution [7] of Si by E + is crucial to the vinylsilane cyclizations discussed below.

Scheme 1

Chart 2

Other interesting properties of silanes fail to conform to the abovementioned analogies. For example, one of the major advantages of silanes for synthetic chemists is their great stability under comparatively drastic conditions. This permits a latent functionality to survive unharmed through many reaction steps, later to be liberated when required. As in many other situations, proper choice of the reagents is the key to accomplishing a successful set of transformations. Hosomi and Sakurai [S] found that titanium tetrachloride is a generally applicable catalyst for the addition of allylsilanes to aldehydes and ketones. With other Lewis acids the reaction was limited to highly activated aldehydes such as chloral [9] or perhalogenated acetone [lo]. Addition takes place regioselectively at the y-center of the allylsilane, as shown in the example of Scheme 1 [ll]. Note the formation of a positive charge to the silicon. Complex (I) is stabilized by its conversion into (2), which contains a strong 0-Si bond. The silyl ether can then be cleaved to a P,y-unsaturated alcohol or cyclized to the furanone (3). Chiral homoallylic alcohols were recently prepared by the reaction of allylsilane

with C12Ti(OR*)2(OR* = (S)-1-phenylethoxy [12a]), and optically active allylsilanes can be obtained via palladium-catalyzed asymmetric Grignard coupling [12b]. The reaction of carbonyl compounds with allylsilanes was discovered independently by both Calas and Sakurai. It is today generally referred to as the Sakurai reaction [13] in recognition of his group's contribution in demonstrating the general applicability of this allylation procedure [13]. In contrast to the Tic&-catalyzed reaction, the intermediate in the fluoride-mediated reaction exhibits properties more consistent with an ally1 anion, and only the primary allylic center attacks the carbonyl group [14]. This loss of regioselectivity is not important in the case of symmetrical components, as shown in the elegant synthesis of (+)-ipsdienol (8) by reaction of the allylsilane (6) with the unsaturated aldehyde (7) (cf. Scheme 2) [15]. The 1,2-addition observed is rather exceptional; normally, both open chain [16] and cyclic [17] Michael acceptors undergo conjugate addition. The regio- and stereoselectivity is better than that observed in comparable reactions with cuprates. The intermolecular Sakurai reaction prepared the way for intramolec-

Allyl- and Vinylsilanes

tion, as demonstrated in the transformation of the allylic silane (15)via the sterically favorable chelate complex (16) into the trans-hydrindanone (17)(Scheme 5) [21].

Scheme 2

2. HCI/CH;OH

SiMe, (6)

HO

70%

(7)

(8)

Scheme 5 PhP3\/SiMe3

TBAF: Tetrabutylammonium fluoride

ular allylsilane cyclizations, first accomplished by the group of Majetich [18] through fluoride treatment of the enone (9) to give the exocyclic olefin (lo), as shown in Scheme 3.

(14)

o + c Y L H

(13)

M e 3 s d c H 3

\1'

Scheme 3

Schinzer [19] made a major contribution by introducing ethylaluminum dichloride as a catalyst for the intramolecular Sakurai reaction. The procedure also lends itself to the preparation of spirocyclic compounds, and propargyl silanes react to yield allenes. Both of the latter features are illustrated in the transformation of the propargyl silane (11)into the diastereoisomerically pure spiroallene (12) (Scheme 4). In this case, titanium tetrachloride was found to be the optimal catalyst [20]. Scheme 4

n e

133

S

i

M

e

3

The stereochemistry of the reaction can be particularly well controlled by chelate forma-

An earlier step in the same example provides an illustration of a general method for the synthesis of cis-configured allylsilanes: reaction of the aldehyde (13) with the Seyfarth-Fleming ylid (14) to give (15)[22]. (For information regarding the regio- and stereochemical outcome of the reaction see ref. [22a]). Only one mode of cyclization was possible with substrate (9), but starting material (18) is susceptible to a multitude of reaction pathways: 1,2-, 1,4-, and 1,6-addition, as well as a- or yattack by the allylsilane are all possible! Fortunately, not all the theoretically possible reactions occur if the conditions are carefully controlled. Treatment with EtAIClz leads exclusively to the predicted y-adduct (19) (R = H). In contrast, fluoride-catalyzed reactions lead to mixtures of the 1,2 and 1,4 adducts (20) and (21) respectively, as shown in Scheme 6 (cf. ref. [14]). Note the structure of the quarternary center in (19); this outcome would not be readily achieved with the traditional Michael addition. With R = CH3 in (18)the sesquiterpene (+)-

134

Cyclization Reactions

nootkaton (19) (R = CH3) [23] is obtained in a single step, an example that serves to demonstrate the importance of the Sakurai reaction in terpene chemistry.

Scheme 7

Scheme 6

(20) 35%

(21) 32%

Another example from terpene chemistry is the total synthesis of (+)-epi-widdrol by Majetich and Hull [23a] (Scheme 6a). The allylsilane (214 adds in a 1,6-addition reaction catalyzed by boron trifluoride etherate to form the 5-7 ring system (2fb),which is then transformed into epi-widdrol by conventional procedures. (See ref. 23b for the synthesis of 5 - 5 , 5 - 7, 6 - 5, and 6 - 7 bicyclic ring systems by intramolecular addition of allylsilanes and ref. 23c for p-quinone methide initiated cyclizations.) Scheme 6a SiMe,

(2W

(216)

The mode of cyclization can be controlled not only by the catalyst but also by the terminator. Whereas 1,6-addition leads to the seven-membered ring system of (23) in the cyclization of allylsilane (22),the five-membered ring system (25) is obtained starting from the propargylsilane (24) via l,Caddition, as shown in Scheme 7 [20].

Vinylsilanes are equally versatile as terminators of intramolecular substitutions. The corresponding intermolecular reaction has been known over thirty years [24], but the potential for cyclization was first exploited in the early 1980s. Vinylsilane terminators permit excellent control over the regio- and stereochemistry in a cationic cyclization, as illustrated in a general way in Chart 2. In addition, the relatively effective stabilization of a carbocation by the psilicon atom prevents undesirable WagnerMeerwein rearrangements and hydride abstractions, so cyclization products can normally be isolated in good yield [25]. An illustrative example (Scheme 8) is found in the synthesis of the trans-hydrindan (29)by Kuwajima et al. [26], which bears an exocyclic double bond. Scheme 8 also shows a route to the starting material (28) via cuprate addition of (27) to the cyclohexenone (26). (Another general route starts with trimethylsilyl acetylenes.) The intermediate acylium ion was generated in this case by treatment of the acid chloride with silver tetrafluoroborate. Titanium tetrachloride leads to partial isomerization of the thermodynamically unstable (a-olefin (29). Cyclization can be initiated by acid chlorides, aldehydes, ketones, (thio)acetates or allylic alcohols. The method even lends itself to polyene cyclizations like those studied so intensively by

135

Allyl- and Vinylsilanes Scheme 8

k

BrMg

SiMe3

(27) CU.1, 75%

,

C02-tBu (26)

six-, seven- and eight-membered [28a] cyclic ethers with exocyclic double bonds [29]. Sevenand eight-membered rings in particular were long considered to be difficult to prepare, but this perception may now change, as illustrated by the first stereospecific synthesis of a 3-alkylidene oxepan (33)via cyclization of (32) [29] (Scheme 10). Seheme I0

1. MeSSil COP - t BU

2. (COCI), 3. 4 B F 4 71X

’ MEM

W

(32)

Johnson et al. [27] in the context of biomimetic synthesis of steroids and terpenes. This is illustrated in the following example, taken from Burke et al. [28] (Scheme 9). The hydronaphthalene segment (31)of dihydrocompactine can be stereoselectively synthesized from the openchain vinylsilane (30)in a single step. This case results in an endocyclic olefin due to the position of the silicon residue.

-

B

Finally, nitrogen compounds should not be forgotten. The key step in the synthesis of (+)pumiliotoxin A (26) (R = H) by Overman et al. [30] is the iminium ion vinylsilane cyclization of (34,generated by pyridinium tosylate treatment of (34) (Scheme 11). Scheme 11

Seheme 9

Fy/TosOH CH30H, 70%

Vinylsilanes are not limited to the construction of carbocyclic ring systems, however. Overman’s research group has shown that acetalinitiated cyclizations starting from (methoxyethoxy)methyl ethers (MEM ethers) are particularly well suited to the construction of five-,

u

(33)

H

(29)

n

&.

OH

(36) R

=

H or Benzyl

136

Cyclization Reactions

Schinzer, C. Allagiannis, and S. Wichmann, Tetrahedron 44,3851 (1988);d) G. Majetich, Allylsilanes in Organic Synthesis (in: Organic Synthesis: Theory and Application, T. Hudlicky, Ed.); JAI Press, London 1989. [14] H. Sakurai, Tetrahedron Lett. 1978, 3043. [IS] H. Sakurai, A. Hosomie, M. Saito, K. Sasaki, H. Iguchi, J. Sasaki, and Y.Araki, Tetrahedron 39, 883 (1983). [I61 G. Majetich, A. M . Casares, D. Chapman, and Refere w e s M. Behnke,Tetrahedron Lett. 24, 1909 (1983). [I] General information on organosilicon chemis- [I71 T. A. Blumenkopf and C. H. Heathcock, J . Am. Chem. SOC.105, 2354 (1983). try: a) H. Sakurai: “Organosilicon and Bioorganosilicon chemistry: Structure, Bonding, [l8] G. Majetich, R. Desmond, and A. M. Casares, Tetrahedron Lett. 24, 1913 (1983). Reactivity, and Synthetic Application”. Halsted, New York 1985; b) W.P. Weber: “Sil- [19] D. Schinzer, Angew. Chern. 96, 292 (1984); Angew. Chem. Int. Ed. Engl. 23, 308 (1984). icon Reagents for Organic Synthesis”. SpringerVerlag, Berlin 1983; c) E. Colvin: “Silicon in Or- [20] D. Schinzer, J. Steffen,and S. Sdlyom, J. Chem. SOC. Chem. Cornmun. 1986. 829. ganic Synthesis”. Butterworth, London 1983; d) I. Fleming and N. K. Terrett, J. Organomet. [21] D. Schinzer, S. Sdlyom, and M. Becker, Tetrahedron Lett. 26, 1831 (1985). Chem. 164,99 (1984): e) I. Fleming, Chem. SOC. Rev. 10, 83 (1981); f) R. Calas, J. Organomet. [22] D. Seyfarth, K. W. Wursthorn, and R. E. Mammarella, J. Org. Chem. 42, 3104 (1977); I. FlemChem. 200, 11 (1980);g) H. U.Regig, Chem. in ing and I. Paterson, Synthesis 1979, 447; a) D. unserer Zeit, 18,46 (1984). Schinzer, G. Dettmer, M. Ruppelt, S. Sdlyom, [Z] This book, page 33ff. and J. Steffen, J. Org. Chem. 53, 3823 (1988). [3] By FSGO ab initio calculations: G. Simons, M. E. Zandler, and E. R. Talaty, J. Am. Chem. SOC. [23] G. Majetich, M . Behnke, and K. Hull, J. Org. Chem. 50, 3615 (1985); a) G. Majetich and K. 98, 7869 (1976). Hull, Tetrahedron 43, 5621 (1987); b) G. Maje[4] Reviews covering reactions of silanes with electich, J. Defaux, and C. Ringhold, J. Org. Chem. trophiles: a) Z. N. Parnes and G. I. Bolestova, 53, 50 (1988); c) S. R. Angle and K. D. Turnbull, Synthesis 1984, 991; b) cf. E. Winterfeldt, KonJ . Am. Chem. SOC.ill, 1136 (1989). takte (Darmstadt) 1986, 37. [5] S. N. Ushakov and A. M. Itenberg, Zh. Obshch. [24] L. H. Sommer et al., J. Am. Chem. SOC. 76, 1613 (1954). Khim. 7, 2495 (1937). [6] E. Vedejs and F. G. West, Chem. Rev. 86, 941 [25] Review: T. A. Blumenkopf and L. E. Overman, Chem. Rev. 86. 857 (1986). (1986). [7] K. E. Koenig and W. P. Weber, J. Am. Chem. [26] K. Fukuzaki, E. Nakamura, and I. Kuwajima, Tetrahedron Lett. 25, 3591 (1984). SOC.95, 3416 (1973). [8] A. Hosomi and H. Sakurai, Tetrahedron Lett. [27] Review: W. S. Johnson, Bioorg. Chern. 5, 51 (1976). 1976, 1295. [9] S. Calas et al., J. Organomet. Chem. 85, 149 [28] S . D. Burke, J. 0. Saunders, J. A. Oplinger, and C. W . Murtiashaw, Tetrahedron Lett. 26, 1131 (1975). (1985); a) L. E. Overman and A. S. Thompson, [lo] E. W. Abe and R. J. Rosoley, J. Organomet. J. Am. Chem. SOC.110, 2248 (1988). Chem. 84, 199 (1975). [ I l l A. Hosomi and H. Sakurai, Tetrahedron Lett. [29] L. E. Overman, A. Castaiieda, and T. A. Blumenkopf.J. Am. Chem. SOC.108, 1303 (1986). 1978, 2589. [12] a) R. Imwinkelried and D. Seebach, Angew. [30] L. E. Overman and N.-H. Lin, J. Org. Chem. 50, 3669 (1985); a) C. Flann, T. C. Malone, and L. Chem. 97 (1985); 781 Angew. Chem. Int. Ed. E. Overman, J. Am. Chem. SOC.109,6097(1987); Engl. 24, 765 (1985); b) T. Hayashi, M. Konishi, b) L. E. Overman and A. Robichaud, J. Am. Y.Okamoto, K. Kabeta, and M . Kumada, J. Org. Chem. SOC.llf, 300 (1989); c) G. A. Molander Chem. 51, 3772 (1986). and S. W . Andrews, J. Org. Chem. 54, 3114 [I31 Reviews: a) H. Sakurai, Pure Appl. Chem. 54, 1 (1989). (1982); b) D. Schinzer, Synthesis 1988,263;c) D.

This provides a good illustration of the compatibility of the vinylsilane cyclization with a high degree of functionality in the rest of the molecule! (See ref. 30a, 30b, and 30c for related iminium ion and acylium ion initiated cyclizations of vinylsilanes to afford heterocycles.)

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Nazarov and Pauson-Khand Reactions

The Diels-Alder reaction is a universally applicable tool for the construction of six-membered hetero- and carbocylic ring systems. Not only does it result in the simultaneous formation of two bonds, but it also permits control over the regio- and stereochemistry at four centers [l] (see page 54ff.). While the 1,3-dipolar [2+ 31 cycloaddition is an equivalent to the Diels-Alder reaction for the preparation of heterocyclic five-membered systems [ 2 ] , no generally applicable reaction principle is yet available for creating five-membered carbocyclic ring systems. However, particularly in the synthesis of cyclopentanoid natural products, intense efforts have led to a variety of very diverse methods for the construction of five-membered rings [3 - 51. Two examples, the Nazarov and Pauson-Khand reactions, have been selected to be the subject of this articles. Further examples for the construction of five-membered carbocycles will be described in a second article (p. 96ff.).

The Nazarov Reaction In 1957, Nazarov and Zaretskaya [6] described an acid-catalyzed cyclization of divinyl ketones (1) (now usually involving Lewis acids) to cyclopentanones (4) and (5) via the cationic intermediate (2) and the cyclic cation (3) (see Scheme 1).

Scheme 1

Broader application was nevertheless hampered by lack of control with respect to the position of the double bond (a mixture of (4)and (5) resulted, as shown in Scheme 1); drastic reaction conditions, leading to side reactions of the cationic intermediates; and unsatisfactory access to the starting materials (I). Consequently, the Nazarov reaction was long considered more as a mechanistically interesting possibility for rationalizing certain side reactions observed in terpene chemistry [7] than as a preparatively useful method. This

138

Cyclization Reactions

changed however, after Denmark et al. [8] described a new variation of the Nazarov reaction with silyl substituted divinylketones. Here, the stabilization associated with a positive charge 0 to the silicon atom in (2) and (3)@-effect [9]) is exploited to assure the position of the double bond in the final product. In addition, the exemplary ability of silicon to serve as an electrofugal leaving group largely prevents further side reactions (e.g., rearrangements) of the cationic intermediates. However, before discussing the details of the corresponding reaction pathway, mention needs to be made of some of the recent synthetic routes to unsymmetrically substituted silyl- and stannyl-substituted divinyl ketones. These new syntheses have helped to remove a major obstacle to broader application of the new siliconderived Nazarov reactions [gal. Vinylmagnesium compounds (7) can be reacted in a general synthesis with a,p-unsaturated aldehydes such as (6) to yield allylic alcohols (8) that are then oxidized with NiOl to the divinyl ketones (9),as shown in Scheme 2 C8l. Scheme 2

ocHo

the presence of a Lewis acid such as AlC13 (Scheme 3). The subsequent base-catalyzed reaction with the aldehyde (12) and dehydration via a mesylate to yield (13)are straightforward. Scheme 3

n - C7HISCH2COCI/AICIS

JfsnBu3

SnBuS

(10)

65%

1. LD4 - 78oc

n'-C7H15

SnBu3 (11) +

2. MsCI.

EtsN (85%) 0HC-fn-C5H11 OBn

(7 2)

Electrophile and nucleophile can also be exchanged by a Shapiro reaction [ll]. For ex1. M F / - 20°C ample, the triisopropyl benzenesulfonyl hydra+ JfMgBr >2. NH4CI (91%) zone (19,derived from tert-butylmethyl ketone We3 (14), can be deprotonated with sec-butyllithium (6) (7) to an intermediate carbanion that adds to a$PH unsaturated aldehydes [S] to afford (16) (Scheme 4). The Shapiro reaction is especially attractive because, at least in some cases, the carbanions of unsymmetrically substituted ketones can be generated regioselectively. A fascinating route to divinyl ketones has been described by Stille et al. [lZ]. The universal C , building block carbon monoxide is coupled in a palladium-catalyzed reaction with viDirect acylation of the Grignard reagent (7) nyl silanes and vinyl iodide to yield unsymwith a,$unsaturated acyl chlorides is not suc- metrically substituted divinyl silanes [12a]. The cessfull, but the trans-l,2-bis(tri-n-butylstan- necessary vinyl iodides are sometimes not readny1)ethene (10) [lo] can be acylated to (11)in ily available, but they can be replaced by the

Nazarov and Pauson-Khand Reactions Scheme 4 NH-Tri~yl

r;

0

1. sec-BuLi (2.02 equiv.)

2.

jCHO Me$

SiMe,

SiMeg

3.NiOp (60%)

(16)

corresponding vinyl triflates [12b]. Vinyl triflates such as (18) can be prepared from the ketones (17) by reaction with base and triflic anhydride. The mixed trimethylsilyl-/trimethylstannylethene (19) can serve as the other component in the coupling reaction with (18) to afford the divinyl ketone (20) (Scheme 5). Of course, the Stille reaction is certainly not limited to the preparation of silyl- or stannyl-substituted divinyl ketones [l2].

of (21) carried out by Denmark's research group (Scheme 6): 0 As expected, stabilization of the positive charge p to the silicon atom leads in most cases to a defined position for the double bond in the products (22) and (23); 0 conrotatory electrocyclic ring closure furnishes cis-fused ring systems exclusively; 0 the major product is the cis-trans-diastereoisomer (22), and stereoselectivity is particularly high with large residues R. Scheme 6

-

ca. SO 70%

(21)

(22) 78

Scheme 5

94

Me ( 1 7)

Pd(PPh3)JCO/UCI

07%

SiMe3

(20)

The foregoing examples show that silyl-substituted divinyl ketones are available by a number of different routes, and interesting aspects of chemo- [8a] and stereoselectivity [8a, 131 can be studied using a host of different substrates. Three general rules can be deduced from the ferric chloride catalyzed cyclizations

139

(23) :

:

22 6

R = CH, R = C(CH3)J

The stereochemical outcome is also influenced to some extent by the size of the substituents on the silicon atom. However, according to recent findings of Chenard et al. [14], large substituents on silicon can induce the elimination of a proton instead of the silyl group. The double bond in the product (25) derived from (24) does not form at the expected position (Scheme 7). This underscores the fact that the stabilization of a p-cation is a relatively weak effect! As a rule, the regenerative behavior of aromatic systems is always dominant, leading to elimination of a proton if one of the double bonds of the starting material is part of an aromatic system. The usefulnes of the modern version of the Nazarov reaction is vividly illustrated in the

140

Cyclization Reactions

Scheme 7

etherate with high cis-selectivity to the bicyclic skeleton (29) and to the tricyclic system (32), which can be converted in a subsequent Wittig reaction to ( +)-Ag('2)-capnellene(33) [12b] (see ref. 12c for an application of a Nazarov reaction in steroid chemistry).

0

Scheme 9 Me3Sn

Si-

lk

A

(25)

Pd(PPhJJCO/LiCI

Me

87%

-

(27)

synthesis of more complex cyclopentanoid systems, as shown in Scheme 8. Treatment of the previously mentioned tributylstannyl divinyl ketone (13)with boron trifluoride, followed by equilibration, leads to the thermodynamically more stable prostaglandin precursor (26) with the trans-configuration. The position of the double bond is exactly as predicted [lo]. Scheme 8 (13)

1. B F g , E t F

lW°C, (70%)

Me SiMe3

1. Red. __j 2. Tf2NPh

1. BF3 ' Et20

2.basic A1203 (56%)

Me Me

see

1

(26)

1 OBn

Me

1

-

% SiMe3

&

Me Me

Me

(32)

1. H2/Pd

The Stille reaction is ideally suited for the iterative annulation of five-membered ring systems such as the tricyclo[6.3.0.6"]undecane that forms the basic skeleton of many natural products. Key steps in the synthesis of (&)A9(")-capnellene are two Stille and two Nazarow reactions, as shown in Scheme 9. The triflate enolates (27) and (30) are converted in a palladium-catalyzed reaction with (trimethylsily1)vinyl stannane (19) to the divinyl ketones (28)and (31).Both systems are cyclized by BF3-

2. CH2=PPh3

(33ye

The Pauson-Khand Reaction This procedure is an example [16] of the everincreasing number of organometallic reactions [I71 that not only offer unusual selectivities but are also relatively simple to carry out experimentally. One reaction component is the air-

Nazarov and Pauson-Khand Reactions

stable dicobalt hexacarbonyl complex (36),easily prepared from acetylenes (34) and the relatively inexpensive dicobalt octacarbonyl(35). In intermolecular reactions, strained ring systems such as norbornadiene (37) are particularly easily converted to adducts such as (38). The net effect of this remarkable cyclopentenone synthesis is addition of an alkene to an alkyne with simultaneous insertion of CO. Moreover, high selectivities are possible, as shown in Scheme 10. Thus: insertion of the CO group generally occurs in the vicinity of the larger group of the alkyne (R’ in (34)); 0 in the addition to cyclic systems such as (37) the em-product (38) is formed preferentially. (For a discussion of regiocontrol see ref. 17a, b); for stereochemical considerations see ref. 17c, d):

141

is illustrated by the synthesis of the complex natural product shown in Scheme 11. Scheme I 1

(39)

Scheme 10 1. KO -t-& 2. MCPBA

(34)

‘R2

‘co

R

k2

(36)

(ref. 19)

4 OH

This elegant one-pot cyclopentenone synthesis is compatible with the presence of a number of functional groups. However, it is best to protect as ethers any polar hydroxy groups close to the reaction center. The scope of the reaction

OH

d

(44)

(45)

Intramolecular versions causing several rings to be formed simultaneously are especially popular, since problems of regiochemistry are

142

Cyclization Reactions

avoided through the linkage of the reaction components. The key step in the total synthesis of linearly condensed coriolin (45) by Magnus et al. [IS] is the reaction of the alkynene (39) with CO(CO)~ to yield the tetrahedral bimetallic cluster (40). This is followed upon heating of (40)by CO insertion and generation of the bicyclic system (41).The stereoisomeric product is also formed in 15% yield. Hydrogenation, alkylation, and Wacker oxidation to (42)is followed by a base-catalyzed aldol condensation to give a tricyclic ketone, which is in turn epoxidized with rn-chloroperbenzoic acid (MCPBA) after deconjugation to (43). The epoxide allyl alcohol rearrangement is another interesting step, one yielding the precursor (44),which has already been converted by Trost [19a] and Danishefsky [19b] to the antitumor agent coriolin (45).(See ref. 19c for an application to the synthesis of a silylated and highly functionalized bicyclic system). Not only linearly but also angularly condensed triquinanes can be constructed with the aid of the Pauson-Khand reaction, as demonstrated in Scheme 12. The tricyclic system (47) is formed by boiling alkyne (46)for three to four days with excess Co(CO)* [20]. The unsatuScheme 12

rated ketone is then converted into the natural product (48) in a few additional steps. One limitation of the method became apparent with the attempted synthesis of (50)via conversion of the cobalt complex derived from (49), as shown in Scheme 13. The steric hindrance associated with tetra-substituted alkynes cannot be overcome even in an intramolecular reaction. (See ref. 20a for a new application to racemic pentalenes):

MF

Scheme 13

Me

(isocomeneprecursor)

On the other hand, remote quarternary centers are not detrimental to the reaction, and even allyl ethers survive the requisite thermal treatment. This is illustrated in the conversion of (51)(isomeric mixture) to (52)(isomeric mixture), shown in Scheme 14 [ZO]. Scheme 14

1.

(35) (30%)

2. Li/NH3

(35)

~

(50)

(49)

Me

A

+ (35) ;&M

-

Benzene 34d, 35%

’

1. LiMepCu 2. MeLi

(47)

(48) (7 : 3 with exocyclic alkene)

Apparently, the degree of substitution of the double bond plays an important role. However, strained ring systems can very often be constructed without difficulty. Carceller et al. [21 J succeeded in producing the first application of the Pauson-Khand reaction to the synthesis of a perhydrotriquinane system (54) by treating the alkynene (53)with C O ~ ( C O(Scheme )~ 15):

Nazarov and Pauson-Khand Reactions Scheme 15

1.

(35)

2. 3 d. 160 OC. 64%

(53) ‘ O F

143

the cationic species generated upon Lewis acid treatment of the cobalt complexes of propargyl ethers (Scheme 17). An allylsilane such as (57) can serve as a nucleophile (in a kind of Sakurai reaction [9]), causing cyclization to the cyclooctene complex (58) upon BF3 treatment. Another aspect of the reactivity of the cobalt complex (58) is illustrated in the subsequent Pauson-Khand reaction, where annulation yields a mixture of a regioisomers (59/60). Scheme 17

JiMe3 The Pauson-Khand reaction is not limited to the preparation of carbocylic systems. The connection of alkyne and alkene subunits to produce oxygen-containing systems is particularly easy via ether synthesis (Scheme 16). The yields first reported in the cyclization of (55) to (56) were low [22], but a considerable improvement was achieved when the substrate (55) was adsorbed on silica gel in the presence of air [23].

--

Scheme 16

(57)

,

CO. Norbornene

(58)

(59)

+ regioisomer (60)

C02(CO),

0

a) A, N,(29%)[22]

References

b) S O p , 02(75%)[23]

(55)

(56)

The ability of cobalt complexes such as (36) to add to alkenes with insertion of CO illustrates only one aspect of the reactivity of these organometallic compounds. (For PausonKhand cycloadditions of polymer-linked substrates see ref. 23a). A final example may provide hints of undiscovered possibilities that might be unveiled by the combination of new organometallic reactions. Thus, cobalt complexes of alkynes are capable of stabilizing a neighboring positive charge, thereby permitting attack of nucleophiles (Nicholas reaction) [24]. In a new modification, Schreiber et al. [25] have investigated the reaction of nucleophiles with

[1] Compare P. Wetzel, Nachr. Chem. Tech. Lab. 31, 979 (1983). [2] Review: A. Padwa: “1,3-Dipolar Cycloaddition Chemistry”, 2. volumes. John Wiley, New York 1984. [3] J. March: “Advanced Organic Chemistry”. John Wiley, New York 1985, p. 745. [4] Reviews: a) B. M . Trost, Chem. SOC. Rev. 1 f, 141 (1982); b) M . Raimiah, Synthesis 1984, 529; c) L. A. Paquette, Top. Curr. Chem. 119, 1 (1984); d) N. E. Schore, Chem. Rev. 88, 1081 (1988). [5] For the alkinone cyclization of Dreiding see P. Welzel, Nachr. Chem. Tech. Lab. 31, 710 (1983). [6] a) N. I. Nazarou and I. I. Znretskaya, Zh. Obshch. Khim. 27, 693 (1957); Review: b) C. Santelli-Rouvier and M . Santelli, Synthesis 1983, 429.

144

Cyclization Reactions

[7] G. Ohloff; K. H . Schulte, and E. Demole. Helv. Chim. Acta 54, 2913 (1971). [8] a) T. K. Jones and S. E. Denmark, Helv. Chim. Acta 66, 2377 (1983); b) ibid. 66, 2397 (1983). [9] Compare the contributions on silanes in this volume (page 131ff.); a) For a convenient method of preparing dienones from silylated cyanohydrins and ketones see: S. Hiinig and M . bller, Chem. Ber. 114, 959 (1981). [lo] M. R. Peel and C. R. Johnson, Tetrahedron Lett. 27, 5947 (1986). [11] Review: R. H. Shapiro, Org. React. 23, 405 (1976). [12] a) W.F. Goure, M. E. Wright,P. D. Davis, S. S. Labadie, and J. K. Stille, J. Am. Chem. SOC.106, 6417 (1984); b) G. T. Crisp, W. J. Scott, and J. K. Stille, ibid. 106, 7500 (1984); c) J.-F. Lavalle'e and P. Delongchamp, Tetrahedron Lett. 29, 6033 (1988). [13] S. E. Denmark, K. L. Habermas, G. A. Hite, and T. K. Jones, Tetrahedron 42,2821 (1986). [14] B. L. Chenard, C. M. Van Zyl, and D. R. Sanderson, Tetrahedron Lett. 27, 2801 (1986). [IS] P. Magnus and D. Quagliato, J. Org. Chem. 50, 1621 (1985). [16] a) P. L. Pauson and I. U.Khand, Ann. N . Y. Acad. Sci. 295,2 (1977);b) Review: P. L. Pauson, Tetrahedron 41, 5860 (1985). [17] Cf. a) K. H. Diitz and M. Popall, Tetrahedron 41, 5797 (1985); b) Quadron synthesis: P. Magnus, L. M. Principe and M . J. Slater, J. Org. Chem. 52, 1483 (1987); c) M. E. Kraft, J . Am. Chem. Soc. 110, 968 (1988); d) S. E. Mac-

Whorter, V. Sampath, M . M . Olmstead, and N. E. Schore, J. Org. Chem. 53, 203 (1988); e) A. M . Montana, K. M . Nicholas, and M . A. Khan, J. Org. Chem. 53,5193 (1988); f) P. Magnus and D. P. Becker, J. Am. Chem. SOC. 109, 7495 (I 987). [181 P. Magnus, C. Exon, and P. Albaugh-Robertson, Tetrahedron 41, 5869 (1985). Cf. this book, p. 323ff. [19] a) B. M. Trost and D. Curran, J. Am. Chem. SOC. 103, 7380 (1981); b) S. Danishefsky, R. Zamboni, M . Kahn, and S. J. Etheridge, J. Am. Chem. SOC.103, 3460 (1981); c) J. Mulzer et al., Liebigs Ann. Chem. 1988, 891. [20] N. E. Schore and M. J. Knudsen, J. Org. Chem. 52, 569 (1987); a) N. E. Schore et al., J . Am. Chem. SOC.110, 5224 (1988). [21] E. Carceller, V. Centellas, A. Moyano, M . A. Pericas, and F. Serratosa, Tetrahedron Lett. 26, 2475 (1985). [22] D. C. Billington and D. Willison, Tetrahedron Lett. 25, 4041 (1984). [23] S. 0. Simonian, W. A. Smit, A. S. Gybin, A. S. Shashkov, G. S. Mikaelian, V. A. Tarasov, I. I. Ibragimov, R. Caple, and D. E. Froen, Tetrahedron Lett. 27, 1245 (1986). [23] a) N. E. Schore and S. D. Najdi, J. Am. Chem. SOC. 112, 441 -442 (1990). [24] H. D. Hodes and K. M. Nicholas, Tetrahedron Lett. 1978, 4349. [25] S. L. Schreiber, T. Sammakia and W . G. Crowe, J. Am. Chem. SOC.108, 3128 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Po 1yepoxide Cyc1izat ions

Biomimetic syntheses (cf. this book, p. 232ff.) are based on biogenetic principles, and they have often proven to be simple and efficient approaches to the preparation of natural products. A classic example is the cationic cyclization of isoprenoid polyenes to polycyclic terpenes and steroids. Cane and Westley recently offered a convincing explanation for the biosynthesis of polyether ionophoric antibiotics [l], complicated molecules consisting of linear chains of substituted tetrahydropyran and te-

trahydrofuran rings, and it constitutes a direct challenge to biomimetic synthesis. Consider, for example, monensin (3), whose biological precursor is the triene ( I ) . Enzymatic oxidation of ( I ) yields a triepoxide (2).Opening of the first epoxide ring in (2)initiates a cascade of ring expansions producing all five of the ether rings of monensin in a stereochemically defined manner. The hypothesis of triene-triepoxide biosynthesis not only explains the similar oxidation pattern and identical stereochemistry of

0

Monensin B

Cyclization Reuctions

146

the majority of known polyether ionophore systems, it has also been confirmed experimentally: three of the oxygen atoms in monensin come not from the carboxyl groups of acetate, propionate or butyrate, but from molecular oxygen. It has long been known that polyepoxides are capable of undergoing interesting transformations provided the oxirane rings are in a suitable spatial arrangement. Many years ago, de Meijere reported the facile rearrangement of trioxahomobarrelene (4) to trioxatrishomocubane (4, which is composed exclusively of tetrahydrofuran units [2]. As Simmons [3] and Paquette [4] discovered, triepoxide (6) under the influence of acid yields the topologically unique heterocycle a molecule whose structure is impossible to represent in a planar diagram.

(a,

yw

Nw (9)

KOH ____j Dioxane, H 2 0 70 %

HO

(10)

the generation of 2,5-bistetrahydrofurandiyl systems [6]. A highly stereocontrolled reaction with exclusive formation of the tetrahydrofuran system via a 5-exo-tet-reaction was observed. The model systems were synthesized from trienes bearing terminal hydroxymethyl groups, taking advantage of the Sharpless epoxidation procedure. This permits a substantial degree of control over the stereochemistry of the outer epoxide rings, with only the internal double bond epoxidized in a stereo-random fashion [e.g. (11)-+ (12)+ (13)and its diastereoisomer

&os& 0

(4)

(5)

The transformation of epoxidized polybutadienes (9) to oligotetrahydrofuran systems (10) [ S ] upon treatment with potassium hydroxide is even closer to the problem at hand. As usual, the oxirane rings are opened here with inversion; all-cis-alkenes thus result in threo-ring closures, while all-trans-alkenes yield erythro-configurations. Hoye has carried out fundamental model investigations of the stereochemical consequences of such cascade reactions on stereoisomeric triepoxides, with special attention to

(1341.

+

(13)

Curiously, even though (13) is obtained in high optical purity, its reaction with KOH in aqueous solution leads to a complete loss of

Polyepoxide Cyclization

147

[S], substances containing a highly functionalized tetrahydrofuran ring as the central structural element. Construction of the diepoxide (22) in enantiomerically pure form followed the well-estab-

L

1 N NaOH +

R = H

OCH3

optical activity. This is because compounds (14) and (14,with terminal epoxide groups, are further transformed under the reaction conditions to the enantiomeric compounds (164 and ( 1 7 ~ ) . This instance of “racemization” is unusual in that at no point along the reaction path is a symmetrical intermediate to be found, and the alternative initial reactions lead to diastereoisomeric primary products. When the reaction is performed in methanol as solvent, the final nucleophilic ring-opening is induced by methoxide, so asymmetry is maintained and the result is a separable diastereoisomeric mixture of (16b) and (17b). The above example illustrates the basic problems associated with biomimetic polyepoxide cyclization: success depends upon a high degree of stereocontrol in the polyepoxidization as well as on a regioselective initiating step. Selective initial attack can be problematic even in simpler cases based upon this approach, as in the fragmentation of a bisepoxide to give a substituted tetrahydrofuran [7]. A first impressive success was achieved by Nicolaou in the course of total synthesis of the elfamycin antibiotics

a: (i) t-BuOOH, (-)-DET, Ti(OiPr),, CH,CI,

- 2OoC; (ii) t-BuPh,SiCI,

Irnidazole, DMF, 0-25OC; b: (i)NaBH,, PhSeSePh. EtOH, 60OC;

(ii) 30% HO ,,

0-25OC

c: (i) t-BuOOH, (-J-DET, Ti(OiPr),, CH,CI,

- 2OOC; (ii) n-Bu,NF, THF, 0-25OC;

(iii) H, Lindlar cat., Hexane, 25OC; d: (i) m-CPBS, CH,CI,

- 2OoC; (ii) Me,CO,

cat, CSA, 25OC; (iii) H,, 5% PdlC, EtOAc, 25OC; (IV) cat. 25OC; (V) CH,N, e: (i) KCH,SOCH,, (ii) t-BuMe,SiCI,

RuO,, NalO,, MeCN-CCI,-H,O, Ether, O°C;

toluene- Me,SO, - 2OoC; Irnidazole, DMF, 0-25OC.

148

Cyclization Reactions

lished Sharpless methodology up to the last step, which was based on the experiences of Kishi with similar systems [9]. Kinetic resolution after oxidation of (18) yielded (19) (selectivity 50:l) [lo]. Transformation of (19) into the allylic alcohol (20) was followed by another enantioselective epoxidation (selectivity 30: 1). A new allylic alcohol system (21) was subsequently developed, and this was oxidized with m-chloroperbenzoic acid (selectivity 15:1) and transformed into (22).Regioselectiveopening of an oxirane ring in (22) was initiated by deprotonation a to the ester function, which brought about a p-elimination. Reverse attack of the resulting free alkoxide function at the second epoxide ring yielded unequivocally after silylation, and in 90% yield, the all-cis-substituted tetrahydrofuran (23),which could be utilized as an optically active component in various elfamycin syntheses [S]. In the case of most ionophoric antibiotics of the monensin type, the hydroxyl groups found in elfamycin are not required on the ether ring. This eliminates the possibility of simply continuing to exploit the Sharpless epoxidation for stereocontrolled introduction of epoxide functions. Two research groups have independently [l l , 121 attempted to solve this problem by carrying out model experiments based on “macrocyclic stereocontrol” as opposed to “acyclic stereocontrol”. It was known from the fundamental investigations of Still [13] that diastereoselective reactions can be realized on the periphery of a macrocyclic system. As Vedejs was able to demonstrate [14], chiral centers in medium-sized rings can also be employed very efficiently for the stereocontrol of epoxidations. Macrolides were chosen as the templates, since these could be prepared by established methods, and the carboxylate groups that result after hydrolysis are well suited to initiating the required polyepoxide fragmentation. This was the approach taken by Schreiber in the synthesis of the 12-membered lactone (24)

and its subsequent oxidation with peracid to give primarily the diastereoisomer (25) with a stereoselectivity of 9.5: 1 [ll]. Hydrolysis with potassium hydroxide generates the carboxylate group as an internal nucleophile, the attack of which initiates the opening of a first epoxide ring with simultaneous lactonization followed by opening of the second epoxide to give an ether. The resulting 1,3-diol system is ultimately trapped with acetone to give (26).

2. Acetone, H0

c

7J-J -

m CIC,H,COsH

(27)

NaHC03. CH,CI, 59%

1) 0.1 N NaOH

2) HOAc

Still [12] examined in a model study of polyepoxide cyclization the triepoxide (28), isolated as the sole product on epoxidization of the 16-membered macrolide (27). The method also proved amenable to this complex system, producing upon hydrolysis and spontaneous

Polyepoxide Cyclization

cyclization crystalline (29). Only because the triepoxide (28) differed stereochemically from the postulated monensin precursor at one of the three epoxide centers is the product not identical to the corresponding segment in the natural product. It would be necessary to alter the conformation of the macrocyclic triene in order to utilize this scheme for the synthesis of the natural ionophore. The most recent efforts to effect biomimetic access into polyether systems once again utilize the Sharpless method for enantioselective generation of the key intermediates. Two different research groups [lS, 161 reported a new strategy almost simultaneously, one in which epoxide rings are prepared stepwise by the asymmetric oxidation of terminal allylic alcohols, prepared as necessary by chain extension in a “building-block” approach. The principle can be seen from the syntheses of the bisepoxide (32) and the trisepoxide (35/36). Allylic alcohol (30) is easily obtained by allylic oxidation of geranyl acetate, and this is then epoxidized enantioselectively to (31). Oxidation followed by a Wittig reaction is used for the chain extension of (34,and release of the previously protected hydroxy group opens the way to another Sharpless epoxidation. Hydrogenation then leads to the bisepoxide (32). Paterson has shown [16] in the case of R = tert-butyl that (32) can be cyclized with cam-

phorsulfonic acid to the diol(33). On the other hand, the work of Robinson [IS] demonstrates that if R = methyl, clean cyclization to (33) occurs only if the ester is hydrolyzed with porcine liver esterase.

tBu02C

I

(34) CHzCIz, RT mCPBS, NaHCOS

0=+Q Q -+OH

(37)

+

=Gw-QpH

0

(38)

In order to test the method for the preparation of tricyclic polyether systems, Paterson gained access to the system (34)by conventional chain-lengthening techniques applied at both ends of (31) [16]. Epoxidation of (34)provided only a 1:l isomeric mixture, but direct cyclization of this mixture gave the diastereoisomeric lactones (35)and (36)as the sole products, and these were readily separated. Compound (37) reveals the same stereochemistry as in the Ci3- C27segment of etheromycin. With the exception of a missing methyl group, (38)is identical with the polyether fragment (29),prepared via “macrocyclic stereocontrol” by Still. On comparison of both approaches the acyclic stereocontrol applied by Paterson appears superior, due to its higher flexibility.

y - - )- y A (-) DTE, Ti(OPr),

0~~ tBuOOH

HO

p13-i (30)

HO

>-

OAc

149

150

Cyclization Reactions

Finally, it should be noted that polyether ionophores are probably not the only natural products whose biosynthesis involves polyepoxide cyclization. Polyepoxide intermediates have been postulated [17], for example, in the biosynthesis of polyene mycotoxins such as the aurovertines (39).

References [l] D. E. Cane, W. D. Celmer, and J. W. Westley, J. Am. Chem. SOC. 105, 3594 (1983).

[2] C. Weitemeyer and A. de Meijere, Angew. Chem. 88, 721 (1976) Angew. Chem. Int. Ed. Engl. 15, 686 (1976) C. Weitemeyer, T. PreuJ, and A. de Meijere, Chem. Ber. 118,3993 (1985). [3] H. E. Simmons and J. E. Maggio, Tetrahedron Lett. 1981, 287. [4] L. A. Paquette and M. Vazeux, Tetrahedron Lett. 1981, 291. [5] W. J. Schultz, M. C. Etter, A. V. Pocius, and S. Smith, J. Am. Chem. SOC. 102, 7981 (1980). [6] T. R. Hoye and J. C. Suhadolnik,J. Am. Chem. SOC. 107, 5312 (1985); 109, 4402 (1987); Tetrahedron 42, 2855 (1986); T.R. Hoye and s. A. Jenkins, J. Am. Chem. SOC. 109, 6196 (1987). [7] P. G. Wuts,R. D’Costa, and W. Butler, J. Org. Chem. 49,2582 (1984). [S] R. E. Dolle and K. C. Nicolaou, J. Am. Chem. SOC. 107, 1691 (1985). [9] N. Minami, S. S. KO,and Y.Kishi, J. Am. Chem. SOC. 104, 1109 (1982). [lo] V. S. Martin, J. S. Woodward, T. Katsuki, Y. Yamada, M. Ikeda, and K. B. Sharpless, J. Am. Chem. SOC. 103, 6237 (1981). [ I l l S. L. Schreiber, T. Sammakia, B. H u h , and G. Schulte, J. Am. Chem. SOC. 108, 2106 (1986). [12] W.C. Still and A. G. Romero,J. Am. Chem. SOC. 108, 2105 (1986). [I31 W. C. Still and I. Galynker, Tetrahedron 37, 3981 (1981). [14] E. Vedejs and D. M. Gapinski, J. Am. Chem. SOC. 105, 5058 (1983). [l5] S. T. Russell, J. A. Robinson, and D. J. Williams, J. Chem. SOC. Chem. Commun. 1987, 351. [16] I. Paterson, I. Boddy, and I. Mason, Tetrahedron Lett. 1987, 5205. [I71 R. Vleggaar, Pure Appl. Chem. 58,239 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Syntheses of Macrocyclic Ethers

It is well known that it is difficult to construct large-ring compounds in good yield, particularly those with eight to eleven members [l]. Ring-closure reactions to form macrocycles are generally hindered for entropy reasons, but in the case of medium-sized rings enthalpy effects also come into play, especially Pitzer strain and transannular interactions. The classical synthetic work of Ruzicka and Ziegler was motivated by the challenge of preparing interesting natural products, and the same goal has led to repeated attempts to build on the earlier work

and develop new productive routes to macrocyclic systems. There now exists a multitude of practical methods for accessing lactones, lactams, and carbocycles with various ring sizes. In contrast, it is only recently that macrocyclic ethers have become a focus of synthetic interest, here again because of the discovery of structurally unusual, biologically active natural products (most of which, remarkably, are of marine origin). These include simple systems such as laurencin ( I ) [2], but also such complicated structures as the brevetoxins [3, 41 (e.g., (3)),with eleven condensed, five- to ninemembered oxygen-containing rings, presenting a seemingly impossible synthetic problem. Brevetoxin A (3) is of particular interest. It is the most potent member of a family of polyether toxins produced by dinoflagellates,whose occasional excessive growth (“red tide”) is responsible for massive fish kills as well as human poisoning. Compound (3)has the ability to bind in a unique way to the sodium channels of stimulable membranes.

Me

0

CHO Brevetoxin A

(3)

152

Cyclization Reactions

The laurencin skeleton (2) has been the primary target of synthetic studies in the heterocyclic eight-membered ring series. The first challenge was developing suitable preparative methods, ones that would be consistent with controlled introduction of the substituents typical of ( I ) . A wide range of fundamental studies had already confirmed that construction of the eight-membered ring system itself presents problems: neither classical cyclizations based on the dilution principle [ 5 ] nor conventional ring enlargement procedures [6] offered satisfactory, generally applicable possibilities. Paquette [7] devised one of the few efficient ways of making eight-membered heterocycles, and this was adapted by Masamune to permit the first synthesis of ( I ) [ S , 91.

sible for synthesizingmacrocyclic ethers of various ring sizes, where the necessary substituents are introduced with a maximum degree of stereochemical control and condensed systems are constructed as far as possible with the correct stereochemistry. Three strategies can be distinguished: cyclization leading to the formation of either ( I ) a C - 0 or (2) a C - C bond, usually through intramolecular trapping of reactive intermediates, and (3) modification of a lactone (for which a broad spectrum of synthetic methods exists), into a cyclic ether of the same ring size.

C - 0 Cyclization Ley has reported that, depending upon the catalyst, acid-catalyzed reaction of a-phenylselenyl-substituted, unsaturated P-ketoesters of type (6) involves either C- or 0-alkylation with migration of the selenium residue [lo]. Particularly with p-toluenesulfonic acid the kinetically favored product is (3, a result of cyclization via the enolate oxygen atom. One of the reported examples involved an eight-membered ring.

0

)L\

Ei

(5)

In this method the eight-membered ring is generated indirectly starting with the bicyclic intermediate (4), accessibleby means of a simple Robinson-Schopf condensation. Nevertheless, this approach has the disadvantages that one has no control over the relative configuration of the side chains in (4), and (4) is also not degraded regiospecifically, so the desired compound (5) must be isolated from a mixture of products. Finally, a multistep manipulation of the functional groups in (5) had to be used to complete what is so far the only total synthesis of ( I ) . More recent investigations have been aimed at developing the most versatile strategy pos-

0

P2R

SePh>-

cat. pTosOH

A particularly clever method of synthesizing an oxocenone system depends on enlargement of a &lactone ring by two carbon atoms, entailing the formal insertion of a C = C double bond between the ring oxygen and the C = O group of the lactone. From numerous examples it was known that alkinyllithium compounds react at low temperature with lactones to yield a monoadduct, and that this gives an acetylenic ketone on hydro-

Syntheses of Macrocyclic Ethers

lysis. Schreiber [Ill] found that in certain cases heating such adducts in the presence of HMPT results in their conversion to oxocenones via ring opening of the hemiacetal followed by intramolecular endocyclic conjugate addition (in yields up to 73%!). However, the success of this ring enlargement is dependent upon the substitution pattern of the &lactone, and even more upon the substituents on the acetylene. The most suitable reactants were found to be ct,a'-disubstituted lactones and alkoxysubstituted propargyl systems.

CH&N MA

Me

(75)

a) 1. rn-Cl-CGH,,C03H 2. Et,SiH.BF,

+R = H

b) ALMe,,

CHC , L,

O°C

+R = CH,

153

Another method, developed by Nicolaou [12], appears to be very efficient and versatile; here, a sulfonium ion (readily generated from a dithioketal) is captured intramolecularly by an OH group. Starting from (12),ring closure leads exclusively to (14), apparently thanks to stereochemical control by the angular methyl group. The same effect can also be exploited for stereocontrolled manipulations at the newly introduced center. Thus, oxidation to a sulfoxide or sulfone permits subsequent replacement of the thioether function by a methyl group or a hydrogen atom. This occurs with retention of configuration, leading to the trans-fused systems (f5a)and (I%), precisely the arrangement required for a brevetoxin synthesis and indicative of the intermediate participation of an oxonium ion.

C - C Cyclization Intramolecular capture of an oxonium ion by a suitable double bond, resulting in the production of a new C - C bond, has proved to be a particularly effective technique for the preparation of medium-ring cyclic ethers. The first example of this type was an intramolecular modification of the aldol condensation developed by Mukaiyama [13]. Kocienski has shown that it is applicable not only to five-, sixand seven-membered cyclic ethers, but also to eight-membered systems, as in the conversion of (16)into (17) [14].

d

( 1 7)

Systematic investigation of this promising reaction yielded additional results worthy of note:

154

Cyclization Reactions

If two cyclization possibilities exist, there is a clear preference for the formation of the smaller ring; e.g., starting from (I@, only the eight-membered ring (17) is observed, with no trace of the alternative ten-membered ring. A template effect of the titanium catalyst 0 appears to be responsible for the facile production of eight-membered rings - without any need for high dilution! This evidently involves coordination with the oxygens from both the silylenol ether and the acetal groups. 0 High stereoselectivity usually constitutes a welcome "bonus". Cleavage of the cyclic acetal gives the product (17)(R = alkyl) as the only diastereoisomer observed, regardless of the stereochemistry of the starting material (R' = H, R2 = alkyl or R' = alkyl, R2 = H). 0

R

R 2eq. SnCI,

a) R = SiMe3

b) R = H

Overman has since been able to show [IS] that eight- and nine-membered cyclic ethers can also be obtained in good yield by direct cyclization of simple unsaturated acetals, and with high regio- and stereoselectivity. For example, reaction of (18a) gives the cis-substituted product (194 and the corresponding trans-isomer in a ratio of 30: 1. The silyl group does not play a decisive role in this remarkably smooth formation of an eight-membered ring, because the analogous Lewis acid-induced cyclization of (18b) yields isomer (19b) with similarly high diastereoselectivity. It is not yet entirely clear mechanistically why endocyclic ring formation is favored in other cases as well, with the larger ring system

often being the only one produced when there are two possible oxocyclic products [e.g., only the unsaturated eight-membered ring (19) and not the alternative seven-membered ring with an exocyclic double bond]. The observed regiochemistry and the preferred formation of a cis-dimethyloxocene can be rationalized in terms of cyclization of an oxonium ion with the conformation (20). Subsequent transannular deprotonation promoted by oxygen could explain the exclusive formation of the cis-double bond in (19) as well as all the other examples reported.

Conversion of Lactones to Cyclic Ethers Although it is tempting to utilize lactones as starting materials for the synthesis of cyclic ethers and then take advantage of the carbonyl functions for the introduction of substituents, successful application of this approach was long delayed due to a lack of suitable methods. An important incentive was the availability of a series of effective procedures for the synthesis of medium-ring lactones [161. One possibility 1. Tebbe reagent

THF, py. toluene

0 (23)

0

(22) 1.

P

R

-

BH,, THF

C)-R CH20H

(24)

(25) R = C6H13

155

Syntheses of Macrocyclic Ethers

is that developed by Holmes, and employed in the synthesis of simple 2,8-substituted oxocanes ~171. The starting lactone (23)is readily accessible from the substituted cycloheptenone (22) via Baeyer-Villiger oxidation. The second side chain is introduced by methylenation of the lactone with Tebbe's reagent and then hydroboration of the unstable enol ether (24), leading mainly to the cis product. Oxidation of (25) to the aldehyde, Wittig homologization, and hydrogenation results in production of the parent system (2). Nicolaou has developed an alternative route for the conversion of lactones to cyclic ethers [18], and it offers considerable flexibility, as evidenced by a series of examples involving lactones of differing sizes. This method entails reaction of carbon nucleophiles with thiolactones, which are readily prepared from the corresponding lactones. In contrast to the reaction with lactones themselves, the tetrahedral addition intermediates can in this case be captured by electrophiles R X . The resulting thioether function is readily removed by reduction. Particularly important is the observation that both the addition of al-

-

l . Etti. MF. 78 O C

2. M d

n/

S

PhMs, 100%

n

kyllithium and the homolytic cleavage of the thioether are highly diastereospecific when the starting materials are substituted lactones. The final products display primarily a cis configuration, as shown, for example, in a short total synthesis of (2). The potential of this method for the synthesis of brevetoxin fragments can be seen from the straightforward synthesis of the bicyclic system (28).

Q

1. Meti. THF,

2. MeJ

- 78 Dc

__7 3. PhJSnH QH PhMs. 100 O C

(27)

(28)

With the brevetoxins in mind as targets, Nicolaou has produced yet another method for preparing oxobicyclic and even complex oxopolycyclic structures [19]. The key step in this brilliantly simple approach is an intramolecular reductive coupling of a macrodithionolactone (29) to the bicyclic system (32). The thioether functions in (32)can be chemically transformed into either cis- or trans-linked polycycles. This coupling process, which is reminiscent of the acyloin condensation and the McMurry reaction, has been tested with a whole series of tetracyclic systems of varying ring size. As an example the sequence (33)-, (34)+ (35)/(36)may

\L

e_j

Q + Q 0

S

Mal, SMe R'S

R

Me

(34

Cyclization Reactions

156

1 (33)

Qay-& H

MeS

H

(34)

H H

2.2 eq. AgBFq

(34) I

H

Et3SiH CH,CI,.

H

25OC

>

H

H

H

H

In connection with the challenging brevetoxin problem Nicolaou has also developed an interesting method for the stereocontrolled anellation of 5- and 6-membered cyclic ethers by intramolecular ring opening of suitable epoxides [20]. Starting from (37), a simple trick was used to ensure that the ordinarily predominating 5-exo-ring closure to a tetrahydrofuran system (38)would be replaced by a 6-endo-ring closure, providing access to the tetrahydropyran system (39).The key innovation: provision of a pathway involving a favorable allylic substitution. This method permitted Nicolaou to synthesize (42)(in enantiomerically pure form!), a further building block for the brevetoxins. The route proceeded from (40) via (41),incorporating only a few additional steps.

H

(35)

The bicyclic lactones required as starting materials were prepared using standard normal macrolactone syntheses starting from the appropriate hydroxy acids. In the present example, two enantiomorphic hydroxy acids were coupled to form the meso compound (33) (X = 0), which was then converted to the corresponding thio derivative with the aid of Lawesson’s reagent*) (33) (X = S). Reductive coupling was accomplished with Na naphthalide/ methyl iodide, yielding the cis-fused tetracycle (34) as its racemate. Treatment with n-Bu3SnH provides a generally applicable method for converting the disulfide into an olefin, which is selectively hydrogenated to the cis-isomer (35); the trans-compound (36) can be prepared by reaction of (34) with Et3SiH and AgBF4.

5 - ex0 (38) Br

Y

Me

0.1 eq.

cy\

CH2C12. 25OC

H

H

H

(41 )

C02Me

H

H

H

The methods described in this article apparently remove most of the barriers to a stereoselective synthesis of polycyclic systems like the brevetoxins, and it is probably only a question of time before the first total synthesis of such a system is reported.

*) [2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-di-

thiadiphosphetane]:

Br

6- endo (39)

(37)

Syntheses of Macrocyclic Ethers

K. C. Nicolaou, M. E. Duggan. and C.-K. Hwang, J. Am. Chem. SOC.108, 2468 (1986); K. C. Nicolaou, C. V. C. Prasad, C.-K. Hwang, M. E. M. Braun, Nachr. Chem. Tech. Lab. 33, 1066 Duggan, and C. A. Veale, J. Am. Chem. SOC. (1985). 111, 5321 (1989). D. J. Faulkner, Nat. Prod. Rep. 1, 251, 551 T. Mukaiyama, Org. React. 28, 238 (1982). ~ 1 3 1 (1984): 3, l(1986). G. S. Cockerill, P. Kocienski, and R. Treadgold, c141 Y. Shimizu, H.-N. Chou, H . Bando, G. Van J. Chem. SOC.Perkin Trans. I 1985, 2093. Duyne, and J. C. Clardy, J. Am. Chem. SOC.108, L. E. Overman, T. A. Blumenkopf, A. Castaiieda, cl51 514 (1986). and A. S. Thompson, J . Am. Chem. SOC. 108, Y. Y. Lin, M. Risk, S. M . Ray, D. Van Engen, 3516 (1986). J. Clardy. J. Golik, J. C. James, and K. NakReviews: K. C. Nicolaou, Tetrahedron 33, 683 anishi, J. Am. Chem. SOC.10,3, 6773 (1981). (1977); T. G. Back, Tetrahedron 33, 3041 (1977); Vgl. z. B. M. L. MihailoviC, 2.CekoviC,J. StanS. Masamune, G. S. Bates, and J. W. Corcoran, kovit, N. PavloviC, S. KonstantinoviC, and S. Angew. Chem. 89, 602 (1977); Angew. Chem. DjokiC-Mazinjanin, Helv. Chim. Acta 56, 3056 Int. Ed. Engl. 16, 585 (1977); I. Paterson and M. (1973): N. J. Leonard, T. W.Milligan, and T. L. M. Mansuri, Tetrahedron 41,4569 (1985). Brown, J. Am. Chem. SOC.82,4075 (1960). R. W. Carling and A. B. Holmes, J. Chem. SOC. F. Nerdal, J. Buddrus, W. Brodowski, and P. Chem. Commun. 1986, 565. Weyerstahl, Tetrahedron Lett. 1966, 5385; L. A. K. C. Nicolaou, D. G. McGarry, P. K. Somers, Paquette and M. K. Scott, J. Am. Chem. SOC. C. A. Veale, and G. T. Furst, J. Am. Chem. SOC. 94, 6751 (1972): H. S. Kasmai and H . W. Whit109, 2504 (1987). lock, J. Org. Chem. 37, 2161 (1972). K. C. Nicolaou, C.-K. Hwang, M. E. Duggan, K. L. A. Paquette, R. W.Begland, and P. C. Storm, Bal Reddy, B. E. Marron, and D. G. McGarry, J. Am. Chem. SOC.90, 6148 (1968). J. Am. Chem. SOC.108, 6800 (1986). T. Masamune and H. Matsue, Chem. Lett. 1975, K. C.Nicolaou, M. E. Duggan, C.-K. Hwang, and 895. P. K. Somers, J. Chem. SOC.Chem. Commun. T. Masamune, H. Murase, H. Matsue, and A. 1985, 1359; K. C. Nicolaou, C. V. C. Prasad, P. Murai, Bull. Chem. SOC.Jap. 52,127,135 (1979). K. Somers, and C.-K. Hwang, J. Am. Chem. SOC. W. P. Jackson, S. V. Ley, and J. A. Morton, 111, 5330, 5335 (1989). Tetrahedron Lett. 22, 2601 (1981). S. L. Schreiber and S. E. Kelly, Tetrahedron Lett. 25, 1757 (1984).

References [l]

[2] [3] [4] [5]

[6]

[7]

[S] [9] [lo] [ll]

157

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Halolactonization: The Career of a Reaction

The formation of halolactones (2) from olefinic a) in H,OINaHCO, carboxylic acids ( I ) (“halolactonization”) was (1) # H,C - CH - (cH,)”- C O , ~ + (2) discovered by Bougault [l], Fittig [a] and 1 ./ X Stobbe [3] towards the beginning of this cen@ (3) (X = Br, I) tury. For decades, this reaction shared the fate b) in aprotic solvents without base: of Sleeping Beauty, until, in the fifties, due to the enormous interest in mechanistic investi0 6 - R gations, halolactonizations were studied in Jdgreater detail [4]. The current view is that haloCH,=CH- (CH,), # lactonization may proceed via two alternative x-x J mechanisms, depending upon the reaction conR = H, Alkyl ditions. With aqueous base ( I ) forms the corresponding carboxylate and halogen adds to the double bond with reversible formation of the cyclic halonium species (3). Neighboring group participation by carboxylate causes SN2cyclization to the lactone. The second mechanism works for acids and esters in aprotic neutral solvents (ether, acetonitrile, etc.). Halogen and the carboxyl oxygen add to the double Fig. I . The mechanism of halolactonization bond in a concerted fashion to form the oxonium ion (4, which is deprotonated or deThe synthetic applicability of halolactonizaalkylated by X- to form lactone (2) [S]. In both variations, the reaction is generally reversible. tion crucially depends upon the degree of regioand stereocontrol. As was demonstrated by Barnett [6], the regio-chemistry of kinetically controlled halolactonization is largely consistent with Markownikow’s rule. Thus, for unsymmetrically substituted ene-acids, oxygen adds to the more and halogen to the less highly substituted olefinic carbon. For symmetrically substituted olefins entropy factors control the I regiochemistry. Given a choice, the order of (2) n = 1,2

Halolactonization

preference is 0-lactone > y-lactone > &lactone B E-lactone. In terms of Scheme 1, this means that pathway A ("exocyclic attack) is generally faster than pathway B ("endocyclic attack"). An additional effect acting in the same direction may be the tendency to minimize nonbonding repulsions between the 1,Zbond and the rest of the ring. For thermodynamically controlled halolactonizations, the relative energy of the lactone is the crucial factor. Thus, P-lactones slowly rearrange to their y-lactone isomers, whereas y-lactones remain unchanged that underthermodynamic equilibrating conditions control may [7]. beIt achieved appears most reliably in the case of iodolactonization, preferably in aprotic solvents (e.g., acetonitrile).

H#2=CH-C(CHs)a-CO,H

(6)

Po

(CHda

Q

------)

0

+ Hs Xe (8)

(7)

a& (10)

(9)

CHS +

x

CH3

(12)

(11)

Scheme I

159

terpreted in terms of diaxial [ 9 ] opening of the halonium intermediate (15). Halonium ion (16) might be formed reversibly, but the subsequent cyclization step would lead to intolerable ring strain. Thus, the conversion of (13) into (14)

(13)

Most experimental data on halolactonization find a satisfactory interpretation in light of these considerations. For instance, the irreversible bromolactonization (NaHC03in H20, Br3 of (6) furnishes p-lactone (7) (entropy control), whereas reversible iodolactonization (NaHC03 in H20, 12,24 h) leads to y-lactone (8).The reaction of (9) to (10)(entropy control) and of (11) to (12) (Markownikow control) may be similarly understood [8]. In general, halolactonization of 4,5-ene-carboxylic acids gives y-lactones, and that of 5,6-ene-carboxylic acids gives 6-lactones. The stereochemistry of the reaction is similarly predictable. In particular, annelations like the reaction of (13) to (14) always lead to cisfused ring systems, a result which may be in-

-0

m = 2,3; n = 1,2

(13) (m

I

(14) =

3)

4'"'

160

Cyclization Reactions

b.

Fig. 2 Corey’s application of the halolactonization. a. Prostaglandins”

controls the relative configuration of three contiguous stereocenters in one step! For a long time halolactonization was regularly employed for the configurational assignment and purification of polycyclic ene-carboxylic acids (e.g. of the norbornene type) [lo, 111.

b. Gibberellic acid GA3 (30)j6

After some preliminary work by several authors [12] the full synthetic potential of the reaction was realized by E. J. Corey, who utilized it in the synthesis of complex natural products [13]. Thus, prostaglandin PGF, (17) was prepared from key intermediate (18) (“Corey lactone al-

Halolactonization

161

dehyde”), which in turn was available by the (26)is formed from (24)via (25)by intramolecDiels-Alder halolactonization sequence (19)4 ular Diels-Alder-reaction and elimination of (20)+ (21)+ (22) + (23).This methodology hydrochloric acid. Further elaboration furhas been adapted in industrial prostaglandin nishes (277, which on hydroxylactonization syntheses and now represents one of the stan- gives (28).The remaining double bond in ring dard approaches to this important class of com- A is then submitted to iodolactonization to propounds. vide (29) and, after certain additional transforMotivated by this success, the Corey group mations, (30).Regiocontrol is achieved in both used the regio- and stereochemical potential of lactonizations by the principle of diaxial openhalolactonization in the syntheses of even more ing of the corresponding epoxide and halonium complex natural products like thromboxane B2 intermediates, respectively. [14] and erythronolide B [lS]. A particular Corey’s success stimulated similar work in highlight is their synthesis of gibberellic acid other groups [17]. For instance, in DanishefGA3 (30) [16], one of the Mount Everests in sky’s synthesis of racemic vernomenine (38) Organic Synthesis. A combination of halolac- [18], (31)was prepared by two successive Dielstonization with a related hydroxylactonization Alder additions to propiolic ester. Iodolactonallows the proper functionalization of ring A ization selectively furnished (32) and - after OMe

CO,H NaHCOj

I

3.H30@ 4 . O H @

‘2

H

H

0

(37)

0

0 1. OH@

0

0

H

(32)

H

3. n c p

0

(33)

(35)

’0 (34)

(36) ,OH

1. Li-CH2-C02Li

3. H30@

(37)

O

Fig. 3 Danishefsky’s synthesis of ( fj-vernomenine (38)’’

(38)

(2)-Vernornenine

162

Cyclization Reactions H

elimination of HI - (33) in accordance with Bredt’s rule. Although the peracid epoxidation H CH, 2. y-noc of (33) is performed via the free acid, no hydroxylactonization occurs, and the epoxide (39) function in (34) may be used for the regiocontrolled addition of di-lithium acetate and formation of the y-lactone ring. As in Corey’s prostaglandin synthesis, the elegant combination of IQ IQ a Diels-Alder reaction with halolactonization allowed the concise construction of a complex substitution pattern, which could then be used in subsequent modifications. Ultimately, all the functional groups in ring B of (38) have emanated from these two key reactions. Following the current trend, halolactonizations have also been used for “acyclic stereoselection”[ 191. The regiochemistry in acyclic systems obeys rules very similar to those applicable to cyclic analogues, which means that five- and six-membered lactones are the favored products. Stereocontrol is much harder to achieve in acyclic cases, although the literature reports numerous examples with high diastereoface selection. For instance, in an incomplete synthesis of rifamycin S, the Corey group attempted the iodolactonization of acid (39) and found (40) to be the only product [20]. Similarly, the conformationally less strained 6-lactone (44) is formed in high excess over (45) from acid (43) [21]. (44) has been used in a stereocontrolled synthesis of the pheromone 01multistriatin (46)[22]. On the other hand, kinetic control apparently accounts for the cisarrangement of the hydroxyl- and CHJ-groups in the lactone (48) which was elaborated into epilitsenolide C [23]. Obviously the OH-function exerts here a strong influence on the diastereofacial selectivity of iodolactonization, an effect also observed by other authors [24]. One of the fundamental principles in modern asymmetric synthesis is the application of chiral auxiliaries, from which (by some highly stereocontrolled process) chiral information is transFig. 4 Halolactonization ox acyclic olefins (Contri- ferred to the desired reactive site in the subbutions by Core?’, Bartlett”, and K~tzenellenbogen~’) strate. Halolactonization is one of many reHsC-2H

1. NaHCO$H20

’

Halolactonization

163

COpH

0 HsC NBSl

Br

(50)

CHiR ( R ) -(51) major

(49)

(R = CHS, Ph) Br

(S)- (51) minor

(52)

Fig. 5 Asymmetric synthesis of a-hydroxycarboxylic acid according to Terashima

actions [25] that have been utilized for this purpose. As shown by Terashima [26], the proline derivative (49) undergoes highly selective bromolactonization on treatment with NBS in DMF to form (50), which is then converted to the a-hydroxy acid (R)-(51) with ee-values of >go%. Inspection of models shows that efficient lactonizations of (50)/(52) can occur only for a coplanar arrangement of the N -CO -C, - Cpkeleton. Under these circumstances (50) is favored over (52) due to smaller non-bonding interactions between the methyl and carboxyl functions. Numerous other applications have been reported [27], and it may be said in conclusion that the career of halolactonization (and related reactions [28]) has been truly remarkable. Mechanistic understanding of the reaction and reliable regio- and stereocontrol have undoubtedly been responsible for its rise from a laboratory curiosity to a key reaction in organic synthesis.

References [l] M. J. Bougault, Compt. rend. 139 (1904); Ann. Chim. Phys. 14, 145 (1908); 15, 296 (1909), 22,

125 (1911).

c21 R. Fittig, Liebigs Ann. Chem. 226, 366 (1884), 216, 52 (1883), 304, 222 (1898), 331, 142 (1904). c31 H. Stobbe, Liebigs Ann. Chem. 308, 77 (1899), 32i, 119 (1902). [4] E. E. van Tamelen and M. Shamma, J. Am. Chem. SOC. 76, 2315 (1954). [5] R. T. Arnold, M. de M . Campos, and K. L. Lindsay, J. Am. Chem. SOC. 75, 1048 (1953); M. de M . Campos, J. Am. Chem. SOC. 76,4480 (1954); L. do Amaral and S. C . Melos, J. Org. Chem. 38, 800 (1973). [6] W . E. Barnett and W . H. Sohn J. Chem. SOC. Chem. Commun. 1972, 472; Tetrahedron Lett. 1972, 1117. [7] G. W . Holbert, L. B. Weiss, and B. Ganem, Tetrahedron Lett. 1976, 4435. [8] W . E. Barnett and L. L. Needham, J. Org. Chem. 40, 2843 (1975). [9] D . H. R. Barton and R. C . Cookson, Quart. Reviews 10, 44 (1956). [lo] V. I. Staninets and E. A. Shilou, Russ. Chem. Rev. 1971, 272. [11] M . D. Dowle and D. I. Dauies, Chem. SOC. Rev. 1979, 171. [12] H. 0. House, R. G. Carson, H . Miiller, A. W. Noltes, and C . D . Slater, J. Am. Chem. SOC. 84, 2614 (1962). E. Wenkert, L. H. Liu, and D. B. R. Johnson, J. Org. Chem. 30, 722 (1965). [13] E. J. Corey, N. M . Weinshenker, T. K . Schaaf, and W . Huber, J. Am. Chem. SOC. 91, 5675 (1969); E. J. Corey and R. Noyori, Tetrahedron Lett. 1970, 311. [14] E. J. Corey, M. Shibasaki, and J. Knolle, Tetrahedron Lett. 1977, 1625. ~~

164

Cyclization Reactions

[l5] E. J. Corey and coworkers, J. Am. Chem. SOC. 100, 4618, 4620 (1978). [16] E. J. Corey and coworkers, J. Chem. SOC.100, 8031, 8034 (1978). cf. also R. L. Danheiser in “Strategy and Tactics in Organic Synthesis”, T. Lindberg, Editor, Academic Press, N. Y. 1984, p. 22. [I71 Prostanoids: E. D. Brown, R. Clarkson, T. J. Leaney, and G. E. Robinson, J. Chem. SOC. Chem. Commun. 1974,642; E. D. Brown and T. J. Lilley, J. Chem. SOC.Commun. 1975, 39. B. M. Trost, T. M. Timko, and J. L. Stanton, J. Chem. SOC.Chem. Commun. 1978,436. Vitamine D: B. Lythgoe, M. E. N. Nambudiry, and J. Tideswell, Tetrahedron Lett. 1977, 3658. - [3]Peristylene: P. J. Garratt and J. F. White,J . Org. Chem. 42, 1733 (1977). - Frulanolide: W. C. Still and M . J. Schneider, J. Am. Chem. SOC.99, 948 (1977). Senepoxide and Seneole: G. W.Holbert and B. Ganem, J. Am. Chem. SOC.100,352 (1978). - Canadensolide: M. Kato, M. Kaeyawa, R. Tanaka, K. Kuwahara, and A. Yoshikoshi, J . Org. Chem. 40, 1932 (1975). Pseudomonic Acid: G. W. J. Fleet, M. J. Gough, and T. K. M. Shing, Tetrahedron Lett. 24, 3661 (1983). Monensin: D. B. Collum,J. H. McDonald III, and W.C. Still, J. Am. Chem. SOC.102,2118 (1980). Tirandamycin: R. E. Ireland, P. G. M . Wuts, and B. Ernst, J. Am. Chem. SOC.103,3205 (1981). [I81 S. Danishefsky, P. I. Schuda, T. Kitaharund, and S. J. Etheredge, J . Am. Chem. SOC.99, 6066 (1977). [I91 P. A. Bartlett, Tetrahedron 36, 2 (1980). [20] E. J. Corey and T. Hase, Tetrahedron Lett. 1979, 335. [21] P. A. Bartlett and J. Myerson, J. Am. Chem. SOC.100, 3950 (1978). [22] P. A. Bartlett and J. Myerson, J . 0rg.Chem. 44, 1625 (1979). [23] S. W. Rollinson, R. A. Amos, and J. A. Katzenellenbogen, J. Am. Chem. SOC.103,4144 (1981). [24] A . R. Chamberlin, M . Dezube, P. Dussault, and M. C. McMills, J . Am. Chem. SOC.105, 5819 (1983).

[25] J. W. ApSimon and R. P. Seguin, Tetrahedron 35, 2797 (1979), Tetrahedron; D. Valentine and J. W. Scott, Synthesis 1978, 329. Asymmetric Synthesis, J. D. Morrison, Editor, Academic Press, N. Y., 1984, Vol. 2. [26] S. S. Jew, S. Terashima, and K. Koga, Tetrahedron 35, 2337, 2345 (1979); S. Terashima, M. Hayashi, and K. Koga, Tetrahedron Lett. 21, 2733 (1980). [27] Review: P. A. Bartlett in “Asymmetric Synthesis”, J. D. Morrison, Editor, Academic Press, N. Y., 1984, Vol. 3B, p. 411. See also: T. Takana, M. Hirama, and K. Ogasawara, J. Org. Chem. 45, 3729 (1980); E. J. Corey, J. 0. Albright, A. E. Barton, and S. Hashimoto, J . Am. Chem. SOC. 102, 1435 (1980); S. Batmangherlich, A. H. Davidson, and G. Procter, Tetrahedron Lett. 24, 2889 (1983); D. R. Williams, B. A. Barner, K. Nishitani, and J. G. Philip, J . Am. Chem. SOC. 104, 4708 (1982). P. M. Wovkulich,P. C. Tang, N. K . Chadha, A. D. Batcho, J. C. Barrish, and M. R. Uskokovich,J. Am. Chem. SOC.111, 2596 (1989). [28] E. g. Carbonate Extension: S. Julia and B. C. Furer, C. R. Acad. Sci. 257, 710 (1963). P. A. Bartlett, J. D. Meadows, E. G. Brown, A. Morimoto, and K. K. Jernstedt, J. Org. Chem. 47, 4013 (1982); A. Bongini, G. Cardillo, M. Orena, S. Sandri, and C. Tomasini, Tetrahedron 39, 3801 (1983); L. E. Overman, J. Am. Chem. SOC. 98,2901 (1976); H. W.Pads and B. Fraser-Reid, J. Org. Chem. 48, 1392 (1983). - Iodolactamization: M. J. Kurth and S. H. Bloom, J. Org. Chem. 54, 411 (1989) and cited lit. - Phosphonate Extension: P. A. Bartlett and K. K. Jernstedt, J . Am. Chem. SOC.99, 4829 (1977). Iodoetherification: R. A. Johnson, F. H. Lincoln, J. L. Thompson, E. G. Nidy, S. A. Miczak, and U.Axen, J. Am. Chem. SOC.99, 4184 (1977); S. D. Rychnousky and P. A. Bartlett, J . Am. Chem. SOC.103, 3963 (1981). M. Labelle and Y. Guindon, J . Am. Chem. SOC.111, 2204 (1989).F. Freeman and K. D. Robarge, J. Org. Chem. 54, 346 (1989) and cited lit.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

C. Organotransition Metals in Synthesis

Transition metal chemistry has aquired enormous importance in organic synthesis Over the last few years. As will be shown in this section, vinyl and aryl couplings and substitutions can be performed with high efficiency using palladium or chromium intermediates.

Literature: S. G. Dauies, Organotransition Metal Chemistry: Application to Organic Synthesis, Pergamon Press, Oxford, 1982. Transition Metals in Organic Chemistry, (R. Scheffold, Editor), Salle-Sauerlander, Frankfurt, 1983. R. F. Heck, Palladium Reagents in Organic Syntheses, Academic Press, N.Y., 1985.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

New Aromatic Substitution Methods

Agressive reagents and rather vigorous conditions are usually considered prerequisite to successful aromatic substitution reactions. The desire to synthesize more and more complicated target molecules calls for alternatives to classical methods - such as the electrophilic aromatic substitution (1)-+ (2) - alternatives in which regioselectivity plays a key role. Z

(3)

of the amide group, which in many cases dominates over the effect of other substituents, is attributed to the chelation indicated in formulas (5b) and (6b). NHR

NLiR

z

(4)

More than forty years ago, Gilman [la] and Wittig [l b] independently demonstrated that anisol is metallated in the 2-position when treated with butyllithium. This fundamental discovery opened the way to an important synthesis of 1,Zdisubstituted arenes. Two step introduction of an electrophile E+ by the sequence (1)-+ (3)-+ (4) is regiospecific regardless of the o/m/p-directing effect Z has in the “normal” electrophilic aromatic substitution (f) -+ (2). The ortho lithiation of carboxamides (5a) [2] and ( 6 4 [3] is an extraordinarily useful reaction with a broad scope. The ortho directing effect

The synthesis of the alkaloid ellipticine (If), accomplished by Snieckus and Watanabe [4a] (see Scheme l), illustrates that this method may be applied successfully to heteroaromatic systems. The alkoxide ( 9 4generated from amide (7) and indole aldehyde (8),is deprotonated in situ to give (9b) (“tandem metallation”). Cyclization occurs when the reaction mixture reaches room temperature. Subsequent oxidation by air produces the quinone (10). The further transformation to ellipticine (11)was accomplished by following standard procedures. More recently, Snieckus and coworkers have shown that the carbamate group also exhibits a strong ortho directing effect. When a solution of the intermediate (12b), generated by ortho lithiation of carbamate (124, is allowed to warm to room temperature, migration of the

168

Organotransition Metals in Synthesis

Scheme 1 Synthesis of ellipticine by Snieckus and Watanabe.

1) s-BuLilTMEDAIEtpO

R

0

CONEt,

(94

(7)

s-BuLi - 78%

R

R

CONE$

= CH20CH3

1) CH3Li 2) HI/CH30H

C",

3) SnClp

(1 1 ) Ellipticine

(10) R = CH20CH3: 26% R = CH, :76% R = CH,C,H, : 40%

amide group occurs, ultimately producing the phenol (124. The overall transformation may be considered as an anionic ortho Fries rearrangement [4b].

fJ0yNEt2

R

- 78%

(124 R = OCH,, CI, CH,

s R

N

E O

t

2

Ortho alkylation of aromatic aldehydes (13) can be accomplished in an original way by protecting the carbonyl group in situ with lithium dialkylamide to give (14a). Deprotonation and alkylation are followed by cleavage of the protective group in the course of acidic work up [S]. The intermediate (14b) is obviously very similar to an N,N,N',N'-tetramethylethylenediamine complex of an organolithium compound. Investigations by Gschwend [6a] and Meyers [6b] have demonstrated that the oxazolidine moiety also directs metallation to the ortho position. However, this effect is not as powerful as in the case of the carboxamide group [3a]. Nucleophilic reagents are able to attack carboaromatic compounds more readily if they contain in addition to the oxazolidine residue an appropriate leaving group such as

Aromatic Substitution Methods

169

CHO

c1 ( 13)

CHO

C1

80%

OCH3.Thus, alkylation of (15) may be accomplished by treatment with Grignard reagents in an addition-elimination sequence [7].

C02CIT,

An intramolecular variation of this method permits, for example, transformation of the oxazolines (16) into chromanes (174 and (17b)or into indanes (184 and (18b). When nicotinic acid derivatives (19) are treated with organomagnesium or organolithium compounds, dihydropyridines (20) result, after adding methyl chloroformate to quench the addition product. Chiral oxazolines, valuable in other contexts as well [8], may be used to introduce a nucleophilic reagent in a diastereoselective manner into the y-position. The predominance of isomer (204 over (20b) may result from complexation (21)prior to addition. As a consequence, the methyl group is transferred preferentially to the upper face (indicated by the letter a) of the pyridine ring [9].

( 2 0 U ) : R' = CH,, R2 = H (2Oh): R' = H, R2 = CH, ( 2 0 ~ )(2Ob) : = 94 : 6

1-71)

OCH,

I

N@x5 HCH3

Li....0,

+

(20a)

CH,

Dihydroquinoline (22),available in an analogous, diastereoselective way, enabled Meyers and Wettlaufer to successfully carry out an experiment [lo] proposed almost twenty years earlier by Berson and Brown [ll]: the transfer

170

Organotransition Metals in Synthesis

of chirality from a 4-aryldihyropyridine (e.g. (23)),containing an asymmetric carbon atom, to a biphenyl derivative with axial chirality. Indeed, aromatization of aldehyde (24, which leads to quinoline (24, occurs without racemization.

arene ( I ) [12]. Metallation of the chromium complex (26) occurs exclusively at the 6-position [13], whereas tetralol (27)itself is lithiated at C-8 [14].

n

I

COzCH,

122) d.e. 76%

1 a @yHO H i

2%.

8

C

The addition of carbanions to arene-complexes (25) initially results in cyclohexadienyl complexes (28), which can be transformed in situ into substituted arenes by oxidation. O

N'

H

(S)-123)

H

80%

(27)

1) CH,0S02F 2) NaBH., 3) Oxalic acid/Si02 4) KOH

H

( S ) - ( 2 4 )e.e. 80%

New possibilities for aromatic substitution are also opened by complexation with transition metals. Chromium arene tricarbonyl complexes (25) are most commonly employed for this purpose. The transformation of ( I )into (25) results - apart from the obvious steric consequences - in reduced electron density in the arene. As a consequence, the acidity of the ring protons is enhanced, and addition of nucleophiles is distinctly facilitated.

H, c A

a

4

H

84'%

d 1291

1) LiC(CI;%t-Bu

/

Cr(CO),H

H

COzt-Bu

312

99

(1)

C

:

1

92%

(25)

The directing effect of a substituent Z in complex (25) is significantly different from that in

Further typical reactions of the chromium complexes are the meta nucleophilic acylation of resorcinol dimethyl ether by the reagent (29)

g

Aromatic Substitution Methods

or the addition of ester enolate (30)to an indole chromium tricarbonyl complex [15). In a synthesis of the antibiotic frenolicin (33, described by Semmelhack and Zack [16], chromium complex ( 3 1 4 was chosen as the starting

material (see Scheme 2). The lithium compound (31b), generated by regioselective deprotonation, is transmetallated to (31c) and subsequently coupled with 2-hexenyl bromide to produce the alkene (32).Introduction of the side

Scheme 2 Synthesis of (f)$renolicin by Semmelhack.

Me3si6

4

P'

75 % 1) LiNR2 2) CISiMe3

3) BFQ

0

35%

OH 0

OH 0

Pr

,,,,,

+

0 (35)

( )-Frenolicine

Pr = n-C3H,

C02H

Pr

-@(j ,,,,I

0

97 %

171

=

C02H

0 71%

C0,Me

"'I

C0,Me

172

Organotransition Metals in Synthesis

chain at C-3 is accomplished by nucleophilic addition of the lithiated nitrile (33).Finally, oxidation with iodine liberates the arene (34).The further transformations leading to the quinone (35)are outlined in Scheme 2. Precursors of anthracyclinones, for example (37) and (41), are also available from chromium arene tricarbonyl complexes. Thus, Kundig and coworkers [171 have successfully transformed 1,Cdimethoxy naphthalene via the corresponding chromium complex into ketone (36). From this intermediate, anthracyclinone (37) can be synthesized by standard methods.

=

OCH,

QJ

OCH,

OCH3

H3C0

(38) (87%) 1) n-BuLipMEDA

q HjCO

7

2

w

OCH,

@LCriC0),

(391

4) HjO@ 5 ) HOQ

OCH,

91 %

\ I

OCH,

OCH, 62%

QCH,

0

(36) (65%)

0

OH

0

OH OH

0

WH

H3C0

0

OH OH

(41)

(37)

The vinylogous addition of a protected acetaldehyde cyanohydrin to a dihydronaphthalene chromium complex is a key step in the synthesis of 11-deoxydaunomycinone ( 4 4 , described by Uemura and coworkers [lS]. The intermediate (38) is lithiated in the position ortho to the methoxy group and subsequently added to amide (39) to produce the lactone (40), whose transformation into (41) was completed by known methods. Novel aromatic substitutions are characterized by both regioselectivity and mild reaction conditions. Future syntheses of complicated natural and biologically active aromatic prod-

bCH3

ucts will almost certainly make frequent use of these methods.

References [la] H. Gilman and R. L. Bebb, J. Am. Chem. SOC. 61, 109 (1939); b) G. Wittig and G. Fuhrmann, Ber. Dtsch. Chem. Ges. 73, 1197 (1940). W . H. Puterbaugh and C . R. Hauser, J. Org. Chem. 29,853 (1964). - Recent applications: J. E. Baldwin and K. W . Bair, Tetrahedron Lett. 1978, 2559; A. S. Kende and S. D. Boettiger, J. Org. Chem. 46,2799 (1981). a) P. Beak and R. A. Brown, J. Org. Chem. 47, 34 (1982); b) P. Beak and V. Snieckus, Acc. Chem. Res. 15, 306 (1982).

Aromatic Substitution Methods 141 a) M . Watanabe and V. Snieckus, J. Am. Chem. SOC.102, 1457 (1980);b) V.Snieckus, Bull. SOC. Chim. Fr. 1988, 67. PI D. L. Comins and J. D. Brown, J . Org. Chem. 49, 1078 (1984). _161_ a) H. W . Gschwend and Ali Hamdan, J. Org. Chem. 40, 2008 (1975);b) A. I. Meyers and E. D. Mihelich, J. Org. Chem. 40, 3158 (1975). [7] A. I. Meyers, M. Reuman and R. A. Gabel, J. Org. Chem. 46, 783 (1981). [8] A. I. Meyers in: Asymmetric Reactions and Processes in Chemistry. ACS Symp. Ser. 185, Washington 1982, p. 83. [9] A. I. Meyers, N. R. Natale, D. G. Wettlaufer, S. Rafii, and J. Clardy, Tetrahedron Lett. 1981, 5123. [lo] A. I. Meyers and D. G. Wettlaufer,J. Am. Chem. SOC.106, 1135 (1984);previous syntheses of chiral binaphthyl compounds by nucleophile aromatic substitution: A. I. Meyers and K. A. Lutomski, J. Am. Chem. SOC.104, 879 (1982);J. M. Wilson and D. J. Cram, J. Am. Chem. SOC.104, 881 (1982). [ll] J. A. Berson and E. J. Brown, J. Am. Chem. SOC. 77, 450 (1955).

173

[12] See: M. F. Sernmelhack, G. R. Clark, R. Farina, and M . Saeman, J. Am. Chem. SOC.101, 217 (1979); W. R. Jackson. I. D. Rae, M . G. Wong. M. F. Semmelhack, and J. N. Garcia, J . Chem. SOC.Chem. Commun. 1982, 1359. [13] M. Uemura, N. Nishikawa, K. Take, M. Ohnishi, K. Hirotsu, T. Higuchi, and Y.Hayashi, J. Org. Chem. 48,2349 (1983). [I41 M . Uemura, S. Tokuyama, and T. Sakan, Chem. Lett. 1975, 1195; and references cited therein for a discussion of the effects responsible for regioselectivity in the introduction of a second substituent. N. Meyer and D. Seebach, Chem. Ber. 113, 1304 (1980). [15] M. F. Sernmelhack, G. R. Clark, J. L. Garcia, J. J. Harrison, Y. Thebtaranonth, W. WuvJ and A. Yamashita, Tetrahedron 37, 3957 (1981). [I61 M. F. Semmelhack, and A. Zask, J. Am. Chem. SOC.105, 2034 (1983). [17] E. P. Kiindig, V.Desobry, and D. P. Simmons, J. Am. Chem. SOC.105, 6962 (1983). [18] M . Uemura, T. Minami, and Y. Hayashi, J . Chem. SOC.Chem. Commun. 1984, 1193.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Pal lad ium-Catalyzed A r ylat ion and Vinylation of Olefins

Although the following reaction (equation 1) is stoichiometrically correct, it does not proceed under “classical” conditions. However, after addition of a palladium catalyst, this transformation does occur and is known since 1974 as the Heck reaction [l, 21.

+H

R’-X

I

R

+

NEt3

FR +

R

HtEt3Xe

The process starts with an oxidative addition of RX, producing the organopalladium species (1) (Fig. 1). Complexation of the olefin, giving (2),is followed by C - C bond formation, which Pd(ll) 0

reduction

HNEt,X

(5)

&R R’

q

@

H-Pd-X

R’-Pd-X

I

3

d

R’

(4)

X

(I)

+

hR

R’ - Pd - X

1-

(3)

Fig. 1 Proposed rnechunism j o r

results in the new organopalladium intermediate (3).A subsequent p-elimination affords coupling product (4) and the hydrido palladium species (5). Base-induced reductive elimination of HX from (5) regenerates the Pd(0) species, thereby closing the catalytic circle. It should be noted that many other similar coupling reactions are known, but these usually involve transmetallation steps to give organopalladium intermediates (I) [2]. To avoid precipitation of metallic palladium, a stabilizing ligand is required. Triaryl phosphanes are usually employed for this purpose; occassionally such donor solvents as acetonitrile or dimethylsulfoxide suffice. The trialkylaminc plays a threefold role: besides trapping HX it also catalyzes the 0-elimination (3)-+ (4) (5) and finally reduces Pd(I1)-salts to the catalytically active Pd(0). This facile reduction makes it possible to start with the more convenient Pd(I1) compounds, which may also be converted in situ to Pd(0) by phosphanes or olefins. Apparently, the optimal recipe for the catalyst mixture must be established independently for each reaction, though the combination Pd(OAc)*,P(Arylh, and triethylamine often allows successful coupling at temperatures of 100- 140°C [l, 21. One prerequisite for the Heck reaction is the absence of p-elimination at the stage of palladium compound (I). Thus, the component R‘X should be devoid of sp3-hydrogen atoms at the p-position. This limitation restricts the Heck re-

the t1ci.h

reaction.

Arylation and Vinylation of Olefins Ph-Br

+

L

h

_ j Pd(ol NEt3 73%

Ph

Ph

syn -elimination

syn -addition

H

pk

$\''

Pd-Br

'I,,

1'

Ph

HH

rotation

H

Pd - Br

''1,

\\$"

Ph

Ph

H

Ph

Fig. 2 Stereochemistry qf the u r j l u t i o n .

Ph-Br

+

/co2H

action (equation 1) to compounds in which R' is aryl, heteroaryl, vinyl, or benzyl. Bromides, iodides, and, more recently, trifluoromethane sulfonates (triflates) have been found to be sufficiently reactive to serve as the component R'X

c31.

The stereochemistry of the Heck reaction is the following. Step (2) + (3) occurs as a synaddition, and step (3)+ (4) is a syn-elimination. As depicted in Fig. 2, these two steps dictate an overall inversion of the olefin geometry if a di-

75% pco2H

C02Me

I

H

b' NHZ

CN

+ =/

Ph-l

Ph-Br

+-/

(---Jyo2 Ph

mBr+ =;/

53%

I

H

53%

C4H9 42 % ( + 40% of other phenylhexenes)

' /_/CIHO

"9

+ &

Ph

+

+"

+ =/

40% ==(,

Ph

Ph

"

=;/Ph C02Me

2Ph-Br

"9 "9 +

2

60%

OBrJ357% M e O 2 C y y

175

M e O 2 C d P h

pPH

78%

Ph

(6)

Fig. 3 Arylation and heteroarylation of olefins [Conditions in most cases: 2% Pd(OAc)2, 5% P(Aryl),, triethylamine, ca. 120"C, several hours] [ j , 21.

176

Organotransition metals in Synthesis

The regiochemistry of the process is governed primarily by steric effects, with C -C coupling occurring at the less substituted carbon of the olefin. It is important to note that the Heck reaction works for almost all types of olefins. Although electron-deficient alkenes are particularly efficient, weakly electron-rich substrates can also be used. The reaction is compatible with a wide variety of functional groups, and it often does not even require rigorous exclusion of air and water. The essential points so far discussed are effectively demonstrated by the examples compiled in Fig. 3. Given the appropriate stoichiometry, even a double arylation is possible, as shown in the case of product (6). It is interesting to note that allylic alcohols prefer to undergo p-elimination in the direction of the hydroxy group, leading ultimately, after tautomerization of the intermediate enol, to saturated carbonyl compounds. Equation 2 illustrates this transformation, which involves an intramolecular redox process. An efficient protocol has recently been published for performing the Heck reac-

substituted alkene is used as starting material. When the corresponding (@-olefin is introduced into the reaction, a 79% yield of the $2diphenyl-1-propene is formed, preferentially with the E-configuration. The degree of observed stereoselectivityis strongly influenced by the reaction conditions, however, and in the case of vinyl halides selectivity is essentially lost due to isomerization via n-ally1palladium complexes. Monosubstituted alkenes usually give only coupling products with the E-configuration (eq. 1; Fig. 3) [l, 23.

-

(E,Z): (Z,Z) = 9:1

J 0

\

NH

/

Fig. 4 Vinylation of olefins [Conditions similar to those of Fig. 31.

Arylation and Vinylation of Olefins

tion under solid-liquid phase transfer conditions [4], a procedure that permits coupling at or near room temperature. Crucial here are the use of tetrabutylammonium chloride in DMF and potassium carbonate as base. These very mild conditions even permit effective coupling to acrolein as the acceptor olefin. Electron deficient olefins must be used as substrates for the vinylation reaction (Fig. 4) [l, 21. Otherwise, stable n-ally1 palladium complexes arc cormed, that are also responsible for the lack of stereoselectivity in such couplings. Dienes like (7) and (8)can be produced in the usual way, but in certain cases n-ally1palladium intermediates can be trapped by secondary amines to furnish allylic amines such as (9)and (10).However, this process is sometimes accompanied by side reactions, and regiochemistry can also be a problem. An impressive four-fold coupling has been explored for converting the [2,2]-paracyclophanediene tetrabromide (11) into the [2,2]paracyclophanehexaene (12) (eq. 3) [S]. This multi-step transformation is not restricted to styrene as olefinic component, and it makes available a variety of compounds of type (12) which can be easily cyclized to structurally very interesting [2,2]-paracyclophanes with benzannulation at both bridges. Ph

>

m;:

Br

Ph

(3)

Ph

(12)

Surprisingly, few applications of the Heck reaction have so far been reported in natural product synthesis. One recent example (eq. 4)

177

involves the coupling of bromoenone (13) with the silylated ally1 alcohol (14) to provide the prostaglandin B, methyl ester (15) in very high yield [6]. C02Me Br

+

Pd(OAc)2 PPh3 NEt3 100%, 24 h

92% .-.

OSiMe2t-Bu

(74) Q

C02Me

(4) (75)

OSiMe2t-Bu

Recently, the use of vinyl triflates in place of vinyl halides - a procedure independently developed by two groups in 1984 - has remarkably increased the flexibility and applicability of the Heck reaction [7, 81. Carbonyl compounds may now serve as precursors for the regioselective generation of enolates by standard methods (cf. Fig. 5). Thermodynamic control leads to vinyl triflate (16)and finally - after the coupling step - to diene (17). On the other hand, generation of the enolate under kinetic conditions, giving intermediate (18), eventually leads to formation of the isomeric diene (19). Both (17)and (19) are obtained without a shift of the double bond, making these systems regioselectively available from 2-methyl cyclohexanone. The two other examples in Fig. 5 serve to underscore the scope and efficiency of this reaction. As shown in equation 5, a Heck reaction of the tricyclic vinyl triflate (20) with a functionalized acrylate derivative gives the diene (21) [9]. Although the yield is rather low, this synthesis of compound (21), a precursor of lysergic acid, is more efficient than any known alternative. Vinyl triflates can also be coupled-with

178

Organotransition metals in Synthesis

& A6 & A6

C0,Me

/ : : : .*

1. BrMgN(iProp)P

b\

(7 7)

C0,Me

>

1.LDA

C02Me

84%

2. TfpNPh 91%

H

T G C02Me T--+

(1 6)

Tf = S02CF,

+

6

>

(19)

(78)

H- =-+OH 100%

Fig. 5 Coupling reaction of vinyl trijlates according to Stille [ 8 ] [Conditions: 2% Pd(PPh&Cl2, NEt,, DMF, 75 "C.

vinyl silanes to provide dienyl silanes in good yield [lo]. Interestingly, the use of the corresponding iodides instead of triflates requires addition of silver nitrate to avoid desilylation. A one-pot version of the Pd-catalyzed coupling of phenols to alkenes and alkynes has recently been published [l I], involving the corresponding phenyl fluoroalkanesulfonates as key intermediates.

tion of cyclic systems. Numerous heterocycles have been prepared in this way over the course of several years, just one example being illustrated in equation 6 [12]. The great effort spent in producing indole moieties [13] by palladium catalysis is justified by the manifold biological activities exhibited by these heterocycles (e.g. mitomycines).

C02Me

OTf MeOfl\rf\y/CO@

@ \

Pd(OAc)p, PPh3 Me NEtaDMF 60% 24 h 26%

OAPh (20)

>

@

Me l C o 2 t B U (5)

\

OAPh (21)

As is true for many other reaction types, intramolecular application of the Heck reaction opens elegant new possibilities for the construc-

Ac

Ac

Only very recently have several groups reported progress in the synthesis of carbocycles using intramolecular Heck reactions (Fig. 6). Thus, bromodiene (22)can be cross-coupled to furnish conjugated dienes (23) and (24), respectively [14]. With palladium the methylene cyclohexene derivative is formed with good selec-

VT%+ +Q+g E

E

E

E

(22)

E = C0,Et

3% Pd(0) 5% RhCI(PPh,),

E

E

(23)

(24) (74%) (63%)

10 : 1 1.5

YBr f X = CH X = N

(25)

(27)

84% 90%

(26) (28)

n Pd(PPh$,

C0,Me

CH3CN. 7OoC 86%

129)

Bu9 C 0 2 M e + Bu$.$COM ,e (30)

4 :1

(31)

77

(33)

50100oc

(34)

(35)

Fig. 6 Intramolecular Heck reactions leading to carbocycles [14, 15, 161.

tivity, whereas Wilkinson’s catalyst affords the bis-exo-methylene cyclopentane with a reasonable degree of preference. Regioselectivity in these reactions is hard to predict, and it is heavily dependent upon the origin of the catalyst and the metal used, as well as on the nature of other substituents present and the chain length.

Arylation and Vinylation of Olefins

179

With the fluorene-type starting materials (25) and (23,smooth conversion has been achieved to the spiro compounds (26) and (28), respectively. It is apparent that these dienes are ideal 4x-components in Diels-Alder reactions, giving polycyclic compounds in excellent yield [141. In 1988, Negishi [lS], Larock [16], and their coworkers made further important contributions to the synthesis of fused, bridged, and spirofused systems as shown by additional examples in Figure 6. One problem encountered when cyclic olefins are used as substrates is a lack of regioselectivity with respect to the position of the double bond, as illustrated for iododiene (29), which gives two regioisomeric spiro compounds (30)and (31)in a ratio of 4: 1. In certain cases this drawback can be overcome by the additive (and base) silver carbonate [17], which allows smooth preparation of the cisfused bicyclic compound (33). On the other hand, acceptor substituents also strongly influence the position of the double bonds. Thus, transformation (34)+ (35)is relevant to many other examples. It should be noted that most of the starting materials for these intramolecular Heck reactions are rather easily prepared by standard carbanion chemistry (e.g., enolate alkylations). For this reason we may expect many applications of this strategy to the assembly of polycyclic systems in the near future [l8].

References [l] R. F. Heck, Acc. Chem. Res. 12, 146 (1979). R. F. Heck, Org. React. 27, 345 (1982). [Z] For general reviews on palladium-induced reactions see: J. Tsuji, “Organic Synthesis with Palladium Compounds”, Springer, Berlin 1980. B. M . Trost and R. R. Verhoeven, “Organopalladium Compounds in Organic Synthesis and in Catalysis”; in Comprehensive Organometallic Chemistry (Ed. Stone/Wilkinson/Abel), Vol. 8, Chapt. 51, p. 799. R. F. Heck, “Palladium Reagents in Organic Synthesis”, Academic Press, New York 1985.

180

Organotransition metals in Synthesis

[3] Recently the activation of aryl chlorides by pretreatment with NiBrJNaI has been reported: J. J. Bozell and C. E. Vogt,J. Am. Chem. SOC. 110, 2655 (1988). [4] T. Jeffery, J. Chem. SOC.,Chem. Commun. 1984, 1287; Tetrahedron Lett. 26, 2667 (1985); Synthesis 1987, 70. [5] 0. Reiser, S. Reichow, and A. deMeijere, Angew. Chem. 99, 1285 (1987); Angew. Chem. Int. Ed. Engl. 26, 1277 (1987). [6] H. Naora, T. Ohnuki, and A. Nakamura, Bull. Chem. SOC.Jpn. 61,2859 (1988). [7] S. Cacchi, E. Morera, and G. Ortar, Tetrahedron Lett. 25, 2271 (1984); Synthesis 1986, 320. [8] W .J. Scott, M. R. Pena, K. Sward, S. J. Stoessel, and J. K. Stille, J. Org. Chem. 50, 2302 (1985). [9] S. Cacchi, P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett. 29, 3117 (1988). [lo] K. Karabelas and A. Hallberg, J. Org. Chem. 53, 4909 (1988). [ll] Q.-Y. Chen and Y. B. He, Synthesis 1988, 896.

[12] M . Mori, K. Chiba, and Y. Ban, Tetrahedron Lett. 1977, 1037. [13] For a recent review see: L.S. Hegedus, Angew. Chem. 100, 1147 (1988);Angew. Chem. Int. Ed. Engl. 27, 1113 (1988). Also see ref. 17. [I41 R. Grigg, P. Stevenson, and T. Worakun, Tetrahedron 44, 2033 (1988). [IS] E. Negishi, Y. Zhang, and B. O’Connor, Tetrahedron Lett. 29, 2915 (1988); B. OConnor, Y. Zhang, E. Negishi, E-T. Luo, and J.- W. Cheng. Tetrahedron Lett. 29, 3903 (1988); Y.Zhang, B. OConnor, and E. Negishi, J. Org. Chem. 53, 5888. [I61 R. C. Larock. H. Song, B. E. Baker, and W.H. Gong, Tetrahedron Lett. 29, 2919 (1988). [17] M . M. Abelman, T. Oh, and L.E. Overman, J . Org. Chem. 52,4130 (1987). [18] For similar reactions involving organotin compounds see: J. K. Stille, Angew. Chem. 98, 504 (1986); Angew. Chem. Int. Ed. Engl. 25, 508 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Regio- and Stereoselective Aryl Coupling

Bi- and polyaryl systems are fairly common in biologically active natural products, and they have recently become of increasing interest in connection with the development of such novel materials as organic semiconductors and liquid crystals. The “classical” techniques [l] for preparing biphenyls require rather drastic conditions and display limited regioselectivity, so they are rarely suitable for the synthesis of polyfunctional systems. Organo-transition-metallic reactions have opened many new possibilities in recent years, particularly with respect to catalytic processes [a]. The use of transition metals for aryl coupling is certainly not new. Consider, for example, the Ullmann coupling reaction of aryl halides with copper; but even this reaction has now been shown to occur under much milder conditions - room temperature instead of 200°C - when nickel complexes are used [3]. Palladium compounds seem to be even more versatile than nickel species. Thus, electrophilic Pd(I1) compounds such as Pd(OAc)* facilitate the direct coupling of arenes, presumably via ArPdOAc intermediates. ArH

+

ArPdAr

Pd(OAc),

HOAc

---+

+ Ar-A?

f

ArPdOAc

A d

---+

Pda

Nevertheless, this reaction has not yet been developed into a catalytic process, and yields are modest even in the intramolecular reaction (1) (2) ~ 4 1 .

-

On the other hand, the postulated intermediates ArPdX can be generated not only by insertion of Pd(I1) into an aromatic C - H bond, but also by transmetallation of arylmetal systems, and especially by oxidative addition of aryl halides and related electrophiles to Pd(0) complexes. ArH

ArM

insertion

x m e t e l l a t r o n

1’

ArPdX Oxidative addition

ArX

The latter method is of particular importance, since it offers the chance for a direct catalytic reaction. The Pd(0) catalyst is often prepared in situ, for example by the reduction of Pd(I1) salts with phosphanes or tertiary amines. This can be the source of a certain amount of confusion, because the reaction equation refers to the use of a Pd(I1) salt, obscuring the role of Pd(0) (see e.g. (3)-(4)).

182

Organotransition metah in Synthesis

A comparison of this example [5] with direct palladization reveals that coupling via oxidative addition followed by an insertion offers not only higher yields but also two other decisive and fundamental advantages: palladium is required only in catalytic amounts and the position of the halogen substituent guarantees regioselectivity with respect to at least one reactant. In the present intramolecular example the site of attack on the coupling partner is also determined, though this is of course not generally the case. Particularly with intermolecular reactions, mixtures of isomers must be anticipated. In such situations it is more appropriate to resort to an alternative coupling method cross-coupling of an electrophilic ArX species with an arylmetal Ar'M, where the ArPdX species resulting from oxidative addition is converted by transmetallation with Ar'M - rather than by insertion as above - into a diarylpalladium, which on reductive elimination releases the coupled product and regenerates Pd(0) to perpetuate the catalytic cycle.

-

Ar'M

Oxidative

ArX + PdC

ArPdAr'

addition

Reductive

ArPdnX

+ R'-M

0a +

SnMe3

I

(5)

(6)

cat. PdCiAPPh& THF,rell'ux 95%

'

fqMe I:

(7)

The tin compound (6) was here prepared by transmetallation of the corresponding lithiated heterocycle. It is worth noting that tin compounds can also be prepared by palladium-catalyzed stannylation of aryl halides, a reaction which tolerates a wide range of substituents ~131.

+ Pdo

Ar-Ar'

This reaction is a special case (R = Ar) of Kumada-Negishi cross-coupling between organometallic species and organic halides or related electrophiles, a method that has been developed into a powerful tool for C-C bond formation [6, 71. R-x

systems has been tested for suitability as the organometallic partner, including ones based on M = Li, Mg, Cu, Zn, Hg, Ti, B, Al, Zr, Sn, and T1. The best yields appear to result from metals with moderately electropositive character, but like Li and Mg compounds these are incompatible with many functional groups. Compounds of B [S], A1 [9], Zr [lo], or Sn [11] are superior from this point of view, and they also offer advantages with respect to chemo- and regioselectivity. Tin and boron compounds are especially useful, since simple, regiospecific routes are available for their preparation: by transmetallation, for example. This methodology also permits coupling of heteroaryls [lZ].

+

R-R'

+ MX

Kumada-Negishi cross-coupling

The best catalysts have been found to be Ni(0) and Pd(0) compounds. A wide variety of

One particularly attractive reaction scheme was used by Snieckus in a series of examples [15 - 171. Lithium derivatives prepared by ortho-transmetallation [I41 from suitable aromatic substrates were regioselectively transformed into boron derivatives and then utilized in cross coupling reactions. For example, starting from (10) first (12) and then (13) were prepared.

Regio- and Stereoselective Aryl Coupling

183

W 1. Mg

H1lC5-Br

2. ZnCI2

( 1 7)

Ar16,Ar6Ar2 l.A

2. A&,

cat.

A: 1. BuLi, TMSCI; 2. BBr,, CH,CI,, 3. 5%aq. HCI

- 78’;

Cat.: 3% Pd(PPh,),, 2 M aq. NaHCO,, toluene, reflux

The reaction sequence can also be carried out iteratively in an efficient way provided the coupling partner Ar’Br bears a further directing group. This method lends itself to the directed synthesis of polyphenylene systems of type (16), which could well prove significant in the context of conducting systems.

A new method for preparing the commercially interesting liquid crystal (19) has recently been described, one that again depends on cross-coupling [l 81. Here the requisite zinc or titanium compound (18)(M = Zn, Ti) is synthesized from (17) by transmetallation of the Grignard reagent, and high-yield coupling is possible even on a large scale to systems such as (19).

Coupling reactions should also be applicable to the stereocontrolled synthesis of axially chiral biaryl systems. Until recently, only a few examples were available, the most impressive of which was due to Meyers, and utilized the optically active oxazoline (20) [19].

An a-methoxy group activated by the oxazoline function is subject to nucleophilic aromatic substitution by means of a Grignard reagent, giving primarily the dinaphthyl derivative (21) with a diastereomeric excess (de) of 84%. Diastereoselection is even greater in a case involving an Ullmann reaction, in which an optically active binaphthol is used as auxiliary: (22)+(23). The stereoselection here is evidently a result of a well-ordered 14-membered ring transition state [20]. Intramolecular coupling has been elegantly employed recently by Bringmann to improve the yield and selectivity in a total synthesis of naphthylisoquinoline alkaloids [21]. It was shown that even in highly substituted cases such as (24) an intramolecular palladium-cata-

184

Organotransition metals in Synthesis

OZN7$T0*

,

J.

J.

0

lyzed coupling leads to the helical systems (25) and (26)in good yield, high regioselectivity,and astonishing stereoselectivity - in contrast to the experience with an intermolecular reaction lacking the fixation provided by the ester group. However, the two products interconvert at room temperature with a half-life tlI2< 1 min. On the other hand, if the lactone ring is opened with base one obtains the configurationally stable, axially chiral dinaphthyl systems (27) and (28),which can be separated and converted into naturally occurring naphthylisoquinoline systems. The method would be even more elegant if it were possible to control the atropisomer ratio CH30

H3CO

4.7

(25)

:

(26)

Bn H3CO

Bn

CH3

HJCO

(27)

CH3

(28)

by means of the ring opening reaction, for example by careful choice of the ring-opening reagent. This goal has in fact been achieved with the “axially-prochiral” (better: “axially-prostereogenic”) system (30), prepared from (29) by coupling. Reduction under the influence of the

0

0

(29)

(30)

* Red.

AIMe,,

Bn

Jme

95 oc 76%

RedAl:

1

CHJ

(31)

:

(32)

23

:

77

RedAl: 95

:

5

Regio- and Stereoselective Aryl Coupling

existing chiral centers yields preferentially, depending on the conditions, either one of the two atropisomers (31) or (32). These can in turn be converted into various types of natural alkaloids. Selective manipulation of a neighboring prostereogenic center - in example (30), the carbonyl group of the lactone ring - is thus one important way of achieving an atropisomerically selective biaryl synthesis, either, as in the present case, by internal asymmetric induction, or by means of an external chiral auxiliary. It is quite possible that this idea may be developed into a valuable general method for the stereocontrolled synthesis of axially chiral biaryl systems.

References c11 Review: M. Sainsbury, Tetrahedron 36, 3327 (1980). For a recent review of modern strategy see G. Bringmann, R. Walter, R. Weirich, Angew. Chem. 102, 1006 (1990); Angew. Chem., Int. Ed. Engl. 29, 977 (1990). c21 Cf. e.g.: L. S. Hegedus, Angew. Chem. 100,1147 (1988); Angew. Chem. Int. Ed. Engl. 27, 1113 (1988); J. P. Collman, L. S. Hegedus, J. R. Norton, and R. G. Finke: “Principles and Applications of Organotransition Metal Chemistry”. 2nd ed., University Science Books, Mill Valley, CA/USA 1987. c31 M. F. Semmelhack,P. Helquist, L. D. Jones, L. Keller, L. Mendelson, L. S. Ryono, J. G. Smith, and R. D. Stauffer. J. Am. Chem. SOC.103,6460 (1981). For a new example of the preparation of poly (2,5-pyridindiyl), see: T. Yamamoto. T. Ito, K. Sanechika, K. Kubota, and M. Hishinuma, Chem. Ind. 1988, 337. c41 R. B. Miller and T. Moock, Tetrahedron Lett. 1980, 3319.

185

[5] D. E. Ames and A. Opalko, Tetrahedron 40, 1919 (1984). [6] M. Kumada, Pure Appl. Chem. 52, 669 (1980); E. Negishi, Acc. Chem. Res. 15, 340 (1982). [7] Cf. e.g.: H.-U. ReiJig, Nachr. Chem. Tech. Lab. 34, 1066 (1986). [8] N. Miyaura, T. Yanagi. and A. Suzuki, Synth. Comm. 11, 513 (1981); N. Miyaura, T. Ishiyama, M. Ishikawa, and A. Suzuki, Tetrahedron Lett. 1986, 6369. [9] E. Negishi, T. Takahashi, S. Baba, D. E. van Horn, and 0.Kado, J. Am. Chem. SOC.109,2393 (1987);A. Ohta, M. Ohta, Y.Igarashi, K. Saeki, K. Yuasa, and T. Mori, Heterocycles 26, 2449 (1987). [lo] E. Negishi and T. Takahashi, Synthesis 1988, 1. ell] J. K. Stille, Angew. Chem. 98, 504 (1986); Angew. Chem. Int. Ed. Engl. 25, 508 (1986). [12] T. R. Bailey, Tetrahedron Lett. 1986, 4407. [I31 N. A. Bumagin, I. G. Bumagina, and I. P. Beletskaya, Dokl. Akad. Nauk. SSSR 274, 1103 (1984) and ref. cited. [14] Review: V. Snieckus,Lect. Heterocyclic Chem., J. Heterocycl. Chem. Suppl. 7, 95 (1984). M. J. Sharp, W. Cheng, and V. Snieckus, Tetrahedron Lett. 1987, 5093. T. Alves,A. B. de Oliveira, and V.Snieckus,Tetrahedron Lett. 1988, 2135. W. Cheng and V. Snieckus, Tetrahedron Lett. 1987, 5097. E. Poetsch, V. Meyer, and H . Bottcher, DBP 3736489.8 (28. 10. 1987); Merckpatent cit. in E. Poetsch, Kontakte 1988, 15. A. I. Meyers and K. A. Lutomski. J. Am. Chem. SOC.104, 879 (1982). S. Miyano, S. Handa, K. Shimizu, K. Takami, and H. Hashimoto, Bull. Chem. SOC.Jap. 57, 1943 (1 984). G. Bringmann, J. R. Jansen, and H.-P. Ring, Angew. Chem. 98, 917 (1986); Angew. Chem. Int. Ed. Engl. 25, 913 (1986); G. Bringmann, J. R. Jansen, A. Hille, and H. Reuscher, Symposia-inprint “66me Colloque International, consacre aux Plantes Mtdicinales et Substances d’Origine Naturelle”, Angers 1988, p. 181. ~~

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Benzannulat ion React ions Employing Fischer Carbene Complexes

Many valuable syntheses of functionalized sixmembered carbocycles and heterocycles entail the use of transition metals [I]. An example is the benzannulation reaction first reported by Dotz in 1975 [2], in which alkynes and a$unsaturated chromium carbene complexes (1) are cocyclized to give hydroquinone derivatives - initially as the chromium tricarbonyl complexes (2) - in a reaction that has received much attention. This unique process, also called the “Dotz” reaction, allows preparation of a

R‘ I

r ( C 0 ) 5 + Ill

I

R2

OCH, (1)

OH

-co_

(”. *;r(co)3 / R2 OCH,

(2)

Fig. 1 Plausible mechanism for the cocyclization of alkynes and a$-unsaturated chromium carbene complexes according to Dotz [3],

Fischer Carbene Complexes

variety of oxygenated benzene derivatives under mild conditions and from readily available starting materials. Many applications related to natural product synthesis have been published during the past decade [3]. Two mechanistic pathways are commonly discussed. The more plausible one is depicted in Figure 1: coordination of the alkyne to the metal and formation of the metallacyclobutene (4), followed by electrocyclic ring opening and insertion of carbon monoxide to give vinylketene complex (3). Electrocyclic ring closure to a cyclohexadienone complex, and subsequent proton transfer, completes the formation of the hydroquinone complex. There are arguments for and against this mechanism [4]. Several of the intermediates can be isolated or trapped in special cases, but the description of intermediate (4) as a metallacyclobutene has recently been questioned on the basis of quantum mechanical calculations [S].

181

The unsaturated unit in carbene complex (I) can be part of an acyclic or a cyclic olefin, or even of an aromatic or heteroaromatic ring. In addition, there are no severe restrictions with regard to the alkynes to be incorporated. However, electronically “neutral” alkynes usually give the highest yields and the fewest side products. One drawback is only moderate regioselectivity, especially with alkynes that have groups R‘ and R2 of similar size. All these features contribute to the high synthetic value of the Dotz reaction. Synthesis of vitamin K1(20)is illustrated in Figure 2. Two regioisomeric hydroquinone chromium tricarbony1 complexes (5) and (6) are formed from the phenyl carbene complex and an enyne [ 6 ] . In this example only one quinone derivative results after oxidation. Vitamin K1(20)can alternatively be generated by a two-step protocol, where the demetallation is performed first by use of CO under pressure.

Fig. 2 Synthesis of vitamin Kjcz0) according to Dotz et al. [6].

188

Organotransition metals in Synthesis

This permits recovery of chromium hexacarbonyl, which is required for the synthesis of the carbene complex (see below). The conversion of the hydroquinone derivatives into the vitamin follows published procedures. Other vitamins of the K- and E-series have been prepared in relatively few steps by a similar strategy [S]. To solve the problem of poor regioselectivity observed in intermolecular reactions with substituted aryl carbene complexes, Semmelhack and coworkers performed the Dotz reaction in an intramolecular fashion. Carbene complex incorporating a - OCHzCHzO- tether, undergoes cyclization under mild conditions in a regiospecific way. After oxidation, a naphthoquinone derivative was isolated in reasonable yield, and this served as an intermediate on the way to the antibiotic desoxyfrenolicine [q.

(a,

proaches to anthracyclinones, which are of great medical interest as cytostatic agents [S]. Also, furochromones [9], indole derivatives [lo], and mitomycin analogs [ I l l have been prepared employing heteroaryl carbene complexes as starting materials. The crucial cocyclization steps from typical examples are compiled in Figure 3. Addition of acetic anhydride/ triethylamine diminishes formation of side products in most cases. An essential prerequisite to all these interesting syntheses is the availability of the corresponding carbene complexes. Fortunately, the direct method of Fischer and Maasbol [12] is usually effective. Addition of organolithium compounds to chromium hexacarbonyl and reaction of the intermediate with a hard alkylating agent (usually Meerwein's salt) provides a relatively simple, yet highly flexible entry to Fischer carbene complexes. (CO),CrCO

(7) 9H

,o"

(CO),Cr=C,

1Desoxyfrenolicine

0

~ i "

R

,OC% (CO),C r=C, R

51% [from (7)]

&02H

. )

IWC,0eBF8

U

HO

+ R-Li

Ev

The advantages of the benzannulation reaction for selective construction of naphthoquinones have been exploited in several ap-

Complementary methods have been developed for the preparation of a,p-unsaturated carbene complexes. Aldol-type condensations are made possible by taking advantage of the very high acidity of protons c1 to the carbene carbon (pK, z 8). For ketones, the aldol addition step requires BF3-activation, while elimination to the unsaturated complex is assisted by pyridine [131. An efticient one-pot-procedure described by Aumann employs aromatic aldehydes with triethylamine/chlorotrimethylsilane as condensating agent [14]. Thus, a variety of a,p-unsaturated carbene complexes is easily available on

Fischer Carbene Complexes

OCH,

EtO-

=<

OR

RO

OCH,

R = Sit-BuMe,

EtO- E

OCH,

(c0).=,Cr3

OAc

EtO

10 h. THF. 65 OC

R

189

,-,

43 %

RO

OAc

e

A Ac20/NEt3

CH,-N,

8 h, THF, 65 % '

Et 0%

CH3

38%

32%

Fig. 3 Preparation of heterocyclic systems by benzannulation reactions [U - 111.

1 eq. pyridine

(CO)SCr -

5 670

2soc EtZO

the basis of flexible methods and simple starting materials.

Another interesting strategy for generating the desired double bond at the carbene center involves preparation of an alkynyl-substituted carbene complex followed by cycloaddition onto this unit. Such pericyclic reactions occur because the triple bond is activated by the extremely strong electron-withdrawing effect of the carbene-chromium moiety. Relatively complicated a$-unsaturated carbene complexes can be obtained by this route and then used as precursors for the Dotz reaction. Often, cycloaddition/benzannulation is performed as a one-pot-procedure, the overall reaction then being referred to as a tandem-process. Typical examples are collected in Figure 4, which demonstrate the potential of these straightforward reactions for the preparation of complex organic compounds [lS]. Interestingly, in the case of the pyrazole-substituted carbene complex it is the C = N bond that is engaged in the cocyclization. Other recent publications dealing with the synthesis of heteroannulated cyclohexadienone derivatives [161 and phosphaarenes [171 by re-

190

Organotransition metals in Synthesis OSiMeg

‘SiMe, 1) Ph- 5 - P h

1) Me3SiCHN2 25 ‘C

2) ce‘”

2) NH&I

%

H20

\

76%

CH3

A

Ph

Ph

THF. 45 OC

H- z - S i M e 3

(co)&r%

THF, 55 OC

r. t.

a2 %

;“.08cE 51%

SiMe,

37% (2 : 1)

Fig. 4 Cycloadditions to alkynyl carbene complexes ,followed by benzannulation according to Wulff et al. [15].

lated reactions of chromium carbene complexes can only be noted in passing. Finally, it is necessary to contest the assertion that all attempts to devise less toxic substitutes for the chromium complexes required in all the benzannulation reactions reported herein have so far failed.

References [l] Review: N . E. Schore, Chem. Rev. 88, 1081 (1 988). [2] K. H. Dotz, Angew. Chem. 87, 672 (1975); Angew. Chem. Int. Ed. Engl. 14, 644 (1975). [3] Reviews: K. H. Diitz, Angew. Chem. 96, 573 (1984); Angew. Chem. Int. Ed. Engl. 23, 587 (1984); K. H. Dotz, H. Fischer, P. Hofmann, F. R. Kreissl, U.Schubert, and K. Weiss,Transition Metal Carbene Complexes, Verlag Chemie, Weinheim 1984; K. H. Dotz in Organometallics in Organic Synthesis (A.de Meijere, and H. tom Dieck, Eds.), Springer Verlag, Berlin 1988. [4] See ref. [3] a n d K. S. Chan, G. A. Peterson, T. A. Brandvold, K. L. Faron, C. A. Challener, C. Hyldahl, and W.D. Wulff;J. Organomet. Chem.

334, 9 (1987); J. S. McCallum, F.-A. Kunng, S. R. Gilbertson, and W. D. Wulff Organometallics 7, 2346 (1988). [5] P. Hofmann, and M. Hammerle, Angew. Chem. 101,940 (1989); Angew. Chem. Int. Ed. Engl. 28,

908 (1989). [6] K. H. Diitz, 1.Pruskil, and J. Miihlemeier, Chem. Ber. 115, 1278 (1982). [7] M. F. Semmelhack, J. J. Bozell, L. Keller, T. Sato, E. J. Spiess, W.D. Wulff; and A. Zask, Tetrahedron 41, 5803 (1985). [8] For recent advances see: K. H. Dotz and M. Popall, Chem. Ber. 121,665 (1988): W .D. Wulff and Y.-C. Xu, J. Am. Chem. SOC. 110, 2312 (1988) and earlier work of these groups. [9] A. Yamashita, A. Toy, and T. A. Scahill, J. Org. Chem. 54, 3625 (1989). [lo] W.D. W u w ,J. S. McCallum, and F.-A. Kunng, J. Am. Chem. SOC.110, 7419 (1988). [ll] W. Flitsch, J. Lauterwein, and W. Micke, Tetrahedron Lett. 30, 1633 (1989). [12] E. 0. Fischer and A. Maasbd, Angew. Chem. 76, 645 (1964); Angew. Chem. Int. Ed. Engl. 3, 580 (1964). [I31 W.D. Wulffand S. R. Gilbertson, J. Am. Chem. SOC.107, 503 (1985). [14] R. Aumann and H. Heinen, Chem. Ber. 120, 357 (1987).

Fischer Carbene Complexes [lS] [4 + 21 Cycloadditions: W. D. Wulff; P.-C. Tang, K. S. Chan, J. S. McCallum, D. S. Yang, and S. R. Gilbertson, Tetrahedron 41, 5813 (1985). [3 + 21-Cycloadditions: K. S. Chan and W.D. WuVJ J. Am. Chem. SOC.108,5229 (1986). [ 2 + 21-Cycloadditions: K. L. Faron and W.D. Wulff;J. Am. Chem. SOC. ff0,8727 (1988).

191

[16] W. E. Bauta, W.D. Wuw, S. F. Pavkovic, and E. J. Zaluzec, J. OrgChem. 54, 3249 (1989). [17] K. H. Dotz, A. Tiriliomis, K. Harms, M . Regitz, and U.Annen, Angew. Chem. 100, 725 (1988); Angew. Chem. Int. Ed. Engl. 27, 713 (1988).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Methylenations with Tebbe-Grubbs Reagents

In 1978 Tebbe and coworkers [1] described a clean preparation of the unusual compound (I), formed by the reaction of trimethyl aluminum with titanocene dichloride. CpzTiClz + 2 A1Me3

toluene

p

CpzTi,

, /Me ,Al\ C1 Me 2

(I)

#

n

(1)

. P = o

+

C H 4 + AlMezCl

Complex ( I ) is of particular interest because of the role it plays in olefin metathesis and polymerization [2]. These reactions are very important from an industrial standpoint, and they undoubtedly involve the metallacyclobutanes (2). The existence of such intermediates has been confirmed by Grubbs, who has prepared a wide variety of heterocycles (2) by reaction of ( I ) with olefins in the presence of a Lewis base [3, 41. CpzTi

equilibrium with the metallacyclobutane (2). It should be noted here that complexes of the type Cp2Ti=CH2 * PMe3have been isolated and characterized by Bickelhaupt [S].

,Me A1 \ / \ c1 Me

The 16e-compound (3) is an example of a Schrock-type carbene complex of an early transition metal, in which the polarity of the metal carbon bond is the reverse of that observed in a Fischer carbene complex. One thus anticipates high nucleophdicity at carbon and electrophilicity at the metal.

,CHz\

+ Lewis base

R'

(1)

Lig,Met=CHz R3P=CH2

4

R' =;(R2

Whereas the Tebbe reagent ( I ) is extremely sensitive to oxygen and moisture, metallacyclobutanes (2) are fairly stable and can even be handled in air for brief periods. Compound ( I ) may be regarded as a Lewis acid/Lewis base adduct of the carbene complex (3),which also exists in

-

Lig,Met-cHz e Q

R3P-CH2

The striking similarity to Wittig reagents is immediately apparent; indeed, (3) is applicable to carbonyl olefination reactions. The possibility of using (f) for this purpose was actually suggested by Tebbe [I], but it was not until two years later that the potential of this reaction with respect to organic synthesis was exploited by Grubbs and Evans [6]. It was discovered that esters and lac-

Tebbe-Grubbs Reagents

tones can be converted very smoothly into enol ethers by reaction with (1) (Fig. l), a transformation that is not feasible with phosphorous ylides. Methylenation of both carbonyl functions in (5)provides triene (6) in high yield. Compounds (4) and (6) are of some interest since they are potential starting materials for the Claisen rearrangement and for an intramolecular Diels-Alder reaction, respectively. Carbene complex (3),generated from either (1) or (2),is very well suited for olefination of carbony1 compounds that are prone to enolization

[7]. Ireland’s group provided an impressive example in a synthesis of the lasalocid-A building block (8)from (7) and (I). In contrast to the analogous Wittig reaction, no racemization was observed. The metallacyclobutanes (2) have been found to be clearly superior in cases involving starting materials and/or products that are sensitive to Lewis acids. Thus, the ketene acetal (10) is obtained in reasonable yield from the cyclic carbonate (9) [4]. However, if the reactive carbonyl group is adjacent to a quarternary carbon atom, (3)acts as a base, forming a titanium enolate [7]. Two examples illustrate these alternative modes of reaction, which are apparently distinguished by steric factors:

0

Fig. 1 Methylenation of esters, lactones, ketones, and carbonates with (1) or ( 2 ) .

193

H3 c, o.TiCpz

Titanium enolates of this type are relatively unreactive, and they fail to undergo aldol additions. However, such transformations can be effected with the enolates (11) generated from (3) and acid chlorides [S]. The metal center in this case displays higher Lewis-acidity, as shown by addition to benzaldehyde yielding the adduct (12), which may be regarded as a combination of the synthons (14,(19,and (16).Carbene complex (3) thus serves as the equivalent of the dianion (15). Protonation of titanium enolate (11) to give methyl ketones (13) is of less preparative interest since simpler alternatives are available. All reactions involving (3)and a carbonyl compound presumably involve the oxametallacyclobutane (17) (cf. the Wittig reaction). The oxophilicity of the early transition metals provides the force in this cYcloaddition-O r h a d Y , an “orthogonal” cycloreversion to olefin (18)and

194

Organotransition metals in Synthesis

.c1 PR;

/

(20)

(111

+ PhCHO

R = n-Bu, s-Bu, t - B U ,

]+He

Ru

ph

(12)

a

69% for

R

0

CH,Ph

RKCH~

I 13)

0

OH

R" (141

8 o @'Ph ,C, H H (15)

=

76-97%

(21)

-0

new four-membered ring system (22)can be prepared, and this adds to carbonyl compounds to give the substituted allene (24). Apparently, intermediate (22) decomposes preferentially to the titanium vinylidene complex (23).Typical examples of this one-pot preparation of highly substituted allenes are collected in Fig. 2.

(16)

polyoxotitanocene would be expected to take place, but if X is a good leaving group it migrates to the metal and generates enolate (19). Cp2Ti=CH2

(3) i

R X

%Ti,

7 04R (191

=

alkyl

aryl, OR, NR2

(CpzTiO), +

R

X

One unfortunate limitation of this method is that only the methylenation reagent (3)is available. No route has yet been found for preparing and utilizing derivatives of (3)that would permit, for instance, an ethylenation. Only the opposite extreme is practical - transfer of a sterically very demanding alkylidene substituent - accomplished with the aid of the related zirconium complex (20)[9] or the Schrock compound (21) [lo]. On the other hand, a remarkable allene synthesis has been achieved with (3) [ll]. Starting with metallacyclobutane (2) and an allene, the

Other useful synthetic applications of titanacyclobutanes - e.g. carbonylation reactions are so far rare [4]. A reductive coupling of nitriles providing, after hydrolysis, pketoenamines has recently been described [l2], and Grubbs and Meinhart have reported the reaction of titanacyclobutenes with heteroatom multiple bonds [13]. Nevertheless,several interesting examples of this methylenation in natural product syntheses were reported shortly after the method was discovered. The Tebbe reagent (1)can apparently be applied to relatively complex molecules with great success [14- 181. Exceptional elegance and eficiency characterize the reaction sequence developed by Grubbs and Stille [18] in their synthesis of the tricyclic terpene A(9,'2)-capnellene(31).A triene is first generated from cyclopentadiene magnesium chloride

Tebbe-Grubbs Reagents Starting material

Product allene

Carbonyl compound

II

A

II

i

195

Ph

Ph

Ph

Ph

58%

75%

Ph

KPh i

a

Ph

YPh

B

72%

Fig. 2 One-pot preparation of substituted allenes with ( 2 ) .

2k

TosO

DMAP = M e 2 Nc N 25 OC

Fig. 3 Key steps in the Grubbs and Stille synthesis of A~y~'2J-capnellene.

and a functionalized alkylating agent, and this triene undergoes an intramolecular Diels-Alder reaction to yield the tricyclic compound (25)

(Fig. 3). Thus, all four stereogenic centers in the ultimate target (31)are correctly established in a single step! The key reaction of (25) with (f) in

196

Organotransition metals in Synthesis

the presence of 4-dimethylaminopyridine results in the relatively stable metallacyclobutane (26). Only upon heating to 90°C does this intermediate cleave in the opposite direction to give the new carbene complex (23, which is trapped intramolecularly by the ester group forming the strained cyclobutene en01 ether (28) in quantitative yield!

References

[l] F. N. Tebbe, G. W. Parshall, and G. S. Reddy. J. Am. Chem. Soc. 100, 3611 (1978). [2] See L. R. Gilliom and R. H. Grubbs, J. Am. Chem. Soc. 108, 733 (1986) and references cited therein. [3] T. R. Howard, J. B. Lee, and R. H. Grubbs, J. Am. Chem. SOC.102,6876 (1980). [4] Short review: R. H. Grubbs et a/., Pure Appl. Chem. 55, 1733 (1983). [5] B. J. J. van de Heisteeg, G. Schat, 0.S. Akkerman, and F. Bickelhaupt, J. Organomet. Chem. 310, 1.EtOiCCHNz C25 (1986). BF1. O E t l [6] S. H. Pine, R. Zahler, D. A. Evans, and R. H. 2. NaCl i H Grubbs, J. Am. Chem. Soc. 102, 3270 (1980). 150°C i‘H3 [7] L. Clawson, S. L. Buchwald, and R. H. Grubbs, 7 3% Tetrahedron Lett. 25, 5733 (1984). [8] J. R. Stille and R. H. Grubbs, J. Am. Chem. SOC. 105, 1664 (1983). 93% DMAP [9] S. M. Clft and J. Schwartz, J. Am. Chem. SOC. f‘) 106, 8300 (1984). [lo] R. R. Schrock, Acc. Chem. Res. 12,98 (1979). [11] S. L. Buchwald and R. H. Grubbs, J. Am. Chem. SOC.105, 5490 (1983); see also T. Yoshida and E. Negishi, J. Am. Chem. SOC.103, 1276 (1981). [12] K. M. Doxsee and J. B. Farahi, J. Am. Chem. SOC. 110, 7239 (1988). J. D. Meinhart and R. H. Grubbs, Bull. Chem. SOC. [13] Standard methods were used to convert the Jpn. 61, 171 (1988). apparently superfluous - but for this approach [14] C. S. Wilcox, G. W. Long, and H. Suh, Tetraheessential - vinyl substituent into a methyl group, dron Lett. 25, 395 (1984). leading finally to the cyclobutane (29). Regiose- [lS] W . A. Kinney, M. J. Coghlan, and L. A. Paquette, J. Am. Chem. SOC.107, 7352 (1985). lective ring enlargement with ethyl diazoacetate [16] J. W.S. Stevenson and T. A. Bryson, Chem. Lett. in the presence of BF3 and decarboxylation af1984, 5. fords the immediate precursor to A(9,’2)-capnel- [IA R. E. Ireland, S. Thaisrivongs, and P. H. Dussault, lene, which is in turn obtained - as might be J. Am. Chem. Soc. 1f0,5768 (1988). expected from these authors - by a methylen- [18] J. R. Stille and R. H. Grubbs, J. Am. Chem. SOC. 108, 855 (1986). ation with the Tebbe reagent (1). [19] L. F. Cannizo and R. H. Grubbs, J. Org. Chem. A procedure for the in situ preparation [19] of 50, 2386 (1985). ( I ) is certain to further enhance the attractiveness [20] J. J. Eisch and A. Piotrowski, Tetrahedron Lett. 24, 2043 (1983). of this and other “exotic” metallorganic reagents [2l] K. Utimoto et al., J. Org. Chem. 52, 4410 (1987); in the eyes of organic chemists. A more convenTetrahedron Lett. 30,211 (1989) and earlier work ient approach to a similar reagent starting from of this group. titanocene &chloride, CH212,and zinc dust has [22] T. Kauffmann et al., Angew. Chem. 98, 927, 928 been reported by Eisch [20], who also describes (1986);Angew. Chem., Int. Ed. Engl. 25,909,910 (1986) and earlier work of this group. various reactions of this system. Other variants in which early transition metals play a role in [23] M. Mortimore and P. KociPnski, Tetrahedron Lett. 29, 3357 (1988).

-

I

methylenation may also involve carbene complexes of the type L,Met=CH2 [21-231.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

D. Electrochemistry in Selective Synthesis

Review: L. Eberson, in “Modern Synthetic Methods”, Vol. 2, p. 1. R. Scheffold, Editor, Salle-Sauerlander, 1980.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Anodic Oxidat ion and Amidoalkylat ion

Generally speaking, electrochemical procedures play a negligible role in the design and execution of multistep syntheses. This is astonishing, because a number of reactions, some of them quite unusual, can be conducted easily and efficiently with the aid of “electric current” [l, 21. Moreover, the equipment required is far less extensive than often imagined. The precise instructions for anodic oxidation of amides published by Shono et al. in Organic Syntheses provide a good example, offering a simple route to gram quantities of versatile intermediates [3]. The facile anodic oxidation of amines has long been known. Stepwise liberation of two electrons and one proton leads to the iminium ions (f), which react with available nucleophiles to give compounds (2). Hemi-aminals are formed in aqueous medium, and these decompose to form aldehydes (Figure 1). Stronger nucleophiles may also intervene in aqueous solution, as demonstrated by the formation of aminonitriles from N-methyl pyrrolidine [l].

Fig. 1 Mechanism of the anodic oxidation of amines.

cp?

&H3

-2e

p c .

59%

c’ H3

+

-4: 1

L

K

Unfortunately, poor regioselectivity limits the utility of this approach to an otherwise interesting set of intermediates. However, a versatile synthesis of tetrahydroquinolines (4) from aniline derivatives relies on the electrochemical preparation of 0,N-acetals such as (3).The latter forms an iminium ion with the Lewis acid titanium tetrachloride, giving good yields of the target molecules (4) upon cyclization with electron-rich olefins [a]. Amides, carbamates, sulfonamides, and amino phosphates also readily undergo anodic oxidation [l]. Due to the electron withdrawing effect of their nitrogen substituents, the corresponding products are significantly more stable and hence easier to isolate and handle. Figure 2 offers a series of characteristic examples, which also reflect the regioselectivity of this amethoxylation.

200

Electrochemistry in Selective Synthesis

The order of reactivity is always CH3 > CH2 > CH. Clear regiochemical discrimination, high yields, and stable products are the features that make this reaction valuable. The resulting compounds can be regarded as masked w-oxocarboxylate derivatives, which is why treatment with acid (e.g., in the presence of methanol) provides the ring-opened acetal (8).

c H3

R

=

alkyl, aryl, OR’, NR2

Similarly, the sulfonamide (7) derived from L-proline reacts with phenylhydrazine to give hydrazone (9)which undergoes cyclization in a Fischer reaction to form indole (f0).This example clearly illustrates the advantage of the sulfonamide group, as L-tryptophane (If) is liberated without significant racemization through electrochemical reduction and subsequent saponification [4]. PhNHNH,

___, ZnC1,. A

C~LOQCOKHJ

ah,. moZCH I

SOzAr

I’

HN I

SO~AI’

H

IYI

I

CO,H

W

H

Z

‘’I’

H

Fig. 2 Anodic oxidation of amides, carbamates, sulfonamides, and aminophosphates (in methanol and employing Et4N’ArSOc as electrolyte).

Compounds of type (12) become particularly valuable when the alkoxy group is replaced by other nucleophiles. This process is called amidoalkylation in the case of C-nucleophiles [S].

Anodic Oxidation and Amidoalkylation

0 Nu II - I R’-C-N-CH-R3 I R2

+ Nuo

iCH300

201

\

- He, - C O P

+ CH30H

0 II

route C

R’-C,@

R”

N = CHR3

0 CO,H II - I R’ - C - N-CH- R3 I

R2

(7 3)

Fig. 3 Precursors of acyl iminium ions for amidoalkyiation.

Such reactions have been known for a long time, and they involve the very reactive acyl iminium ions (13) (Figure 3). Using classical methods, (12) and (13) can be obtained by the condensation of amides with

aldehydes and alcohols (route B), but this approach is subject to limitations with respect to the aldehyde component. For this reason the Shono process (route A) is an attractive alternative. Cyclic compounds in particular are of-

Fig. 4 Transformations starting with a-methoxy substituted carbamate (6).

202

Electrochemistry in Selective Synthesis

ten less readily available by other synthetic means [ 6 ] . C-C connections to 0,N-acetals are even feasible with arenes, either in an intermolecular or intramolecular fashion [l].

Q 9

OCH~ c HO

0 ;.;.a I$ C6H5

CHO

Taking the well-examined case of carbamate (6) as an example, Figure 4 illustrates the broad

range of substituted and functionalized pyrrolidine derivatives available from a single key intermediate. Each time, a Lewis acid is used to generate an acyl iminium ion, and this reacts with a nucleophile. Furan, silyl enol ethers, enol acetates, allyl silanes, Grignard reagents, and organolithium compounds (the latter in the presence of BF3),isonitriles, and phosphites are all potential reactants. CH acids such as acetoacetate or malonate derivatives have also been used [l]. Most of the products afford opportunities for further transformations; the unexploited potential - in particular with respect to alkaloid synthesis - is readily apparent.

Fig. 5 [3

An extension of the strategy permits the alkylation of substances such as (5) with u-methoxy alkyl halides, yielding the up’-dimethoxylated amide (14) (Figure 5). Compounds of this type react with allyl silane in the presence of titanium tetrachloride, where two-fold amido alkylation provides indolizidine derivative (15). “Normal” allylation is here followed by cationic olefin cyclization. Removal of chlorine with Raney nickel reveals that this [3 + 31anellation is stereoselective. Addition of n-butyllithium yields (16) - a pheromone specific for the pharaonic ant [7]. As is demonstrated by example (13,up’-dimethoxy substituted piperidines can be prepared by a sequence of two electrochemical ox-

+ 3]-anellation according to Shono (71.

0 -4e

CHeOH

I

COzCH3

71%

CH30QOCH3 COyCH3

(171

203

Anodic Oxidation and Amidoalkylation

idations [S]. Subsequent reaction with allyl silane yields the bridged bicyclic compound (18). Alternatively, heating with ammonium chloride eliminates methanol from (17) to give the 1,Cdihydropyridine (19) [l]. Generally speaking, a-methoxylated amides or carbamates lend themselves to enamide synthesis simply by methanol elimination. Thus, an additional position of these nitrogen heterocycles is accessible for functionalization, as demonstrated by the Vilsmeier formylation and hydroboration of (20).

(20) 66%

I

C02CH3

0-5

oc

QCHO I

tion of allyl silane to (22) yields the a-substituted P-acetoxypiperidine (25), the stereochemistry of which has not been reported. A supplementary method for preparing N,Oacetals (12) by electrochemical means starts with N-protected a-amino acids and involves oxidative decarboxylation (Figure 3, route C). This approach has been used to prepare alkaloids [lo] and even to modify certain oligopeptides [ll]. If the a-amino acid contains a second stereogenic center, as is the case with the L-threonine derivative (26), nucleophilic substitution of the N,O-acetal (27) leads to a protected amino alcohol (28) with moderate to good diastereoselectivity [12, 111.

t-BuMe,SiO

t-Bu Me,Si 0

(26)

I

(27)

E = C0,Me

I

Nucleophile (Lewis acid)

C02CH3

Nevertheless, electrochemical activation of the P-position is also an alternative, at least as far as the piperidine derivative (21) is concerned. Thus, suitable electrolysis conditions provide (22), with the enamide as a probable intermediate [9]. Aminal (23) is also formed during workup, which together with (22) can be transformed into the tetrahydropyridine (24). Addi-

A

Nucleophiles: CH,MgCI, -SiMe3/TiCI, P(OR),/TiCI, etc.

H

E’NXNU

t-BuMe,SiO

(24

These transformations have been presented in order to provide some insight into the immense synthetic potential of the a-methoxylated amides and carbamates that are conveniently accessible from amines or amino acids. It is easy to conceive of a vast number of further applications in the synthesis of heterocycles [13] or other biologically active compounds t-111.

References [I] T. Shono, Tetrahedron 40, 811 (1984) and cited lit. [2] T. Shono: “ElectroorganicChemistry as a New Tool in Organic Synthesis”, Springer, Heidelberg 1984. - T.Shono, Top. Curr. Chem. 148, 131 (1988).

204

Electrochemistry in Selective Synthesis

[3] T. Shono, Y. Matsumura, and K. Tsubata, Org. Synth. 63, 206 (1985). [4] T. Shono, Y.Matsumura, K. Tsubata, K. Ushida, T. Kanatawa, and K. Tsuda, J. Org. Chem. 49, 3711 (1984). [S] Review: E. H . Zaugg, Synthesis 1984, 85, 181. [6] For a different approach to the preparation of precursors for cyclic N-acyl iminium ions see: W.N. Speckamp and H. Hiemstra, Tetrahedron 41, 4367 (1985) and cited lit. [7] T. Shono, Y.Matsumura, K. Ushida, and H. Kobayashi, J. Org. Chem. 50, 3243 (1985). [8] T. Shono, Y. Matsumura, K. Tsubata, Y. Sugihara, S . Yamane, and T. Aoki, J. Am. Chem. SOC.104, 6657 (1982). [9] T. Shono, Y. Matsurnura, 0. Onomura, T. Kanazawa, and M . Habuka, Chem. Lett. 1984, 1101. - T.Shono, Y.Matsumura, 0. Onomura, M. Okagi, and T. Kanazawa, J. Org. Chem. 52, 536 (1987).

[lo] T. Shono, Y. Matsumura, K. Tsubata, and K. Uchida, J. Org. Chem. 51, 2590 (1986). - T. Shono, Y. Matsumura. 0. Onomura, and M. Sato, J. Org. Chem. 53, 4118 (1988). [I I] D. Seebach, R. Charczuk, C. Gerber, P. Renaud, H. Berner, and H . Schneider, Helv. Chim. Acta 72, 401 (1989). [I21 P. Renaud and D. Seebach, Angew. Chem. 98, 836 (1986); Angew. Chem. Int. Ed. Engl. 25,843 (1986). [13] Synthesis of f3-lactams: T. Shono, K. Tsubata, and N. Okinaga, J. Org. Chem. 49, 1056 (1984). - Enantioselective synthesis of the carbapenem ring system: s. Asadi, M. Kato, K. Asai, T. Ineyama, S. Nishi, K. Izawa, and T. Shono, J. Chem. SOC.,Chem. Commun. 1989, 486.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

E. Bio-oriented Methodology

The growing emphasis on biochemistry has caused many organic chemists to become aware of the potential for enzymatic reactions in classical organic transformations as carbonyl reduction or ester hydrolysis. These reactions can be performed with extreme stereoselectivity in suitable cases by employing microorganisms or isolated enzymes. A different impetus has come from increasing knowledge about biosynthesis, which has inspired many chemists to model their synthetic routes after biogenetic

patterns. This is an attempt to imitate nature although the reagents and conditions employed are rarely physiological. Such strategies have been termed “biomimetic”.

Literature: J. B. Jones, Enzymes in Organic Synthesis, Tetrahedron 42, 3351 (1986); Biosynthesis: Comprehensive Organic Chemistry, Editors D.H . R. Barton and W. D. Ollis, Pergamon Press, Oxford, 1979, VOl. 5.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Enzymes in Organic Synthesis, I

Enzymatic processes have a longstanding tradition in organic synthesis [2]. Two basic approaches must be distinguished the first, called “fermentation”, employs microorganisms in a fermentation broth containing glucose, amines, mercaptans, and nutrient salts [I]. The reaction product is formed in a complex sequence by the microorganisms; it must then be isolated from a highly dilute aqueous solution, either by crystallization or by extraction with an organic solvent and subsequent chromatography. Examples of this methodology are the large-scale production of citric, lactic or malic acids, penicillin, cephalosporins, tetracyclines, vitamin BIZ,macrolides, and so on. The second option is “microbial transformation” [2], which means that a defined organic substrate, generally an advanced synthetic intermediate, is subjected to an enzymatically induced transformation under physiological conditions. The enzyme can be administered via the living microorganism, in analogy to fermentation, or in isolated form, preferably immobilized on a solid support. The enzyme acts as a catalyst, so that there is no fundamental difference between this procedure and a “normal” step in an organic synthesis. The advantage of enzyme catalysis lies in the mild conditions and the high chemo-, regioand stereoselectivity, which, in general, cannot be achieved by purely chemical means. Disadvantages, on the other hand, include high dilution, laborious workup, and a rather severe limitation with respect to applicable substrates

and reaction types. Hydroxylations, carbonyl and double bond hydrogenations, and hydrolyses of ester, amides, and glycosides can routinely be performed enzymatically, and then only if the substrate is accepted by the enzyme. This article highlights certain microbial transformations that have already found their way into industrial practice. Some have become indispensable operations in the large-scale manufacture of important drugs.

Steroids One of the milestones in the synthesis of clinically important corticoids was the microbial hydroxylation of progesterone (I) and Reichstein’s (S)-17-acetate(3).Remarkably, both 1 laand 11p-hydroxylations are possible, depending upon the microorganism. Meanwhile, the technical know-how associated with steroid hydroxylations has been developed to such a degree that any position in the steroid nucleus, (with the exception of C-3, 4, 5 and 8) can be hydroxylated with high regio- and stereocontrol. Thus, the aldosterone antagonist spirorenone (7) can be prepared by dihydroxylation of androstenone (9,followed by ten standard chemical transformations [5]. The anti-phlogistic and anti-rheumatic effect of corticoids is enhanced by introduction of a 1,Zdouble bond, a transformation achieved enzymatically for a

208

Bio-oriented Methodology

broad spectrum of substrates, as illustrated by the conversion of (8) into (9) [6].

r;ii3ij e Colletorrichum

HO

(5)

dH

Progesterone (I)

10 chem.

++ steps

HO

(6)

*chemically

9

Spirorenone (7)

...OH

..-OH

0 Cortisone d C (3) H

Z

O

H

( 8 ) (X-Y = CHz-CHz) HzoH

c@

0

...OAC

CLmrklrill

hmtu

HzoH

Reichstein-(S)-l7-acetate ( 3 )

(9) (X-Y

CH=CH)

a key intermediate for the preparation of many important steroid hormones. Quite recently, however, a much superior route has been developed starting with microbial degradation of

LiPCHzoH ..*OAC

HO

0

(4) ( 118)

Hydrocortisone-17-acetate

With very few exceptions, steroid drugs are prepared by structural modification of naturally occurring derivatives. For many years, Marker's degradation of diosgenine was used worldwide to obtain 16-dehydropregnenolone,

Mymban.

------+

Enzymes in Organic Synthesis I

209

Scheme 1 Total synthesis of estrone (20) and D-norgestrel (22) via a microbially modiJied Torgov procedure

r91

(6 MgCl Me0

Me0

(14)

(13)

(19a)

++

Estrone methyl e t h e r (20)

Me0

Me-C-Et

~~0I

,

0

the side-chain in sitosterol [lo] or stigmasterol [7], both available from soybeans or tall oil at very low prices. Androstendione (AD, 11) and androstadiendione (ADD, 12) are produced in multi-ton quantities as intermediates for the large-scale synthesis of a variety of semisynthetic steroid derivatives.

2)

MeOH/HCI

’

(22) D-Norgestrel

In gestagens like D-norgestrel (22) the replacement of the “natural” 18-methyl group by the “unnatural” ethyl unit has been found to give a significant increase in physiological activity. Thus, a multistep Torgov route is justified for the total synthesis of (22) (Scheme 1). Again, the key step, namely enantiotopos-selec-

210

Bio-oriented Methodology

tive reduction of the prochiral dione (15) to the enantiomerically pure keto-alcohol (16), requires microbial assistance. The ensuing acidcatalyzed aldol condensation leads specifically to (13,which is then converted into the estrone derivatives (19a/b) by purely chemical operations [9]. Estrone methyl ether (20)is available, in principle, from (19),as are 19-norsteroids via Birch reduction, but the method has so far only been used for the production of unnatural 18ethyl derivatives such as (22). Although a very efficient “chemical” asymmetric total synthesis of estrone has been developed utilizing a proline-catalyzed Robinson

annulation ((23)+ (24) + (25)) [lo], the microbial version of the Torgov procedure appears to be superior.

0

(23)

-3 0

OH

+(19)

Scheme 2 PGE, (31) synthesis (Miyano (121, Sih [13], and Kurozumi (141). 0

HO,C&(CH,0),

+

- C0,Me

J )H -Ph

0

-

c;:;: c-

CH2fCH,),-CO,H OHO L 0 P

+

h

THPO

0

THPO (28)

HO

(27)

(26)

xz2

(30)

Ph

I

bT6-co2H Homer

&6-c02H

COZH

RO

I

OH (30) (R = THP) (-)-(37) (R = H; PGE,)

Enzymes in Organic Synthesis I

Prostaglandins

21 1

Me

All clinically important prostaglandins *are made by “chemical” total synthesis. Microbial transformations so far play only a minor role. A i B ( C I B j D For instance, Miyano, in his “cyclization approach” [12], used microorganisms for the optical resolution of the styryl intermediate (27), Me whose (R)-enantiomer was then converted into (-)-PGE, (31) via (28), (29),and (30) (Scheme 2). An alternative microbial route was found by Me Me Sih [13], who accomplished the microbial re(2R,4’R,8’R) - a - T o c o p h e r o l (41) duction of triketone (32)to (33).This was then transformed into (-)-(31) by established cuprate-addition methodology. Direct hydroxylation of the cyclopentahe nucleus was also attempted, but it yielded (37)with a disappointingly low ee-value of 36% 1141. Microbial Me I I I carbonyl reduction may solve the tricky sterI E F i F I D eoproblem of the 1S(S)-hydroxyfunction. Thus, (39) was obtained selectively from (38),and then elaborated into sulprostone (40), which is applied clinically as a cervix dilatator [lS]. Lip- a-Tocopherol (Vitamin E ) ase-catalyzed ester hydrolysis has successfully been applied in asymmetric syntheses of car- Commercially available vitamin E (41) is to some extent produced semi-synthetically from bacyclin derivatives [15a]. P-tocopherol, or - in racemic form - by total synthesis. However, to meet anticipated future Kloeckera jensenii demands for the optically pure material, great efforts have been invested in developing an &CYOPh asymmetric synthesis of (41) suitable for large PhCO 0 scale application. The chiral center in the chroI1 0 (3x1 mane ring is generally introduced via optical resolution, while the correct configuration at C-4’18’ is achieved by asymmetric induction, --++ preferably with microbial assistance. Two &CH20Ph retrosynthetic disconnections, a and b, have I PhCO emerged, involving the chirally methylated OH II three-carbon and four-carbon fragments B and O (391 F, respectively. Both B and F result from mi0 ?H It crobial transformations. Thus, the three-carbon c-’ -NHSO,CH, fragment B stems from the enantiotopos-speL C H z O P h cific hydroxylation of isobutyric acid [I61 to OH AH form (S)-(42),which may then be elaborated to both enantiomers of (44) by appropriate proSulprostone (40) I

I

4

?4

I

212

Bio-oriented Methodology

Scheme 3 Synthesis of optically pure a-tocopherol (41) (Cohen and Saucy [ 1 6 ] ) .

tective-group manipulations [17]. The phytol side-chain is then assembled by SchlosserFouquet couplings [18] via intermediates (47)-(53). As (44) is available in either configuration, any one of the four stereoisomers of (41) may be prepared with equal ease (Scheme 3). The four-carbon synthons F are procured by microbial hydrogenation of the olefins (55)/ (58),which yield the y-lactones (57) and (59) in optically pure form. These key fragments may then be connected either by Schlosser-Fouquet methodology ((57)+ (60)+ (61)+ (62)+ (63) -+ (64))or alternatively by Wittig olefinations ((59)+ (67))[19] (Scheme 4).

Aminoacids and Aminoalcohols Enzymatic C - C-connections have rarely been carried out. Nevertheless, one synthesis of ephedrine (69) is based on an observation by Neuberg [20] that benzaldehyde forms (R)-(68) in the presence of fermenting glucose. Reductive amination transforms (R)-(68)diastereoselectively into (69).This method, although currently subject to replacement by purely chemical alternatives, is one of the milestones in the development of industrial microbial synthesis, similar in this sense to Reichstein’s synthesis of

213

Enzymes in Organic Synthesis I Scheme 4 Synthesis of optically pure a-tocopherol

0

Me

"Yeast"

EtO

(4f) (Leuenberger, Sckmid,and Zell 1191).

0 Me EtOK/Z/OH

LfMe

H@ _j

0

OMe (55)

HBr

Eto,C&Br

(57)

Me

0

(57)

(56)

Me T H P O A B r

1) DIBAL 21 DHP/H @

1) Mg

Me

1) H30@

THPO 2) TsOLi2CuC14

A 21 TsCl (62)

1) PPh3

CI

H

P

O

A

3) (61) as MgBr derivative

(6-6)

7

T

Me

(67)

H

1) PPh3

3 (41)

2) BuLi

3) + (67)

3, A C O $ &

Me

CH=O

Me

Me

4) HgPt

5) Oeacetylation

ascorbic acid [22]. Interesting, but not yet applied in large scale production, is the enzymatic C -C coupling of phenols with pyruvic acid or racemic serine to form L-tyrosine or L-dopa,

respectively [23]. This reaction most likely proceeds via dehydroserine, which is then attacked by the aromatic system in a Friedel-Crafts type process.

214

Bio-oriented Methodology ’ 4 Ph-C. ‘H

OH ph%Me

0

fermenting

Glucose (Sofcharomyces cereuisiae)

__+ HZNMC

HdR

R-(68)

the Sharpless epoxidation is worth mentioning: the antibiotic fosfomycin (74) is prepared from (73) with >95% ee [25].

>

PH F’h*Me NHMe L-Ephedrine (69)

Benzylpenicillin (70)

6-APA (71)

+ Ph-CH-C02H I NH2

L-Tyrosine

D,L-Serine

Erwl&

hnbicoto

A m p i c i l l i n (72) enzym.

HO Hb

1

L -Dopa

H2TH-C02H NH2

Me

H.

H

PO3H2

(73)

Fosfomycin (74) ) 90% yield

In conclusion, microbial transformations have become indispensable in modern pharmaceutical industry, despite the fact that they As pointed out at the beginning, practically all are generally more expensive and more difficult important antibiotics are produced by fermen- to perform than purely chemical operations. tation. The main class - the penicillins - suf- Experts in the field say that a microbial transfers the great drawback of rapidly increasing formation is equivalent to three to five chemical bacterial resistance. This can only be remedied steps from the standpoint of costs and effort, by exchanging the “natural” phenylacetic side- which means that enzymatic reactions will only chain in (70) for other acyl residues (e.g. (R)- be invoked if all else fails. phenylglycine in ampicillin, (72). The amide can be hydrolyzed with penicillin acylase without affecting the p-lactam ring, thereby generating References 6-aminopenicillanicacid (6-APA, (71)) which is [1J A comprehensive review is given in the series a) reacylated chemically or, more recently, enzy“Economic Microbiology”, Vol. 1- 5, A. H . matically. In favorable cases, enzymatic de- and Rose, Editor, Academic Press, New York; b) re-acylation may be combined [24]. Last but “Biotechnology”, H.-J. Rehm and G. Reed (editors), VCH Publishers, Weinheim. not least, an interesting microbial analogon to

Antibiotics

Enzymes in Organic Synthesis I [2] Reviews in ref. [l] and K. Kieslich, “Microbial Transformations of Non-Steroid Cyclic Compounds”, 1st edition, Thieme, Stuttgart 1976. A. Fischli in “Modern Synthetic Methods”, R. Scheffold (editor), Otto-Salle-Verlag, Frankfurt 1980. - J. B. Jones in “Application of Biochemical Systems in Organic chemistry”, Part 1, J. B. Jones, C. J. Sih and D. Pearlman (editors), Wiley, New York, 1976. - J. B. Jones in “Asymmetric Synthesis”, Vol. 2, J. D. Morrison (editor), Academic Press, New York, 1983. - J. B. Jones in “Enzymic and Non-Enzymic Catalysis”, P. A. Wiseman and N. Blakeborough (editors), Ellis Horwood/Wiley, Chichester/ New York, 1980. [3] H. C. Murray and D. H. Peterson, US-Patent 2,602,769(1950); B. D. R. Collingsworth, M . P. Brunner, and W. J. Haines, J . Am. Chem. SOC. 74, 2381 (1950). [4] See review by K. Kieslich in ref. [ l a ] , Vol. 5, Chapter 8 (1980). [5] K. Petzold, H. Laurent, and R. Wiechert,Angew. Chem. 95, 413 (1983), Angew. Chem. Int. Ed. Engl. 22, 406 (1983). [6] R. Wiechert,K. Kieslich, and H. Koch, Belg. Patent 835,427 (1974). [7] C. H. Sih, H. H. Tsai, and Y. Y. Tsong, J . Am. Chem. SOC.89, 1956 (1967); U.Schoemer, C. K. A. Martin, Biotechnol. Bioeng. 22, 11 (1980); J. C. Knight and H. G. Wovcha, Steroids 36, 723 (1980). [8] Review on estrone-synthesis: G. Quinkert and H. Stark, Angew. Chem. 95,651 (1983); Angew. Chem. Int. Ed. Engl. 22, 637 (1983). [9a] H. Kosmol, K. Kieslich, R. Vossing, H.-J. Koch, K. Petzold, and H. Gibian, Liebigs Ann. Chem. 701, 199 (1967); C. Rufer, E. Schroder, and H. Gibian, Liebigs Ann. Chem. 701, 206 (1967); b) C. Rufer, H. Kosmol, E. Schroder, K. Kieslich, and H. Gibian, Liebigs Ann. Chem. 702, 141 (1967).

215

[lo] U. Eder, G. Sauer, and R. Wiechert, Angew. Chem. 83, 492 (1971); Angew. Chem. Int. Ed. Engl. 10, (1971); Z . G. Hajos and D. R. Parrish, J. Org. Chem. 39, 1615 (1974). [ll] See for example J. S. Bindhra in “The Total Synthesis of Natural Products”, Vol. 4, 1st edition, J. A. Simon (editor), Wiley, New York, 1981. [12] W.J. Marsheck and M. Miyano, Biochem. Biophys. Acta 316, 363 (1973). [13] C. J. Sih et al., J . Am. Chem. SOC.97,865 (1975). [I41 S. Kurozumi, T. Toru, and S. Ishimoto, Tetrahedron Lett. 1973, 4959. [l5] K. Kieslich et al., DOS 2853637. [I61 N. Cohen, W. Eichel, R. Lopresti, C. Neukom, and G. Saucy, J. Org. Chem. 41, 3505 (1976); Helv. Chim. Acta 64, 1158 (1981). [17] C. T. Goodhue and J. R. Schaffer, Biotechnol. Bioeng. 13, 203 (1971). [18] G. Fouquet and M. Schlosser, Angew. Chem. 86, 50 (1974); Angew. Chem. Int. Ed. Engl. 13, 82 (1974). [19] H. G. Leuenberger, W. Boguth, R. Barner, M . Schmid, and R. Zell, Helv. Chim. Acta 62, 455 (1979); M. Schmid and R. Barner, Helv. Chim. Acta 62, 464 (1979); R. Zell, Helv. Chim. Acta 62, 474 (1979). [20] C. Neuberg and J. Hirsch, Biochem. Z. 115,282 (1921). [21] D. Groger, DOS 1543691 (1969). [22] The procedure is performed according to P. A. Wells et al., Industrial and Engineering Chemistry 29, 1385 (1937); 31, 1518 (1939). [23] H. Enei et al., Agr. Biol. Chem. 36, 1861 (1972), 37, 725 (1973). [24] R. Okachi et al., Agr. Biol. Chem. 37, 335, 1953 (1973). [25] R. F. Whiteet al., Appl. Microbiol. 22,55 (1971).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Enzymes in Organic Synthesis, 11

Although originally more within the domain of industrial synthesis, enzyme-mediated reactions have increasingly found application in academic laboratories to meet the steadily developing requirements for enantio- and diastereodifferentiation. As a result, the numerous purely chemical methods of EPC synthesis [l]have been supplemented by a variety of enzymatic alternatives.

Carbonyl Reduction Baker's yeast is an efficient reageat for the enantioselective reduction of many prochiral ketones [2]. Because of their bifunctionality, pR

0 L C 0 2 E t

ketoesters of type (1) have received particular attention, although in many cases the enantiocontrol is not overwhelmingly high [3]. (S)-P-Hydroxybutyric acid ( 2 4 is generated with ee-values between 70 and 97%, and it can be separated from the enantiomer ( 3 4 via the crystalline 3,5-dinitrobenzoate [4]. Mori, however, in his early synthesis of the pheromone (9-sulcatol (5) [ S ] , still used (2a) in optically impure form and then converted it into the key intermediate tosylate (4). The substituent R exerts a crucial effect on the ee-value and configuration of the hydroxy product. (la) is reduced (S)-selectively, while ( l b- d ) are all obtained in the (R)-configuration with varying enantiomeric excess [3]. Sih re-

Baker's yeast

(1) ?H R k C 0 z E t

+

OH R&C02Et

(3)

(2) ( a ) : R = Me (b): R = E t

(20)

1) DHP/H@

3) T s a

(c): R = n-Propyl (d): R = n - B u t y l

OTHP Me&CHzOTs

(4)

2

l)kmq/ca * 2) €I30 0

OH C1&C02R1

(5)

+

OH & C 0 2 ,R C '1 ,

(7)

R'

(8) ee

55 (7) (b): n - P r o p y l 25 (7) (c): n - B u t y l 2 5 (7)

(a): E t

''

1) NMe3 2) H300>

R'

('70)

ee ('70)

(d): n - P e n t y l 75 (8)

(el: n-Hexyl

(fl : n - O c t y l @

PH

Me3N&C0,H'

95 (8) 97 ( 8 )

CI"

(9) L-

Carnitine hydrochloride

217

Enzymes in Organic Synthesis II

cently discovered that it is the alcohol component that controls the microbial reduction of (6). With increasing chain length of R , the configuration switches from (S)- to (R), reaching a maximum of approximately 95% ee for n-hexyl [6]. (L)-Carnithine hydrochloride (9) can be prepared in two steps starting from (8.' (R)-3-Hydroxybutyrates like (3a) need not necessarily be obtained by microbial carbonyl reduction, although this is possible with thermophilic bacteria. A better method is the acidcatalyzed depolymerization of PHB (polyhydroxybutyrate (10)) [7, 81, which is stored by many microorganisms as an energy source; e.g. PHB accounts for nearly 70% of the dry weight of Zoogloea ramigera! (3a), (24, and naturally occurring (R)-pulegone ( i f ) are the chiral components in Mori's synthesis of the western corn rootworm pheromones (20a/b) [7]. Thioketal (18) furnishes the acidic methylene unit, which is first alkylated with bromide (15) - in turn prepared from (11)via (12), (13),and (14) - and then with (16) or (17). Desulfurization with Raney nickel followed by acylation with propionyl chloride results in (204 and (20b),respectively. Seebach has shown [9] that the formiate (21) can be reduced with baker's yeast to give (R)(22) with an enantiomeric selectivity of 4: 1. Kinetic resolution obviously occurs via a mobile keto-enol equilibrium of (R)- and (S)-(2f),from which the (R)-enantiomer is removed selectively. Pure (R)-(22)is available by way of the crystalline 3,5-dinitrobenzoate, and may be employed in a number of natural product syntheses. The reduction of a-alkylated P-ketoesters with baker's yeast has been studied by R. W. Hoffmann. For instance, the conversion of (23) to (24) proceeds (S)-selectively with respect to C-3, whereas a 6.4: 1 (R,S)-mixture is obtained at C-2. 0-Silylation and aldol condensation with the dianion of 4-methyl-3,5-dione leads to (24), which is cyclized to give (2s)-stegobinone, the pheromone of the bread beetle [lo]. The low enantioselectivity (ca. 40% ee) found in the

A

\

(10)

(34

Polyhydroxybutyrate (PHB) Me OH

Me

OAc

(12)

(R)-Pulegone (1I)

H OTHP

(2a)

+

------+

b, (16)

THPO H

(3a) -.-

(17)

+

1) BuLt

Me Me

2)

+ (16) or (17)

A 3) Raney NI 4) EtCCl

dco2Et Baker's yeast

Me

> HoACOzEt (22)

218

Bio-oriented Methodology

reduction of ( l b )can be increased to about 85% if (27) is used instead; the sulfur is removed reductively at a later stage. In this way anhydroserricornine (31),a pheromone of the cigarette beetle, may be obtained via the intermediates (29)and (30) [113.

Me

* (24)

w

1) 0-Silylation

*’

Me Me

Me3Si?

0

0

0

Me M e Me

(25)

and it serves as the starting material for an ambitious synthesis of trichothecene derivatives like anguidine (46) [14, 151. It can be seen that (33)provides C-2, 3, 4, 5, 6, 12, 14 and 15 of the target compound; however, the only stereocenter derived from the starting material is that at C-5; all the other chiral centers must be elaborated in the course of the synthesis. This laborious process commences with the two-step inversion of the 4OH group (33 + 34), and is continued via (35)-(38) with the diastereoselective construction of the 2,3-diol moiety. Lactonization of (38) to (39)shows a 3: 1 selectivity for the 3-position. The synthesis of ring A is completed by activating the 6-position of (39)through introduction of a hydroxymethylene group. (40) is then converted into (41)and (42)by stereocontrolled Robinson spiro-annelation. (42) adds methyl lithium at the 9-position, and the lactone is opened reductively to give (43) after triacetylation. The 2,3 diol is deacetylated selectively, and the 2-hydroxyl function is then used for closing ring B via an acid-induced SN2’-reaction. Finally, (45) is converted into (46) by six routine steps.

Chiral Methyl Branching

A new synthetic potential has been created by the microbial reduction of 2-prochiral cyclopenta-1,3-diones and industrial-scale steroid synthesis is based on just such an operation [12]. Recently, this approach has been extended to other 1,3-diones, including (32) [13]. (33) is the main product, separated from minor amounts of (34) by column chromatography,

The incorporation of chiral methyl branching in carbon chains is one of the central problems in the synthesis of polypropionates or isoprenoids. A simple solution is provided by the microbial hydroxylation of isobutyric acid, which furnishes enantiomerically pure (S)-3-hydroxy2-methylpropionic acid (56) [16a], the enantiomer of the formyl reduction product (22).(56) has served as a central chiral unit in many natural product syntheses [16b], one of the most spectacular being the synthesis of ( +)-phyllantocine (47),the aglycone of phyliantoside, which has interesting antileukemic properties [17]. Retrosynthetic analysis of (47)leads to the fragments (48)and (49),which can be derived from

Enzymes in Organic Synthesis II

219

Scheme 1 Trichothecene synthesis according to Brooks [i4,iY].

&

0

Baker'syeast

,

14

O&H

O

+

2

(33)

1) TBDMS - CI

(34) DMF

2) HoAoH

H

(34)

1 '&Me OSiMe2

<5

I

tBu

'0'

1',

O

3

(33) 10

1) TsCl

X

(35) 0

5:l-

2) Base

selectivity

(37)

(45)

perilla aldehyde and the hydroxy acid (50, respectively. Perilla aldehyde is converted into the cyanohydrin (50), which gives (52) after stereoselective hydroboration, presumably via the borane (51). Lactonization under Mitsunobu

3) BZCl

(38)

Anguidine (46)

139)

BZ = -CPh

conditions (i.e., inversion of configuration at C-2) furnishes (53),which is converted into (54) and (55) by Kochi decarboxylation and stereocontrolled C-benzylation. The second fragment, (49),is obtained by reducing (56) to (57)

220

Bio-oriented Methodology

Scheme 2 Synthesis of (+)-phyllantocine [i7]. Me02C

Ph

'Me OMet

Me BnO

(47)

(48)

(49)

1 ) KCN

--+

H ( )-Perilla-aldehyde

+

(50)

1 0O , Bn

A-OBn (57)

OH

I

1 ) E10&- N= N-C02EV PPh3

C02H BnO-0

'

(52)

-icq-

Pb(OAc).+Cu(OAc),

2) Jones oxid.

>

O\CHpBn

(53)

H 1 ) LDA

(= 48)

&' ' p : 2 0 B n

OCH20Bn

(54)

Me Ho&CO,H

'\CH2-

(55)

F?"

j

Bn

--+ Ho\j\/oBn 1 ) Jones oxid. 3) Me,CuLi

and converting the unprotected carbinol function into an isopropenyl moiety (58). Schlosser deprotonation and cation exchange provides the organometallic species (59),which is added

Me OH

1 ) tBuOK/BuLi

CH2

to the lactone (55) to give (60).Transketalization closes the spiro-fused ring to (60), and this is then elaborated into (47) by six additional steps.

Enzymes in Organic Synthesis ZI

Asymmetric C - C Connection Acetyl transfer to such aldehydes as benzaldehyde or cinnamaldehyde has been observed in fermenting glucose by Neuberg [I21 and Fuganti [18]. The initially formed acyloin intermediate is reduced to the diol, e.g ( 6 3 , which is obtained enantio- and diastereomerically pure, but in low overall yield and only after tedious workup [IS]. It may nevertheless be prepared in gram quantities, so it has been util-

ized extensively in monosaccharide synthesis. For example, (63) yields the "multipurpose" carbonyl compounds (64alb) upon ozonolytic cleavage, and these in turn add organometallic reagents with high selectivity. (65) is thus available from (64), and it may be elaborated into the 2-deoxymonosaccharide (66). The same principle has been applied in the synthesis of the western pine-beetle pheromone (+)-exobrevicomin (71) from (64a),and in the synthesis of the pheromone (-)-frontalin (74)from (64b).

Scheme 3 Enzymatic C - C connection according to Fuganti [18].

Go

p h y C ' H

Baker's yeast

A

D-GILJC

(a): R = H (b): R = Me

1) BnCl

(63) (- 20% yield)

HO,

(64)

0 It

0 1) Ph-CCI II

OH

PhCO,

OBn

OTs

-

LMgBr (72) *M 9e 7? 2) 1) Na104 H30@

2) 1) PhCH2CI

Me

Bn = CH,-Ph

Me

OBn

X

(64b)

M'e

221

3) NaBH4

OBn

OBn

(+)-exo-Brevicomin

M

e 5

a Me I 3

4) O?/Me+

(73)

5) HdPd

(-)-Frontalin (74)

222

Bio-oriented Methodology

Enantiodfferentiating Hydrolysis of Diesters

The further conversion of (80) to the target compound (83) closely follows the Merck synthesis of thienamycin [22]. An interesting recent development is the optical resolution of racemic carboxylic acids, alcohols, and esters by enzymatic transacylation reactions in organic solvents, thus providing ready access to a variety of enantiomerically pure compounds [23]. In conclusion, despite obvious similarities, microbial catalysis is handled differently in industrial and academic syntheses. Industrial chemists are primarily concerned with finding the optimum enzyme for a given transformation (e.g. steroid hydroxylation), while academic chemists are more interested in using enzymes for the “invention” of new chiral building

Sih has shown in a series of pioneering studies that enzymes like porcin-liver esterase (PLE) exert a strong enantiodifferentiating effect on the hydrolysis of enantiotopic ester groups [19]. This concept has since gained enormous popularity world-wide [20]. A representative example is the synthesis of the carbapenem antibiotic (-)-carpetimycin (83) from the aminoglutaric diester (75) [21]. Monoester (76) is obtained with 96% ee from the PLE-catalyzed hydrolysis of ( 7 9 , and it may be cyclized reductively to give (77). Stereocontrolled aldol addition leads to (78) and, after some additional manipulations, to (79)and (80).

Scheme 4 Synthesis of carpetimycin A according to Ohno [2i]. PLE --+

MeO,C/\I\CO,Me NH-2

HO,C /\I\CO,Me

H20

NHZ

z> 1) NaBH

2)

Acp

NHZ (76)

(75)

(77)

I) H@/CH,OH

I

OH

Me0,C

2) HdPd 3) MegiiCI

Me,C ‘ NHZ

NH

I

SiMe,

(78)

(79)

1) CrO$Pyridine

5 steps

-++ 0

%2:HA0 c’

(83)

CO2Bn’

Carpetimycin A

Im = lmidazolyl 2 = -CO,-CH,-Ph

Enzymes in Organic Synthesis 11

blocks (“chirons” [24]), which are then incorporated into the architecture of complex natural products.

References [l] “Enantiomerically Pure Compound”-Synthesis.

[2]

[3]

[4] [5] [6] [7]

[8]

[9] [lo]

[ll] [I21 [13]

Extensive reviews in “Asymmetric Synthesis”, Vol. 2-5, Editor J. D. Morrison, Academic Press, New York, 1983/85. Review: C. J. Sih and J. P. Rosazza, Application of Biochemical Systems in Organic Chemistry, Part I, Editors: J. B. Jones, C. J. Sih, and D. Perlman, Wiley, New York, 1976. See also this book, p.228. R. U. Lemieux and J. Giguere, Can. J. Chem. 29, 678 (1951); B. S. Deol, D. D. Ridley, and G. W . Simpson, Austr. J. Chem. 29,2459 (1976); G. Frater, Helv. Chim. Acta 62, 2829 (1979); A. I. Meyers and R. A. Amos,J. Am. Chem. SOC.102, 870 (1980); K. Hintzer, B. Koppenhofer, and V. Schurig, J. Org. Chem. 47, 3850 (1982); D. D. Ridley and M. Stralow, J. Chem. SOC.,Chem. Commun. 1975,400. E. Hungerbiihler, D. Seebach, and D. Wasmuth, Helv. Chim. Acta 64, 1467 (1981). K. Mori, Tetrahedron 37, 1341 (1981). C. J. Sih et al., J . Am. Chem. SOC.105, 5925 (1983). K. Mori and H . Watanabe, Tetrahedron 40,299 (1984). D.Seebach and M. Ziiger, Helv. Chim. Acta 65, 495 (1982). Synthesis of (3a) with thermophilic bacteria: D. Seebach, M. Ziiger, F. Giovannini, B. Sonnleitner, and A. Fiechter, Angew. Chem. 96, 155 (1984); Angew. Chem. Int. Ed. Engl. 23, 151 (1984). M. Ziiger, F. Giouannini, and D. Seebach, Angew. Chem. 95, 1024 (1983); Angew. Chem. Int. Ed. Engl. 22, 1012 (1983). R. W . Hoffmann et al., Chem. Ber. 114, 2786 (1981). R. W. Hoffmann, W . Helbig, and W. Ladner, Tetrahedron Lett. 23, 3479 (1982). See the preceding article in this book. D. W.Brooks, P. G. Grothaus, and W . L. Irwin, J. Org. Chem. 47, 2820 (1982).

223

[14] D. W.Brooks, P. G. Grothaus, and J. T. Palmer, Tetrahedron Lett. 23, 4187 (1982). [l5] D. W. Brooks, P. G. Grothaus, and H. Mazdiyasni, J. Am. Chem. SOC.105,4472 (1983). [16a] C. T. Goodhue and J. R. Schaeffer, Biotechnol. Bioeng. 13, 203 (1981). [16b] e.g. D. A. Evans, C. E. Sacks, W . A. Kleschick, and T. R. Taber, J. Am. Chem. Soc. 101, 6789 (1979); D. B. Collum, J. H. McDonald III, and W.C. Still, J. Am. Chem. SOC.102, 2218 (1980); A. I. Meyers et al., J . Am. Chem. SOC.105, 5015 (1983); S. Masamune. B. Imperiali, and D. S. Garvey, J. Am. Chem. SOC.104, 5528 (1982); H. Nagaoka and Y. Kishi, Tetrahydron 37, 3873 (1981); W.R. Roush and A. D. Palkouitz, J . Am. Chem. SOC.109, 953 (1987). [I71 P. R. Mcguirk and D. B. Collum, J. Am. Chem. SOC.104, 4496 (1982). [18] C. Fuganti et al. in a series of papers: J. Org. Chem. 49, 543 (1984); Tetrahedron Lett. 24, 3753 (1983);J. Chem. SOC.Perkin Trans. I, 1983, 241, Tetrahedron Lett. 23, 4143 (1982). Review: Ciba Found. Symposium f l f , p. 112, Pitman, London, 1985. [19] C. J. Sih et al., J. Am. Chem. SOC.97, 4144 (1975). [20] Reviews: Y.-F. Wang,C . 4 . Cheng, G. Girdaukas, and C. J. Sih, Ciba Foundation Symposium 111, p. 128, Pitman, London 1985; M . Ohno, ibid., p. 171; H.-J. Gais and K. L. Lukas, Angew. Chem. 96, 140 (1984); Angew. Chem. Int. Ed. Engl. 23, 142 (1984); M. P. Schneider et al., Angew. Chem. 96, 52,54, 55 (1984); Angew. Chem. Int. Ed. Engl. 23, 64, 66, 67 (1984); P. Mohr, N. Waespe-Sarcavic, C. Tamm, K. Gawronska, and J. Gawronski, Helv. Chim. Acta 66,2501 (1983); C. R. Johnson and T. D. Penning, J. Am. Chem. SOC.108, 5655 (1986). [21] T. Timmori, Y. Takahashi, T. Izawa, S. Kabayashi, and M. Ohno, J. Am. Chem. SOC.105,1659 (1983). [22] T. N. Salzmann, R. W. Ratclvfe, B. G. Christensen, and F. A. Bouffard, J. Am. Chem. SOC.102, 6161 (1980). [23] Review: C. S. Chen and C. J. Sih, Angew. Chem. 101,711 (1989); Angew. Chem. Int. Ed. Engl. 28, 695 (1989). [24] S. Hanessian, “Total Synthesis of Natural Products: The ‘Chiron Approach”’, Pergamon, Oxford-New York, 1983.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Enzyme Chemistry Valuable New Applications

A steadily increasing number of applications demonstrates that the exclusion of enzyme-catalyzed reactions from organic synthesis would be unthinkable, and that such reactions ought to be included in all synthetic planning [I]. This applies particularly to reactions that involve enzymes requiring either no coenzyme, or else one that is easily regenerated, as well as to transformations employing microorganisms such as baker’s yeast, which can be carried out in any laboratory. This review is intended to demonstrate recent advances in the use of enzymes by providing examples drawn from a few important types of reactions, with particular attention to broad applicability. Before starting the survey, however, it is important to note two key methodological developments. In contrast to earlier assumptions, it has now been proven that many enzymes retain their activity in nonaqueous solvents. Indeed, operating in a non-aqueous environment actually provides a number of advantages [2]: Reactions that cannot be carried out in aqueous solution due to unfavorable equilibria (e.g., esterifications)may be facilitated. Many enzymes are more stable in organic solvents than in water. Organic substrates are usually more soluble in organic solvents than in water, but the enzymes remain insoluble. This may make it possible to recover the enzymes directly, thereby eliminating the need for immobilization.

Product isolation is often more difficult from dilute aqueous solutions. Specific non-aqueous applications are included in the examples that follow. Another technique that may prove of great utility is what is known as membrane-enclosed enzymatic catalysis (MEEC), whereby an enzyme is introduced into a reaction in the form of a solution that is encased in commerical dialysis tubing [3]. The reaction mixture itself is often a twophase system consisting of organic solvent and buffer. Since the enzyme is contained in a sealed package, it can be recovered for subsequent use after the reaction is complete by dialyzing it against a buffer solution. The advantage of this technique over immobilization on a solid carrier, confirmed in a number of typical cases, is that there is no significant loss of enzyme activity. Moreover, it is possible to achieve high activities per unit volume of enzyme. Mass transport through the membrane is rate-determining, however, so reaction rates tend to be low.

Ester Hydrolysis Ester hydrolysis with the aid of hydrolases has long been employed in organic synthesis, particularly for the kinetic resolution of chiral carboxylic acids and alcohols. However, given the mild reaction conditions involved, the method should also be considered more generally for

225

Enzyme Chemistry

critical ester hydrolyses involving labile systems. Porcine liver esterases (PLE) and various lipases are most frequently utilized because they are inexpensive and are tolerant of a wide range of substrates. It has recently been demonstrated [4, 51 that results comparable to those from PLE can be obtained with an easily prepared crude extract from fresh hog liver, a factor that is likely to decrease the cost of frequent applications of the method and to increase its popularity. Withesell was able with such a crude liver extract, which is also available commercially, to separate pure enantiomers from a racemic mixture of the esters ( l a ) and ( l b )[ 5 ] . In the case of (la),six days of reaction yielded an approximately 1:1 mixture of (-)-(2a) and ( +)(fa)which could readily be separated by chromatography. Recrystallization of the alcohol yields (-)-(2a), while hydrolysis of (+)-(la) gives ent-(2a),both in high optical purity. Optically active alcohols ( 2 4 and (2b)are valuable chiral auxiliaries for asymmetric synthesis, and since they are so readily accessible by this route they might well become popular substitutes for the more frequently employed 8-phenylmenthol.

(3)to achieve an acceptable enantioselective hydrolysis [6], but this made the method competitive with Sharpless oxidation. After 60% conversion, 92% ee was found for the unhydrolyzed ester, which could be separated by distillation.

(3)

(9- (4)

(R) - (3)

A disadvantage of such resolutions is the fact that the hydrolyzed alcohol must be separated from residual ester; moreover, only 50% of the educt is subject to transformation into the desired enantiomer. From this standpoint, the use of prochiral or meso-diesters is ideal, since enzyme-catalyzed selective cleavage of one of the two enantiotopic ester groups leads quantitatively to a single enantiomer. This principle has been exploited in many instances, and has found wide application [lf- h]. The possibilities are suggested in Scheme 1. Scheme 1 R

A

R02C

I

C02R

R

R*

R02C

.L

(?)-(l)

I I

I

CO,R

R

(a): R = Ph

(b): R = CMe2Ph &OH

;C02R

H02C R

An older example, where lipase turned out to be the best enzyme with respect to cost, yield, and enantioselectivity, proves that it is often necessary to modify the substrate chemically as one step in the optimization process. Only after changing the acid residue to butyrate (R = C3H7)was it possible in the case of glycidyl ester

I

I

+

AcO

OAc

HO

OAc

HO

OAc

A few examples in which enantioselective hydrolysis of meso-diester is the key step in the synthesis of a natural product or a chiral intermediate will demonstrate the versatility of the

226

Bio-oriented Methodology

method and point out the main factors that must be taken into account. “Dissymetrization” by selective enzymatic hydrolysis is beautifully illustrated by Ohno’s synthetic approach to nucleosides and pseudonucleosides [lfl.

cation of the substrate. Thus, the 2-aminoglutarate ester (12) (Z = H) yields primarily the (R)-isomer (13) on hydrolysis with porcine liver esterase, while the Boc-protected derivative is preferentially hydrolyzed to the (S)-isomer (f4) Clfl.

X = 0, CH,

The quasisymmetric half ester is frequently obtained in high optical yield, and in some cases it can be easily transposed into the opposite enantiomeric series through chemoselective reaction. A fine example is the versatile tetrahydrophthalate half ester (lo),prepared by Gais and Ohno on a 100 mol scale using porcine liver esterase. (10)was obtained in 98% yield with an ee of at least 98% [lf, 7, 81.

aIllI:l

PLE

a C I l L H 3

(9)

(10)

1. Na, EtOH. NHJ. - 78‘C

1. (COCI), CHC13, 25OC

2. NH,CI:

2. NaBH,.

HCI

EtOH,

PhCH3. 1 1 0 OC

0 ent-(1 I )

One aspect worth mentioning is the fact that the enantioselectivity of an enzyme is often reversed as a result of a simple chemical modifi-

It is of great preparative importance that one can also hydrolyze enantioselectively the corresponding meso-diacetate rather than the meso-diester; indeed, the selectivity of lipases often proves superior to that of esterase [9]. Moreover, the product isolated often belongs to the opposite enantiomeric series. This complementary method is particularly important when the hydrolysis of a carboxylate ester fails to yield high enantioselectivity, as with the diester (15).PLE hydrolysis of (15)provides (16) with only 75% ee [lo]. (16)is of interest, because it can be transformed into an intermediate for a commercial synthesis of biotin. However, Sih later discovered [11] that (f 7) is transformed into (18)by PLE with 92% ee, and (18) can also be converted to the desired interme-

227

Enzyme Chemistry

diate. Such a problem can also be solved by searching for a more suitable enzyme system [12], but the required effort is likely to be too great in most cases.

y

form such 2-nitroallyl esters as (28),compounds of special interest as two-fold Michael acceptors.

ff ---+ AcofroH

NO,

yy""

Liposs

AcO

(20)

OAc

HO

""

OAc

(26)

(25)

(24)

AcofroAc \

PLE

(79)

Acetyl cholinesterase

ent- (20)

Other noteworthy enantioselective hydrolysis relate to cyclic and adyclic 1,3-diacetoxy systems. Depending on which enzyme is employed, both enantiomeric forms of the valuable intermediate (20) can be prepared from (19) [13 - 151, which is in turn readily available from cyclopentadiene via a reaction involving singlet oxygen. Acetyl cholinesterase, the enzyme leading to ent- (20),was discovered only after a long search [l5], but applied to the related meso-diacetate (21) it allowed a short asymmetric synthesis of the enone (23) [16], an intermediate in an eficient prostaglandin synthesis.

Lipase-catalyzed hydrolysis of the diacetate (24) provides ready access to large amounts of the valuable glycerol derivative (25) in enantiomerically pure form [17, 181. Seebach used hydrolysis of the diacetates of 2-nitro-1,3-diols with crude extracts of fresh hog liver [4, 191 to obtain in optically active

Esterification and Transesterijication It has long been known that esterases also catalyze enantioselective esterifications, but the fact could not be exploited preparatively because the preferred reaction in aqueous solution is hydrolysis. For the same reason it was not thought possible to carry out enzymatic transesterifications. 0

II

0

0

II RCOR~

II

+ RCOH

RCOH

+

R'OH

0 II RCOR'

+

II R ~ O H# R C O R ~

#

0

+ R~OH

Enantiospecific esterification acquired practical significance for the resolution of enantiomers only after techniques had been developed for suppressing the competitive hydrolysis. This can be accomplished on the one hand by carrying out the reaction in a two-phase aqueousorganic solvent system [20,21], especially if the product is readily soluble in the organic phase and only slightly soluble in the aqueous phase while the reactants display the opposite solution behavior. Reaction is then driven even further in the direction of esterification. Another possibility offered itself when it became known that enzyme reactions can also be carried out in pure organic solvents [2]. Klibanov was able to show that under these conditions a whole

228

Bio-oriented Methodology

range of optically active alcohols and carboxylic acids become amenable to esterification or BOCHN- -H \L transesterification with lipase [22]. Klibanov recently employed this technique for the regioselective acylation of primary hydroxyl groups in sugars as well [23]. Enzymatic esterification in nonaqueous sol(32) Lactate vents has also been used for the preparation of HO H dehydrogenase lactones [24, 261. Thus, Gutman described the ' R X C02H R C02H lipase-catalyzed lactonization of racemic y-bu(34) (33) tyrolactone systems (29) [25]. When R = CH3 this reaction leads after 36% conversion to the specificity and high enantioselectivity, accepts optically pure y-lactone (30),whereas with 60% a series of unnatural 2-oxoacids (33) as subconversion it is possible to isolate optically pure strates, and with NADH it converts them into educt. Very recently, Sih has reported using lip- a-hydroxy acids (34) [28]. Coupled with an apase-catalyzed esterification for the direct con- propriate system for the regeneration of densation of diacids with diols leading to ma- NADH, this reaction offers a useful route to the crocyclic lactones [26]. valuable a-hydroxy carboxylic acid system. One peculiar feature here relative to enzymes RY--C02CH3 d generally is that both L- and D-lactate dehyi)H (+.)-(29) R drogenases are available, providing access in HQ ,o + Hi ( V C 0 Z C H 3 principle to both enantiomeric series [29].

a

(s)-(30)

R

OH

(R)-(29)

Carbonyl Reduction

Enzymatic C - C Bond Formation

Enzymatic reductions of aldehydes and ketones, particularly P-keto esters, have been well investigated; in some cases, they are even performed on a commercial scale [lc]. But to the chemist at the bench, reductions with baker's yeast are the only ones of practical importance [lc], and applications of this type have already been the subject of comprehensive reviews [l]. Nevertheless, a recent example reveals the extent of the optimization that may be required in a particular case in order to carry out a successful yeast reduction on a large scale. Thus, a total of 80 yeast strains were tested before an optimal yield with maximal selectivity was achieved in the case of the reduction of (31) to (32), the key step in an effective synthesis of statine derivatives [27]. L-Lactate dehydrogenase, an inexpensive enzyme that appears to possess broad substrate

The most important of the preparatively useful methods for enzymatic C- C bond formation is the aldolase-catalyzed aldol addition, especially since it requires no cofactors. It is true that the specificity of the aldolase isolated from rabbit muscle is restricted with respect to the nucleophilic aldol component - the most common substrate is dihydroxyacetone phosphate (DHAP) (36) - but the enzyme is tolerant of a host of aldehydes [lf, 91. Now that Effenberger has developed a simple route to the previously expensive DHAP [30], broader application of this highly selective reaction to system (37)may be expected. The aldol addition has already been employed for the synthesis of a series of unnatural sugars and sugar analogs. Very recently the method has been applied to the synthesis of glycosidase inhibitors of the nojirimycin type [31].

R

a,

8

+-OPO:, .k,HO,

R

4

OH

A further reaction that has long been known for enantioselective C - C bond formation is the enzyme-catalyzed cyanohydrin formation based on mandelonitrile lyase, readily isolated from bitter almond flour. Optical yields in aqueous solution have always been modest, however, due to competition from the simple acid-catalyzed addition of HCN, which leads to racemates. This problem can be avoided by carrying out the reaction in a nonaqueous solvent such as ethyl acetate, permitting cyanohydrins to be prepared with more than 90% ee [32]. This technique is likely to stimulate new interest since the resulting cyanohydrins may be readily converted into the important p-amino alcohols and u-hydroxy carboxylic acids.

A

Dioxygenase

229

aoH

Enzyme Chemistry

xCN

HO Enzyme

H + H C N +

(35)

R

H

(38)

After protection of the OH groups, the resulting cyclohexadiendiol (39), prepared on a kilogram scale, was subjected to radical polymerization. What resulted was a reactive precursor of polyphenylene (41),an interesting aromatic polymer that could then be obtained simply by heating. This oxidation yields chiral systems starting from substituted benzene derivatives. Thus, the reaction with toluene (R = H) is both regioand enantioselective, giving the diol (42) (R = H), which promises to be a versatile chiral intermediate. For example, Hudlicky has prepared in this way the isopropylidene-protected derivative (42),which can be converted in a simple series of reactions involving oxidation with ozone and subsequent aldol cyclization into the optically active cyclopentenone (44) [34].

Hydroxylation Hydroxylation of nonactivated aliphatic and aromatic systems is one of the most remarkable reactions that can be accomplished enzymatically, since with few exceptions there exist no equivalent chemical methods. Nevertheless, apart from a few important but very specialized oxidations in the steroid and terpenoid fields and certain selective hydroxylations of aromatics, such reactions have so far found little application. Some time ago reports appeared from industrial sources [lf, 331 of the remarkable conversion on a commercial scale of benzene to cisbenzene glycol (39)with the aid of a dioxygenase enzyme present in a whole-cell system.

Outlook The use of biochemical methods in organic synthesis is certain to increase. One need only consider how few of the 2000 known enzymes have so far been exploited in this sense especially given that more than 200 are commercially available. Beyond this, the ongoing intensive

230

Bio-oriented Methodology

search for modified, natural, and tailor-made artificial enzymes is also likely to open up new possibilities. The synthesis of complex, biologically active substances such as polysaccharides containing multienzyme systems is a further direction likely to attract considerable attention in the future. There remain a few important classes of organic reactions for which no enzymes have been discovered in nature, including cycloadditons of the Diels-Alder type, and sigmatropic rearrangements other than the Claisen rearrangement. Here there is a chance for progress on the basis of a fascinating new development, namely the use of monoclonal antibodies as catalysts [35]. Antibodies to substances that represent stable analogues of the transition state of a reaction have been found to be capable of catalyzing the corresponding chemical reaction. Bartlett and Schultz [36] have provided a recent example involving the endobicyclic system (44,which may be regarded as analogous to the probable transition state (45) of the Claisen rearrangement of chorisminic acid to prephenic acid. One of the eight specific monoclonal antibodies for (46) that were tested led to an enormous acceleration in the rate of rearrangement of chorisminic acid to prephenic acid. The rate of reaction was two-thirds of the one obtained with chorismate mutase, the natural enzyme for this Claisen rearrangement! Extensions of antibody catalysis to other classes of reactions are certainly to be expected [37].

[2] [3] [4] [5] [6] [7]

[8]

[9] [lo] [ll]

[12] [13] I

HO

(46)

References [l] Reviews: a) J. Mulzer, Nachr. Chem. Tech. Lab.

32, 520, 589 (1984); see this book, p. 207ff.; b) H.-U. ReiJig, Nachr. Chem. Tech. Lab. 34, 782 (1986); c) C . J. Sih and C.-S. Chen, Angew.

[14] [l5] [16] [17]

Chem. 96,556; Angew. Chem. Int. Ed. Engl. 23, 570 (1984);d) G. M. Whitesides and C . H. Wong, Angew. Chem. 97, 617; Angew. Chem. Int. Ed. Engl. 24, 617 (1985);e) J. B. Jones, in J. D. Morrison (Ed.): “Asymmetric Synthesis”. Vol. 5, p. 309; New York 1985;f) R. Porter and S. Clark (Eds.): “Enzymes in Organic Synthesis”, Ciba Foundation Symp. 111, London 1985; g) J. B. Jones, Tetrahedron 42, 3351 (1986); h) M. Schneider and E. H. Reimerdes, Formum Mikrobiologie 1987, 65, 303; i) H. Yamada and S. Shimizu, Angew. Chem. 100,640;Angew. Chem. Int. Ed. Engl. 27, 622 (1988); C.-H. Wong and G. M . Whitesides: “Enzymes in Synthetic Organic Chemistry”, Pergamon Press 1989. A. M. Klibanov, Chemtech 1986,354;C . S. Chen and C . J. Sih, Angew. Chem. 101, 711 (1989); Angew. Chem. Int. Ed. Engl. 38, 695 (1989). M. D. Bednarski, H. K. Chenault, E. S. Simon, and G. M. Whitesides, J. Am. Chem. SOC.109, 1283 (1987). D . Seebach and M . Eberle, Chimia 40, 315 (1986). J. K. Whitesell and R. M . Lawrence, Chimia 40, 318 (1986). W . E. Ladner and G . M. Whitesides, J. Am. Chem. SOC.106, 7250 (1984). H.-J. Gais and K. L. Lukas, Angew. Chem. 96, 140 (1984);Angew. Chem. Int. Ed. Engl. 23,142 (1984); H.-J. Gais, K. L. Lukas, W . A. Ball, S . Braun, and H. J. Lindner, Liebigs Ann. Chem. 1986, 687. M. Schneider, N. Engel, P. Honicke, G. Heinemann, and H . Gorisch, Angew. Chem. 96, 55 (1984); Angew. Chem. Int. Ed. Engl. 23, 67 (1984). K. Laumen and M . Schneider, Tetrahedron Lett. 1985, 2073. S. Iriushijima, K. Hasegawa, and G. Tsuchihashi, Agr. Biol. Chem. 46, 1907 (1982). V.-F. Wang and C. J. Sih, Tetrahedron Lett. 1984,4999. Cf. e.g., A. S. Gopalan and C . J. Sih, Tetrahedron Lett. 1984, 5235. Y.-F. Wang, C.-S. Chen, G. Girdaukas, and C . J. Sih, J. Am. Chem. SOC.106, 3695 (1984). K. Laumen and M. Schneider, Tetrahedron Lett. 1984, 5875. D. R. Deardorff; A. J. Matthews, D . S. McMeekin, and C. L. Craney, Tetrahedron Lett. 1986, 1255. C . R. Johnson and T. D. Penning, J. Am. Chem. SOC. 108, 5655 (1986); 110, 4726 (1988). V. Kerscher and W . Kreiser, Tetrahedron Lett. 1987, 531.

Enzyme Chemistry [18] Cf. D. Breitgofl, K. Laumen, and M. Schneider, J. Chem. SOC.Chem. Commun. 1986, 1523; H.

[19] [20] [21] [22] [23] [24] [25] [26]

Suemune, Y. Mizuhara, H . Akita and K. Sakai. Chem. Pharm. Bull. 34, 3440 (1986). M . Eberle, M. Egli, and D. Seebach, Helv. Chim. Acta 71, 1 (1988). B. Cambou and A. M . Klibanov, J. Am. Chem. SOC.106, 2687 (1984). C.-S. Chen, S.-H. Wu, G. Girdaukas, and C. J. Sih, J. Am. Chem. SOC. 109, 2812 (1987) and ref. cited. G. Kirchner, M . P. Scollar, and A. M. Klibanov, J. Am. Chem. SOC. 107, 7072 (1985). S. Riva, J. Chopineau, A. P. G. Kieboom, and A. M . Klibanov, J . Am. Chem. SOC.110, 584 (1988) and ref. cited. A. Makita, T. Nihira, and Y. Yamada, Tetrahedron Lett. 1987, 805. A. L. Gutman, K. Zuobi, and A. Boltanski, Tetrahedron Lett. 1987, 3861. G. Zhi-Wei and C. J. Sih, J. Am. Chem. SOC. 110, 1999 (1988).

[27] P. Raddatz, H.-E. Radunz, G. Schneider, and H. Schwartz, Angew. Chem. 100, 414 (1988); Angew. Chem. Int. Ed. Engl. 27,426 (1988). [28] M.-J. Kim and G. M . Whitesides, J. Am. Chem. SOC.110, 2959 (1988).

231

[29] B. L. Hirschbein and G. M. Whitesides, J. Am. Chem. SOC. 104,4458 (1982). [30] F. Effenberger and A. Straub, Tetrahedron Lett. 1987, 1641. [31] T. Ziegler, A. Straub, and F. Effenberger, Angew. Chem. 100, 737 (1988); Angew. Chem. Int. Ed. Engl. 27, 716 (1988). [32] F. Effenberger, T. Ziegler, and S. Forster, Angew. Chem. 99, 491 (1987); Angew. Chem. Int. Ed. Engl. 26, 458 (1987). [33] D. G. H. Ballard, A. Courtis, I. M . Shirley, and

S. C. Taylor, J. Chem. SOC.Chem. Commun.

1983, 954. [34] T. Hudlicky, H. Luna, G. Barbieri, and L. D. Kwart, J. Am. Chem. SOC.110, 4735 (1988). [35] Reviews: A. Maelicke, Nachr. Chem. Tech. Lab. 35, 1054 (1987); R. A. Lerner and A. Tramontano, Scientific American, March 1988, p. 42; P. G. Schultz, Science 240, 426 (1988). [36] D. Y.Jackson, J. W. Jacobs, R. Sugasawara, S.

H. Reich, P. A. Bartlett, and R. G. Schultz, J. Am. Chem. SOC.110,4841 (1988). [37] P. G. Schultz, Angew. Chem. 101, 1336 (1989); Angew. Chem. Int. Ed. Engl. 28, 1283 (1989).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Biomimetic Natural Product Syntheses

The term “biomimetic syntheses” has been adopted for synthetic strategies that attempt to imitate in uitro either a proven biosynthesis or a speculative biogenetic pathway. Since Clemens Schopfs classic example of the preparation of tropinone ( I ) [l] from succinaldehyde, methylamine, and acetonedicarboxylic acid, a large number of natural product syntheses, both simple and highly elegant, have been accomplished using a biomimetic strategy.

”?

,CHO

+

HzN-CH3

+

HzC‘CHO

The in uitro imitation of the cyclization of squalene oxide (2) to lanosterol (3) is regarded as a particularly elegant biomimetic synthesis, developed by W. S. Johnson and his research group in the sixties [2]. Thus, acid-catalyzed cyclization of an appropriate polyene leads directly to the steroid analog (4) with seven chiral centers, six of them created in a highly stereoselective manner. Since Johnson’s pioneering work, many variations of this type of reaction have been applied in diverse steroid syntheses.

HZC,

,co

fl’ c,

HzCYOzH \@

pH = 5-9

-Sn.-----O

-2H10

0

0

c le

4

&Me3

(5)

U

-2cq

(1)

+

flp .t\

0

0

U

H

H OCHzCHzOH

(4)

OCH~H C~OH

CHzC HzOH

c

Biomimetic Natural Product Syntheses

Synthesis of “regular” steroids (i.e. steroids with a five-membered D ring) is also possible, provided an allylsilane group is used as the terminator for this “zipper reaction” [3]. Thus, tetraene (5) af€ords the isomers (6)and (7) in 34% yield when treated with SnC14. The hydroxyethoxy side chain is subsequently removed to provide, after oxidation, a mixture of epimeric ketones (a),which can be separated by chromatography. Here again, six chiral centers are formed stereoselectively in a single step.

The cyclization of polyenes with chiral auxiliary groups leads to enantiomerically pure steroids. The biogenesis of the yellow amino acid muscaflavin ( i i a ) , isolated from fly agaric and from hygrocybes, is thought to start with DOPA (9), which might be cleaved to the intermediate (lo), a derivative of glutacone &aldehyde. Final formation of the seven-membered ring of muscaflavine can be rationalized in terms of the condensation outlined in Scheme 1 [4].

Scheme I Biogenesis and synthesis of muscajlavine [4]. CHO

( l l a ) :R = H ( l l b ) :R = CH,

(9)

H,CO,C

CH2 - CH - COZCH, I NHTSOC

+

233

CH2- CH - CO2CH3 H3CW

,

x

AHTSOC

(13a):X = O o (13b): X = OCH, (perchlorate)

234

Bio-oriented Methodology

Musso et al. [4] attempted to synthesize intermediate (10) in order to investigate whether it would indeed cyclize to muscaflavine (11a). To this end, pyridylalanine (12)is converted via N-oxide (13a) into methoxypyridinium salt (13b), whose ring is subsequently opened by pyrrolidine, giving the very sensitive enamine (14). However, all attempts to convert (14) into the acid (lo),postulated to be an intermediate in the biosynthesis, failed. Although the amino protective group in (14) can be removed by base, only the enamine is hydrolyzed in the subsequent treatment with acid, while the oxime ether moiety remains intact. Thus, esterification with diazomethane leads to the five-membered ring products (16a) and (16b),whose formation may be rationalized by assuming cyclization of the tautomers (15a)/(15b).However, the methyl ester of racemic muscaflavine ( l i b ) is indeed obtained (after treatment with diazomethane) if the mixture (16a)/(16b)is heated in the presence of acid. The amino acids (15a) and (1%) are

probably restored in this process. It may be that they than undergo cyclization to the sevenmembered ring of (11a) directly via the conformer (1%'). On the other hand, cleavage of the oxime moiety to give the intermediate (lo), followed by cyclization, might also be considered a plausible pathway for the formation of (11a). The resolution of racemic muscaflavine diester (lib) can be achieved by column chromatography on potato starch. The isomeric compounds dibromophakellin (17) and oroidine (18) are marine products isolated from the sponges Phakelliaflabellata and Agelas oroides, respectively. The biogenetic re-

Scheme 2 Biomimetic synthesis of dibromophakellin (17) r

IS]. 7

(19a): R = H (19b) : R = CH,

H

Br

,

HBr

Br

(23) 50%

(21) 70%

(20) 73%

Biomimetic Natural Product Syntheses

lationship of the two molecules is evident, and the in vitro isomerization of oroidine (18) to dibromophakellin (17) appears to be both a simple and a creative approach to synthesis of the latter. Nevertheless, Buchi and Foley [S] chose instead to investigate the oxidative cyclization of dihydrooroidine (23), whose synthesis is outlined in Scheme 2. Esterification of citrulline (194affords (19b), which is reduced with sodium amalgam to the aldehyde, condensed with guanidine, and treated with aqueous hydrochloric acid to give imidazol (20) in a one-pot reaction. Basic hydrolysis affords the amine (21), reaction of which with pyrrole derivative (23) finally leads to dihydrooroidine (23).The biomimetic cyclization is accomplished in two steps: first, an unstable intermediate thought to have the structure (24) is produced by treatment of (23) with bromine. Subsequent reaction of the salt (24) with potassium-tert-butoxide affords racemic dibromophakellin (17) in quantitative yield. Thus, even very optimistic synthetic strategies turn out to be successful in some cases! Parazoanthoxanthin A (25), also a marine product, has been synthesized in the same research group by following the putative bioge-

H ~ *N C

biogenesis

synthesis

N,

o~H

11

235

netic pathway: dimerization of two arginine moieties, followed by decarboxylation [6]. Indeed, when heated in hydrochloric acid in the presence of FeC13, imidazole (26) dimerizes to give parazoanthoxanthin A (25)in 50% yield [7]. With this result in mind, the following mechanism has been proposed a posteriori: acid-catalyzed elimination of water from (26) might lead to vinyl imidazol(27), and this could react with another molecule of (26) to give the salt (28). Further electrophilic substitution and in situ oxidation would finally result in the natural product (25).

Numerous aromatic natural products are formed in uiuo from acetate units via poly-pcarbonyl compounds. This biogenetic pathway was first postulated by Collie at the beginning of the century. Robinson later revived the idea, which was finally proven by Birch [S]. When Harris and his group pioneered the corresponding biomimetic syntheses [S], the preparation of the starting polyketones turned out to be the most difficult problem, whereas their cyclization occurred more or less spontaneously. In a synthesis [9] of emodine (34, a substance found in numerous plants, fungi, and lichens, the polyketone (30a) is synthesized in a rather simple way by condensation of the diester (29)with the dianion of acetylacetone. Naphthalene derivative (31) arises in 39% yield from spontaneous cyclization of (304 via triketone (30b).The formation of the third ring results from an alkaline aldol condensation, leading to ketone (32) in 94% yield. Aromatization and cleavage of the

236

Bio-oriented Methodology

phenol ether gives the anthrone (33),which is easily oxidized to anthraquinone (34).

ml

EtO

0 moE

I

L0 O

(300)

OH OH 0

0

1

OH 0

00

* @A

0

‘OH

I

(31) 39%

f30b) 85 %

MeOWKOH

OH OH 0

25%

I

OH 0

I

OH

OH CH3

c H3

0

(32) 94%

(33) 7 8 %

1

CH30

0 -MethyltetrahydroOCH3

triphyophylline

in a plethora of creative and imaginative syntheses, but also in the development of numerous useful synthetic methods. Particularly fundaSimilar biomimetic syntheses have been used mental and fascinating syntheses of eicosanoids to prepare several isoquinoline alkaloids, in- originated with Corey and his coworkers. The cluding 0-methyl-tetradehydrotriphyophylline same group also succeeded in carrying out a (isolated from tropical lianes of the genera Tri- biomimetic prostaglandin synthesis. phyophyllum and Ancistrocludus), whose bioThe biosynthesis of prostaglandins starts synthesis is known to involve polyketone inter- from unsaturated Czo-fatty acids like arachimediates [lo]. donic acid (35). Radical reactions [12] could For almost three decades, prostaglandins, or lead via intermediates (36u),(36b),and (36c)to - in more general terms - “eicosanoids”, have endoperoxides, including the isolable [13] fascinated biologists, biochemists, and synthetic PGH2 (33, and this turns out to be a starting organic chemists [Ill. In fact, the combined material for several prostaglandins, for example efforts of hundreds of chemists resulted not only PGF;?,.

Biomimetic Natural Product Syntheses

(35)

237

(36a)

OH

PGHz (37)

H? zH HO

OH

Corey's biomimetic synthesis [14], which is indeed very similar to the biosynthesis, is outlined in Scheme 3. The isomeric alcohols (38a) and (39a) are separated and converted into the corresponding mesylates. By substitution with hydrogen peroxide dissolved in diethyl ether, hydroperoxides (38b) and (394 are obtained, which upon mercuration yield dioxolanes (40) and (41). Subsequent formation of a carbocyclic five-membered ring is the key step, induced by treatment with Bu,SnH followed by introduction of oxygen. The resulting hydroperoxides (42) and (43) are immediately reduced and then reacted with pyridinium tosylate in methanol. The acetals (44) and (45) are thereby obtained in the ratio of 2: 1 with 60 to 90% yield, in both cases as C* epimeric mixtures. The ratio of the products (44):(45) does not depend on whether (40) or (41) is used as the starting material. Exclusive formation of stereoisomers with a cis configuration for the alkyl side chains (i.e., (44) via endo,endo-(42) and (45) via exo,exo-(42)) is

very surprising. This stereochemicaloutcome is explained by the authors as follows: the spzhybridized carbon radical (46) is stabilized by interaction with a) an electron lone pair from the closest peroxide oxygen atom, and b) the Rorbital of the other carbon chain. Thus, the conformation (46) occurs, assuming that, for steric reasons, the two C - H bonds are directed inward. Starting from this favored conformation, disrotatory ring closure leads either to exo-exo orientation of the side chains in (42) [-+(44)] or endo-endo orientation in (43) [+ (45)]. The thermodynamically more stable, naturally occuring trans isomers, e.g. PGFz,, do not result from this reaction, and it is still a matter of speculation why the enzyme complex of prostaglandin synthetase affords the trans product in vivo. After separation from (45), the cyclic acetal (44) is oxidized to the ketone (47) and subsequently isomerized by acid catalysis to enone (48). Stereoselective reduction with Noyori's

238

Bio-oriented Methodology

Scheme 3 Corey’s biomirnetic synthesis of prostaglandins [14].

LiAlH,-binaphthol complex leads to carbinol (49),whose conversion into PGF2, had already been described in the literature [lS].

Imitating nature often helps in the search for new synthetic strategies, and the synthetic chemist is sometimes persuaded by nature to

Biomimetic Natural Product Syntheses

OxoCH3

HO (47)

(48)

(49)

1. H.OO

follow (successfully!)a synthetic pathway that, without knowledge of biogenesis, he would never have tried.

References [l] J. Thesing: “Clemens Schopf”, Chem. Ber. 112, I (1979); C. Schiipfand G. Lehmann, Liebigs Ann. Chem. 518, 1 (1935); cf. R. Robinson, J. Chem. SOC.111, 762 (1917).

239

[2] W. S. Johnson, K. Wiedhaup, S. F. Brady, and G. L. Olson, J . Am. Chem. SOC.90, 5277 (1968). [3] W. S. Johnson, Y.-Q. Chen, and M. S. Kellogg, J. Am. Chem. SOC.105, 6653 (1983). [4] H. Barth, G. Burger, H. Dopp, M. Kobayashi, and H.Musso, Liebigs Ann. Chem. i981, 2164. [5] L. H. Foley and G. Biichi, J. Am. Chem. SOC. 104, 1776 (1982). [6] L. Cariello, S. Crescenzi, G. Prota, and L. Zanetti, Experientia 30, 849 (1974). [7] M. Braun, G. Biichi, and D. F. Bushey, J. Am. Chem. SOC.100,4208 (1978). [a] T. M. Harris and C. M. Harris, Tetrahedron 33, 2159 (1977) and ref. cited therein. [9] T. M. Harris, A. D. Webb, C. M. Harris, P. J. Wittek, and T. P. Murray, J . Am. Chem. SOC. 98, 6065 (1976). [lo] G. Bringmann and J. R. Jansen, Tetrahedron Lett. 25, 2537 (1984), G. Bringmann, Tetrahedron Lett. 23, 2009 (1982). [ll] R. Noyori and M. Suzuki, Angew. Chem. 96,854 (1984); Angew. Chem. Int. Ed. Engl. 23, 847 (1984) and references cited therein. [12] In the lipoxygenation of fatty acids by soybean lipoxygenase, a high-spin Fe(II1) form of the enzyme’s active site seems to play a key role, this pathway competes favorably with free-radical biogenesis: see: E. J. Corey and R. Nagata, J. Am. Chem. SOC. 109, 8107 (1987). [13] M . Hambery and B. Samuelsson, Proc. Natl. Acad. Sci. USA 70, 899 (1973). [14] E. J. Corey, K. Shimoji, and C. Shih, J. Am. Chem. SOC. 106,6425 (1984); Chem. Eng. News, 3. Sept. 1984, p. 7. [l5] E. J. Corey and R. Noyori, Tetrahedron Lett. 1970, 311.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

F. Synthesis with Ex-Chiral-Pool Starting Materials

In view Of the Of a variety Of compounds in enantiomerically Pure form (e-g. carbohydrates or amino acids) it is obvious to to use these materials in the synthesis of more sophisticated target molecules. This strategy, the so-called “ex-chiral-pool-synthesis”, has been applied hundreds of times; several typical examples are described in this chapter.

Literature: S. ffanessian, Total Synthesis of Natural Products: The “Chiron” Approach, Pergamon Press, Oxford, 1983. D. Seebach, H. 0. Kulinowski, Nahr. Chem. Tech. 24,4151 (1976).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

( R )- and ( S )-2,3-Isopropylidene Glyceraldehyde Unbiased” Chiral Starting Materials

“

The manifold aspects of natural product synthesis have received enormous attention during the past decade. Along with the development of new methodology, the demand for efficient and versatile ex-chiral-pool starting materials has become a central issue [I]. This trend has rekindled interest in an old compound prepared more than fifty years ago by H. 0. L. Fischer [ 2 ] : (R)-2,3-isopropylidene glyceraldehyde (1). Inexpensive D-mannitol can be converted into its di-acetonide and then submitted to glycol cleavage with lead tetraacetate in benzene to furnish (1)in acceptable overall yield [3]. Polymerization and racemization can be avoided

H-C-CO,H

I

Scheme 1 HO-CHz

H~C-O-CO-R’

I

I

HO-C-H I HO-C-H

HY-O-CO-R~ H~C-O-CO-R~

2 (CHahOO

I

H-C-OH I

___)

ZnCh

(5)

H-C-OH I

CH2-H D-

Mannitol

cxo-FHz

H3C H3

1. H&*

0-CH

HO-C-H I

PWOAc)4,

I

H-C-OH I

H-6-0 H#!!-OXCH3 ’Diacetonide”

CH3

Benzene

H\

P

F H7-OXH3

H2C-0

(R)-fl)

Hg

if acetic acid arising from the lead tetra-acetate is removed by stirring the crude material with solid potassium carbonate in ether [4]. The glycol cleavage can also be performed with sodium metaperiodate in THF/water [S]. After distillation, (1) can be stored in the freezer for months without decomposition. In the first synthetic applications, aldol condensation of (1) with dihydroxyacetone provided D-fructose in low yields [6a], and a Strecker reaction led to amino acid (2) - un-

244

Ex-Chiral-Pool Starting Materials

selectively [6b], of course. More useful was catalytic hydrogenation of (1)to the chirally modified glycerol derivative (S)-(3) whose terminal carbinol units are clearly differentiated by the acetonide protecting group. This allows the preparation of optically active monoglycerides (4) and triglycerides (5). Despite being optically pure, (5) shows no specific rotation, in analogy to the natural triglycerides [7]. Unfortunately, the mannitol route is only applicable to the (R)-enantiomer of (1).L-Mannitol is difficult to prepare, so alternative methods had to be developed for the synthesis of (S)-(f). One procedure utilized L-arabinose as the starting material [Sa]. Other routes have been devised from ascorbic acid [Sb] and tartaric acid [Sc]. However, all these procedures are far less efficient than the old Fischer methodology. Both enantiomers of (1) have been used in the synthesis of glycidol derivatives (6),which are key intermediates on the way to aryloxypropanolamines (7), important P-blockers (e.g. propranolol, R = iPr, Ar = a-naphthyl) [9]. More recently, epoxides (6) have also been prepared via Sharpless epoxidation [IOa] and enzymatic resolution [lob]. An early application of (S)-(1) prepared from ascorbic acid, is the synthesis of (R)-amino+hydroxybutyric acid (GABOB), an important hypotensive antiepileptic drug [ll]. Scheme 2

1. HsO'

1.T C l

Hfl-R

CHI-OAr I H-C-OH I HpC-OTS CHrOAr I HC-OH H~C-NHR (7)

Moue

po*r

HC

I'p

HaC (6)

Scheme 3

roH

Ascorbic Acid

(S)-fl)

In contrast to these more or less obvious elaborations of the three-carbon skeleton in (1) and (3) Stork's work clearly suggests the enormous potential of such chiral building blocks. The basic strategy in his synthesis of the prostaglandin PGE, (14) entailed transcription of the chiral center in (R)-(1)to C-11 of the target molecule (14) (Scheme 4). The remaining functionality in (I) served for the required chain elongation and ring closure operations [12]. Thus, hydroxyether (9) was obtained by a stereo-unselective aldol-type addition and then converted into a y-lactone by treatment with acid. Application of the cyanohydrin-anionmethodology allowed ring closure to cyclopentane (10) by intramolecular alkylation. After oxidation of the side chain, sophisticated protective group manipulations were applied to differentiate between the 3- and 4-hydroxyfunctions. Formation of the 1-carbonyl group is followed by elimination of 3-OMOM to give the enone (11).After protection of the remaining 4OH-group the side chain at C-3 is introduced into (11)in optically active form by using the

Isopropylidene Glyceraldehyde

245

Scheme 4 0

1. Me02C-CH - (CH2)6- CH= CH - C p , ,

(R)-'7'

2 H3C-O-CH&l/(iPr)flEt

>

0-MOM

(UOMCI)

H30+

> A

(CH2)6-CH=CH-C8H17

H27

0-MOM

OH

-

1. TsCl 2. DlBAL

Gr--+ 4. Et-O-CH=CHd HCI

Er::--:H = CH - C8H17

0-

(CH2),-CH=CH-C8H1,

TsO

I

0 I

*om

EtoY

Na(Me3Si)2N

5: HO

2. H30+ 4. CH&

CN (Cki2)6-C02Me

1. Na104/KMn04

HO'

0 -MOM

(10)

THP

(73)

I

OH

principle of kinetic resolution. Cyclopentenone (11) selects from racemic cuprate (12) the (R)enantiomer with >99.5% ee to form prostanoid (13), which is transformed into the desired PGE, by a known procedure. A truly Japanese multi-step synthesis (Scheme 5) was developed by Kitahara, Mori and Matsui for the macrolide brefeldin A (19) [13]. (S)-(3) was converted into the tosyloxynitrile (15) in 15 steps. Base-catalyzed cyclization generated (16),which was elaborated into (19) by alkylative chain elongation and macrolactonization. The alkyl component (18) was obtained from (S)-glutamic acid; it can be de-

rived from (S)-(3)as well [14], so that in the end all the chirality of (19)stems from (R)-(I). (R)-(I)was also used by Corey in an early synthesis of (11R)-HETE (23).The key step in this rather long sequence [14] (Scheme 6) is the regiocontrolled ring opening of vinyl epoxide (20) with the lithium acetylide-TMEDA-complex to furnish (21) which is then coupled with cuprate (22). The synthesis was completed by Lindlar-hydrogenation of the triple bonds and removal of the protecting groups. The renaissance of monosaccharide synthesis [16] has led to a re-evaluation of ( I ) as the simplest member of the aldose family, from

Ex-Chiral-Pool Starting Materials

246 Scheme 5

d

which, according to Emil Fischer’s concept, any other aldose can be obtained by chain elongation [6a]. However, in sharp contrast to the early work on Fischer-Kiliani-type reactions, stereocontrol is now a routine affair. For example, an efficient route to 2-deoxypentose derivatives like (24) has been found to be the addition of allylmetals to ( R ) - ( f )[17]. A related approach to hexose derivatives (25) uses the ZnC12-catalyzed addition of 1,3-dioxygenated dienes [18]) (so-called “Danishefsky dienes” [18]) to the carbony1 group of (f). Less efficient is the high pressure induced cycloaddition of l-methoxybutadiene to (R)-(f)[19], which produces a mixture of all four diastereomers. Unrivalled popularity has been achieved, however, by the Sharpless-Masamune method [20] due to its wide applicability and high degree of stereocontrol. In the case of (R)-(f),Wittig-Horner chain elongation and reduction of the resulting ester leads to the allylic alcohol (27),which can be converted into any one of the four diastereomers of aldehyde (28)via tartrate-directed epoxidation and regiocontrolled epoxide opening. Nevertheless, the rather long sequences resulting from this methodology have inspired alter-

CHz-OCH2Ph

MEMO--

--CX!-(CH~)S<

CHS bSiMeatBu

?H

+ 11 steps HO-, a

C/

H

,

(19)

Brefeldin A

MEM = Me0-CHpCH2+CH2-

Scheme 6

1. HC =CLi

/ (CH4.p- CH2-CH2- N(CH&

1. BuLi 2. CsCN

’

HMPMHF 2. CISiMe$Bu

Br Gc5H11

3 , H 2 C = C = C < (CH2)3C0&H3

o\si /

\

(21)

=A b

C

o\si I

5 /

\

- C02CH3

3 - (CHP)3

H

l

1. H9Lindlar 2. Bu4NF 3. H30@

I

OH

(11R)-HETE (23)

> (22)

Isopropylidene Glyceraldehyde

247

Scheme 7

(25)

22 kbar

OX0

native procedures for one- or two-carbon chain elongations [20a]. A large group of experiments is based on the general concept of converting (1) into a functionalized olefin and then using the double bond in typical addition reactions or pericyclic rearrangements. A variety of transition state models have been discussed for these processes. If the “antiperiplanar effect” of the oxygen [21] is accepted as the stereocontrolling principle, two reactive conformations (29) and (30) are plausible. Apparently both geometries are involved in various types of addition reactions. For instance, arylic ester (31) adds methoxide [22] and amines [23] via (30)to form syn [24]adducts like (32),which can be converted into p-lactam (33) [23]. Similarly, the Diels-Alder addition of cyclopentadiene to (31) apparently proceeds via (30) in a highly stereocontrolled manner [25]. High syn-stereoselection via (29) has been observed for (2,3)-Wittig type rearrangements [26]. Wittig-cyclopropanation of

(26)

(34) leads - via (29) - to the anti [24] diastereomer (35), which is an intermediate in a synthesis of chrysanthemic acid (36)[27]. Butyl cuprate shows an 81 :19-preferencefor the antiadduct (37) [28], and the same diastereomeric ratio was observed for the 1,3-dipolar cycloaddition of nitrile oxides to olefin (38). The predominant diastereomer (39) was transformed into 2-deoxyribose [29]. However, copper-induced addition of diazoesters to (41)proceeded in a totally unselective fashion, furnishing a 55 :45-mixture of cyclopropane esters (42)/(35) [28]. Similarly, Claisenrearrangements in different variants showed almost no selectivity ~291. Numerous other applications of (1)have been reported [30, 311, which clearly demonstrate the wide popularity of this chiral three-carbon fragment. Due to its simplicity, it is totally unbiased, and appropriate manipulation and chain elongation makes it possible to elaborate almost any desired target structure. This is the

248

Ex-Chiral-Pool Starting Materials

Scheme 8

main advantage of (1)over other "chirons" [32] like the inevitable D-glucose, which are overloaded with unwanted functionality and demand extensive protective group and degradation chemistry.

Preparation of ( R ) -2,3Isoprop y lidene Glyceraldehyde Anhydrous zinc chloride (1.80 kg, 13.2 mol) in acetone (10 1) was treated in portions with D-

mannitol(l.0 kg, 5.49 mol) at 5°C. The mixture was stirred at room temperature for 6 h; then potassium carbonate (2.3 kg, 16.6 mol) in water (2.1 1) was added slowly, followed by ether (2 1). After standing overnight the mixture was filtered and the residue was washed with ether/ acetone (1:1, 3 1). The combined filtrates were concentrated under reduced pressure and the crude product was dissolved in dichloromethane (2 l), washed with water to remove zinc, dried (MgS04), and evaporated. The residue was recrystallized in a minimum amount of lig-

Isopropylidene Glyceraldehyde

roin (Soxhlet apparatus) to furnish 1,2:5,6-di0-isopropylidene D-mannitol (950 g, 66%) as analytically pure crystals with m. p. 118 - 120°C. The diacetonide (64 g, 244 mmol) in dichloromethane (1300 ml) or in benzene (2000 ml) was treated in small portions with colorless lead tetraacetate (108.2 g, 244 mmol) at room temperature for 1-2 h. The mixture was filtered and the filtrate was evaporated under reduced pressure at 40°C. The residue was diluted with ether (300 ml) and stirred with anhydrous potassium carbonate at room temperature for 30 min. After filtration the aldehyde was distilled (b.p. 4S°C/12 torr) to give (R)-(f) (29 g, 46%) as a colorless liquid.

References [l] D. Seebach and H. 0.Kalinowski, Nachr. Chem. Tech. Lab. 24, 415 (1976). See also: J. W. Scott, in “Asymmetric Synthesis”, Vol. 4, p . I, J. D. Morrison and J. W.Scott, eds., Academic Press,

N. Y., 1984. [2] Son of Emil Fischer, 1888-1960. [3] H. 0. L. Fischer and E. Baer, Helv. Chim. Acta 19, 519, 524, 532 (1936); Helv. Chim. Acta 17, 622(1934); J. Biol. Chem. 128, 463 (1939). [4] R. Dumont and H. Pfander, Helv. Chim. Acta 66, 814 (1983). Cf. also the procedure from the author’s laboratory at the end of this article. [5] J. Mann, N. K. Partlett, and A. Thomas, J . Chem. Research (S) 1987, 369. [6a] H . 0. L. Fischer and E. Baer, Helv. Chim. Acta. 19, 519, 524 (1936). [6b] H. 0.L. Fischer and E. Baer, Helv. Chim. Acta 19, 532 (1936). [7] H. 0. L. Fischer and E. Baer, Chem. Reviews. 29, 287 (1941). [Sa] S. B. Baker, J . Am. Chem. SOC.74, 827 (1952). [Sb] A. B. Mikkilineni, P. Kumar, and E. Abushanab, J. Org. Chem. 53, 6005 (1988); M. E. Jung and T. J. Shaw, J . Am. Chem. SOC.102, 6304 (1980). C. Hubschwerlen, Synthesis 1986, 962. [Sc] Cf. V. Juger and V. Wehner, Angew. Chem. 101,512 (1989); Angew. Chem. Int. Ed. Engl. 28, 469 (1989) for the synthesis of 2-0-benzyl-glyceraldehydes. [9] M. E. Connolly, F. Kersting, and T. Dollery, Prog. Cardiovasc. Dis. 19,203(1976). W.L. Nel-

249

son and T. Burke, J . Org. Chem. 43,3641 (1978). D. E. McClure, E. L. Engelhardt, K. Mender, S. King, W.S. Saadri, J. R. HufJ: and J. J. Baldwin, J. Org. Chem. 44,1826 (1979). 6.this book, p. 292f. [IOa] K. B. Sharpless et al., J. Am. Chem. SOC.109, 5765 (1987). [lob] Manufactured by various companies, e. g. BASF AG, Ludwigshafen. [ I l l M. E. Jung and T. J. Shaw, J. Am. Chem. SOC. 102, 6304 (1980). [I21 G. Stork and T. Takahashi, J. Am. Chem. SOC. 99, 1275 (1977). [13] T. Kitahara, K. Mori, and M . Matsui, Tetrahedron Lett. 1979, 3021. [I41 S. Takano, E. Goto, M. Hirama, and K. Ogasawara, Heterocycles 16, 951 (1981). [15] E. J. Corey and J. Kang, J . Am. Chem. SOC.103, 4618 (1981). [I61 D. Hoppe, Nachr. Chem. Tech. Lab. 30, 934 (1982); G. McGarvey, M. Kimura, T. Oh, and J. M. Williams, J . Carbohydrate Chem. 3, 125 (1984). [17] R. W.Hoffmann, A. Endersfelder, and H.-J. ZeiJ, Carbohydrate Res. 123, 320 (1983). J. Mulzer and M . Kappert, Angew. Chem. 96,726 (1984); Angew. Chem. Int. Ed. Engl. 23, 704 (1984). [18] S Danishefsky, S. Kobayashi, and J. F. Kerwin, J. Org. Chem. 47, 1981 (1982). S. Danishefsky and B. Simoneau, J . Am. Chem. SOC.111,2599 (1988). [I91 J. Jurczak, T. Bauer, S . Filipek, M. Tkacz, and K. Zygo, J. Chem. SOC.Chem. Commun. 1983, 540. [20] M. G. Finn and K. B. Sharpless, in “Asymmetric Synthesis”, J. D. Morrison, ed., Academic Press, N. Y.,1985, Vol. 5, p . 247; B. E. Rossiter, ibid., p. 193. [20a] A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici, and P. Pedrini, J. Org. Chem. 54,693 (1989) and ref. [21] P. Caramella, N. G. Rondan, M. N. Paddon-Row, and K. N. Houk, J. Am. Chem. SOC.103, 2438 (1981); see also K. N . Houk et al., Science 231, 1108 (1986) and this book, p. 3ff. [22] J. Mulzer and M. Kappert, Angew. Chem. 96, 726 (1984); Angew. Chem. Int. Ed. Engl. 23,704 (1984). [23] H. Matsunga, T. Sakagami, H. Nagaoka, and Y. Yamada, Tetrahedron Lett. 1983, 3009. [24] syn-anti-nomenclature: S. Masamune, Sk. A. Ali, D. L. Snitman, and D. S. Garvey, Angew. Chem. 92, 573 (1980); Angew. Chem. Int. Ed. Engl. 19, 557 (1980). [25] J. Mulzer and M. Kappert, Tetrahedron Lett. 26, 1631 (1985).

250

Ex-Chiral-Pool Starting Materials

[26] R. Briickner, Chem. Ber. 122, 193, 703 (1989). [27] J, Mulzer and M. Kappert, Angew. Chem. 95, 60, (1983); Angew. Chem. Int. Ed. Engl. 22, 63 (1983). [28] M. Kappert and J. Mulzer, unpublished results. [29] A. Kozikowski and A. K. Gosh, J . Am. Chem. SOC.104, 5788 (1982);cf. p. 86f. [30] J. Mulzer, K. D. Graske, and B. Kirste, Liebigs Ann. Chem. 1988, 891. J. K. Cha and S. C. Lewis, Tetrahedron Lett. 25, 5263 (1984). [31] Review: K. Jurczak, S. Pikul, and T. Bauer, Tetrahedron 42, 447 (1986). Further applications: T. Suzuki,E. Sato, S. Kamada, H. Tada, K. Unno, and T. Kametani. J. Chem. SOC. Perkin Trans I, 1986m 387. B. M. Trost, J. Lynch, P. Renault, and D. H. Steinman, J. Am. Chem. SOC.108,284 (1986). Y.Kobayashi, Y.Kitano, T. Matsumoto, and F. Sato, Tetrahedron Lett. 27, 4775 (1986). J. Leonard and G. Ryan, Tetrahedron Lett. 28,

2525 (1987).S. Pikul, M . Kozlowska, and J. Jurczak, Tetrahedron Lett. 28, 2627 (1987). J. Mulzer, A. Angermann, and W.Munch, Liebigs Ann. Chem. 1986, 825. J. Mulzer, P. de Lasalle, and A. FreiJler, Liebigs Ann. Chem. 1986, 1152. J. Mulzer and C. Brand, Tetrahedron 42, 5961 (1986). J. Mulzer, A. Angermann, C. Seilz, and B. Schubert, J. Org. Chem. 51, 5294 (1986). J. Mulzer, A. Angermann, W.Munch, S. Schlichthorl, and A. Hentzschel, Liebigs Ann. Chem. 1987, 7. J. Mulzer, L. Autenrieth-Ansorge, H.Kirstein, T. Matsuoka. and W.Munch, J . Org. Chem. 52,3784 (1987). J. Mulzer, B. Biittelmann, and W. Munch, Liebigs Ann. Chem. 1988, 445. J. Coe and W. R. Roush, J. Org. Chem. 54, 915 (1989). [32] Total Synthesis of Natural Products: The "Chiron" Approach, s. Hanession, Pergamon Press, 1983.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Chiral Building Blocks from Carbohydrates

Carbohydrates are particularly attractive as renewable raw materials for the chemical industry: The price of 1 kg of sucrose ranges from ca. US $ 0.17 (world market price) to US $0.71 (EEC price) [l]. However, cane sugar itself is rarely used as a building block for chemical synthesis; instead, it is most often degraded to ethanol, with a deplorable loss of chirality [2]. Glucose, the most frequently employed starting material, costs about $ 6.15 per kg, but it is still less expensive than many common organic solvents (see ref. 3 for price comparisons). The chirality inherent in carbohydrates is of greatest interest for the synthesis of noncarboh! drate compounds, and over the last two decades it has led to a rapidly growing subspecialty in the general field of organic synthesis. Evidence is provided by the appearance of a number of reviews and books [4] on the subject, and even a special section in the Specialist Periodical Reports (Carbohydrates) of the Royal Chemical Society: “The Synthesis of Optically Active Non-Carbohydrate Compounds”. Nevertheless, a number of obstacles stand in the way of direct incorporation of carbohydrates into other types of natural products. The first is “overfunctionalization”, since sugars possess several chiral centers and hydroxy groups of similar reactivity. The second problem is the lack of carbonyl groups and double bonds desirable for further synthetic transformations. Out of the large number of reported synthetic

applications, this report will stress two aspects of the use of carbohydrates as chiral templates: 0 How can the number of hydroxy groups be reduced, with simultaneous creation of carbonyl groups and double bonds? 0 What methods are available for the transformation of the heterocyclic furan and pyran systems into carbocycles? The first challenge can be met formally by oxidation and hydroxy group elimination, an approach that has been systematically applied by Lichtenthaler and coworkers. Indeed, carbonyl groups and double bonds can be introduced at almost any point in the pyranose skeleton [3]. A few examples may serve to illustrate this “dihydropyran strategy”.

Dihydropyranones Important starting materials include derivatives of glucal or hydroxy glucal, such as (2) or (3).These can be prepared by taking advantage of improvements on the original procedures of Fischer [S] and Maurer [6], as shown in Scheme 1. Both (2)and (3) can be transformed into substituted dihydropyranones via BF3-catalyzed reaction with meta-chloroperbenzoic acid (MPBA). The BF3-catalyzed reaction takes a totally different course from the normal epoxidation of glycal esters: attack of peracid on the

Ex-Chiral-Pool Starting Materials

252 Scheme 1

Scheme 3

roH

0 rOAC

r OBZ

~ O B Z

rOBz

rOBZ

r OBZ

BzoQ

AcO

OBz

(3. Bz = Benzoyl

(3)

initially formed allylcarbenium ion (4) yields the intermediate (3,which fragments to the product (6) (Scheme 2). Dihydropyrans lacking substituents at C-2 are obtained from glucal derivatives such as (2). Scheme 2

r OBZ 0 BzO

-

0

(6)

\

002

2-Hydroxy glucal esters such as (3) ought to hydrolyze to compounds with carbonyl groups at C-2. This result is best achieved preparatively by hydroxyl aminolysis to (7) [S], followed by liberation of the ketone through treatment with acetaldehyde [9, 101 (Scheme 3).

The P-substituent can be eliminated by treatment with sodium acetate. Thus, the desired goal has been achieved with a short sequence of reactions, and only one chiral center remains in the target molecule (9).However, this chiral center occupies a strategically important position adjacent to the double bond of the a$unsaturated carbonyl group, and it can be the source of a high degree of asymmetric induction: in Michael additions, for example (see below). A relationship to the report on 0-glycosides [11] is established through the bromide (lo), which can be obtained directly by homolytic bromination of (8)[12], or from the 2-hydroxyglucal ester (3) via NBS bromination in the presence of an alcohol [13]. Synthesis of cisglycosides from mannose (P-D-mannosides) presents serious problems for the normal KO-

Cliirtrl h i / d i i i < q Blocks ,from Carbohydrates

nigs-Knorr reaction, but the 2-0x0-P-glycosides that are readily obtained from the bromide (10) permit efficient synthesis of this difficult type of P-D-manno-oligosaccharide simply by reduction of the keto group. The option is also available to introduce an amino group via the oxime. These methods are equally applicable to disaccharides such as lactose [14], the cheapest of the low molecular weight carbohydrates apart from sucrose, leading to oligosaccharides with an internal p-D-mannose or P-D-mannOSamine unit. Transposition of the carbonyl group to the 4-position is possible with the P-methylglycosides (13), derived from the pyran-3-one (9). Treatment of (13) with zinc borohydride leads to ( I d ) , a process that includes simultaneous elimination of the methoxy group [l5] (Scheme 4): Scheme 4 OBz

F!

253

since both the double bond and the pyranoside ring are easily cleaved. 6-Deoxy sugars are important intermediates in the synthesis of glycosidic antibiotics. They are usually obtained either from rhamnose or by reduction of 6-iodo sugars. An alternative is to prepare them starting from dihydropyranones of type (17), which rearrange under mild conditions to (19) in the mechanistically interesting reaction shown in Scheme 5. The process is apparently initiated by elimination of benzoic acid to the isolable intermediate ( I d ) , followed by protonation, acyl migration, and attack of the nucleophile from the back of (20) [16].

H2b

Scheme 5

+ Bu,NOAc OCH~

BzO

0

79x

BzO

OCH, 0

H3C

0 OBzO B C H ,

Ph

Grignard reagents and organolithium comThe following examples illustrate the utilipounds undergo 1,2-addition with these substrates, but the addition of lithium dimethyl- zation of these enantiomerically pure pyrone cuprate occurs with simultaneous transesterifi- units in natural product syntheses. The soft cation to afford the saturated 4-keto compound coral constituents (-)-bissetone (21) and (-)(15) [17]. An AlCl,-catalyzed cycloaddition of, palythazine (23)have been prepared through a for instance, cyclopentadiene yields the y-endo very simple reaction sequence starting from anullated tricyclic system (16) [17] (selectivity dihydropyran (9). The "E-conformation of (9) 10:1). Adduct (16)is an attractive starting ma- causes addition of the lithium enolate of aceterial for cyclopentanoid natural products, tone to take place preferentially (4: 1) from the

Ex-Chiral-Pool Starting Materials

254

Scheme 7

SchemP 6

b,;&

1. NH20H

85x

/,2. CH300

1. Pd/H2

_ 1 . Ag-lrrilale _j

2. K2C0d

57%

MeOH

3. PdlH2

H3C'''

(26)

NMe

OH

Scheme 8

P-side (i.e., from the front), which after deacetylation affords (21) [18] (Scheme 6). Oximation and saponification leads to (22), and the a-amino ketone prepared from (22)by hydrogenation then dimerizes to a dihydropyrazine, which is converted to (23) by air oxidation [lo]. The previously unknown absolute configurations of (21) and (23) were firmly established as S,S by this series of sterically unambiguous transformations starting from glucose. The construction of the pyrano[2,3-b]dioxane system starting from 3-keto halo sugars such as (24) and diols such as (25) is impressively illustrated by the synthesis of spectinomycin (26) [19] (Scheme 7). A BF3 catalyzed reaction with MCPBA is used twice in the convergent synthesis of (-)anamarine (33)from glucose [20]. The first step, OAc r)Ac conversion of (27) to (28),is analoguous to the conversion of (3) to (6). Compound (28) is re- - - > o Q Y i - + OAc OAc duced with zinc amalgam to remove the allylic (33) acetaxy group, and the resulting deconjugated double bond is subsequently equilibrated to the Reaction of the ylid derived from the phosthermodynamically more stable position, giving phonium salt (30) with the open-chain moiety (34, which is also derived from glucose, leads (29)(Scheme 8).

Chiral Building Blocks from Carbohydrates

primarily to the cis-olefin (32). Here again the combination of MCPBA and BF,-etherate is appropriate for oxidation to the lactone. The synthesis of anamarine (30) is completed by isomerization and an exchange of protecting groups [20].

255

(35) are intermediates in the process, forming the carbocycles (37) after ring opening to (36), as shown in Scheme 9. Scheme 9

Carbocycles The relationship between the previously described dihydropyranones and pyranoside carbohydrates is clearly apparent, and the same is true in the furanose series, but an analogy is not so obvious with respect to most carbocycles. Many important natural products are biogenetically derived from hexoses, including shikimic acid, which plays an important role in the biosynthesis of aromatic amino acids. It is tempting to try to carry out similar processes in the laboratory. Hanessian wrote concerning the construction of carbocycles from carbohydrates in a book that appeared in 1983 [4c]: “. .. there is a need to further develop this aspect of the utilization of carbohydrates in synthesis”. In fact, systematic investigations in this area reach back little more than a decade. The very first great success in the conversion of carbohydrates to carbocycles, the Ferrier rearrangement, was actually discovered by chance, as Ferrier [21] himself reported. Such transformations can be divided into three major groups, depending upon the nature of the decisive cyclization step: ionic cyclization, radical cyclization, or cycloaddition. A latent methyl ketone and an aldehyde function are both present in such 5,6-unsaturated glycosides as ( 3 4 , so - in principle - cyclization to a cyclohexanone derivative should be possible after opening of the pyran ring. Acid catalysis proved unsuccessful under a variety of conditions, but treatment with aqueous mercuric acetate was eventually shown to give the desired cyclization products. There is reason to believe that organomercury compounds such as

(34)

OTs

CH2Hg0Ac 3HBzO J+ /

L o +Bzo (35)

OTs

CH2Hg0Ac

BzO

(36) OTS

(37)

OTs

Interestingly, the expected formation of a five-membered ring by displacement of the tosyl group was not observed. Indeed, this mercury mediated cyclization has not yet been extended to the formation of five-membered rings in spite of intense efforts by Ferrier’s group [22]. However, the Ferrier rearrangement is applicable to such sugar derivatives as the DielsAlder adduct (40), which can be prepared from the orthoquino dimethide (38) and the unsaturated pyrone (39) (Scheme 10). Olefin (41) is then prepared from (40) in a sequence of five steps, and this is easily rearranged to (42) by treatment with mercuric acetate [23]. Pseudo sugars can also be prepared by the Ferrier rearrangement [24]. In a typical Ferrier reaction both the nucleophile and the electrophile are present in the same sugar molecule. In many cases, however, the unit that is to be the source of a nucleophilic center must first be separately attached to the

256

Ex-Chiral-Pool Starting Materials

a ocHZoH

Scheme 10

0

70%

+

~

elegant syntheses of shikimic acid make use of activation by phosphonates such as (45), leading in one step to the protected shikimic acid (46) (Scheme 12) [27, 281. (See ref. 30b, c for syntheses of optically active shikimic acid from the “chiral pool”). Scheme 12

, Acetone/H20

(4 1 )

H OEt

A simple but very flexible synthetic strategy has been developed by Suami and Tadano and H coworkers [29]. Essential to the success of their (42) approach was prior fixation of the open-chain form of the sugar and selective protection of the Schemci I I primary hydroxy group (the OH group at C-6 GLucose +in a hexose). Both conditions can easily be met OTs for almost any sugar by thioacetal formation and tritylation of the primary hydroxy group. The reaction sequence from D-ribose to the known thioacetal(47) and conversion of the lat\ ter to the malonic ester (48)is straightforward (43) CH3 (44) CH3 (Scheme 13). After deprotection, the primary hydroxyl sugar framework. An exahple of this approach to the construction of carbocycles is the brefel- group is next oxidized to an aldehyde, and basedin synthesis of Ohrui and Kuzuhara [25] induced cyclization is followed by acetylation (Scheme 11).Many earlier syntheses of this type to afford (49).The new chiral center is generated embody the same principle [4e]. The key step in many cases with remarkable stereoselectivity. is ring closure of the C-H acid ester (43) An allylic alcohol obtainable from (49) is conderived from glucose to afford a five-membered verted to the “pseudo sugar” (50) by hydroboration. Pseudo sugars contain a carbon atom ring (44). Activation may also be achieved by the in- in place of the pyranose oxygen, which may be troduction of a wide range of C - H acidic com- of pharmocological interest in the context of ponents (e.g., nitro groups). Two independent glycosidase inhibition.

&

Chiral Building Blocks from Carbohydrates Scheme 13

Scheme 14

D-Ribose - -

7 / O b o

>

w

TrO (47)

BnO

SEt

?

0

LiCH2P(OMa)2 I1

THF

0 x 0

H3C02C, ,C02CH3

-

257

1. PCC

1. ring-opening

.2 Oxidation

OBn OBn (48)

0 x 0

H3C02C C02CH3

A

'

O

i OBn -

OBn OBn

(49)

-

> A c o ~ o A c OAc OAc

(50)

Bn = Benzyl

Several other reagents in addition to malonic ester are available for the introduction of acidifying functional groups. For example, lithium alkylphosphonates have found successful applications in sugar chemistry. These react with lactones such as (494 to form adducts (49b)that exist primarily in the cyclic lactol form. Ring opening and oxidation lead to dioxophosphonates, which cyclize to (49c) (Scheme 14; see ref. 29 b, c for similar examples). No additional oxidation step is necessary in the Fujimoto-Belleau reaction as applied by Vasella [29d] to the pseudo lactone (494 (Scheme 15). Addition of the lithium enolate of tert-butyl acetate to (494 is followed by ring opening and cyclization to afford the highly functionalized cyclohexanone (49e) in 51% yield. The "malonic ester method has proved useful for the construction of highly functionalized pseudo sugars, but it requires a relatively long reaction sequence [30a b, d]. Cyclohexanones with fewer substituents can also be obtained by other routes. Perhaps the most popular sugarlike starting material for natural product syn-

OBn

Qo

x

0

0 (49c) Bn = Benzyl

Schemcj 1.5 0 1. LiCH.$O$-Bu

EtsSiO

OSiEt,

A (- 78 lo 20 51 %

oc)

(494

kEt,

(49e)

theses is the keto sugar (51), easily obtainable from diacetone glucose. The major reason for this popularity may be the excellent diastereoselectivity observed in addition reactions to the carbonyl group at C-3. A similar selectivity is observed in the hydrogenation of the Wittig product (52), which is further transformed into the ketoaldehyde (53)(Scheme 16). Cyclization of (53)leads to cyclohexanone (54) with defined stereochemistry at C-4 and C-5 and sufficient functionality to permit further transformations ~311. As a rule, anionic cyclization leads to deoxy compounds. The precursors must be carefully

258

pJ

Ex-Chiral-Pool Starting Materials

Scheme I7

Scheme 16

96%

2.H' 1. HdNi 3.Na104 83%

~

0

(52) (EIZ mixture)

(53)

H 1. DBU

2. Ac*o/pY 44%

0

(54)

H ./o.'

(55) (56)

fJ5) selected to avoid the elimination of P-leaving groups. This restriction is can be circumvented by taking advantage of the increasingly popular radical cyclization of carbohydrate precursors, in which there is also no danger of epimerization of chiral centers adjacent to carbonyl groups. The configuration of the newly created chiral center naturally remains open, and depends on the nature of the protecting groups and the geometry of the double bond, as shown by the work of Wilcox [34], Rajan Babu [33], Redlich [34], Giese [35], Vasella [36a], Bartlett [36b], and Fraser-Reid [36c, 371. The problem is illustrated by the reaction of the ( E ) and (2) isomers (55)and (56) to afford the stereoisomers (58) and (59), respectively (Scheme 17) [32a]. Yields depend upon the configuration of the double bond and upon whether or not the starting materials are acetylated, as shown in Table 1. Cascade or tandem reactions to afford polycyclic products are also possible provided the double bonds are arranged suitably in the starting material. This is illustrated by the double

(56)

R

yield (57 58)

ratio (57/58)

H H COCH3 COCH3

80% 80% 82% 80

2: 1 6: 1 1:l 5: 1

+

radical cyclization of (59) to the tetracyclic product (60),which may be a useful precursor for further transformations to polyquinane systems (Scheme 18) [37]. Scheme 18

Cycloadditions The unsaturated pyranones discussed in the first section of this chapter are excellent sub-

Chiral Building Blocks from Carbohydrates

strates for all types of cycloadditions [4b, 221, including the addition of carbenes as well as [2 + 21, [2 + 31, and [2 +4] cycloadditions [38]. Photochemical [2 + 23 cycloadditions very often prove quite difficult to scale up, a disadvantage that is avoided by the use of dichloroketene. Redlich and Lenfers were able to convert the carbohydrate enol ether (61) to the adduct (62)in over 80% yield (Scheme 19) [39]. The chlorine atoms can be reductively removed to (63)by treatment with zinc in acetic acid. Scheme 19

R R

(6 1 )

259

example from the glucose series: bromide (64), which is readily available from glucose, is reductively opened to the unsaturated aldehyde (65) with activated zinc. This aldehyde was found to be rather labile, and it was therefore treated immediately with N-methylhydroxylamine to afford the nitrone (66). Nitrones such as (66) cannot be isolated due to spontaneous [2+ 31 cycloaddition to (67) (Scheme 20). The isomer with a 1,2-trans arrangement of the nitrogen and the neighboring alkoxy group is the sole product, formed in a kinetically controlled reaction. Isoxalines of type (67)can then be opened reductively (HJPt) with cleavage of the C-N bond. (See ref. 43 for examples of hetero Diels-Alder reactions with unsaturated sugars).

0

(62): R = C l

(63): R = H

Scheme 20 F

Br

Zn

RO

-

OCH3 65-88%

OR

(64)

MsNHOH

Ro%RO CHO

RO

(65)

An intramolecular version of a [2+3] cycloaddition is applicable to glucose [40], mannose [41], and galactose [42]. The effectiveness of this methodology, introduced by Vassella and coworkers, can also be seen in its implimentation by other groups (see ref. 22 and 23). The principle may be illustrated by a simple

References [l] Zuckerind. 115,505 (1990). [2] Ethanol from renewable raw materials, see Nachr. Chem. Tech. Lab. 32, 316 (1984). [3] F. W. Lichtenthaler in Atta-ur-Rahman (Ed): “Pyranoid chiral building blocks: preparation from monosaccharides and utilization for natural product synthesis”. Springer-Verlag, BerlinHeidelberg 1986, p. 227. [4] a) F. W. Lichtenthaler, Pure Appl. Chem. 50, 1342 (1978); b) B. Fraser-Reid and R. C . Anderson: “Carbohydrate Derivatives in the Asymmetric Synthesis of Natural Products”. Fortschr. Chem. Org. Naturst., Springer-Verlag, Wien 1980, p. 1; c) A. Vasella: “Chiral Building Blocks in Enantiomer Synthesis - ex Sugars”, in R. Scheffold (Ed.): “Modern Synthetic Methods 1980”. Salle und Sauerlander. Aarau 1980, p. 174; d) T. D. Inch, Tetrahedron 40, 3161 (1984); e) S. Hanessian: “Total synthesis of Natural Products: The Chiron approach. Pergamon, New York 1983; f) F. W. Lichtenthaler, Kontakte (Darmstadt) 1984, No. 2, p. 30. [5] a) E. Fischer and K . Zach, Ber. Dtsch. Chem. Ges. 47, 196 (1914);b) W. Roth and W. Pigman, Methods Carbohydr. Chem. 2, 405 (1963). [6] a) K. Maurer, Ber. Dtsch. Chem. Ges. 66,955 (1933);b) R. J. Ferrier and N . Prasad, J. Chem. SOC.C f 969,570.

260

Ex-Chiral-Pool Starting Materials

[7] P. Jarglis and F. W.Lichtenthaler, Tetrahedron Lett. 23, 3781 (1982). [S] F. W.Lichtenthaler and P. Jarglis, Tetrahedron Lett. 21, 1425 (1980). [9] F. W. Lichtenthaler, E. S. H. El Ashry, and V. H. Gockel, Tetrahedron Lett. 21, 1429 (1980). [lo] P. Jarglis and F. W. Lichtenthaler, Angew. Chem. 140, 643 (1982); Angew. Chem. Int. Ed. Engl. 21, 625 (1982). [ l l ] See this book, p. 277ff. 1121 F. W . Lichtenthaler, P. Jarglis, and W. Hempe, Liebigs Ann. Chem. 1983. 1959. [13] F. W. Lichtenthaler, E. Cuny, and S. Weprek, Angew. Chem. 95, 906 (1983); Angew. Chem. Int. Ed. Engl. 22, 891 (1983). [14] a) F. W. Lichtenthaler, E. Kaji, and S. Weprek, J. Org. Chem. 50, 3505 (1985); b) F. W. Lichtenthaler and E. Kaji9 Liebigs Ann. Chem. 1985, 1659. [l5] F. W. Lichtenthaler, U. Kraska, and S. Ogawa, Tetrahedron Lett. 1978, 1323. [16] F. W. Lichtenthaler, S. Nishiyama, P. Kohler. and H. J. Lindner, Carbohydr. Res. 136, 13 (1985). [17] P. Kohler, Dissertation, Darmstadt 1986. [lS] M. Brehm, W. G. Dauben, P. Kohler, and F. W. Lichtenthaler, Angew. Chem. 99, 1318 (1987); Angew. Chem. Int. Ed. Engl. 26, 1271 (1987). [19] E. Cuny and F. W.Lichtenthaler, unpublished. [20] F. W . Lichtenthaler, K. Lorenz, and W. Y.Ma, Tetrahedron Lett. 28, 47 (1987). [2l] R. J. Ferrier, J. Chem. SOC.Perkin. Trans. 1, 1979, 1455. [22] Review of prostaglandines from sugars: R. J. Ferrier and P. Prasit, Pure Appl. Chem. 55, 565 (1983). [23] S. Chew and R. J. Ferrier, J . Chem. SOC.Chem. Commun. 1984, 911. [24] C. German, P. Hirsch, and F. W.Lichtenthaler, 4th Carbohydrate Symposium, Darmstadt 1987, Abstracts No. A-96. [25] H. Ohrui and H. Kuzuhara, Agric. Biol. Chem. 34. 395 (1980). [26] Carbocycles from dialdehydes and nitromethane: W . F. Lichtenthaler, Angew. Chem. 74, 84 (1964); Angew. Chem. Int. Ed. Engl. 3, 211 (1964); Fortschr. Chem. Forsch. 14, 556 (1970). [27] G. W.Fleet, T. K. M. Shine, and S. M. Warr, J . Chem. SOC.Perkin 1, 1984, 905. [28] S. Mirza and A. Vasella, Helv. Chim. Acta. 67, 1562 (1984). [29] K. Tadano, H. Maeda, M. Hoshino, Y. Iimura, and T. Suami, J. Org. Chem. 52, 1946 (1987). a) M. Lim and V. E. Marquez, Tetrahedron

[30]

[31] [32] [33]

[34]

[35] [36]

[37] [38] [39] [40] [41] [42] [43]

Lett. 24, 5559 (1983); b) cf. ibid. 24,4051 (1983); c) Generalized method: H.-J. Altenbach, W . Holzapfel, G. Smerat, and S. H. Finkler, ibid. 26, 6329 (1985); d) S. Mirza, L.-P. Molleyres, and A. Vasella, Helv. Chim. Acta. 68, 988 (1985); e) Palladium catalyzed cyclization of vinyl epoxides cf.: S. Achab, J.-P. Cosson. and B. C. Das, J . Chem. SOC.Chem. Commun. 1984,1040. a) K. Tadano, H. Maeda, M. Hoshino, Y.Iimura, and T. Suami, Chem. Lett. 1986, 1081; b) Shikimic acid: T. Suami, K. Tadano. Y. Yoshidide, and Y. Iimura, Chem. Lett. 1985, 37; c) H. J. Bestmann and H. A. Heid, Angew. Chem. 83, 329 (1971);Angew. Chem. Int. Ed. Engl. 10,336 (1971); d) K. Tadano, K. Habakuba, H . Kimura, and S. Ogawa, J. Org. Chem. 54, 276 (1989). T. Suami, K. Tadano, Y. Ueno, and C. Fukabori, Chem. Lett. 1985, 1557. a) C. S. Wilcox and L. M . Thornasco, J . Org. Chem. 50, 546 (1985); b) C. S. Wilcox and J. J. Gaudino, J. Am. Chem. SOC.108, 3102 (1982). a) T. V.Rajan Babu, J . Am. Chem. SOC.109,609 (1987); J. Org. Chem. 53, 4522 (1988); b) T. V. Rajan Babu, T. Fukunaga, and G. S. Reddy, J . Am. Chem. SOC.l l f ,1759 (1989). a) H. Redlich and W.Sudau, 4th European Carbohydrate Symposium. Darmstadt 1987. Abstract No. A-93; b) H. Redlich, J. B. Lenfers, and W.Bruns. Liebigs Ann. Chem. 1985, 1570. B. Giese and K. Gronninger, Tetrahedron Lett. 25, 2743 (1984). a) R. Meuwly and A. Vasella, Helv. Chim. Acta. 64, 997 (1985) and ref. cited b) P. A. Bartlett, K. L. McLaren. and P. C. Ting, J. Am. Chem. SOC.110, 1633 (1988); c) G. D. Vite, R. Alonso, and B. Fraser-Reid, J. Org. Chem. 54, 2271 (1989). R. Tsang and B. Fraser-Reid, J. Am. Chem. SOC. 108, 2116 (1986). Aspects of the [2+4] cycloaddition with sugar derivatives. H . Redlich and J. B. Lenfers, 4th European Carbohydrate Symposium. Darmstadt 1987. Abstract No. A-86. B. Bernet and A. Vasella, Helv. Chim. Acta 62, 1990 (1979). B. Bernet and A. Vasella, Helv. Chim. Acta 62, 2400 (1979). B. Bernet and A. Vasella, Helv. Chim. Acta 62, 2411 (1979). J. C. Lopez, E. Lameignere, and G. Lukacs, J. Chem. SOC.,Chem. Commun. 1988, 514.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

II. Applications in Total Synthesis A. Synthesis of Classes of Natural Products

Natural product synthesis is one of the most fascinating and rewarding fields of organic chemistry. In contrast to past decades when such syntheses served primarily as the ultimate proof of a postulated structure (e.g. morphine or strychnine), natural product synthesis is now the battlefield for demonstrating new methodologies or superior strategies. Sometimes a whole class of natural compounds, like alkaloids or cembranoids will profit from such developments. More frequently, however, it is one specific compound that becomes the focus of synthetic interest, and within a short period of time, ten or more synthetic routes emerge, based

on totally different strategies and starting materials. Coriolin, frontalin and statine are striking illustrations of this phenomenon. Finally, non-natural targets sometimes receive a great deal of attention due to their exotic structures and for unusual properties; such is the case with fenestranes and dendrimers. Literature: Strategies and Tactics in Organic Synthesis, (Th. Lindberg, Editor), Academic Press, N.Y., 1984. Creativity in Organic Synthesis, (J. S. Bindra and RBindra, Editors), Academic Press, N.Y., 1975. The Total Synthesis of Natural Products, (J. Ap. Simon, Editor), John Wiley, N.Y., Volumes 1-8.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Some Recent Highlights From Alkaloid Synthesis

Alkaloids have stimulated the imagination and creativity of synthetic organic chemists for many decades. This is due not only to the manifold physiological effects of many alkaloids but even more to the complexity of the ring structures and functionality that is characteristic of this class of compounds. Woodward‘s syntheses of quinine [l] and strychnine [a] were milestones in the development of modern natural product synthesis. In this connection, it may be interesting to have a look at some of the recent developments in the synthesis of alkaloids.

by crystallization can (1) be obtained diastereomerically pure.

&

COzH

/

H/N

3

B I

(1)

4

1

+

/

H/N

(14

/

Hz

Lysergic Acid ( I ) Although ergolines (general formula (2))are of increasing importance in gerontology, it was lysergic acid ( I ) , that received great attention worldwide due to the abuse of its diethyl amide (LSD) as a hallucinogen. Altogether six syntheses of (f) have so far been reported, over a period of more than thirty years [3 - 81. The following discussion deals only with the three most recent: by Ninamiya [6], Rebek [7], and Oppolzer [ S ] . Any synthesis of (f) has to anticipate the tendency of ring C to undergo aromatization ((I + (la)). This problem can be circumvented by reducing the 2,3-double bond of the indole system early in the synthesis, and regenerating it at the very end. Another problem is spontaneous epimerization at C-8; only

Retrosynthetic disconnection (Scheme 1) shows that simple indole derivatives served in all these cases as the starting materials. Normally, an appendage must be introduced at C-3 by Mannich procedures; this is unnecessary; of course, if one starts with L-tryptophan. Routes a-c differ in the way rings C and D are annulated to the A/B-indole nucleus. Routes a and b use a Friedel-Crafts type annulation of C to A, whereby a 10-ketone is generated, suitable for the annulation of ring D. Ninamiya’s synthesis [6] (Scheme 2) is modelled after Woodward’s precedent [3] up to intermediate (12).Acylation of (12)generates (13), which is submitted to a photoinduced, conrotatory electrocyclization of the triene system.

264

Classes of Natural Products

Scheme I Retrosynthetic analysis of ( I ) .

(5)

CO2R’ I

L-Tryptophan (6)

m Scheme 2 Synthesis of ( k ) - ( i )according to Ninamiya [6].

&!:: C02H

C02H I

I

H”

1.HdNi

Ti2

(91

‘ ”“ H :Q y Bz”

+ NaBH4

* 1. SOCI*

(10)

1. LiAlH4

Q:-++

BZ”

1. oso4

2. Na104 3. Cr03 MeOH

,

&? \

BZ /N

0

II

BZ = C-Ph

Alkaloid Synthesis

265

Scheme 3 Synthesis of optically active (I) according to Rebek [7]. AlCl

A

04c02Br zB: ;$ 0

@,NHBz

CH2Br \ ZniTHF

\

BZ”

\

H”

S0 A

H

CH2,Br M e

1. NaH/Mel

-

\

2. HBr

BZ”

&

(20)

(19) Separation from the 3a-epimer

L-Tryptophan (6)

H“

CH,

(27) Lysergine

This permits ring D to be closed in (14) with defined relative stereochemistry at C-9/10. Borohydride reduction leads to an epimeric mixture at C-5, whereas C-8 is protonated stereoselectively to form a cis-annulated system. Diastereomer (16) is obtained by crystallization, and it is then converted into (1) via oxidative disconnection of the dihydrofuran to form (17) and dehydration to (18). The rest of the synthesis was already known [3]. Optically active (1) has been obtained from L-tryptophan by Rebek [7] (Scheme 3). Following route b (Scheme l), Friedel-Crafts annulation is accomplished by way of the azlactone

(20) without epimerization at C-5. Ring D is annulated in a multistep sequence starting with a chelate-controlled [9] Reformatsky-type spiroannulation that gives (22) selectively. SN2-cyclization via (23)closes ring D, which is bridged by a y-lactone, (24), and the latter is opened to give hydroxyester (25). Dehydration and Nbenzoylation generates Ninamiya’s intermediate (18) as a mixture of 8-epimers (= (26)). Other ergolines such as lysergine (27) have also been prepared as an outgrowth of this work. Oppolzer’s synthesis of racemic ( I ) [ S ] (Scheme 4) features is an intramolecular DielsAlder reaction ((33)+ (34))as its key step (route

266

Classes of Natural Products according to Oppolzer [8].

Scheme 4 Synthesis of (*)-(I)

1. NaOHlMeOH (N-Ts +NH)

TS"

2. CH2=0, Me2NH 3. CH3NO$Me0,C-C

Me02C

w2

200 OC

v

w 2. TiCI3. H2N-OMe.

H"

-

C0,Me

N-OMe

5---

/

3

4

M e:& ;

+

HN

I. MeOSO#

/

3

4

HN

(33)

(+)

('1

3. KOH

(34)

Scheme 5 a-Acyliminium-olefin cyclization according to Speckamp [iOJ

R

9

H n = 1,2

H R4'

= HQ(N&H, or R'(RMgX)

FI

0

H E-C
H

(35)

3C-CO2Me

>

Alkaloid Synthesis

c in Scheme 1). Phosphorane (28), prepared from the known alcohol (8) (R = Ts), is condensed with the aldehyde (29)to give (30).After N-deprotection, the side chain at C-3 can be introduced via a Mannich reaction, and the resulting nitro compound (31)is then reduced to the oxime ether (32).Thermal Diels-Alder cycloreversion generates (33), which undergoes the expected aza-Diels-Alder cyclization to furnish (34)as a mixture of stereoisomers. Straightforward manipulations - including deconjugation of the 8,g-double bond - lead ultimately to (I).

Acyliminium Cyclizations Cationic olefin cyclizations have frequently been used in the construction of polycyclic frameworks. An interesting adaptation of this

261

concept to N-heterocyclic systems has been devised by Speckamp [lo] (Scheme 5). Thus, succinimides are first N-alkylated with an o-alkenyl appendage and then reduced to the hydroxylactam, which provides an acyliminium cation (35)under acid-catalyzed dehydration. 6Endo-trig cyclization followed by formiate addition leads to (36).The 5-exo-trig product (37) is not observed [ll]. Applications of this reaction to the synthesis of racemic elaeokanine B [12] (Scheme 6a) and perhydro-histrionicotoxin [13] ((38), Scheme 6b) are self-explanatory. The example of (38) illustrates the possibility of spiroannulation by invoking a Grignard addition for introduction of the alkenyl appendage. It was necessary to overcome the inherent tendency toward the formation of six-membered rings in Hart's synthesis of the pyrroli-

Scheme 6a Synthesis of racemic elaeokanine B 1121.

HOn

1

w-

Et02C- N= N - C02Et

1. HO/OH/H@

TGy-+ 0

_ j MeOH quant.

Scheme 6b Synthesis of racemic perhydro-histrionicotoxin (38) [131.

0

14 d 42 OC

' I' H

__j 2. NaBH4 3. DIBAL

Elaeokanine B

268

Classes of Natural Products

explained by assuming an aza-Claisen rearrangement of (44) to (49, which gives (46) under Markownikow-control. The stereocontrol over

zidine alkaloid (- )-hastanecine ((39),Scheme 7) [14]. Interestingly, the intermediate (44) cyclizes to a five-membered ring (46). This can be

Scheme 7 Synthesis of pyrrolizidine alkaloids according to Hart [14]. HO-H,C

H

OH

OH

2 m 6

?H

4

HO

(40) 0

(39) (-)-Hastanecine

::+' I

BnO

C02H

(41) (R)-Malic acid

-

BnO

87%

1. NaBH4 2. HC0$

0

0

(43)

ooc 40

(47)

'H

Scheme 8 Synthesis of (+)-heliotridine according to Charnberlin [16].

H

n

1. KfiOdMeOH

1. HgClgHfl

A 2. LDAlHMPA 3.MeOH

(53)

2. LiAIH4

(54)

0 (

(55)

+ )-Heliotridine

C-8 is interpreted via an intermediate (48). Similar aza-Claisen rearrangements have been used in alkaloid synthesis by several authors [l5]. It is not clear in the present case why a direct Speckamp cyclization does not occur. (46)is converted into (39) by hypoiodite-induced fragmentation of the superfluous 2-side chain into the 2-iodide, which is removed reductively. In a related synthesis of (+)-heliotridine ((53, Scheme 8) [16], the desired five-membered ring is obtained by using the highly polarized olefin

(50) for the acyliminium cyclization step. Due to the considerable stabilizing effect of the S,Sketene acetal, (52)forms regioselectively, and it is then converted into (55) by straightforward operations. Speckamp has also used his acyliminium cyclization in the construction of complex polycyclic alkaloids like vindorosine ((64), Scheme 9) [17]. The quaternary center is generated by a 1,5-electrocyclizationof the pentadienyl anion (59) [18] to form (60). The disrotatory course

Scheme 9 Synthesis of aspidosperma alkaloids according to Speckamp [f 71. 0 N- Bn

0

0

n

0

0

\FCH2'CLCH2-CO$Bu

(57)

Z N B n

tBuOLi

OJ

(58)

1.I-electrocyclic

1. H30@

A

2. NaBH4

OH

(60)

C0,tBu

HCI MeOH

(67)

& +&liC 0

CO,CH, I

Me

Me

(63)

Vindorosine (64)

Bn = CH2Ph

270

Classes of Natural Products

of the reaction suggests that (59) must have a (Z)-imine geometry. The nucleophile in the acyliminium cyclization is the enol double bond of the 0-ketoester formed from (64 by ketal cleavage. Cis-annulation and re-enolization produces (62),from which (64)is pr_epared in a laborious sequence.

Interestingly, cyclizations of the type (59)-+ (60) can be performed enantioselectively under the influence of ephedrine-derived additives, so that (64) may in principle be obtained in nonracemic form [18a].

Scheme 10 Synthesis of bridged macrolactam alkaloids according to H . H. Wasserman [19].

1. ( B o c ) ~ ~ 2. 2,CLutidine.

2. PhthN-(CH2)2Br NaHlDMF

-

i

Boc

(67)

Ly,) R

!

Me0

(69)

w

0

I Boc

H

Br

1.

(64

I Boc

R = C13C-CH2-O-C- II

1. Cl3CCH2-0-C-CI

2. Me30@ BFlo 3. NaHCO3/H@

A

("Zip Reaction")

$H

JH

0 II

e

P

BOC= ~ B u - 0 - C -

NaH, Fyridine, CuCl 2. BFjHOAc

Me0

(73)

(69)

+

qdc2 ?

(73)

Me 0

‘I

I Boc

Alkaloid Synthesis

1. BFYHOAC 2. AcCl 3. Na6H3CN HOAc

271

3

(74)

A

N>

3. ZnlHOAc 4. DMAP/high dilution

HN..-n./Nd

Ac

(75)

&Me (76) (Chaenorhine)

Macrocyclic Alkaloids

group. The stabilizing effect rests on Coulomb interactions between the carbanion, its counWasserman developed an interesting strategy terion, and the dipole. Meyers applied this confor the synthesis of macrocyclic polyamine lac- cept to benzyl-type a-amino carbanions [21]. tam alkaloids like chaenorhine ((76),Scheme 10) To introduce chirality, L-valine (77) was con[19]. The approach is connective, based on cou- verted into the t-butyl ether (78) and treated pling of the two fragments (69) and (73). The with N,N-dimethylformamide dimethyl acetal medium-sized ring in (69)is generated by means to give the amidine (79). Acid-catalyzed exof the “zip-reaction” [20], which converts (67) change of dimethylamine for tetrahydro-p-carinto (68). Component (73) is obtained in race- boline, followed by N-protection and deprotonmic form from isovanillin (70)by Ullmann con- ation, furnished the dipole-stabilized carbanion densation of phenol (71) and bromide (72).Cy- (80). Alkylation with bromide (81) proceeded clocondensation of the aminoester (73) and the stereoselectively (de 96%) to give (82),which iminoether (69)generates dihydropyrimidinone produced (S)-deplancheine (83) after O-depro(74) under elimination of methanol. After re- tection and cyclization [22]. placement of the Boc-group by acetyl, the dihydropyrimidine heterocycle is cleaved reductively to give (75).The second macrocyclic ring Intramolecular Diels-Alder is closed by converting the methyl ester into an Reaction activated ester (pentafluorophenyl), removing the N-protecting group with zinc, and forming Intramolecular Diels-Alder reactions are indisthe amide under DMAP catalysis and high di- pensable tools in natural product synthesis lution conditions. [23]. Their application to alkaloid synthesis

-

Alkylation of Dipole Stabilized Car banions A simple expedient for stabilizing carbanions is substitution with a highly dipolar functional

was pioneered by Oppolzer [S] and Magnus [24], who have reported a number of examples. Boeckman recently described an especially elegant synthesis of lycorine precursors (e.g. (88)) involving Diels-Alder cyclization of (87) [25]. This intermediate was generated in a novel way,

272

Classes of Natural Products

Scheme 11 Alkaloid synthesis via alkylation of dipole-stabilized carbanions [22].

J

2. CI-CHflMe 3. nBuLi

183)

starting with a Strecker-type condensation of an isoindole and a cyclopropane aldehyde to give aminonitrile (84).Removal of cyanide leads to an iminium ion (85),which undergoes a rapid vinylcyclopropane-type ring enlargement to the spiro ammonium ion (86). DBU-induced elimination furnishes (87). The high degree of stereocontrol in the Diels-Alder step is due to the rigid geometry of (87).

I

VBE = Valinol-tert-butylether

Axially Chiral Naphthylisoquinoline Alkaloids The phenomenon of axial chirality arising from hindered C-C-rotation in a biaryl system is a well-known stereochemical curiosity, but it is also important in certain classes of natural products, including lignans [26] and naphthylisoquinoline alkaloids such as ( -)-ancistrocla-

Alkaloid Synthesis

273

Scheme 12 Lycorine synthesis by intramolecular Diels-Alder reaction according to Boeckman 1251.

toluene

Scheme 13 Synthesis of axially chiral alkaloids according to Bringmann [27].

I

OCH3

ethylarnine (84%)

1. LiAIH4 2. Desoxygenation

7YGGZz (86%)

dine (96). Bringmann [27] described the first asymmetric synthesis of (96), that entails a Heck-type [28] coupling of an aryl bromide to

the ortho-position of a phenol ether (Scheme 13). The components for this connective synthesis are prepared from (89),which is reduced

274

Classes of Natural Products

enantioselectively to give amine (90). A Bischler-Napieralsky reaction and diastereocontrolled reduction furnishes (92). Deblocking of the P-methoxy group, N-benzoylation, and 0acylation with (93)generates (94).Treatment of (94) with a palladium catalyst produces a 3:lmixture of stereoisomers. The major diastereomer (95) is converted without epimerization into (96). This synthesis thus represents one of the rare cases where central chirality (in (94))is used for the introduction of axial chirality (in (95)).

Biomimetic Alkaloid Synthesis The importance of biomimetic concepts in natural product synthesis is discussed elsewhere in this book [29]. Biomimetic cyclizations generating complex alkaloid ring structures in a few steps are particularly fascinating. Kuehne in his synthesis of vindoline alkaloids employed a biomimetic Diels-Alder cyclization as the key step [30] (Scheme 14). Mannich-type conden-

sation of the amino-enamine (99) with lactol (98) gave (loo),which underwent an intramolecular N-alkylation followed by fragmentation of the seven-membered ring to give the key intermediate (101). Spontaneous Diels-Alder cyclization furnished (102)as a mixture of stereoisomers. Standard procedures were used to convert the main component (102) into (103). Intramolecular aza-Diels-Alder reactions were also applied by Heathcock in a series of spectacular biomimetic alkaloid syntheses [31]. Heathcock also studied another type of biomimetic cyclization, the intramolecular Mannich reaction. Early examples reported by Corey were the result of brillant retrosynthetic considerations [32]. Heathcock’s approach to racemic lycopodine [33] (Scheme 15)focuses on the cyclization of amino-diketones (104). Despite epimerization to (105), only one product (107)is formed in this case, because (108)cannot cyclize as a result of the equatorial placement of the ketone appendage. In the synthesis of (116) the requisite amino functionality is introduced via the nitrile, saponification to the acid,

Scheme 14 Biomimetic synthesis of vindoline (103) according to Kuehne (301.

H \ , No CI (97)

;&OH

“I

(98)

H3C0

H3C0 1102) . .

Vindoline (103)

275

Alkaloid Synthesis Scheme 15 Biomimetic synthesis of (+)-lycopodine (116) according to Heathcock [33].

H

a

(107)

H

Me

0

I

a0

HCI, MeOH

1. CICOOEt. Et3N

GGzZ

2. H2N(CH2)aOCH2Ph 3. WIH,

.

&, c/:,f

_ t-BuOK, _j

:;

o*

Ph2C-0

0

[/\/OH

L

O (113)A

P

h

(114)

amide formation, and reduction with lithiumaluminium hydride. Cyclization of (f f 2) to (f 13)requires 14 days to provide a 65%-yield

,@

(1 15)

(116)

of the desired compound. Hydrogenolytic removal of the benzyl group, followed by Oppenauer oxidation to the aldehyde and aldol con-

216

Classes of Natural Products

densation, produces (Ii5),which is hydrogenated to (116).

References [l] R. B. Woodward and W. v. E. Doering, J. Am.

Chem. SOC.67, 861 (1945). [2] R. B. Woodward et al., J. Am. Chem. SOC.76, 4749 (1954). [3] E. C. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann, D. E. Morrison, R. G. Jones, and R. B. Woodward, J. Am. Chem. SOC.78, 3087 (1956). [4] M . Julia, F. LeGoffic, J. Igolen, and M. Baillarge, Tetrahedron Lett. 1969, 1569. [5] R. Ramage, V. W. Armstrong, and S. Coulton, Tetrahedron Lett. 1976, 4311 Tetrahedron Suppl. 37, 157 (1981). [6] T. Kiguchi, C. Hashimoto, T. Naito, and I. Ninamiya, Heterocycles 19, 2279 (1982). [7] J. Rebek jr.. D. F. Tai, and Y.-K. Shue, J. Am. Chem. SOC.106, 1813 (1984). [S] W. Oppolzer. E. Francotte, and K. Buttig, Helv. Chim. Acta 64, 478 (1981). [9] M . T. Reetz, Angew. Chem. 96, 542 (1984); Angew. Chem. Int. Ed. Engl. 28, 556 (1984); E. L. Eliel, in “Asymmetric Synthesis”, Editor J. D. Morrison, Vol. 2, Academic Press, New York, 1983, p. 125. [lo] W.N. Speckamp, Rev.Trav. Chim. Pay-Bas 100, 345 (1981);B. P. Wijnberg, W .N . Speckamp, and A. R. C. Oostueen, Tetrahedron 38, 209 (1982). Recent developments: see P. M . Esch, I. M. Boska, H. Hiemstra, and W .N. Speckamp, Synlett 1989, 38 and ref. [ll] J. E. Baldwin, J. Chem. SOC. Chem. Commun. 1976, 734. [12] B. P. Wijnberg and W. N. Speckamp, Tetrahedron Lett. 22, 5079 (1981). [13] E. E. Schoemaker and W.N. Speckamp, Tetrahedron 36, 951 (1980). [14] D. J. Hart and T.-K. Yang, J . Chem. SOC.Chem. Commun. 1983,135;Tetrahedron Lett. 23,2761 (1983). [151 Review: S.Blechert, Synthesis f 989, 71. [16] A. R. Chamberlin and J. Y. L. Chung, J. Am. Chem. SOC.105, 3653 (1983).

[17] S. J. Veenstra and W . N. Speckamp, J. Am. Chem. SOC. 103, 4645 (1981). [18] R. Huisgen, Angew. Chem. 92, 979 (1980); Angew. Chem. Int. Ed. Engl. 19, 947 (1980). [18a] R. J. Vijn, W. N. Speckamp, B. S. DeJong, and H. Hiemstra, Angew. Chem. 96, 165 (1984); Angew. Chem. Int. Ed. Engl. 23, 165 (1984). [19] H. H. Wasserman, R. P. Robinson, and C. G. Carter, J . Am. Chem. SOC.105, 1697 (1983). [20] U. Kramer, A. Guggisberg, M. Hesse, and H. Schmid, Helv. Chim. Acta 61, 1342 (1978). [21] A. I. Meyers, Aldrichimica Acta 18, 59 (1985). [22] A. I. Meyers, T. Sohda, and M . F. Loewe, J. Org. Chem. 51, 3108 (1986). [23] Review: E. Ciganek, Org. Reactions 32, 1 (1984); D. Craig, Chem. SOC.Rev. 16, 187 (1987); A. G. Fallis, Can. J. Chem. 62, 183 (1984). See also: J. W.Coe and W.R. Roush, J . Org. Chem. 54,915 (1989). [24] P. Magnus, T. Gallagher, P. Brown, and J. C. Hufman, J. Am. Chem. SOC.106, 2105 (1984) and ref. [25] R. K. Boeckmanjr., J. P. Sabatucchi, S. W.Goldstein, D. M. Springer, and P. F. Jackson, J. Org. Chem. 51, 3740 (1986). [26] K. Tomioka, T. Ishiguro and K. Koga, Tetrahedron Lett. 21, 2973 (1980). [27] G. Bringmann, J. R. Jansen, and H.-P. Rink, Angew. Chem. 98, 917 (1986); Angew. Chem. Int. Ed. Engl. 25, 913 (1986). [28] R. F. Heck; “Palladium Reagents in Organic Synthesis”, Academic Press, New York, 1985, p. 187. [29] see p. 232ff. [30] M . E. Kuehne, F. J. Okuniewicz, C. L. Kirkemo, and J. C. Bohnert, J. Org. Chem. 47,1335 (1982). [31] C. H. Heathcock, S. K. Davidson, S. Mills, and M. A. Sanner, J. Am. Chem. SOC.108, 5650 (1986);R. B. Ruggieri, M. M. Hansen, and C. H . Heathcock, J. Am. Chem. SOC.110,8734 (1988); R. B. Ruggieri, K. F. McClure, and C. H. Heathcock, J. Am. Chem. SOC. If, 1530 (1989). [32] E. J. Corey and R. D. Balanson, J. Am. Chem. SOC.96, 6516 (1974). [33] C. H. Heathcock, E. F. Kleinman, and E. S. Binkley, J. Am. Chem. SOC.104, 1054 (1982).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Synthesis of 0-Glycosides

There is scarcely another field in synthetic chemistry that displays such interdisciplinary character as glycoside synthesis [l - 31. Carbohydrates are no longer regarded as merely skeletal supports or energy sources for the cell. Modern analytical methods have provided increasingly detailed insight into the complex nature of glycoconjugates and the dominant role they play, for instance, in the immune system. Synthetic chemistry has already contributed heavily in this field, and it has now accepted the challenge to synthesize ever more extended oligosaccharides. Progress in the analysis of complex oligosaccharide structures and a better understanding of fundamental biological processes depends on the availability of significant amounts of pure oligosaccharides, as does the development of better diagnostic and therapeutic measures.

Koenigs-Knorr Methods In contrast to peptide and oligonucleoside synthesis, where bifunctional monomers are connected linearly, the synthesis of oligosaccharides demands attention to the multifunctional nature of the monomeric units. The joining of three different amino acids can, in principle, lead to six different tripeptides, but three aldohexoses could couple to form 720 trisaccharides [3b]! Thus, in addition to perfecting methods for the linkage of monomers, sophisticated

protecting group techniques must also be developed. This contribution deals only with problems of the first type, which can best be introduced through the classical KoenigsKnorr synthesis. In this synthesis, halo sugars such as (1)function as glycosyl donors. Heavy-metal salts serve as catalysts or - better - as promoters, since more than catalytic amounts are usually employed. The stereochemical outcome of bond formation is a critical function of the substitution pattern of the halo sugars, and particularly of the nature of the substituent at C-2 next to the anomeric center. Generally, two types of substituents can be distinguished: 0 residues that are capable of neighboring group participitation, and 0 substituents without any major direct influence on the reaction at the anomeric center. 0-Acyl substituents (most simply, acetates) fall in the first category. These react under heavy-metal catalysis to form intermediate acetoxonium ions (2), as in the wellknown example of wD-acetobromoglucose (1) (Scheme 1). Nucleophiles (alcohols, in the formation of 0-glycosides) then attack from the opposite side, with formation of 1,Ztrans compounds. pD-Glucosides (4) are thus obtained starting from glucose (route a). Alternatively, ortho esters (3)can also be isolated (route b), and these occasionally decrease the yield of glycosides. It is true that ortho esters can be opened to 1,2-

278

Classes of Natural Products

bBr

Sckeme 1

cat.

7-

AcO

(1)

OAC

rOAC

@ - GLu-0 NHAc

(7) 1 cat, Nu

TGi?

AcO AcO

AcO

(4)

OAc

trans-glycosides under the influence of Lewis acids, but investigations by Kochetow [4] have shown that mixtures of products are likely, especially in the presence of a second alcoholic component. The reaction of (1)to afford (4) is perhaps the simplest example of stereochemical control at an anomeric center. Here it is not even necessary to start with isomerically pure halo sugars. A similar stereochemical course is observed in the reaction with 2-acetamido-2-deoxyglucose or the related phthalimides [2b]. In contrast to the labile acetoxonium ions, the stable 1,3-oxazolines (5) are isolable. They can also be converted to glycosides, as shown by the synthesis of the protected trisaccharide (7) from (5) and (6) (Scheme 2). Occasionally, the cleavage of simple acetamides proves difficult. In such cases the allyloxycarbonyl group, introduced into sugar chemistry by Kunz et al. [4b], can provide similar stereochemical assistance, as in the transformation of (7a) to a 1,2-trans-glycoside. Cleavage of the protecting group to afford (7b) occurs in this case under mild palladium(0) mediated conditions [4c,d].

Nu

AcO&AcO

B z ~= Benzyl; @ - Glu = @ - Glucosylacetate

What about a-D-manno-halo sugars such as with the opposite configuration at C-2? As expected, the acetoxonium ions (9) generated from (8) also open to 1,2-trans-glycosides,but with the difference that the.product is an CI-Dmanno-glycoside (10) (Scheme 3). Evidently

(a),

Scheme 3

AcO

(8)

d (10)

(9)

ROH

Synthesis of 0-Glycosides

stereochemical control poses no difficulties here either, particularly since products of type (10) represent the more stable glycosides due to the anomeric effect [Sb]. On the other hand, the corresponding 1,2cis-glycosides are much more difficult to prepare. (The principle demonstrated here with glucose is essentially applicable to other sugars as well, including galactose and rhamnose). From the discussion above it follows that it is essential to avoid substituents at C-2 that might exert neighboring group effects on the anomeric reaction center. Benzyl ethers have proven to be excellent protecting groups for hydroxy groups, and the azido group serves very well as a precursor to 2-cis-amino-2-deoxyglycosides. However, depending upon the catalyst, the halo sugar, and the substitution pattern of the reaction components, mixtures of cis- and transglycosides are often obtained, and these are not always easily separated. Clean inversion under kinetically controlled conditions with a-halo sugars such as (ii),giving the reactive P-halo sugars (12), is successful only in rare cases (Scheme 4). Nevertheless, such P-halo sugars can be reacted with serine derivatives like (13) to yield the cis-glycoside (14) [6], a building Scheme 4

“‘GO, NEt4Cl

J/

CI

AcO Ho-CH2-+H

NHZ

\

(12)

( 1 3)

N3

block for the construction of 0-glycoproteins W , el. The investigations of Lemieux [7] on the equilibrium between a- and P-halo sugars have been helpful with respect to the difficult problem of cis-glycoside synthesis. Establishment of equilibrium in the presence of a catalyst proceeds via a number of conformationally distinct oxonium ions. In a somewhat simplified picture, the highly reactive P-halo sugar reacts selectively in the presence of a glycosyl acceptor to give the a-glycoside (in the glucose series). The tetraalkylammonium halide catalysts introduced initially by Lemieux [7] proved very selective, but they required long reaction times and highly reactive alcohols. The principle of “in situ anomerization” was later investigated systematically by Paulsen’s group, and was applied to a wide variety of complex oligosaccharide syntheses of the 1,2-cis type [2]. In addition to quarternary ammonium salts, the following catalytic systems can also be employed, (with increasing reactivity): Hg(CN)2 < Hg(CNh/HgBr2(Helferich catalyst) < HgBr,/molecular sieves < AgC104/Ag2C03 < AgS03CF3.The reactivities of the halo sugar and the alcohol also influence the yield and selectivity in glycoside synthesis. Construction of a portion of the pentasaccharide chain of the Forssman antigen will suffice to illustrate the “in situ anomerization” methodology [8] (Scheme 5). The reactivity of a-bromide (15) is decreased by acylation, and the presence of the anchimerically inactive azido group at position C-2 further mandates the reactive catalyst AgC104 for coupling to the 3-OH of the anhydro sugar (16),affording the 1,2-cis-glycoside (1 The synthesis of P-manno-glycosides(19 ) (1,2cis type) is a most difficult problem. The in situ anomerization of the more stable a-halo sugar (18) to the P-halo sugar and subsequent reaction with an alcohol would lead to the formation of a 1,2-trans-glycoside, which could be prepared more easily via the acetoxonium ions

n.

Acoe \

C0,Bzl

YHZ

AcO

N3 OCH2CH I

(14)

C02Bzl

279

I

280

Classes of Natural Products

Scheme 5 Bz? BzO

,OAc +

B

N,

z

ing blocks could be of great diagnostic and therapeutic value. The reactivity of the otherI ? wise unreactive hydroxy group at C-4 is increased in the anhydro form (24, and coupling l O m with the bromide (20) under heterogeneous catalysis affords the desired 1,2-cis linkage in (22) [lo] (Scheme 7). Scheme 7

BzlO

NPhth (17) Bz = Benzoyl; NPhth = Phthalimido

AcO

AcO

+

(20)

Br

described previously. Anomerization of the halo sugar must be avoided if the thermodynamically less stable glycoside is to be prepared. This is best accomplished with a heterogeneous catalyst such as silver silicate on silica gel [9] or silver carbonate, whereby an alcohol replaces the halogen in (18)under essentially SN2 conditions to afford the P-manno-pyranoside (19) (Scheme 6). (See ref. 9a for the use of heterogeneous silver catalysts to prepare p-transglycosides with clean SN2inversion and 9b for radical intermediates to P-glycosides.)

Other leaving groups at C-I

The synthesis of the immunologically essential saccharide sequence from enterobacteriae (enterobacterial corum antigen, ECA) provides an example of this principle. In contrast to most surface antigens, which exhibit species-specific functions, ECA is a widespread family-specific antigen for enterobacteriae, a family that includes a number of pathogenic microorganisms. The availability of such oligosaccharide build-

“Are there alternatives to the Koenigs-Knorr synthesis?” is the challenging subtitle of a review by Schmidt [3b]. The principle disadvantages of the Koenigs-Knorr method are the instability of the requisite halo sugars and the high cost of the often toxic or explosive heavymetal promotors. It would be very useful to devise storable glycosyl donors with both aand P-configurations that could be transferred in a sterically defined manner to glycosyl acceptors. In their development of the “trichloroimidate method”, Schmidt and coworkers [12] reasoned that although protected sugars existed as an equilibrium mi&lre of open chain (23) and cyclic forms (24), they should add trichloroacetonitrile via the predominant cyclic form (24) to give trichloroacetimidates (Scheme 8) ~191.

> - 1. Ag-Silicate (49%) 2. AC20, CF3COOH 3. [O]. Esterification 4. Halogenation

OH (21) N3 A

c C02Bzl O

W

B

e

c

‘

AcO

Synthesis of 0-Glycosides

Scheme 8

Go@

RO

R O 0-

(23)

RO

Scheme 9 (25)

+

N3

HO-n-Cl3H27

R = Pivaloyl

OBn

i

% O ,R

/

(26)

1. BF3.0Et, (94%) 2. NaOCH3 3. H2S

Ro&Z&oG (thermodynamic

281

Ro

(24)

H O & o q K2C03

(78%) (kinetic control)

- C13H27 OH

(27)

OH

affords (27), a metabolite associated with Gaucher's disease. Just as in the Koenigs-Knorr reaction, a- and P-trichloroacetimidates from sugars with C-2 substituents that are capable of neighboring group participation react to give 1,2-truns-glyIntensive investigations into the course of the cosides. A typical example is the formation of reaction revealed that the more stable a-tri- the nonreducible trehalose (29) by reaction of chloroacetimidates are formed under thermo- (25) (R = Ac) with tetraacetylglucose (28) [3b] dynamically controlled conditions (with NaH (Scheme 10). In this case the Koenigs-Knorr as base), while P-imidates (26) are obtained un- reaction provided only low yields of product. Benzyl-protected a-trichloroacetamidates der kinetically controlled conditions (K2C03). The results initially obtained using benzylated such as (25) react with a number of glycosyl glucose with a free anomeric hydroxy group acceptors with preferential inversion at the anoproved applicable to a number of other sugars meric center, thereby affording P-glycosides [3b]. The trichloroacetimidates can be pullfed with the 1,Ztruns configuration [3b]. However, by crystallization, and due to their stability they the ratio of 3-and P-glycosides is strongly deare much easier to handle than the more labile pendent upon the alcoholic component. Prehalides. ferential formation of 1,Zcis glycosides (e.g. a0-glycoside formation is usually achieved by D-glucosides) may also be achieved by starting treating the trichloroacetimidates with BF3eth- with perbenzylated P-trichloroacetimidates. erate in dichloromethane. What stereochemical Reactive catalysts such as trimethylsilyl triflate results can be anticipated using trichloroacet- in ether have proven particularly useful in this imidates in the synthesis of glycosides? The for- reaction. This catalyst even activates such poor mation of a P-glycoside is illustrated by one of leaving groups as acetoxy [13], trimethylsiloxy the many examples [3] from glycolipid synthe- [14], or p-nitrobenzoyloxy groups [IS], and sis. The azido derivative of D-erythro-C18-sphin- even glycals can be used as glycosyl donors. gosine (26)undergoes smooth coupling with the However, the thermodynamically unstable 1,2a-trichloroacetimidate (25) [12] (Scheme 9). Sa- cis-glycosides of mannose or rhamnose (probponification and reduction of the azido group lem cases for the Koenigs-Knorr synthesis as

282

Classes of Natural Products

Scheme 10 ,OAc

R = Ac

(28)

OAc

AcO-~~

Amphotericine B

A m OH

NH

Structure (32) (A = aglycone), with its 1,2cis arrangement, suggests the extent of the challenge; additional problems include the basic nitrogen and the lability of the aglycone. The reactive a-trichloroacetimidate (30) was synthesized first, starting from glucose. Pyridinium p toluenesulfonate (PPTS) catalyzed glycosidation afforded, at 50% conversion, a 40% yield of the 1,2-trans-glycoside (31). Equivalent amounts of the corresponding ortho ester were also formed. Next it was necessary to invert the configuration of C-2. A five-step sequence eventually transformed (31) into (32),the polyene macrolide antibiotic amphotericin B. This is, incidentally, not the first case in which it was necessary to invoke this relatively complicated approach to a 1,Zcis product via inversion of the chiral center at C-2. (See ref. 16a for an alternative route to 1,2-cis-mannoses, and ref.

(31)

1. K2COS/MeOH 2. DMSO, (CFsCO),O 3. NoBH, 4. H F . P y 5. HS(CHJ3SH

well) have still not proven amenable to selective synthesis via imidates, even at low temperatures. One solution to this problem is illustrated by the glycosidation of amphoteronolide B to the amphotericine B [16]. (Scheme 11).

-Me *** .

I

N3

@

= Arnphoteronolide B residue

17 for further applications of the trichloroacetimidate method.) Leaving groups other than trichloroacetimidate have also been introduced at the anomeric center [2d, 3b], perhaps the most promising of which is the sulfonium group 1181. Let us at this point turn to a discussion of direct 1-0-alkylation, also a subject of investigation by Schmidt and coworkers. The reaction is applicable to both protected furanoses and protected pyranoses. The fascinating feature of this synthetic concept is the observed reversal in normal reactivity: the glycosyl donor serves here as the nucleophile, while the acceptor is the electrophile. Triflates of primary alcohols tend to be particularly effective as glycosyl acceptors. In the pyranose series, a-glycosides are the favored products at low temperature, whereas increasing the temperature favors the formation of P-glycosides [19]. Complex glycosides can also be prepared by this reaction

Synthesis of 0-Glycosides

[19a], but the principle is well illustrated by the reaction of the partially benzyl-protected glucose (25a) with triflate (33) to afford (34) (Scheme 12).

283

Scheme 13 OBzl

Scheme 12

OR

(254

NaH. Dioxane

OH

+

TfO-0

P-t (33)

RO

3

H3ce R

OAc OAC I

RT

(34)

OR

=

(36) without OH

(38)

dine under free-radical conditions to afford the corresponding 2-deoxysaccharide. Formation of the P-glycosidic linkage is also possible starting with 2-bromo-2-deoxyglycosyl bromides, which are available through treat2-Deoxyg lycosides ment of acetonides such as (39) with dibromo2-Deoxy sugars are common constituents of methylmethyl ether (DBE) [23]. Oligosaccharglycosidic antibiotics. Acid-catalyzed addition ides from the cytostatic agent mitramycin (a of alcohols to glycals is standard approach to constituent of the aureolic complex) are charthe glycosidic linkage [5a]. The route via 2- acterized by exclusive p-connection of the 2deoxyhalo sugars rarely leads to absolutely deoxy sugars. The disaccharide AB part of the pure adducts, and it is often the thermodyna- recently reported synthesis of both the AB and mically more stable product that predominates EDC (trisaccharide) segments of mitramycin is [20]. Selective formation of the a-glycosidic a good example of the principles involved linkage is possible under very mild condition (Scheme 14). The benzoate of methylrhamnoside (39) (R using the N-iodosuccinimide method [21], in which glycals such as (37) are treated with al- = benzoyl) can be brominated with DBE to cohols (36) in the presence of N-iodosuccinim- give the gluco-dibromide (41). Monobromide ide (NIS) to afford 2-iodo-a-glycosides (38) (40) is also accessible in several steps from the same starting material (R = H). Coupling of (Scheme 13). This reaction bears a clear resemblance to the the two fragments with silver triflate leads to iodolactonization method. The very mild con- the P-glycoside (42),which can then be debromditions of the NIS method even permit the di- inated with tributyltin hydride [24]. An alternative, less familiar route to p-2rect coupling of peptides to sugars [22a]. This methodology was applied in the construction deoxyglycosides begins with glycals such as from (36) and (37) of the trisaccharide (38), (43), which upon treatment with the commerfound in the antitumor antibiotic mussetta- cially available 0,O-dimethyl phosphorodimycin [22b]. The final step in such a synthesis thioic acid afford the a-intermediates (44) exis normally the hydrogenolytic removal of io- clusively (Scheme 15). The intermediates then R = Benzyl

284

Classes of Natural Products

Scheme 14

R*o

(40) Br

+ (40)

*H: B

(41)

d Ag - Triflat e

Br OBz

OBn

OHCO

react with alcohols in a clean inversion to give the P-glycosides (45) [25]. It should be noted, however, that this procedure has so far only been applied in a few cases. (For another synthesis of P-2-deoxyglycosides see ref. [25a].) The limited number of examples included in this contribution clearly demonstrate that much remains to be done before an automatic glycoside synthesis 4 la Merrifield can be re-

bR1 ROH

Base

HO

(45)

S (44)

alized. The experts are currently of the opinion that each complex glycoside synthesis poses its own unique problems. Nonetheless, systems as large as decasaccharides have been successfully synthesized by the research teams of Paulsen and Ogawa with the aid of sophisticated protecting groups and equally sophisticated blocking techniques. In some cases it may be prudent to take advantage of microbial or enzymatic methods. The use of microbes is a particularly attractive alternative for glycosides of homologous aglycones. Indeed, it is certain that mutant strains will make it possible to glycosidize microbially even unnatural substrates [26]. Another more universal route utilizes immobilized enzymes [27]. Much work must still be done to establish the substrate specificity of the various glycosyl transferases.

References [l] Review until 1974: G. Wulff and G. Rohle, Angew. Chem. 86, 173 (1974);Angew. Chem. Int. Ed. Engl. 13, 157 (1974). [2] Reviews of complex glycoside syntheses: a) H . Paulsen, Angew. Chem. 94, 184 (1982); Angew. Chem. Int. Ed. Engl. 21, 155 (1982);b) H. Paulsen, Chem. SOC.Rev. 13, 15 (1984);c) H . Paulsen in J. Streith, H . Prinzbach, and G . Schill (Eds.): “Organic Synthesis: an interdisciplinary Challenge”. Blackwell Scientific Publications, Oxford 1985, p. 317; d) H . Paulsen in “New Synthetic Methodology and Functionally interesting Compounds”. Kodansha, Tokyo 1986, p. 243; e) Glycopeptides: H. Kunz, Angew. Chem. 99,297 (1987);Angew. Chem. Int. Ed. Engl. 26, 294 (1987); f) Oligomannosides: T. Ogawa, H . Yamamoto, T. Kitajima, and M. Sugimoto, Pure Appl. Chem. 56, 779 (1984). [3] Reviews of novel glycoside syntheses: a) R. R. Schmidt in ref. 2c, p. 281; b) R. R. Schmidt, Angew. Chem. 98, 213 (1986); Angew. Chem. Int. Ed. Engl. 25, 212 (1986);c) R. R. Schmidt in W. Bartmann and K. B. Sharpless (Eds.): “Stereochemistry of Organic and Bioorganic Transformations”, VCH Verlagsgesellschaft, Weinheim 1987, p. 169. [4] a) N. K. Kochetkov, 0. S . Shizkov, and A . F. Bochkov, “Oligosaccharides: Synthesis and De-

Synthesis of 0-Glycosides termination of Structure”. Int. Rev. Sci. Org. Chem. Ser. 7, 147 (1973); b) H. Kunz and H. Waldmann,Angew. Chem. 96,49 (1984);Angew. Chem. Int. Ed. Engl. 23, 71 (1984); c) P. Boullanger, J. Banoub, and G. Descotes, 4th European Carbohydrate Symposium, Darmstadt 1987, Abstract No. A21; d) For the application of ally1 esters in the synthesis of 0-glycopeptides see: S. Friedrich-Bochnitschek, H. Waldmann, and H. Kunz, J. Org. Chem. 54, 751 (1989). [5] a) J. Lehmann: “Chemie der Kohlenhydrate”. Thieme Verlag, Stuttgart 1976; b) A. J. Kirby: “The Anomeric Effect and Related Stereoelectronic Effects at Oxygen”. Springer Verlag 1983; c) H. S. El Khadem, Carbohydrate Chemistry: Monosaccharides and Their Oligomers, Academic Press, New York 1988; d) R. W.Binkley, Modern Carbohydrate Chemistry, Marcel Decker, New York 1988. [6] H. Paulsen and J. P. Holk, Carbohydr. Res. 109, 89 (1982). [7] R. U.Lemieux, K. B. Hendricks, R. V.Stick, and K. James, J. Am. Chem. SOC.97, 4056 (1975). [8] H . Paulsen and A. Biinsch, Carbohydr. Res. 100, 143 (1982). [9] H. Paulsen and 0. Lockhoff; Chem. Ber. 114, 3102 (1981). [9] a) H . Paulsen and M. Schiiller, Liebigs Ann. Chem. 1986, 249; b) D. Kahne, D. Yang, J. J. Lim, R. Miller, and E. Paguaga, J. Am. Chem. SOC.110, 8716 (1988). [lo] H. Paulsen and J. P. Lorentsen, Angew. Chem. 97, 791 (1985); Angew. Chem. Int. Ed. Engl. 24, 773 (1985). [l 11 For the formation of imidates see D. C. Neilson in S. Patai (Ed.): “The Chemistry of Amidines and Imidates”. Wiley, New York 1975, p. 349. [lla] J. R. Pougny and P. Sinay, Tetrahedron Lett. 1970,4073. [12] R. R. Schmidt and P. Zimmermann, Angew. Chem. 98, 722 (1986); Angew. Chem. Int. Ed. Engl. 25, 725 (1986). [13] H. Paulsen and M . Paal, Carbohydr. Res 135, 53 (1984). [14] L.-F. Tietze and R. Fischer, Angew. Chem. 95, 902 (1983); Angew. Chem. Int. Ed. Engl. 22,888 (1983). [l5] Y. Kimura, T. Matsurnoto, M. Suzuki, and S. Terashima, J . Anitibiot. 38, 1277 (1985). [16] K. C. Nicolaou, R. A. Daines, T. K. Chakraborty, and Y. Ogawa, J. Am. Chem. SOC.109, 2821

[17]

[l8]

[19]

[20] [2l] [22]

[23] [24] [25] [25] [26]

[27]

285

(1987); a) D. Kahne, D. Yang, J. J. Lim, R. Miller, and E. Paguaga, J. Am. Chem. SOC.110, 8716 (1988). Cf. a) C. AugP, C. D. Warren, R. W.Jeanloz, M. Kiso, and L. Anderson, Carbohydr. Res. 82, 85 (1980); b) W.Kinzy and R. R. Schmidt, Carbohydr. Res. 166,265 (1987); c) Liebigs Ann. Chem. 1987, 407; d) T. Ogawa, M. Sugimoto, T. Kitajima, K. K. Sadozai, and T. Nukada, Tetrahedron Lett. 27, 5739 (1986); e) K. Koike. M. Sugimoto, Y.Nakahara, and T. Ogawa, Glycoconj. J. 2, 105 (1985); f) J. Alais and A. Veyrikres, Tetrahedron Lett. 28, 3345 (1987). a) H. Lonn, Carbohydr. Res. 139, 105, 115 (1985);b) P. Fiigedi and P. Garregg, Carbohydr. Res. 149, C9 (1986); compare also: c) D. Kahne, S. Walker, Y.Cheng, and D. Van Engen, J . Am. Chem. SOC.111, 6881 (1989). R. R. Schmidt, M. Reichardt, and U.Moering, J. Carbohydr. Chem. 3, 67 (1984); a) R. R. Schmidt and A. EJwein, Angew. Chem. 100, 1234 (1988); Angew. Chem. Int. Ed. Engl. 27, 1178 (1988). Cf. T.-M. Cheng, D. Horton, W. Priebe, W. R. Turner, and W. Weckerle, J. Antibiot. 38, 683 (1985). a) J. Thiem, H. Karl, and J. Schwenter, Synthesis 1978, 696; b) Review: J. Thiem, Nachr. Chem. Tech. Lab. 32, 6 (1984). a) H. Kessler, M. Kottenhahn, A. Kling, and C. Kolar, Angew. Chem. 99, 919 (1987); Angew. Chem. Int. Ed. Engl. 26,888 (1987); b) A. Martin and M . Pais, Tetrahedron Lett. 27, 575 (1986). K. Bock, C. Pedersen, and J. Thiem, Carbohydr. Res. 73, 85 (1979). J. Thiem and B. Schottmer, Angew. Chem. 99, 591 (1987);Angew. Chem. Int. Ed. Engl. 26,555 (1987). M. Michalska and J. Borowiecka, J. Carbohydr. Chem. 2, 99 (1983). a) S. Ramesh, N. Kaila, G. Grewal, and R. W. Franck, J. Org. Chem. 55, 5 (1990). Cf. a) T. Hoshino, Y.Setoguchi, and A. Fujiwara, J . Antibiot. 37, 1469 (1984); b) T. Hoshino and A. Fujiwara, ibid. 37, 1473 (1984); c) Z. Vanek, J. Tax, I. Komersova, and K. Eckard, Folia Microbiol. 18, 524 (1973). a) C.-H. Wong, S. Haynie, and G. M . Whitsides, J. Org. Chem. 47, 5416 (1982); b) J. Thiem and W. Treder, Angew. Chem. 98, 1100 (1986); Angew. Chem. Int. Ed. Engl. 25, 1096 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Cembranoid Syntheses

Cembranoids are diterpenes that contain 14membered carbocyclic rings. It turns out that they constitute the most widely distributed of all diterpene families, even though the first representative, cembrene ( I ) , was only discovered in 1965. Many structural variants are now known from both the plant and animal kingdoms, and they display a wide range of biological activity [11. Cembranoids are particularly numerous among the Caribbean horny corals and the Pacific soft corals. Representatives include mukulol (2),asperdiol(3), and anisomelic acid (4). The substances of marine origin frequently contain a cis- or trans-bonded a-methylene lactone ring. These are known as cembranolids, and they are often cytotoxic.

sented the first synthetic challenge. Today, however, it is the deliberate control over the relative and, ideally, the absolute configurations of stereogenic centers in substituted derivatives that provides the stimulus for attempting cembranoid syntheses. A variety of approaches is now available for achieving macrocyclization, including the coupling of terminal allylic halides to 1,5-dienes, intramolecular alkylation and olefination reactions, cationic cyclizations, and ring-contraction and rearrangement processes. Dauben employed for the first synthesis of cembrene (1)the Ni(CO)&duced coupling of a terminal allylic halide to a Wdiene, but this method suffers the disadvantage that it permits very little control over stereochemistry [2]. The simplest and most efficient syntheses have proven to be the biogenetically oriented cationic cyclization of geranylgeranoyl chloride (5) to (6) [3 - 61 and ,

o SnCI, CH2C12.

I (5)

The unusual combination of a 14-membered ring with precisely positioned double bonds, mostly arranged in an (E)-configuration, pre-

- 78%

71%

>

Cembranoid Syntheses

the alkylation of cyanhydrins such as (7) to (8) ~71. Intramolecular Friedel-Crafts acylation of geranylgeranoyl chloride to a 14-membered ring is possible not only with the (EEE) system (5) but also with the ( E Z E ) and the ( E E Z ) isomers [IS]. The sole prerequisite appears to be a 2,3-trans double bond, since otherwise a sixmembered ring results.

'

OEE (IlN

",

(7)

I

-"

1. NaN6iMs.).

72%

It is rather remarkable that geranylfarnesoyl chloride does not undergo cyclization with the terminal double bond in the presence of tin tetrachloride to yield an 18-membered ring. Instead, this reaction again leads to a 14-membered carbocyclic system [6] even though Dreiding models suggest that closure of the larger ring should be feasible. It is clearly apparent that the way is open to a host of cembranoid systems starting from (6) and (8) [4 - 61. Formation of the desired macrocyclic skeleton by the alkylative ring-closure of S-substituted carbanions is also possible in acceptable yield [8 - 10). Unfortunately, however, subsequent cleavage of the activating S-function from the allylic position can lead to problems, since it is often not possible to completely avoid allylic migration. The problems entailed in ring closure by intramolecular olefination will be discussed later. Wender has developed an unusually short route that has the additional ad-

287

vantage of producing enantiomerically pure compounds [ll - 131. He first synthesized the novel system (11) by joining two nucleophilic isoprene synthons with the monoterpene carvone, available in both its enantiomeric forms. Compound (11) is well suited to undergoing macrocyclization. Thus, the activating effect of the alkoxide function facilitates a rearrangement which, regardless of the configuration of the side chain, leads to the 14-membered ring derivative (12) as the only product. Compound (12) can in turn serve as the starting point for a variety of cembranoid systems. For example, it can be readily converted into (-)-(32)-cembrene A (13), a termite pheromone [ll]. The question as to whether the rearrangement takes place as a [5,5]-sigmatropic process or as a succession of [3,3]-sigmatropic steps (oxy-Cope followed by Cope rearrangements) has not been clarified. Both mechanisms could explain the observed stereospecificity provided one assumes that the alkoxide groups in both epimers of (11) are arranged axially in the transition state.

A

A

OMe

288

Classes of Natural Products

Another conceptually interesting approach to the construction of 14-membered rings is also applicable to other systems: namely, the ring contraction of a macrocyclic propargyl allyl ether by means of a Wittig rearrangement ~141.

dehydes (e.g., X = SIR, or SnR3in the presence of a Lewis acid), but these proved unsuccessful. Cyclization of the allylic bromide (16)(X = Br) was finally accomplished with CrC12. As expected, the reaction was anti-selective (antilsyn = 4:l).

p-. BuLi

(OR

85%

(75) X = OH, X‘ = H b) X = H, X’ = OH 0)

The 17-membered heterocycle (14), readily accessible via an intramolecular Williamson ether synthesis, is converted by this anionic rearrangement into the 14-membered carbocycle (15).The advantage of this cyclic modification of the [2,3] Wittig rearrangement from an entropy standpoint is clearly apparent. What is not so obvious is the fact that the stereoisomeric ratio depends upon the solvent, a surprising result that is not consistent with a concerted mechanism. Thus, a (15a):(15b)ratio of 4.5:l is obtained in hexane/THF, whereas the ratio is 1:6 in THF/HMPT. The development of an eficient approach to “acyclic stereocontrol” made it inevitable that this strategy for the directed synthesis of neighboring stereocenters during C-C bond formation [lS] would be applied to the synthesis of cembranoids - either during the preparation of acyclic precursors or in the course of closing the ring. Fundamental work of the latter type was contributed by W. C. Still [16]. Attempts were first made to cyclize (16)by various standard methods for adding allylic systems to al-

TH F

64%

I (4 : 1 diastereoisorneric mixture) (1 7)

Conformational factors attributable to the remote epoxide group are responsible for preferential formation of the diastereoisomer illustrated - a racemic mixture, since (16) was also a racemate - which provides a nice example of the principle of remote stereocontrol [17]. After removal of the (benzy1oxy)methylprotective group, (17) was converted to racemic asperdiol(3). The first synthesis of (3), which had aroused great interest on account of its antitumor activity, was reported by Kato [18], who synthesized the compound in a multistep process starting with (6)and involving a key transannular functionalization step. Compound (6) was in turn prepared by a cationic polyene cyclization. Diastereoselective addition of an allylic unit to an aldehyde has often been employed in cembranoid syntheses. The difficulties encountered by Still in his attempts at simultaneous ring closure-addition are probably attributable to steric hindrance of the unsaturated aldehyde by

Cembranoid Syntheses

289

the P,P’-disubstitution pattern. For this reason, Marshall [19] turned to a propargylaldehyde system, a unit that had already been shown in acyclic models to be more reactive. In fact, this led to a smooth cyclization displaying the synselectivity characteristic of allylstannanes, as shown by the conversion of (18) to (19). The high degree of stereoselectivity argues for a well-coordinated transition state, a circumstance that might be exploited using chiral alkoxy substituents to cause asymmetric induction. However, the primary role of the a-alkoxy substituent in (18) is to serve as the basis for the enol ether function present in (19),which is readily converted into a carboxylic acid for annulating a cis-fused lactone ring [20] found in certain cembranolides.

71% (E/Z > 10/1) (?4)

MOM = CHzOCH3

In order to generate a trans-lactone moiety, such as that found in anisomelic acid (4, Marshall employed the method of Hoppe [22] for anti-selective addition of a titanium substituted allylic carbamate to an aldehyde - in this case at a very early stage in the process: during construction of the acyclic precursor [21]. As might be expected under the conditions employed, (20) and (21) reacted primarily to give (22),with a synlanti-diastereomeric ratio of 5 : 95. Conventional methods were then used to

convert (22)to (23).Ring closure via olefination produced mostly the desired (Z)-product (24) irrespective of the reaction conditions or the nature of the phosphonate. The stereochemistry of the resulting double bond seems to be primarily a function of the macrocyclic environment, since even in the case of diisopropyl phosphonate [(23),X = OiPr], where high E-selectivity has been observed in analogous intermolecular Horner-Emmons reactions, it was still the (2)-isomer that was the principal product. Elaboration of the five-membered ring enabled Marshall finally to complete the first total synthesis of racemic anisomelic acid (4).

Classes of Natural Products

290

We conclude with a strategy in which the stereogenic centers are incorporated as a preformed segment and ring closure is effected elsewhere. This approach has been taken by two different research groups in the synthesis of desepoxyasperdiol, a precursor of (3) [181.

Gc:$

2. 1. BuLi Na/Hg

>

SOzPh

eo C0,Et

_ CH,CN DBU._ LiClj

THF KN(TMS)2 18-crown4 53%

53%

>

f--y S02Ph 3(3)

30%

(32) FO,Et

I

(28)

Marshall chose the system (26) (in racemic form) as a building block [23]. Wittig reaction of (26) with the stabilized yield (25) produced only the (E)-isomer of the product. After conversion of the ester function into a protected hydroxymethyl group, system (27)could be prepared by substitution of the terminal alcohol. This in turn led to the macrocycle (28) via intramolecular alkylation, and (28)was converted reductively in one step to (+)-desepoxyasperdiol. Tius also employed a convergent synthesis, this time one starting with optically active (30) [24]. The requisite chain was built up successively first by alkylation of the anion of (30) with allylic chloride (29).The product (31) ob-

I (E/Z-lsomer mixture)

(33)

tained after desulfonation was then subjected to manipulations at both ends to give an intermediate (32),from which (2)could be obtained by means of an intramolecular Horner-Emmons reaction. This olefination proved to be the major bottleneck in the whole synthetic sequence, since even the use of DBU/LiCl in acetonitrile, which Masamune and Roush have recommended for base-labile systems 1251, gave only a 30% yield of an (E/Z)-isomeric mixture, from which pure (33) could be isolated only

Cembranoid Syntheses

291

with heavy losses. The final conversion of (33) [12] P. A. Wender and S. M. Sieburth, Tetrahedron Lett. 1981, 2471. into (+)-desepoxyasperdiol posed no addi[13] P. A, Wender, S. M. Sieburth, J. J. Petraitis, and tional problems. S. K. Singh, Tetrahedron Lett. 1981, 3967.

References [l] Review: A. J. Weinheimer, C. W. Chang, and J. A. Matson, Fortschr. Chem. Org. Naturstoffe 36, 285 (1979). For a recent review on the synthesis of Cembranes and Cembranolides see: M. A. Tius, Chem. Rev. 88, 719 (1988). [2] W.G. Dauben, G. H. Beasley, M. D. Broadhurst, B. Muller, D. J. Peppard, P. Pesnelle, and C. Suter, J. Am. Chem. SOC.97, 4973 (1975). [3] H. Takayanagi, T. Uyehara, and T. Kato, J. Chem. SOC.Chem. Commun. 1978, 359. [4] T. Kato, T. Kobayashi, and Y. Kitahara, Tetrahedron Lett. 1983,3299. [5] T. Kato, M. Suzuki, T. Kobayashi, and B. P. Moore, J . Org. Chem. 45, 1126 (1980), and ref. cited [6] T. Kato, M . Suzuki, Y. Nakazima. K. Shimizu, and Y. Kitahara, Chem. Lett. 1977, 705. [7] T. Takahashi, H. Nemoto, and J. Tsuji, Tetrahedron Lett. 1983, 3485. [8] M. Kodama, Y. Matsuki, and S. Zto, Tetrahedron Lett. 1975, 3065. [9] K. Shimada, M. Kodama, and S. Ito, Tetrahedron Lett. 1981, 4275. [lo] W.G. Dauben, R. K . Saugier, and I. Fleischhauer, J. Org. Chem. 50, 3767 (1985). [ l l ] P. A. Wender and D. A. Holt, J . Am. Chem. SOC. 107, 7771 (1985).

[14] J. A. Marshall, T. M. Jenson, and B. S. DeHofl, J. Org. Chem. 51, 4316 (1986); 52, 3860 (1987). [lS] Review: D. Hoppe, Nachr. Chem. Techn. Lab. 30,1030 (1982);R. W.Hoffmann, Angew. Chem. 94,569 (1982); Angew. Chem. Int. Ed. Engl. 21, 555; Y. Yamamato and K. Maruyama, Heterocycles 18, 357 (1982). [16] W . C. Still and D. Mobilio, J . Org. Chem. 48, 4786 (1983). [17] See: J. Mulzer, Nachr. Chem. Techn. Lab. 32, 1055 (1984). [18] M. Aoki, Y. Tooyama, T. Uyehara, and T. Kato, Tetrahedron Lett. 1983,2267; T. Kato, M. Aoki, and T. Uyehara, J . Org. Chem. 52, 1803 (1987). [19] J. A. Marshall, B. S. DeHofJ; and S. L. Crooks, Tetrahedron Lett. 1987, 527. [20] J. A. Marshall and S. L. Crooks, Tetrahedron Lett. 1987, 5081. [21] J. A. Marshall and B. S. DeHofl, Tetrahedron 43, 4849 (1987). [22] D. Hoppe and A. Bronneke, Tetrahedron Lett. 1983, 1687. [23] J. A. Marshall and D. G. Cleary, J. Org. Chem. 51, 858 (1986). [24] M. A. Tius and A. H. Fauq, J. Am. Chem. SOC. 108, 1053 (1986). [25] M. A. Blanchette, W. Choy, J. T. Daris, A. P. Essenfeld, S . Masamune, W. R. Roush, and T. Sakai, Tetrahedron Lett. 1984, 2183.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Optically Active Glycerol Derivatives

Unsymmetrically substituted glycerol deriva- of pharmacologically important P-blockers of tives such as ( I ) , (2) and (3) play an important the aryloxypropanolamine type (5). In addition, (I),(2) and (3)and the aldehydes r61e in organic synthesis as versatile chiral C3 derived from them are often used as highly funccomponents. tionalized, chiral C3 components for the asymmetric synthesis of complex natural products [2 -41. Glycerol derivatives are particularly suitable for such syntheses, partly because the enantiomers are readily accessible, either from the chiral pool or more recently by asymmetric They are employed in optically active form synthesis. Moreover, due to latent symmetry, it for the directed synthesis of enantiomerically is possible to move from one enantiomeric sepure natural and unnatural glycerides, as well ries to the other by chemoselective reactions at as glyco-, phospho-, and ether lipids, some of the two ends of the molecules: which show remarkable biological activity. Alkylglycerophosphorylcholines such as PAF (platelet activating factor) (4) [l], for instance, exhibit, in addition to a platelet-aggregating effect, hypotensive and immunostimulant properties, and they have been found to be selectively cytotoxic against a variety of cancer types. Optically active glycerol derivatives are also employed as precursors for the synthesis

(4)

OC3

PAF (Platelet Activating Factor)

(5)

Aryloxypropanolamine

The glyceraldehydes also retain their importance in the field of natural product synthesis as models for asymmetric additions to chiral carbonyl compounds. Traditionally, the preferred compound was 2,3-O-isopropylidene glyceraldehyde [2,3]. Macdonald [ S ] and Reetz [6] recently demonstrated that variously protected glyceraldehydes are more suitable than the acetonide for chelate- and nonchelate-controlled additions of the Grignard and aldol types, since depending on the reagent - and under the control of metal ions - it is possible to synthesize either syn- or anti-adducts.

Optically Active Glycerol Derivatives

I

(7)

OH

q

OH

293

1 OMes

Fig. 1 Synthesis of’the unsymmetrically substituted glycerol derivatives ( l ) , ( 2 ) , and ( 3 ) starting from D-TnannitOl.

Ex Chiral Pool Syntheses The popularity of 2,3-O-isopropylidene D-glyceraldehyde and the glycerol derivative that can be prepared from it by reduction with NaBH4 (f) is a consequence of its ready availability from the cheap D-mannitol(6): by glycol cleavage of the diisopropylidene derivative (7) according to the method of Baer and Fischer, reported in 1934 (Fig. 1). It was only recognized much later that Dmannitol can also be employed for the synthesis of variously protected glycerol systems such as (2) and (if).These are not only more stable than the 2,3-isopropylidene compound (f), but they are also more suitable for certain syntheses,

since differentiation of all three of the hydroxyl groups is assured [5,6,10- 151. The intermediates in the synthesis of (2) and (11) are the derivatives (8) [16], (9) 1171, and (10)[18] (Fig. l), which are also readily available from mannitol. Since it is possible through silylation, tosylation, or tritylation to exploit the differing reactivities of the primary and secondary alcohol functions at the very beginning of the synthesis, fewer protecting-group manipulations are necessary than in the case of syntheses of protected glycerol derivatives starting from the classical educt (7). However, for the preparation of enantiomerically pure products it is important to ensure that no racemization will occur during the synthesis. A benzyl ether moi-

294

Classes of Natural Products

ety is thus the preferred protective group for the secondary alcohol. An acyl group at this position would pose the risk of racemization by acyl migration. Similar complications arise when the primary hydroxyl group is selectively protected as the benzoate [14]. On comparison of the three routes it would seem that the first (starting from (8) [lo]) and the second (starting from (9) with Ar = CsHs [14]) are less favorable, because they entail the removal of protective groups at the primary alcohol function in order to generate the 3,4-diol required for glycol cleavage. However, if p-methoxybenzaldehyde is employed for the double protection of D-mannitol to (9) (Ar = p-CH30-C6H4),it is possible after benzylation of the free hydroxyl groups to open the 1,3-dioxolane ring in such a way that the primary OH function remains blocked as the p-methoxybenzyl ether ( c j (13)); the protective group can in turn be removed selectively by oxidation even in the presence of a benzyl ether function. This route, developed by Welzel [14] probably provides the most straightforward access currently available from D-mannitol to optically active glycerols protected in distinguishable ways at the 2 and 3positions, and it also permits crossover to the other enantiomeric series. Until now, (10) has only been employed for the preparation of (li),a starting point for pblocker systems, but it should also be applica-

-

(12)

ble in a more general way. The fact that glycol cleavage leads to a bisglyceraldehydejoined by a methylidene bridge opens up the interesting possibility of using the “duplication trick” [19] to obtain enantiomerically pure products even if the reaction is accompanied by a small amount of racemization. Thus, statistical arguments ensure that an (R,R)-enantiomer will produce very little (S,S)-product,instead giving mainly the (R,S)-diastereoisomer,which can be separated by recrystallization. Although selective manipulation generally makes it possible to access the L-series from the D-series, there has still been no lack of effort to prepare derivatives of L-glyceraldehyde directly. Since L-mannitol is accessible only with difficulty, use has been made of other educts from the chiral pool. Syntheses of L-glyceraldehyde derivatives now exist from D-sorbitol [20], L-galactono-1,4-lactone [21], L-arabinose [22], L-erythrulose [23], L-malic acid [24], L-ascorbic acid [25 -273, L-dimethyl tartrate [28 - 301, and L-serine [31- 331. Only the last three seem attractive when account is taken both of availability and of the number of synthetic steps involved. It is also possible to carry out on a large scale the degradation of ascorbic acid (14) [25], first described by Jung, thanks to an improvement [26] in which the critical reduction of the enediol unit occurs before introduction of the protective group in the side chain to give (15). An analogous approach has

HO

OH (14)

Ar-CH20

OR OAr (13) Ar = gCH,O-C,H,-

(15)

2.

A 70%

Optically Active Glycerol Derivatives

295

ases or esterases would appear suited to the glycerol system because glyceryl esters are among their natural substrates. However, attempts to produce enantiomerically pure products by enzymatic hydrolysis of chiral acylglycerides met with little success, because acyl miYHO gration often causes partial racemization. Many examples have made it clear that ester hydrolases accept a wide variety of unnatural (18) substrates. It is thus not surprising that Iriuchijima, in a lipase-catalyzed hydrolysis of 1,2also been developed starting from the equally dichloro-3-acetoxypropane (20),was able after accessible isoascorbic acid. more than 50% turnover to recover starting A route based on tartrate esters via (f6),(13, material with an enantiomeric excess of 90% ee and ( f 8 )[28 - 301 is particularly advantageous (although the chemical yield was only 20%) on account of the ready availability of D- and W 1 . L-tartaric acids. The same advantage is assoCL ciated with routes starting from D- or L-serine c A O , , ) , L C [31], which lead to protected glycerol derivatives of both configurations. According to a re(20) vised procedure [32] for which the enantioCL CI meric purity of the product was carefully monC L A O A c + C I A O H itored, ( S ) - ( f )is obtained from L-serine (19) in a yield of 63% with 94.4% ee. The synthesis of In a systematic investigation of enantioselecglycidic esters from serine has also been recently tive, enzymatically catalyzed hydrolyses of esdescribed [32]. ters of epoxy alcohols, Whitesides [36] con1. NaN02, H’ cluded that porcine pancreatic lipase was the most suitable with respect to activity, selectivity, and price. In the case of glycidyl esters ( 2 4 , optical yields are very dependent on the type CH,O OCH3 of ester: the highest enantioselectivity was associated with butyrate. Again, after the addition H O TOH 2. LMIH, of 60% of the theoretically required amount of base, the enantiomeric purity was appreciably higher in the residual educt than in the product, some of which evidently arose by a nonenzyEnzymatic Asymmetric Syntheses matic route. The reaction posed no problems on a 2-mole scale, and it gave (R)-glycidyl buEnantioselective synthesis with the aid of en- tyrate in 81% yield (with respect to a single zymes has undergone an astounding develop- enantiomer) and an enantiomeric excess ee of ment in recent years [34], and it should today 92%. be part of the standard repertoire of every syn0 0 thetic chemist. Successful attempts to synthesize 0 II 0 II h O C R + L>\/OCR + %!OH optically active glycerol derivatives chemoenzymatically were part of this development. Lip(21) ee > 90%

+

-x;ToH

296

Classes of Natural Products

That the success of an enzymatic reaction depends strongly on the choice of the correct system can be seen from the fact that the closely related butyrate of (1)could be enriched with lipase only to an ee of less than 40% [36]. So far, the most advantageous feature of hydrolytic enzymes from the standpoint of optically active glycerol-derivative synthesis has proven to be their ability to distinguish between enantiotopic ester groups present in achiral systems. However, complications caused by acyl migration require that one starts with compounds whose secondary hydroxyl groups are not protected by acylation. This approach has been successfully pursued by several research groups [37 - 391 starting from the benzyl ether (22), which is readily prepared in three steps from glycerol [37 - 391.

A

OAc OAc

(22) enzyme

A +,A, OBn

BzCl

OH OAc

OBz OAc

1. tipase

OBz OTos

be stockpiled for the synthesis of optically active glycerol systems. The usual disadvantage of relying on enzymatic reactions with prochiral substrates is that only one enantiomer is accessible, but this does not apply in the present case because the enantiomers are readily interconverted by means of a few selective chemical manipulations [38]. Klibanov [40] has developed a remarkable modification of enzymatic catalysis with ester hydrolases by exploiting the fact that these enzymes catalyze not only hydrolysis but also transesterification. A suitable ester, such as the proven tributyrin (glycerol tributyrate), is reacted with a racemic alcohol in a two-phase alcohol/ester-water medium in the presence of lipase - preferably in immobilized form. Only one of the enantiomers of the racemic alcohol is transesterified, yielding the corresponding optically active butyrate. Reaction in a twophase system provides several decisive benefits: full enzyme activity is retained, competitive hydrolysis is suppressed relative to transesterification, and highly dilute aqueous solutions are avoided. Enantioselectivity is generally quite good, although only a moderate 67% ee is achieved in the case of 2,3-dichloropropanol (24), presumably because of subsequent racemization. HO, , ) , l C

CL (24)

Lipase

Tnbutynn

0

CL C I A O &

+

Dibutyrin

A very different approach to the asymmetric synthesis of glycerol derivatives with the aid of (S) - (-) enzymes is the enantioselective reduction of suitable prochiral ketones. Thus, Whitesides to product with the ( R ) The reaction leads configuration in 2 88% ee. Following Kreiser’s has described the lactate dehydrogenase reducprocedure, the alcohol can then be converted tion of chloropyruvic acid (25) to chlorolactic to a readily crystallizable derivative such as the acid (26),which can then be cyclized with potosylate (23) [38] and recrystallized to achieve tassium hydroxide to the potassium salt of glyan optical enrichment of 99% ee. Compound cidic acid (27) [41]. Both enantiomers are ac(23)has been found to be so stable that it can cessible, since both D- and L-lactate dehydroTosO

OBz

291

Optically Active Glycerol Derivatives

genases exist - a rare occurance with enzymes. Enantiomeric excesses of > 97% ee are achieved at the 0.25 - 0.5 mol scale. One disadvantage is the fact that NADH is required as a coenzyme, and it would be best if this could be regenerated in situ. The problem can be overcome by coupling the reaction with the glucose 6-phosphate/glucose 6-phosphate dehydrogenase system, but it is still likely to stand in the way of general preparative application. 0 Cl

L-Lactate

(25)

52%

OH

'

-

Baker's yeast

HO

SPh

(28)

HO

0

0

II

(26)

Reductions with Baker's yeast [42] are more popular because they are simpler. Here, too, examples have been reported in the glycerol series [43, 441 including (28).Enantioselectivities are quite acceptable, and pure products can be obtained by recrystallization and subsequently transformed into the standard glycerol derivatives. OH

A-n

differentiation between primary and secondary hydroxyl functions and to inhibit the formation of di- and triacylated products. Dynamic complexation leads to five-membered Sn(1V) alkoxides (29), which then react diastereoselectively with optically active acid chlorides. The best selectivity, 90% de, was achieved with camphanic acid chloride.

SPh

Nonenzymatic Asymmetric Syntheses Finally, attempts have also been made to prepare optically active glycerol derivatives by asymmetric synthesis. Mukaiyama has pursued the most obvious strategy of transforming glycerol directly into optically active derivatives. He first investigated the diastereoselectivityof glycerol esterification with optically active acid chlorides [45]. Reactions were carried out in the presence of BuzSnO in order to enhance the

Mukaiyama also accomplished enantioselective acylation of prochiral glycerol derivatives with the aid of chiral tin chelate ligands [46], prepared from 2-0-protected glycerol using 1,l'-dimethylstannocene and a chiral diamine:

0

+ROf°CR' I1

0 II

R'CCI

0%

OH

The selectivity of this reaction is very dependent on the nature of both R and the acid chloride. When R = TOS, and with benzoyl chloride as the acylating agent, 48% ee is observed (yield 46%). A modification involving the kinetic separation effect gave an impressive 84% ee, but at the expense of a low yield (20%). Solladit5 has pursued his investigations into the synthetic applications of chiral sulfoxides to develop yet another route to protected glycidol [47]. DIBAH reduction in the presence of

298

Classes of Natural Products

tivity of the resulting epoxides. Although it is possible, in principle, to isolate the water-soluble, optically active glycidol (3), it has been found preferable in practice to derivatize (3)in situ [SO, 511. This not only results in a higher OH . 1 . tBuBr, CHCI, refl. yield but also permits an increase in the enan> BnO&S<’ p - To1 2. Et30’ BFF tiomeric purity through recrystallization. The (3 1 ) 3. K,CO,. H O, reaction can be carried out on the molar scale, 0 95% and it gives yields after recrystallization of 40% B n O A (96% ee) in the case of the p-nitrobenzoate (334 (32) and 61% (94% ee) with the tosylate C33b-J. ZnCll of the optically active ketosulfoxide (30), The method therefore appears to be competaccessible in four steps from bromomalonic itive both with the best ex chiral pool syntheses acid, yields the (R,R)-diastereoisomer (31) in and with procedures catalyzed by enzymes. An94% de; this can then be converted by conven- other method recently reported by Julia [52] is tional means into (32).However, in view of the the opening of a racemic glycidol by dimethyl spectacular success of asymmetric epoxidation, sulfide in the presence of optically active dibenthis method is likely to be only of methodolog- zoyltartaric acid. This entails a classical sepaical interest. The technique developed by ration of diastereoisomers followed by recycliSharpless has forced a revision of the notion zation to enantiomerically pure glycidol. Howthat it is impossible to surpass or even equal ever, it is unlikely to win out in a competition by “artificial” means the enantioselectivity and with the Sharpless epoxidation. Although prosubstrate breadth of the enzymatic reactions cedures based on common natural products found in nature. Sharpless epoxidation has now generally are preferred in the laboratory for the been realized even for ally1 alcohol itself preparation of optically active glycerol derivatives, only time will tell which approach will Ti(0i Pr), prove most advantageous on a commercial (+) - DET scale. -OH

tBuOOH. CH2CI,

-

20%

References

(33b):

R = TOS

40% yield 94% ee

(after recrystall.)

This breakthrough was made possible by the introduction of a catalytic version of the method [48 -501. Highly enantioselective epoxidations thus became feasible with simple allylic alcohols otherwise unsuited to the “classical” stoichiometric method due to the reac-

[I] Review: N. Weber, Pharm. unserer Zeit 15, 107 (1 986). [2] J. Mulzer, Nachr. Chem. Tech. Lab. 32, 146 (1984). See also this book, p. 243ff. [3] J. Jurczak, S. Pikul, and T. Bauer, Tetrahedron 42, 447 (1986). [4] S . Takano, Pure Appl. Chem. 59, 353 (1987). [5] K . Mead and T. L. M . Macdonald, J. Org. Chem. 50, 422 (1985). [6] M. T.Reetz and K. Keseler, J. Org. Chem. 50, 5434 (1985). [7] H . 0. L. Fischer and E. Baer, Helv. Chim. Acta 17, 622 (1934);J. Biol. Chem. 128, 463 (1939). [8] J. Kuszmann, E. Tomori, and I. Meerwald, Carbohydr. Res. 128, 87 (1984). [9] H . Eibl, Chem. Phys. Lipids 28, 1 (1981).

Optically Active Glycerol Derivatives [lo] C. Morpain and M. Tisserand, J . Chem. SOC. Perkin Trans. I 1979, 1379. [ I l l H. Eibl, Angew. Chem. 96, 247 (1984); Angew. Chem. Int. Ed. Engl. 23, 257 (1984). [12] P. Welzel,F.-J. Wittler, D. Miiller, and W. Riemer, Angew. Chem. 93, 130 (1981); Angew. Chem. Int. Ed. Engl. 20, 121 (1981). [13] T. Schubert and P. Welzel, Angew. Chem. 94, 135 (1982); Angew. Chem. Int. Ed. Engl. 21,137 (1982). [I41 U. Peters, W . Bankoua, and P. Welzel, Tetrahedron 43, 3803 (1987). [IS] B. Lamm, K. Ankner, and M . Frantsi, Acta Chem. Scand. B 41, 202 (1987). [I61 L. F. Wiggins, J. Chem. SOC.1946, 13. [I71 N. Baggett and P. Stribblehill, J. Chem. SOC.Perkin Trans. I 1977, 1123. [I81 A. T. Ness, R. M. Hann, and C. S. Hudson, J. Am. Chem. SOC.65, 2215 (1943). [I91 Cf. J. Jaques, A. Collet, and S. H. Wilen: “Enantiomers, Racemates and Resolution”. WileyInterscience, New York 1981, p. 430. [20] B. C. Pressman, L. Anderson, and H. A. Lardy, J. Am. Chem. SOC.72, 2404 (1950). [21] S. Morgenlie, Carbohydr. Res. 107, 137 (1982). [22] K. E. Maloney-Huss, Synth. Comm. 15, 273 (1985). [23] H. De Wilde, p. De Clercq, M. Vandewalle, and H. Roper, Tetrahedron Lett. 1987, 4757. [24] T. Tsuri and S. Kamata, Tetrahedron Lett. 26, 5195 (1985). [25] M. E. Jung and T. J. Shaw, J. Am. Chem. SOC. 102, 6304 (1980). [26] C. Hubschwerlen, Synthesis 1986, 962. [27] A. B. Mikkilineni, P. Kumar, and E. Abushanab, J. Org. Chem. 53,6005 (1988). [28] K. Fujita, H. Nakai, S. Kobayashi, K. Znoue, S. Nojima, and M. Ohno, Tetrahedron Lett. 1982, 3507. [29] A. Tanaka, S. Otsuka, and K. Yamashita, Agr. Biol. Chem. 48, 2135 (1984). [30] A. H. Al-Hakim, A. H. Haines, and C. Morley, Synthesis 1985, 207. [31] C. M. Lok, J. P. Ward, and D. A. Van Dorp, Chem. Phys. Lipids 16, 115 (1976).

299

[32] G. Hirth and W. Walther, Helv. Chim. Acta 68, 1863 (1985). [33] M . Larcheueque and Y.Petit, Tetrahedron Lett. 28, 1993 (1987). [34] J. Mulzer, Nachr. Chem. Tech. Lab. 32,520,589 (1984). See also this book, p. 207ff. [35] S. Zriuchijima, N. Kojima, and A. Keiyu, Agric. Biol. Chem. 46, 1593 (1982). [36] W . E. Ladner and G. M. Whitesides, J . Am. Chem. SOC.106, 7250 (1984). [37] D. Breitgofl, K. Laumen, and M. P. Schneider, J. Chem. SOC.Chem. Commun. 1986, 1523. [38] V. Kerscher and W . Kreiser, Tetrahedron Lett. 28, 531 (1987). [39] H. Suemune, Y. Mizuhara, H. Akita, and K. Sakai, Chem. Pharm. Bull. 34, 3440 (1986). [40] B. Cambou and A. M. Klibanov, J. Am. Chem. SOC.106, 2687 (1984); For a direct application to the synthesis of chiral glycerol derivatives see: Y.-F. Wang and C.-H. Wong,J. Org. Chem. 53, 3128 (1988). [41] B. L. Hirschbein and G. M. Whitesides, J . Am. Chem. SOC.104, 4458 (1982). [42] H.-U. Regig, Nachr. Chem. Tech. Lab. 34, 782 (1986). S. Serui, Synthesis 1990, 1. [43] T. Fujisawa, T. Ztoh, M . Nakai, and T. Sato, Tetrahedron Lett. 1985, 771. [44] G. Guanti, L. Ban$, and E. Narisano, Tetrahedron Lett. 1986, 3547. [45] T. Mukaiyama, Y. Tanabe, and M. Shimizu, Chem. Lett. 1984, 401. [46] J. Zshikawa, M . Asami, and T. Mukaiyama, Chem. Lett. 1984, 949. [47] G. Solladie and J. Hutt, Tetrahedron Lett. 28, 797 (1987). [48] S. Y. KO and K. B. Sharpless, J. Org. Chem. 51, 5413 (1986). [49] J. M. Klunder, S. Y. KO,and K. B. Sharpless, J . Org. Chem. 51, 3710 (1986). [SO] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y.KO, H. Masamune, and K. B. Sharpless, J. Am. Chem. SOC.109, 5765 (1987). [5l] S.-K. Kang and D.-S. Shin, Bull. Korean Chem. SOC.7, 159 (1986). [52] B. C i m i t i h , L. Jacob, and M. Julia, Tetrahedron Lett. 27, 6329 (1986).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Asymmetric Syntheses of a-Amino Acids

The rapid development of asymmetric synthesis is impressively reflected in the advances which have been achieved in the synthesis of enantiomerically pure a-amino acids ( I ) [I]. Besides the already classic asymmetric hydrogenations of prochiral dehydroamino acids [2] and chiral racemic dehydroamino acids [3], there are now asymmetric modifications of all the well-known routes to a-amino acids. This applies both to methods that involve C-C bond formation (routes A to D) and to ones in which the C-N bond is formed (routes E and F), including both nucleophilic and electrophilic pathways in each case.

I

R

.

Chiral information is usually derived from a carboxylic acid derivative (symbolized by C*); with few exceptions, chiral substituents at nitrogen have proven to be less effective agents for diastereoselective transformations leading to a-amino acids [4,5].

Via the Enolates of Amino Acid Derivatives: Route A Until recently, the bislactim ether method of Schollkopf [6] seemed unrivalled for the electrophilic introduction of substituents into the a-position of amino acids. Many successful applications were known, ranging from simple alkylation to cycloalkylation, hydroxyalkylation, Michael reaction, and more exotic electrophilic additions, always accompanied by good to very good diastereoselectivity. Two disadvantages of the method must also be noted, however: the need to employ a Meerwein salt in the O-alkylation associated with preparing the bislactim ether (2), and the fact that after cleavage of the derivatized bislactim ether (4) two amino acid derivatives (5) and (6)have to be separated, normally by distillation of the esters. Seebach introduced an alternative method that can probably be regarded as competitive, one that evolved from his investigations of the principle of self-reproduction of stereogenic centers and which also involves a heterocyclic system [7] (cf. this book, p. 10). In its original

301

a-Amino Acids

4

y E

(4)

(6)

>Ao

R

R

1

OMe t

r

(5)

form, diastereomerically pure imidazolidinones (8)or (12)were employed to bring about stereoselective alkylation of a-amino acids. Depending upon the reaction conditions, the imidazolidinones (8) or (12) can be prepared from pivaldehyde and the amide (7) of an enantiomerically pure, natural amino acid. Formation of the enolate of this cyclic N,N-acetal initially destroys the center of chirality of the amino acid. but under the influence of the stereogenic acetal center an electrophile is normally introduced in such a way as to produce anti-adducts (10) and (14) in a highly stereoselective manner. Subsequent treatment with acid releases the branched cl-amino acids without any complications. It is noteworthy that this method requires no external chiral auxiliary, and it generates chiral, nonracemic enolates of the most varied u-amino acids, including functionalized ones. These may be alkylated or hydroxyalkylated with high stereoselectivity, so that the result is a self-reproduction of a center of chirality. Especially intriguing is the ability to generate from a single enantiomerically pure, natural amino acid both enantiomers of an a-derivatized amino acid. Once Seebach had succeeded in making the chiral glycine system (8) (R = H) and its enantiomer available readily and in large quantity by resolution with (S)-(-)-mandelic acid [8] of the diastereoisomeric salts of the nonbenzoylated precursors, the imidazolidone method could be

R

I

R

(9)

I

(13)

\L &.O .H ' R E ent-(lI)

A

E

regarded as a generally applicable, enantioselective synthesis of a-amino acids, one whose potential has clearly not yet been exhausted [7]. Both the Schollkopf and the Seebach methods are based upon cyclic glycine enolate systems. The advantages relative to acyclic glycine enolates are self-evident;nevertheless, there also exist a few successful instances involving the latter. For example, alkylation of the N-protected glycinamide (15) containing a C2-symmetric pyrrolidine derivative as chiral auxiliary proceeds with astonishing diastereoselectivity

c91.

302

Classes of Natural Products /OMOM 1) LDA

MeS

2) RX

(15) /OMOM 1 N HCI

MeS (16)

OMOM

greater than 90: 10 except in the case of acetaldehyde) but also with remarkable enantioselectivity (81 to 97% ee) [13]. It should also be mentioned in this context that Genet has reported a catalytic asymmetric alkylation of the benzophenone imine of methyl glycinate with the aid of a chiral Pd catalyst, providing an optical yield of up to 57% ee [14].

Elect rophi1ic Glycine S ynt hons: Route B

Evans has applied his asymmetric aldol methodology to the a-isothiocyanate system (17),thereby opening the way to a simple prep- As a complementary method to the introducaration of P-hydroxy-a-amino acids [lo]. The tion of electrophiles at the a-position of glycine best results were achieved with the tin triflate derivatives it ought to be possible to place submodification of the aldol reaction, giving syn- stituents at this position by the reaction of elecaldol adducts in form of the heterocycles (18) trophilic amino acid synthons with nucleowith selectivities between 93:7 and 99:l. Ito philes. Williams has recently presented a powand Hayashi [11] have developed an interest- erful method based on this strategy [l5], one ing catalytic-asymmetric aldol approach to the that has rarely been exploited in the past. construction of P-hydroxy-a-amino acids. They demonstrated that the isocyanoacetate ester (20) reacts with aldehydes in the presence of a gold complex containing a chiral ferrocenylphosphine ligand [12] not only with high transselectivity (the (21):(22) ratio is consistently SCNJNIO

Sn(OTfl)*

~

RCHO

(17)

Bi

William's starting point was either the oxazinone (23) or ent-(23), readily prepared from bromoacetic ester and optically active erythroa,P-diphenyl- P-hydroxyethylamine. The latter

a-Amino Acids

is in turn easily synthesized by catalytic hydrogenation of the oxime of benzoin, followed by resolution of the resulting amine with L-glutamic acid. Bromination of (23)or ent-(23)with N-bromosuccinimide yields in high selectivity the anti-bromide (24) or ent-(24).The stereoselectivity of this step is not crucial to the successful realization of the concept, however. This is because weak nucleophiles - particularly in the presence of strong Lewis acids - replace the bromine atom through an elimination-addition mechanism, as shown by the fact that starting from (24)the nucleophile is introduced with a very high degree of retention. Apparently addition to the intermediate iminium ion also prefers to follow an anti-course - this time due to the phenyl groups! Consequently, brominated oxazine systems act as electrophilic glycinates, and they are adaptable to use in a host of C-C coupling reactions. With the nucleophiles indicated, for instance, (24)can be transformed in the presence of ZnClz into the homologous oxazinones (25) with excellent diastereoselectivity. The amino acid is released under reductive conditions, albeit with destruction of the chiral auxiliary - a disadvantage that is not too serious in view of the compounds ready accessibility. In the case of N-t-Boc-protected systems, reduction with lithium in ammonia leads directly to the N-t-Boc-protected amino acid.

303

metric synthesis” - a “matched” case HPLC analysis indicated that there was complete diastereo- and enantioselectivity to (29) (Re,Re selectivity > 2000: l!).

29)

Yamamoto observed diastereoselectivity of up to 96% de on the addition of ally1 boranes to the imino ester (30) [17]. H yNyCOpt

BU

Weinges has described several examples of asymmetric Strecker syntheses, which can be carried out as single-step procedures [lS]. Even though the asymmetric induction is relatively modest, a-amino acids can be obtained enantiomerically pure because the aminonitriles (33) and (34) are crystalline and can be isolated in diastereomerically pure form by recrystallization.

Addition to Imines: Routes C and D The addition of carbon nucleophiles to a-imino esters is a relatively little investigated reaction for the preparation of a-amino acids. In spite of this there have been a number of promising attempts at its diastereoselective realization. An impressive example is due to Steglich and Enders and involves reaction of the acyliminoacetate (27) (R* = menthyl) with enamine (28) (X = CH2or S) [16]. In this “double asym-

Kunz has recently developed an interesting modification of Ugi’s four-component condensation for the synthesis of a-amino acids. Here a carbohydrate template is employed as the amino component [19]. The reaction is carried out in a single step without the need for an organometallic reagent, and it yields the aamino acid derivative (36) with a high degree

Classes of Natural Products

304

of optical induction. One recrystallization suffices to provide 75 to 95% yields of the pure diastereoisomers, which can be hydrolyzed with acid to the free amino acids. O-Pivaloylgalactose is also obtained, and this can be reconverted into the chiral auxiliary (35). Piv?

,OPiv

(35)

OPiv

NH2 HCOOH, THF ZnCI, ' EtzO

Amination of Carboxylic Acid Derivatives: Routes E and I; Asymmetric routes involving the amination of carboxylic acid derivatives have also now been perfected for the synthesis of a-amino acids. This applies not only to the rather more traditional route of introducing the amino function by halogenation and subsequent sN2 substitution of the halide by an N-nucleophile (Route F) but also to the "electrophilic" amination [20] of enolates (Route E).

Direct amination of the chiral enolate of a carboxylic acid derivative was reported almost simultaneously by several research groups [21-241. Their methods differ only in the nature of the group X* employed for asymmetric induction. While Vederas [23] and Evans [22] applied the proven aldol reaction of carboximides of the type (374, Oppolzer [24] relied on derivative (374 and Gennari on the system (374 [21]. The diastereoselectivitiesachieved in all cases using t-butyl azodicarboxylate as aminating agent were relatively good. The a-hydrazinocarboxylic acids (38), which are obtained enantiomerically pure by chromatography, can be transformed into a-amino acids by reduction and removal of the chiral auxiliary. In a later publication Evans reported a direct electrophilic a i d e transfer to chiral enolates [25]. He discovered that the reaction of enolates with arysulfonazides, which normally leads to transfer of a diazo group, could be used to donate an azide group. This requires the availability of the potassium enolate of (37b) together with an electron-rich, sterically demanding arylsulfonazide. Acetic acid serves as a quenching reagent. Under these conditions, good yields and excellent diastereoselectivities are obtained for the substituted a-azidoacetic acid derivatives, which can be hydrolyzed without racemization to a-azidocarboxylic acids. The latter can be regarded as almost ideally protected amino acid derivatives, a great advantage over the previous methods. Alternatively, azidocarboxylic acids can be synthesized by diastereoselective halogenation of the enolate of (374 (Oppolzer [26]) or (37b) (Evans [27]), followed by sN2 substitution with azide ion. This method (i.e., (37) + (39)-+ (40)) appears even more broadly applicable [28] than the previously described direct introduc-

a-Amino Acids

tion of azide, so when the selectivity is comparable it remains competitive even though it entails an additional step. In conclusion, a series of efficient asymmetric synthetic routes has been developed in recent years for the preparation of unusual natural and unnatural amino acids, compounds of great current interest as potential components of modified peptides showing enzyme inhibitory, antimetabolic, and protease-resistant characteristics - further evidence of the enormous potential of modern synthetic methods.

References [l] a) Most recent reviews: R. M. Williams: “Syn-

[2] [3]

[4] [5] [6]

[7]

thesis of Optically Active a-Amino-Acids”, Pergamon Press, Oxford 1989; b) M. J. O’Donnell, ed.: “u-Amino-Acid Synthesis”, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988). Review: J. D. Morrison (Ed.): Asymmetric Synthesis, Vol. 5. Orlando 1985. E. J. Corey, R. J. McCaully, and H. S. Sachdev, J . Am. Chem. SOC.92, 2476 (1970); E. J. Corey, H. S. Sachdev, J. 2.Gougoutas, and W.Saenger, J. Am. Chem. SOC.92, 2488 (1970); J. V. Vigneron, H. Kagan, and A. Horeau, Tetrahedron Lett. 1968, 5681. J. L. Marco, J. Royer, and H. P. Husson, Tetrahedron Lett. 26, 3567 (1985). J. M. McIntosh and R. K. Leavitt, Tetrahedron Lett. 27, 3839 (1986). Reviews: U. Schollkopf, Pure Appl. Chem. 55, 1799 (1983); Top. Curr. Chem. 109, 65 (1983); Chem. Scripta 25, 105 (1985); and in J. Streith, H. Prinzbach, and G. Schill (Eds.): “Organic Synthesis - an Interdisciplinary Challenge”, Proc. 5th IUPAC Symp. Org. Synth., Oxford 1985. Recent publications: D. Pettig and U. Schollkopf Synthesis 1988, 173; U. Schollkopf and J. Schroder, Liebigs Ann. Chem. 1988, 87. D. Seebach, R. Imwinkelried, and T.Weber in R. Scheffoold (Ed.): “Modern Synthetic Methods”, Vol. 4, Berlin 1986; M . Gander-Coquoz and D. Seebach, Helv. Chim. Acta 71, 224 (1988) and

305

ref. cited. See also K. Krohn, Nachr. Chem. Tech. Lab. 35, 183 (1987). [8] R. Fitzi and D. Seebach, Angew. Chem. 98, 363 (1986); Angew. Chem. Int. Ed. Engl. 25, 345 (1986). [9] S. Ikegami, T. Hayama, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett. 27, 3403 (1986). [lo] D. A. Evans and A. E. Weber, J. Am. Chem. SOC. 108, 6757 (1986). For an analogous approach involving u-halocarboxylic acid derivatives and substitution of the halogen atom following an aldol reaction see: D. A. Evans, E. B. Sjogren, A . E. Weber, and R. E. Conn, Tetrahedron Lett. 28, 39 (1987). [11] Y. Ito, M. Sawamura, and T. Hayashi, J. Am. Chem. SOC.108, 6405 (1986). [12] T. Hayashi, Pure Appl. Chem. 60, 7 (1988). [13] Recent application: Y.Ito, M . Samamura, E. Shirakawa, K. Hayashizaki, and T. Hayashi, Tetrahedron Lett. 29, 235 (1988). [I41 J. P. Genet, D. Ferroud, S. Juge, and J. R. Montes, Tetrahedron Lett. 27, 4573 (1986). [l5] R. M . Williams, P. J. Sinclair, D. Zhai, and D. Chen, J . Am. Chem. SOC.110, 1547 (1988) and ref. cited. [I61 R. Kober, K. Papadopoulos, W.Miltz, D. Enders, and W.Steglich, Tetrahedron 41, 1693 (1985). [17] Y. Yamamoto, W . Ito, and K. Maruyama, J. Chem. SOC.Chem. Commun. 1985, 1131. [18] K. Weinges, H. Brachmann, P. Stahnecker. H. Rodewald, M . Nixdorf, and H. Irngartinger, Liebigs Ann. Chem. 1985, 566 and ref. cited. [19] H. Kunz and W. Pfrengle, J. Am. Chem. SOC. 110, 651 (1988). [20] K. Krohn, Nachr. Chem. Tech. Lab. 35, 1047 (1987). This book, p. 198. [21] C. Gennari, L. Colombo, and G. Bertolini, J. Am. Chem. SOC.108,6394 (1986). [22] D. A. Evans, T. C. Britton, R. L. Dorow, and J. F. Dellaria, J. Am. Chem. SOC.108, 6395 (1986). [23] L. A. Trimble and J. C. Vederas, J. Am. Chem. SOC.108, 6397 (1986). [24] W. Oppolzer and R. Moretti, Helv. Chim. Acta 69, 1923 (1986). [25] D. A. Evans and T. C. Britton, J. Am. Chem. SOC.109, 6881 (1987). [26] W . Oppolzer, R. Pedrosa, and R. Moretti, Tetrahedron Lett. 27, 831 (1986). [27] D. A. Evans, J. A. Ellman, and R. L. Dorow, Tetrahedron Lett. 28, 1123 (1987). [28] See also: F. Effenberger, T. Beisswenger, and H. Isak, Tetrahedron Lett. 26, 4335 (1985).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Compactin and Mevinolin

In the biosynthesis of cholesterol, the enzyme 3-hydroxy-3-methylglutaryl("HMG")-CoA reductase catalyzes the conversion of HMG-CoA into mevalonic acid [l]. A distinct relationship has been established between the activity of this enzyme and the rate of cholesterol biosynthesis. Since a high level of serum cholesterol is assumed to be the principal cause of atherosclerosis and coronary heart disease, it is not surprising that there has been an intensive search for drugs capable of regulating precisely this enzymatic reduction [2].

'CoA

HO'

HMG-CoA reductase

HMG - COA

x I

HO

CH,

140 HO-CH2 C, OH

LDL (low-density lipoprotein) fraction, which is known to be the principal medium for cholesterol transport. Indeed, the drug has already been successfully applied in the therapy of hypercholesterolemia. Several natural products with similar structures, for instance mevinolin (2), dihydrocompactin (3), and dihydromevinolin (4,have been found to be even more potent HMG-CoA reductase inhibitors [2]. One of these, mevinolin (2)was recently introduced into clinical application by Merck Sharp & Dohme.

mevalonic acid

Metabolites of several thousand strains of microorganisms have been studied with respect to their ability to inhibit cholesterol biosynthesis, and the research groups of Endo (Sankyo Co) [3] and Brown (Beecham Pharmaceuticals) [4] finally succeeded in finding a specific inhibitor of HMG-CoA reductase: compactin (I). Compactin has been shown to lower the level of lipids in human blood serum, especially the

H (3): R = H ( 4 ) : R = CH3

Pharmaceutical considerations, combined with a rather interesting structure, may explain

310

Individual Natural Products

the remarkable efforts that have been directed toward a total synthesis of these natural products. The first total synthesis of compactin ( I ) was accomplished in the research group of C. J. Sih, and is outlined in Scheme 1 [ S ] . The diol (6), which serves as starting material, is available in enantiomerically pure form by microbical reduction of the ketone (5). After the inevitable diastereomeric mixture has been separated, diol (6)can be converted by known selenium chemistry into the allylic alcohol (7), which is oxi-

dized to enone (8). Addition of cuprate, hydroxyalkylation, and subsequent elimination affords ketone (9),whose hydrogenation leads mainly to the diastereomer (10).Application of the Shapiro reaction, cleavage of the benzyl ether, double esterification with (S)-2-methylbutyric anhydride, and regioselective saponification provides monoester (11).Rather conventional steps suffice to convert the latter into compactin (1). However, unselective carboncarbon bond formation results in four diastereomeric diols (12), necessitating tedious sepa-

Scheme 1 Synthesis of (+)-compactin by Sih.

Ho H

Aureobasidium pullulans

$3

l . NaHlBnCl 2. PhSeBr

3. KOH

OH

6i

HO

(-)-(6) 33%

Po

OEE

BnO

BnO

BnO

\I/

t Joms-Ox. ---

7 ~2)3cu(sph)Li

"'OH

4. DBU

BnO

\

BnO (8)

(9)

J

(7)

80% (2steps)

L

0

1. TsNHNH2 2. LiN(i-Pr)Z

A 3. Li/NH3

10%

(70) 78%

/

0

+ 1. MsCl

3. HnO@ 4. 0;.

(11) 63%

0

6%

Compactin and Mevinolin

HooczMe

0

Bn = CH,C,H, EE = CH, I

,CH,0/CH2CH3

(1)

Scheme 2 Synthesis of (+)-compactin and ( +)-mevinolin by Hirama. H 0 2 C ~ C 0 2 H

V

C

NH2

0

2

0

\1 \1

H

1. yeast

-

CO,H

OH (17)

1

\1 \1 \1

1. LiOMe

OBn

OCNH, 11

B

n

O

d

Osi (14)

O

'+

M

' 4 4 4

e .

/

31 3

0

. -

0

x

OBn

312

Individual Natural Products

:s‘ 0

k0JoBn I

(20) 28% 1. LiN(i-Pr)*

(21) 87%

2. Pd(OAc),, benzoquinone

I +foBn 13%

1. SoClgPy

2. HF/CH3CN

(1) 51%

0

57 Yo

rations [6] at the end of this linear synthesis, whose total yield amounts to only 0.8% based on enone (8). Hirama’s syntheses of compactin (1)[7] and mevinolin (2) [S] are characterized by the coupling of two chiral, non-racemic building blocks (15) and (18),to give triene (19), which can be caused to undergo an intramolecular Diels-Alder reaction (see Scheme 2). The preparation of (15) starts with glutamic acid, which is first converted into lactone (13) by well-known procedures. Cleavage of the ring and silylation [90”/.

91 %

yield, based on converted (13)] leads to the carboxylic ester (14), a suitable precursor for the generation of fragment (15). On the other hand, reduction of keto acid (16)by means of baker’s yeast affords enantiomerically pure alcohol (17). In the conversion of (17) into the bulding block (18) iodolactonization is used to create the second chiral center, also in a stereospecific manner. The triene (19), obtained from fragments (15) and (18) by Horner-Wadsworth-Emmons olefination, indeed undergoes the anticipated in-

Compactin and Mevinolin

tramolecular Diels-Alder reaction, but with poor stereoselectivity: the desired ketone (20) forms in only 28% yield, together with two diastereomeric cis-octahydronaphthalenes. Ketone (20) can be separated from the mixture and reduced to the alcohol (2I), whose conversion into compactin (1) is accomplished via the intermediates shown in Scheme 2. Alternatively, ketone (20) can be dehydrogenated and the resulting enone subjected to a cuprate addition, which ultimately gives mevinolin (2) by an analogous sequence. Another rather plausible and intriguing strategy depends on the coupling of a hexahydronaphthalene derivative (22) (esterified with 2methylbutyric acid) with a &lactone moiety (23). X and Y should here be regarded as substituents capable of connecting (22) with (23). Various research groups have focussed their efforts on constructing fragments of the types (22) and (23), and several total syntheses have been successfully completed using this approach. 0

Y‘-

For example, some chemists have been struck by the structural relationship between “compactin lactone” (23) and glucose. Thus Prugh and Deana converted methyl-a-D-glucopyranoside (24) into enantiomerically pure iodide (25a) in a reaction sequence entailing 12 steps c91. The way is no more straightforward starting with triacetylglucal(219, which is in fact much more expensive than the methylglucoside (24).

313

A key intermediate, epoxide (27), is first prepared from (26) [lo] and then converted in the sequence shown below into a 9 : l mixture of anomers (28a)/(28b).Chromatographic removal of the minor product (28b), tosylation of (28a), and subsequent application of the Finkelstein reaction affords iodide (25b) [ll]. The “asymmetric synthesis” concept has opened other routes to the lactone moiety (23) as well as to compactin (I) and mevinolin (2) themselves. Thus, Kozikowski and Li [l2] used the 1,3-dipolar cycloaddition of nitrile oxides as the key to constructing both the enantiomerically pure lactone moiety (23) [12a] and the racemic hexahydronaphthalene portion [12b] of compactin (I). (R)-Isopropylidene glyceraldehyde (29a) was chosen as the starting material for synthesizing “compactin lactone” (31). This precursor was converted into the alkene (29b), which was then subjected to cycloaddition giving a 4: 1 mixture of isoxazolines [13]. The major product, (30), can be isolated in pure form by chromatography, permitting subsequent conversion into the alcohol (31). Epoxide (35) may be considered as the equivalent of “compactin lactone” (23); thus, the oxirane ring of (35) is opened regioselectively upon treatment with cuprates, and subsequent acidcatalyzed cyclization indeed affords the lactone (36) [141. However, the diastereofacial selectivity of the process leading to (35) proved disappointing: intramolecular Michael addition

-

314

Individual Natural Products HgOAc

1. NaOMe

2. Hg(OAc),

MaOH

\OH

1.

\ OCPh, -

95% MeO,,,Q

NaH

Ph

0 S i/- t

ph

0

'OCPh,

d

-

BnO

d

&/

(30)

H& Ni 0--N

TaOH

En0

HO

92%

0

O p 0 Ph

.Ph

(25b)

(I

85%

with alkoxide ( 3 3 , generated in situ from carboxylic ester (32) via migration of the silyl group, affords the tetrahydrofuranes ( 3 4 4 and (34b)in a ratio of 2: 1. The major product, (34u), is isolated in pure form by chromatography and subsequently converted into the epoxide (35). Straightforward approaches to enantiomerically pure "compactin lactone" (23) as well as

Compactin and kfevinolin

315

to compactin (f), mevinolin (2), and their octahydronaphthalene derivatives (3) and (4, have OH 2. >o been elaborated by a research group at Merck Sharp & Dohme [l5]. The key step is a stereoselective aldol addition involving a chiral acetate. For this purpose, doubly deprotonated (S)oyoH 1. (COCI),. DMSO 2-hydroxy-1,2,2-triphenylethyl acetate ("HY2. Ph,PCHCO@ 80% + TRA") [16] is added to enantiomerically pure aldehyde (374 [17] to give, after transesterification with lithium methoxide, the methyl es1. H,O' ter (38a).Claisen condensation then leads to the / COzEt < formation of keto ester (394, whose stereose2. CIS% 84% lective reduction with sodium borohydride/triethylborane finally affords ( +)-compactin (1).If aldehyde (37b)is instead utilized as the starting material, (+)-mevinolin (2) can be obtained in an analogous way via intermediates (38b) and (39b). The coupling of "compactin lactone" (23) with an octahydronaphthalene moiety has been successfully realized in a synthesis of dihydro(34b) compactin (3) by Falck and coworkers (see Scheme 3) [18]. A Diels-Alder reaction between diene (404 and maleic anhydride is the initial step, leading to the formation of octahydronaphthalene (41).The desired relative configuration with respect to the three chiral centers is successfully accomplished by cycloaddition, giving (40b). Annulation of the second carbocyclic ring is induced by a-deprotonation of sulfone (40b), and this is followed by intramolecular addition of the carbanion to the anhydride moiety. Low stereoselectivity, resulting in a cis/ trans mixture, can be overcome by epimerization after desulfurization with aluminum amal(35) gam. Doubly deprotonated sulfone (41) is a suitable substrate for coupling with iodide (2.56) to give (42). Hydrolysis of the dithiane moiety, another desulfurization, and reduction of the keto group provides the carbinol ( 4 3 , which is obtained in diastereomerically and enantiomerically pure form by chromatography. Four additional steps lead finally to (+)-dihydrocompactin (3). c1 (36) 90% 1.

BH,.THF

%-a

$-$-

'

.'OV0

316

Individual Natural Products 1) LiN(i-Pr),

0 II

y Ph H

"

(38a. b)

(S)-HYTRA

00

H$=C, 'OE,

(39.3, b) (37)-(39): a : R = H b : R = CH,

(1): R = H

Cycloaddition between the a$-unsaturated carboxylic ester (45) and butadienylsulfide (47) is the decisive step in Grieco's synthesis of (+)compactin ( I ) (see Scheme 4) [19]. Both components were prepared in enantiomerically pure form. The three-membered ring of epoxide (27), a compound previously encountered, is first opened in a regioselective reduction. Subsequent elongation of the carbon skeleton gives diene (47) via silane (46). Dienophile (45) is available from racemic acid (44):the latter is resolved by chromatographic separation of the corresponding diastereomeric phenylglycinol amides to give, after saponification and elimination, dienophile (45). Diels-Alder reaction of (45) and (47) is characterized by the desired regio- and stereoselectivity,and adduct (48)is obtained in 70% yield. An attempt to oxidize sulfide (48)to the corresponding sulfoxide leads to

spontaneous formation of the rearranged sulfenic ester, so treatment with trimethyl phosphite gives allylic alcohol (49).Inversion of the configuration of the alcoholic carbon atom by the method of Mitsunobu, acylation, and substitution with lithium dimethylcuprate gives the O-bridged octahydronaphthalene (50). The deprotonated alcohol that results from reduction of the ester moiety in (50) undergoes Grob fragmentation to diene (51). Esterification with (S)2-methylbutyric anhydride, oxidation of the aceta1 moiety to the lactone, and demethylation are the final steps of this convergent synthesis. The Horner-Wadsworth-Emmons reaction has been applied by Heathcock and Rosen as a way of connecting the enantiomerically pure building blocks (54) and (56) (see Scheme 5) [20]. The resulting enone (574, obtained in 42% yield, can be hydrogenated selectively with

Compactin and Mevinolin Scheme 3 Synthesis of (+)-dihydrocompactin by Falck.

1. MegiCVNal 2. PhSOrAmberlyst

3.

cs;

H

91% Ph

1. HgCl$CaCO, CH3CN/HP

3. Li(s-Bu)@H 4. separation of diastereomers

(42) 93%

\- o+

2. HCI 4. PCC-A1203 3. HF/CH3CN

(43)

>

,,$)

= H

(3) 48%

-

40%

31 7

318

Individual Natural Products

Scheme 4 Synthesis of (+)-compactin by Grieco.

1. LiAIH., 2. NaH/Mel

M e O D " " '

0

3. Na/NH3

'OH

'OCPh,

70 %

(t)-(44)

(27)

1. TsCVPy

4. NalHg

Ph

Meouo MeouoMe 78%

1. separation of diastereomers 2. H30 @ 3. DBU

GF

C0,Me

1. Bu4NF 3. Ph3PCH

2. PhSH

C0,Me

0

111

SPh

I

C %Me3

I

(45)

SiMe,

36% from (44)

(47) 94%

(46) 77%

MeouoMe

&; Meo?o .Me

-

1. m-CI -CsH4C03H 2. (Me0)3P

0 SPh

0

(48) 70%

(49) 70%

MeouoM

-& 1. Et02CN=NC0gt

M~O,C

H

H3

2. NaOMe PhCO@

3. Ac20 4. Me&uLi

0

(50) 73%

1. LiAIH4 2. KH. A

Compactin and Mevinolin

MeoYToMe

*

n

dCH3 2. Ag2C0, 3. BBr3

OSiR,

Ph

/'O -

0

0

22%

(1)

(51) 40%

Scheme 5 Synthesis of (+)-compactin by Heathcock.

0

>

0

e

-

H

4 (55)

. Et3N, DMAP

70%

Ph

OSiR

0

OMe

OSiR,

1. P h A O C l

r\,&C02Me

& i 02Me (534

2. separation of diastereorners 3. KOH 4. (COC1)2-DMSO

(53b)

1. HFICH3CN

2. LiCH2P(0)(OMe)2

Ph

/'O

0

OH 0

U ! ( O M e ) ,

0

R3Si0 MeO2C&!(OMe),

(54) 79%

LiCI, DEU

MeO,C/\."

OSiR,

4& /

Me02CToH

1. EtSiH (Ph3P)3RhCI

/

(57a) 42% O

w

O

H

1. separation of

diastereomers

(1) 70%

4& /

/

(576)

3 19

320

Individual Natural Products

respect to the carbon-carbon double bond that is in conjugation with the carbonyl group. Cleavage of the silyl residue and reduction of the keto group (unfortunately with low selectivity) affords a mixture of diols (57b).Once the undesired diastereomer has been removed, acid treatment leads finally to (+)-compactin (f). A surprisingly high degree of "asymmetric induction" accompanies the preparation of phosphonate (54): treatment of anhydride (52)with (R)-phenylethanol gives the diastereomeric esters (534and (53b)in a ratio of 8: 1. After separation of the diastereomers by chromatography, the reaction sequence outlined in Scheme 5 provides ester (54). Enantiomerically pure hexahydronaphthalene (56) is obtained from alcohol (55) by separation of its diastereomeric mandelates.

,,,OAc

Ho-L*7

I

(26)

12 steps

OSiPh,t-Bu

O m (64)

I

2 LiN(i-Pr)p

,,0yOSiPh2t-Bu

53

0

(60)

J I 3 steps

(1): R = H (2): R = CH3

OAc

4

Compactin and Mevinolin

More recently, Clive and coworkers [21] succeeded in alkylating the enolate of lactone (58) with the iodide (59), which provides the diastereomer (60) as single product. Enantiomerically pure (58) and (59) ultimately lead to (+)compactin ( I ) and (+)-mevinolin (2), but it takes 13 steps to achieve the annulation of the second six-membered carbocyclic ring and to fully elaborate the lactone moiety. Keck and Kachensky describe an elegant approach to the hexahydronaphthalene portion of (I)/(2),an approach that relies on an intramolecular Diels-Alder reaction, combined with a rather conventional preparation of the lactone fragment [22]. Again, triacetyl glucal(26) serves as starting material from which the aldehyde (63)is prepared in 12 steps. The latter is combined with ylide (62), itself available from alcohol ( 6 4 , to give allene (64). Thermally induced intramolecular cycloaddition followed

+

321

by reduction of the keto group gives a 1: 1 mixture of diastereomers (65a)and (65b),which can be separated after esterification with (S)-2methylbutyric acid. The result is ( +)-compactin (f), together with stereoisomer (66). Very recently, two research groups succeeded independently in synthesizing ( )-mevinolin (2) [23] and (+)-compactin (f) [24] by following a strategy that relies on a stereoselective cyclocondensation of aldehydes (67u,b)with Danishefsky’s diene (68). Other elegant syntheses of compactin (1)and mevinolin (2) may well be realized in the future. Further modification of these natural products is also the subject of intensive investigation, for instance by means of microbiological hydroxylation or phosphorylation [25].

+

Fq Houo CH3

(68)

\

(69)

CH3

In so far as totally synthetic analogues are concerned, it turns out that biological activity depends largely on the P-hydroxylactone moiety. Thus, synthetic compactin analogue (69), whose lactone portion was prepared by stereoselective aldol addition [16], has also been found to be a potent hypocholesteremic agent [l5, 261.

Ro70siR3 References

[I] See standard textbooks on biochemistry; for instance: A. L. Lehninger: “Biochemistry”. 2nd ed., Worth Publishers, New York 1975, p. 679 - 685; L. Stryer: “Biochemistry”, 3rd ed., W. H. Freeman and Co., New York 1988, p. 555- 559. [2] A. Endo, J. Med. Chem. 28, 401 (1985) and ref. cited therein (review on the isolation and the

322

[3] [4]

[5]

[6]

[7]

[8] [9]

[lo] [11]

[12]

[13] [14]

[IS]

[I61

Individual Natural Products biological activity of compactin and analogous compounds). A. Endo, M. Kuroda, and Y.Tsujita, J. Antibiot. 29, 1346 (1976). A. G. Brown, T. C. Smale, T. J. King, R. Hasencamp, and R. H. Thompson, J . Chem. SOC. Perkin I 1976, 1165. N. Y. Wang, C. T. Hsu, and C. J. Sih, J. Am. Chem. SOC.103, 6538 (1981); C. T. Hsu, N. Y. Wang, L. H. Latimer, and C. J. Sih, J. Am. Chem. SOC.105, 593 (1983). The same problem occurs in the similar linear synthesis described in N. N. Girotra and N. L. Wendler, Tetrahedron Lett. 23, 5501 (1982); 24, 3687 (1983). M . Hirama and M . Uei, J. Am. Chem. SOC.104, 4251 (1982). M . Hirama and M . Iwashita, Tetrahedron Lett. 24, 1811 (1983). J. D. Prugh and A. A. Deana, Tetrahedron Lett. 23, 281 (1982). E. J. Corey, L. 0. Weigel,A. R. Chamberlin, and B. H. Lipshutz, J . Am. Chem. SOC.102, 1439 (1 980). Y. L. Yang and J. R. Falck, Tetrahedron Lett. 23, 4305 (1982); T. Rosen, M. J. Taschner, and C. H. Heathcock, J. Org. Chem. 49,3994 (1984). a) A. P. Kozikowskiand C.4. Li, J. Org. Chem. 50,778 (1985).b) A. P. Kozikowskiand C . 4 . Li, J. Org. Chem. 52, 3541 (1987). V. Jager and R. Schohe, Tetrahedron 40, 2199 (1984). Y.Guindon, C. Yoakim,M. A. Bernstein, and H. E. Morton, Tetrahedron Lett. 26, 1185 (1985); cf. S. Hanessian: “Total Synthesis of Natural Products: The ‘Chiron’ Approach”, Pergamon, New York 1983 and ref. cited therein. Merck & Co (I. Shinkai, J. E. Lynch, and R. P. Volante, Inv.) European Pat. Appl. 86108756.7 (June 27, 1986). M. Braun, Angew. Chem. 99,24 (1987),Angew. Chem. Int. Ed. Engl. 26, 24 (1987) and ref. cited

[17]

[18] [19]

[20] [21]

[22] [23] [24] [25] [26]

therein. See also Merck-Schuchardt ( M S ) Info 88-4 (1988). A review on the preparation of hexahydronaphthalene fragment (22) and on earlier total syntheses of compactin and mevinolin is available in: Synform 2, 83 (1984). A more recent review has been published by T. Rosen and C. H. Heathcock, Tetrahedron 42,4909 (1986).For syntheses of (22) see also: S. Danishefsky, J. F. Kerwin, Jr., and S. Kobayashi, J. Am. Chem. SOC. 104, 358 (1982); N . N. Girotra, R. A. Reamer, and N. L. Wendler, Tetrahedron Lett. 25, 5371 (1984);T. Rosen, M. J. Taschner, J. A. Thomas, and C. H . Heathcock, J. Org. Chem. 50, 1190 (1985); S. D. Burke, J. 0. Saunders, J. A. Oplinger, and C. W. Murtiashaw, Tetrahedron Lett. 26, 1131 (1985). Y. L. Yang, S. Manna, and J. R. Falck, J . Am. Chem. SOC.106, 3811 (1984). P. A. Grieco. R. E. Zelle, R. Lis, and J. Finn, J. Am. Chem. SOC.105, 1403 (1983); P. A. Grieco, R. Lis, R. E. Zelle, and J. Finn, J. Am. Chem. SOC.108, 5908 (1986). T. Rosen and C. H. Heathcock, J . Am. Chem. SOC.107, 3731 (1985). D. L. J. Clive, K. S. K. Murthy, A. G. H. Wee, J. S. Prasad, G. V.J. da Silva, M . Majewski, P. C. Anderson, R. D. Haugen, and L. D. Heerze, J. Am. Chem. SOC.110, 6914 (1988). G. E. Keck and D. F. Kachensky, J . Org. Chem. 51, 2487 (1986). P. M . Wovkulich,P. C. Tang, N . K. Chadha, A. D. Batcho, J. C. Barrish, and M. R. UskokoviC, J. Am. Chem. Soc. i i f , 2596 (1989). S. J. Danishefsky and B. Simoneau, J. Am. Chem. SOC.i f f , 2599 (1989). H. Kuwano et al., J. Antibiot. 36,604,608 (1983); A. Endo et al., J. Antibiot. 38, 328 (1985). J. E. Lynch, R. P. Volante, R. V. Wattley, and I. Shinkai, Tetrahedron Lett. 28, 1385 (1987).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

The Coriolin Story, or The Thirteen-Fo Id W a y

It is a common event in organic synthesis that at unpredictable intervals a certain target molecule becomes “in”, and enormous efforts are concentrated on one arid the same objective. The result is a multitude of syntheses, not necessarily justified by the real importance or practical utility of the compound. The sesquiterpene coriolin ( I ) - a metabolite of the microorganism Coriolus consors, with interesting antitumor activity [l] - is a particularly striking example. Although no clinical use has been made of the substance so far, no less than 13 syntheses were reported between 1980 and 1989 [2 - 131. Typically, only the very early syntheses by Danishefsky [7] and Tatsuta [11] really led to ( I ) - all the other approaches were stopped when a known intermediate was reached.

The fascination of ( I ) as a synthetic target may be attributed to its complicated cis-anticis-fused triquinane [14] skeleton, which is richly adorned with functional groups and stereocenters. Thus, the synthesis of ( I ) requires differentiation of 5 oxygen functions and control of 8 stereocenters! However, closer inspection shows that many of these apparent problems are simplified by structural features of the molecule itself. For example, cis-fusion of cyclopen-

tane rings is energetically favored [l5] over a trans-geometry by 26.8 kJ mol-’; similarly, an epoxide can only be cis-fused to a five-membered ring. This reduces the number of independent stereocenters to five (C-1, 2, 3, 7 and 11). Additional possibilities for exerting stereocontrol are provided by the curved shape of the molecule, which ensures that the p-face is shielded towards attacking reagents in the C/B-section and the cl-face in the A/B-region. Regioproblems that might be connected with the introduction of the double bonds are excluded by the reluctance of C-1/8 and C-2/6 to undergo sp2-hybridization. Armed with these insights we may now turn to a discussion of the individual syntheses. All the syntheses have the di-olefin (2) as a common intermediate, which gives a 1 : l-mixture of ( I ) and epi-coriolin upon epoxidation with hydrogen peroxide. Thus, the various syntheses differ only in the way the A/B/C-system is assembled. Three strategies may be distinguished 1) construction of a C/B-nucleus, to which A is annulated; 2) construction of an A/B-nucleus, to which C is annulated; 3) photochemical one-step formation of the entire A/B/C-system from monocyclic components.

Annulation of Ring A to a BIC-Diquinane This is the most common strategy, represented by eight syntheses [2 - 91 (Schemes 1 - 7). The

324

Individual Natural Products

P

_ - -a =====+ H

HC ,

I

3

H3C5

Scheme 1 Synthesis by Ikegami 121

H (4)

H

m

(5)

THP?

H? 5 steps I

1. tBuOK 1 7

H

(12)

(74)

rnCPBA

;I7 (7 3)

(2)

mCPBA = 3-Chloroperbenzoic acid DBU = 1,8-Diazabicyclo[5.4.O]undec-7-ene

26 Steps from (4) to (1) Overall yield 2% from (5)

The Coriolin Story

retrosynthetic disconnedion of (2) leads back to (3) via a Robinson-type annulation. Alkylation of ketone (3) proceeds stereoselectively from the unhindered u-face, and regioselectively via the thermodynamically more stable enolate. This annulation is typical for all syntheses discussed in this section, with the exception of that by Koreeda [ 6 ] , who used an “umpoled” version that involved adding a cuprate reagent to C-2 in an a$-enone ((33) --* (34) + (35) in Scheme 4). Several methods were tried for constructing the B/C-precursor. Ikegami [2]

started with transannular ring contraction from (4) to (5)(Scheme l),which was then converted into (6) by a lengthy sequence. The 2-methyl group was introduced by a cuprate addition, and methylation of (7) was found to proceed regioselectively due to the low acidity of C-1. Reduction of the 11-carbonyl group furnishes the a-OH with moderate 5: 2 selectivity, whereas allylation of (9)is u-directed as expected. Wacker oxidation of the 4,5-olefin to the methyl ketone and ring closure as described furnishes ( I I ) , an intermediate which has been

Scheme 2 Synthesis by Matsurnoto [3].

BZO

II

H

PhCO

H

30 steps from (15) to ( I ) Overall yield ca. 1%

HO H

z steps4)

0G: ,CH, HO

o 0-Glucose

Catalpol

BzO

tj

+++ 1%

H

325

326

Individual Natural Products

Scheme 3 Synthesis by Magnus IS].

(26)

addressed in slightly modified form by many other authors in later syntheses. A major issue in the final stage of all the coriolin syntheses is the introduction of the 7P-OH function; most authors have adapted Ikegami's approach of generating a 6,7-double bond (in this particular case by deconjugation of the 5,6-enone), which is epoxidized from the p-face to form (14). Ring opening provides the desired 7-OH function in

I/

(2).

osi

0 II

t

1. Li-C=C-SiMe3

3. F @ 4. BuLiIMel

f25)

/

OSi

I

H

-,,

Matsumoto's synthesis (Scheme 2) starts with the cyclopentene dimer (15) and its allylic oxidation to enone (16). Straightforward manipulation leads to (18), whose 11-OH group is in the wrong (p) orientation. At this stage this is actually an advantage, because it permits differentiation of the two carboxyl groups resulting from the oxidation of the 2,7-bridge. Thus, lactone (19) is formed from the 2-carboxyl,

I

H

(27)

\1 \1

6 steps from (25) to (96) 19 steps from (25) to (1)

(96)

(1)

Scheme 4 Synthesis by Koreeda [61. 1.MOM-CI

(30)

OiBu

OiBu

(28)

H OiBu

OiBu

(29)

(31)

"?

H

(32)

BZO,

Me

1. NaBH4

"0 (35) MOM = -CH,-OCH, LDA = LiN(i-Pr),

3. 4-Oxid.

2. MeLi 3. H30@

0 3 -3

2. OH'

H I OAc

H

(36)

(7 7 a)

(1)

12 steps from (28) to ( 7 1 4 22 steps from (28) to (7) Overall yield ca. 2%

The Coriolin Story

whereas the 7-carboxyl can be removed by a Kochi decarboxylation [16]. The further steps via (20),( 2 4 , and (22)are obvious, and the hydroboration of (22) to (224 proceeds from the a-face as expected. Jones oxidation of (224 leads to (9a), a close relative of Ikegami’s intermediate (9); in fact, the synthesis is finished in a fairly analogous fashion. Quite recently, (+)(22a) has been prepared from naturally occuring catalpol by Weinges [4], although in an overall yield of only about 1 % over 22 steps. Altogether, 36 steps would be necessary to convert catalpol into naturally occurring ( -)-(I)! A very concise route to the B/C-nucleus has been devised by Magnus [S], who cleverly made use of the Pauson-Khand reaction (23)+ (24) to convert (26) into (27) as a 3: 1-mixture of 8-epimers. The major isomer was transformed into (I)essentially following Ikegamik route (Scheme 3). Koreeda’s synthesis (Scheme 4) uses a remarkable two-step annulation of ring C to B; dianion (29) is first submitted to a stereocontrolled aldol addition with aldehyde (30)to give ( 3 4 , which immediately undergoes ring closure by alkylation. The intramolecular reaction

helps to overcome potential steric hindrance from the 10-neopentyl substituent. From (32), an enone (33)can be derived, which then serves to annulate ring C via a cuprate addition-aldol condensation sequence. Thus, (35) is obtained and then converted into the Ikegami-type intermediate (Iia).An attempt to invert the 7OH function in (36) failed, so it had to be removed reductively via the acetate. Danishefsky [7] reported one of the very first coriolin syntheses (Scheme 5). The bicyclic B/C-skeleton of (37)was constructed via an elegant conjugate addition-aldol condensation sequence. As conjugate additions in (37) regularly led to attack at the C-1 position, the desired appendage at C-3 was introduced via a Diels-Alder reaction to form (38), which was then converted into (40)by a lengthy sequence. Ring closure as usual affords (4f),from which (2)is prepared in a way similar to that used by Ikegami. However, Danishefsky was the first to succeed in stereocontrolled conversion of (2) into ( I ) , by means of Sharpless-type epoxidations [17]. Schuda’s synthesis (Scheme 6) resembles Matsumoto’s approach (Scheme 2 ) in using a

Scheme 5 Synthesis by Danishefsky [7/.

0 “

C0,Me

139)

23 steps from (37) to (1) Overall yield ca. 0.5%

Me

I

H

327

OSiMeg

I

.

3. PhSeCl 4. Oxid

H

328

Individual Natural Products

HOOC

H

Ru0~Na104/

H

HClIdioxanel

CC14/Hp/ CH3CN

93%

bCOPh

H

(57)

OCOPh

(52) (17%)

H

OCOPh (53)

H Hg(OAc)#HCOONH,

H@

-

OR

SPr

88% HCOOH 89%

(54) R = COPh70HE, (55) R = H

(57)

-4Q DBUlbenrene

CH H

0

(2)

.

OH

OH

(68%)

The Coriolin Story Scheme 7 Synthesis ofoptically active coriolin by Demuth [9].

(63)

0

(64)

H

(65)

329

330

Individual Natural Products

cyclopentadiene-type dimer as the starting material [8]. Thus, (42) is elaborated into (44), which is transformed by oxidation/reduction to the B/C-system (45).The two primary OH functions are differentiated by mono-acylation of the less hindered position. The unprotected hydroxyl group is reduced to give a methyl substituent in (49), wherupon the second CH20H appendage is oxidized and removed by decarboxylation. A mixture of (52)/(53)is thus obtained, which we recognize as closely analogous to Ikegami's intermediate (9).In fact, Schuda completed his synthesis along these lines, the

only modification being that (54) served as the annulating agent, introduced into the 2-position by a Claisen rearrangement. Demuth [9] is responsible for the only practical synthesis of optically active ( I ) so far reported (Scheme 7). The key transformation was photochemical oxadi-n-methane rearrangement of bicyclic enones such as (60)to (61)[18]. To adapt this method to the synthesis of ( I ) , (60) was resolved into its enantiomers and methylated under forcing conditions to give a mixture of (62) and (64). Photolytic rearrangement of this mixture led to the mixture (63)/

Scheme 8 Synthesis by Trost [lo]. Me

CH2-SiMe3

2,

KHIH$<

. AOH

HO

CH2-I

(72)

>

/H@

3. KH/MeS-SMe

HO,

H

Me

H

Me 1. Li/NH3 (+6,7-DB)

0

7 steps

+4

(1)

3. DBU

OH (77)

(78)

24 steps from (42) to ( I ) Overall yield ca. 1%

The Coriolin Story

(65)/(66),from which (66) was removed chromatographically. Stereoconvergent allylation of (63)/(65)with (67) furnished (68) selectively. Ring opening and 4-reduction followed by Lemieux oxidation of the sidechain provided (69), which was cyclized to the Ikegami-type intermediate (70). Introduction of a 7P-OH group led to Trost's compound (78)(Scheme 8). Altogether, Demuth's approach constitutes a rather concise route to the two enantiomers of (1).

Annulation of Ring C to a BIA-Diquinane This concept has so far been realized only by Trost [lo] (Scheme 8). The key step is application of the trimethylenemethane dipole equivalent (72) as an annulating reagent. Thus, ene-dione (70)is protected at the enone function by first adding SMe- to the double bond and

then ketalizing the carbonyl group. The 8-POsition is then activated by thiomethylation. This sets the stage for alkylation with iodide (72) to form (73), which is cyclized to (74). Several obvious steps produce (76), whose epoxide ring is opened reductively to give (77) after base-induced epimerization at C-1. Reduction of the di-enone system produces a non-conjugated enone with a double bond at C-6,7 and, hence, an intermediate similar to Ikegami's compound (13). In fact, the rest of the synthesis closely follows Ikegami's example.

Photochemical One-Step Synthesis of the A/B/C-System The first synthesis of this type - indeed, the very first synthesis of (1) - was reported by Tatsuta [ll] (Scheme 9). De Mayo [2 + 21cycloaddition furnished (79) in moderate yield.

Scheme 9 Synthesis by Tatsuta [ill.

n 1. TsCl

AcO OAc

1. Me2C(OMe)2/Ha

A 2. PCC

TsO (81)

(82)

OH (83)

HO

3. MeLi

(84)

PCC = Pyridiniumchlorochromate

331

20 steps from (51) to (1) Overall yield 0.1%

332

Individual Natural Products

The [4.6.5]-system had then to be transformed into the desired C5.5.51-arrangement. This was achieved via (84,which gave (82) selectively. The expected but undesired Grob fragmentation leading to a 6-ketone and a 7,8-double bond was never observed, presumably due to stereoelectronic factors. Unfortunately, the 6,7epoxide could not be reduced to the desired 7Scheme 10 Synthesis by Mehta [12].

Me 0

7

Me A

_ j

Me

(88)

Mew 0 H

Me0

1.HjPd

2. NaH/Mel

0 0 6 A/4

9

1

H 7 H

H

(90)

(89)

0 H 2 steps

;

Me Me

39eps>

> H

H

(91) H?

H

Me Me 3 steps

-+ +

-0 H

H

(92) 14 steps from (59) to ( 7 ) Overall yield ca. 3%

(1)

H

OH group. Therefore, a 6,7-double bond was created by reduction, and osmylation then produced (83) selectively. Of the remaining operations, the introduction of a 4-ketal by Tl(II1) oxidation is most noteworthy; the rest of the synthesis is more or less obvious. Mehta [12] started with a thermal Diels-Alder reaction to generate (87), which was converted into (88) by photochemical [2 21-cycloaddition. (Scheme 10). Thermal cycloreversion leads to (89),so that, in effect, a metathesislike conversion of (87) to (89)has been accomplished. Further manipulations produce ( 9 4 , which is a derivative of Matsumoto’s compound (22). The rest of the synthesis is therefore modelled after this precedent. Nevertheless, the elegance and brevity with which (89)is prepared deserves high praise. Among many other tricyclic sesquiterpenes, Wender applied his marvellous arene-olefin [2 + 2 + 21-cycloaddition [19] also to (f) (Scheme 11 [13]). Thus, precursor (93) gave about 20% of (94) on irradiation and subsequent removal of the acetate group. Oxidation to the ketone allowed the reductive opening of the cyclopropane ring to give Mehta’s intermediate (91). An alternative approach started from (95),which cyclized to (96) in about 15% yield. The vinylcyclopropane added thiophenol under rearrangement to ( 9 3 , which was desulfurized to (98) and transformed into (99) by a Baeyer-Villiger degradation. The rest of the synthesis appears unexceptional. In conclusion, one cannot but admit the efficiency of photochemical methods in constructing the triquinane skeleton. Wender’s, Mehta’s, and Demuth’s syntheses are considerably shorter than the non-photochemical routes, except perhaps the one by Magnus, although the overall yield is disappointingly low in all the approaches and prohibits any practical application. Nevertheless, from the standpoint of developing and applying new methodology, coriolin has proven a rewarding target.

+

The Coriolin Story

333

Scheme I1 Two syntheses by Wender [13].

AcO

x5$-.

0 H

Me

++ (1) ref. 12

H

H

12 steps from (93) to (1) overall yield ca. 4%

(91)

AcO

Ph-SH/100

_j hv

&CH(OEtL (95)

'L

(96) CH(OEt)2

*H

Li/NH3

OC

mCPBA/H.$J

>

> CH(OEQ2

w

Ho

H

198)

Me Me,-

H OCHO

1. BFg

2. LDA/Me&iCI 3. Pd(0Ac);

>

+steps -3 3

-0 I T

(2)

H OSiMe,

(100) 12 steps from (95)to (1) overall yield ca. 2%

References [l] Isolation: T. Takeuchi, H . Iinuma, J. Iwanaga, S. Takahashi, and H . Umezawa, J. Antibiot. 22, 215 (1969); T. Takeuchi, H . Iinuma, S. Takahashi, and H. Umezawa, J . Antibiot. 24, 631 (1971). Structure Elucidation: S. Takahashi, H . Naganawa, T. Iinuma, T. Takita, H. Umezawa, Tetrahedron Lett. 1971, 1955. H. Nakamura, T. Takita, H . Umezawa, M. Kunishima, and Y.Na-

kayama, J. Antibiot. 7, 301 (1974). Biological activity: H. Umezawa, Heterocycles 13, 23 (1979). Y. Nishimura, Y. Koyama, S. Umezawa, T. Takeuchi, M. Ishizuka, and H . Umezawa, J. Antibiot. 33, 404 (1980). [2] M. Shibasaki, K. Zseki, and S. Zkegami, Tetrahedron Lett. 21, 3587 (1980); K. Iseki, M . Yamazaki, M. Shibasaki, and S. Ikegami, Tetrahedron 37,4411 (1981). [3] T. Ito, N. Tomiyoshi, K. Nakamura, S. Azuma, M. Zzawa, F. Muruyama, M. Yanagiya, H. Shir-

334

[4] [5] [6] [7]

[8] [9] [lo] [Ill

[I21

Individual Natural Products ahama, and T. Matsumoto, Tetrahedron Lett. 23, 1721 (1982); Tetrahedron 40, 241 (1984). K. Weinges, H. Jatridou, H. G. Stammler, and J. Weiss,Angew. Chem. 101,447 (1989); Angew. Chem. Int. Ed. Engl. 28, 441 (1989). C. Exon and P. Magnus, J. Am. Chem. SOC.105, 2477 (1983). M. Koreeda and S. G. Mislankar, J. Am. Chem. SOC.105, 7203 (1983). S. Danishefsky, R. Zamboni, M. Kahn, and S. J. Etheredge, J . Am. Chem. SOC.102, 2097 (1980), 103, 3460 (1981). S. Danishefsky and R. Zamboni, Tetrahedron Lett. 21, 3439 (1980). P. F, Schuda and P. R. Heimann, Tetrahedron 40, 2365 (1984). M . Demuth, P. Ritterskamp, E. Weight, and K. Schaffner, J . Am. Chem. SOC. 108, 4149 (1986). B. M. Trost and D. P. Curran, J. Am. Chem. SOC.103, 7380 (1981). Cf. this book, p. 96ff. K. Tatsuta, K. Akimoto, and M. Kinoshita, J. Antibiot. 33, 100 (1980), Tetrahedron 37, 4365 (1981). G. Mehta, A. V. Reddy, A. N. Murthy, and D. S. Reddy, J. Chem. SOC. Chem. Commun. 1982, 540.

[I31 P. A. Wender and J. J. Howbert, Tetrahedron Lett. 24, 5325 (1983). [I41 L. A. Paquette, Top. Curr. Chem. 79, 41 (1979); 119, l(1984). [IS] S. Chang, C. Mcnally, S. Shary-Terany, M. J. Hickey, and R. H. Boyd, J. Am. Chem. SOC. 92, 3109 (1970). [I61 J. K. Kochi and J. D. Bacha, J. Org. Chem. 33, 2746 (1968). [I71 H. Yamamoto,H. Nozaki, K . B. Sharpless, R. C. Michaelson, and J. D. Cutting, J. Am. Chem. SOC. 96, 5254 (1974). [I81 M . Demuth, B. Wietfeld, B. Pandey, and K. Schajjiner, Angew. Chem. 97,777 (1985); Angew. Chem. Int. Ed. Engl. 24, 763 (1985). [19] P. A. Wender and J. J. Howbert, J. Am. Chem. SOC.103,688 (1981); Tetrahedron Lett. 23, 3983 (1982). P. A. Wender and G. B. Dreyer, Tetrahedron 37,4445 (1981); J. Am. Chem. SOC.104, 5805 (1982). Review: P. Welzel, Nachr. Chem. Tech. Lab. 31, 262 (1983).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Frontalin

Frontalin ( I ) is one of the aggregation pheromones of pine beetles of the family Dendroctonus. As soon as one insect has chosen a particular tree to serve as a breeding ground, the pheromones cause effective further colonization of the same tree by assuring an optimal ratio of the sexes [l]. The female American pine beetle Dendroctonus frontalis (southern pine beetle), as well as the male of the family Dendroctonus brevicomis, produces frontalin, whose structure has been shown to be 1,5-dimethyl-6,8-dioxabicyclo[3.2.l]octane ( I ) [2]. Pheromone isolated from the latter source proved to be enantiomerically pure (S)-(-)(I)*), whereas samples that had been obtained from southern pine beetles consisted of a mixture of (S)- and (R)-enantiomers in a ratio of 85:15 [3].

9 1

1

9

*) More precisely:(ISJR); the enantiomer is (IR,5S). For purposes of simplification,only the configuration at C-I will be indicated in this chapter.

Ideally, both enantiomers of ( I ) should be available for use in outdoor experiments with pheromone traps [4]. The resulting demand for frontalin has so far led to the realization of about thirty different syntheses of the compound. Some must undoubtedly be recognized as noteworthy and elegant, even though the target molecule itself has a rather simple structure. Among the reported syntheses of racemic frontalin ( I ) [S-91, only two that are especially short will be outlined here [5, 61. D'Silva and Peck [ 5 ] succeeded in carrying out a one-pot synthesis of ( I ) by heating a mixture of the methyl allyl alcohol (2),aqueous formaldehyde, and acetone. Methyl vinyl ketone would seem to be a plausible intermediate, perhaps formed in situ from acetone and formaldehyde. The reaction of alcohol (2) with methyl vinyl ketone can be interpreted as either a Diels-Alder addition via (3)or an ene reaction via intermediate (4). Kinzer and coworkers had succeeded some years ago in preparing frontalin ( I )from methyl vinyl ketone and methyl allyl alcohol (2) [2]. Metal-catalyzed photoreaction between methanol and ketones, a technique for preparing l,Zdiols, has been applied by Sat0 and coworkers [6] as the key step in a rather unconventional synthesis of frontalin. The widely accepted mechanism of this carbon-carbon bond forming reaction involves the following steps: light-induced electron transfer within the metal's coordination sphere (a); migration of a proton (b);and, finally, a coupling reaction (c).

336

Individual Natural Products

CH

cocn, H ~ C O

3

Ho\

U

1

( 5 ) 40%

(1)

;?OH; TiCl4

H3cfYcH3 ( I ) 85%

)=O

+

CH30H

-

(4)

TiCb

hv

Based on this concept, a mixture of methanol and heptanedione (5), readily available from formaldehyde and diketene [lo], is irradiated (Hg-lamp) in the presence of TIC4 to provide frontalin (f) in quantities up to several grams. Various syntheses of enantiomerically pure (R)- and (,$)-frontalin exemplify in quite an impressive manner the progress that has recently been made in the preparation of non-racemic chiral compounds. Whereas the earliest approach to (R)- and (S)-(i) involved the resolution of racemic intermediates [l 13, subsequent frontalin syntheses took adavantage of the “ex-

chiral-pool strategy” [12 - 141. More recently, however, a variety of “asymmetric syntheses” have been shown to be the most effective routes to the pheromone [15--23], and there can be no doubt that methods in this third category offer significant advantages. Although the target molecule contains two asymmetric carbon atoms, it is sufficient to ensure control of the configuration at the carbinol-C*, at least so long as either ketone (6) or an appropriate derivative is utilized as an intermediate. In this case, intramolecular acetal formation leads spontaneously to the diastereomerically and enantiomerically pure pheromone ( I ) . HOHzC

CHzOH

I

I

Racemic lactonic acid (7), which can be resolved by means of quinine or cinchonine, serves as the starting material in Moris’ syntheses of (R)- and @)-frontalin (f), as outlined in Scheme 1 [Ill. Reduction of (R)-(7)to the trio1 (8),followed by protection as an acetonide,

Frontalin

337

Scheme 1 Frontalin synthesis according to Mori. H3C G

H

>- 1) HCN 2) H300

-0

’0

(7)

I

OH

resolution

CN

I

65%

64%

1) CH3Mgl 2) H30@

q

C

H

(R)-(1) 47%

“1,

ultimately leads (via the intermediates indicated in the scheme) to (R)-frontalin. In an analogous way, the (S)-enantiomer of the pheromone is available from (S)-lactonic acid (7). Syntheses of frontalin based on the “ex-chiral-pool strategy” have been found to be rather tedious, at least if the target molecule is prepared from D-glucose [12]. For example, in Fraser-Reid’s synthesis of (5‘)-(f) [12a], a sequence of seven steps is required to convert ctD-methylglucose pyranoside into the intermediate (9),whose C-1 -C-4 moiety re-emerges five steps later in the shape of aldehyde (fOu).Chain elongation by a Wittig reaction and subsequent

+ 53,40

3

H 3 : F

(W7)

[al,-52,00

catalytic hydrogenation finally affords (S)-(f). Given the length of the sequence, it is rather surprising that the overall yield was as high as 13%. Up to one gram of @)-frontalin,was produced in this way, and a minor variation of the sequence afforded the (R)-enantiomer as well. In a more recent, (but scarcely shorter) carbohydrate-based synthesis, (R)-and (S)-(f)were prepared from ct-~-isosaccharino-1,4-lactone (106) in overall yields of 8 and 13%, respectively ~131. If the monoterpene (R)-linalool (f f ) was chosen as starting material, one might anticipate a simpler, more straightforward approach to the

338

Individual Natural Products

who began with cleavage by ozonolysis of the more highly substituted double bond of a silylprotected linalool (12), thereby obtaining the corresponding aldehyde. Conversion of this aldehyde into the epoxide (14) was achieved by means of the lithiated silane (13). Another ozonolysis and subsequent reduction with sodium borohydride resulted in cleavage of the second double bond to give the diol (15). It is well known that acid catalysis can lead to the transformation of a-silyl epoxides into ketones; indeed, treatment of (15) with boron trifluoride results in the direct formation of (R)-(l),the internal acetal of ketone (6). The overall yield here amounted to 23-29%, but the fact that optically pure linalool (11) is not readily available clearly constitutes a drawback to this synthesis.

bCH3

'CH,OH

Ph'h=CH-C-Me

1) TsCl

L2)

H? CH3

Hod

1) 0 3 , CH3OH

1) H2; Pd/C/Et3N

CH,

2) ion exchange,

H@

95%

2 ) NaBH4

0

0

Y-

LiEtgEH

7?

pheromone ( I ) , because this should permit direct incorporation from the starting material of what is to be C-1 in the target. Such a synthesis was accomplished by Magnus and Roy [I41

(14) 95%

(15) 6 5 %

I

B F j . OEti CHjOH

-

+H3

H3 0

Frontalin

339

Scheme 2 Frontalin synthesis according to Sakito and Mukaiyarna.

Compared to the “ex-chiral-pool approach”, the method of “asymmetric synthesis” is in some respect riskier. First, this strategy might actually favor the undesired “wrong” enantiomer; moreover, the attainable stereoselectivity might prove to be sufficient. Despite these concerns, “asymmetric synthesis” now represents the most effective approach to frontalin.

Sakito and Mukaiyama, whose synthesis is outlined in Scheme 2, used the ester (17) as starting material for both (R)- and (S)-frontalin [lS]. Their methodology depends upon the chiral auxiliary reagent @)-proline, which is converted via diamine (16)into the bicyclic aminal (17). Successive addition of the Grignard reagents (18)and (19)leads first to the ketone (204,

340

Individual Natural Products

and in the key step which determines the con). figuration of ( I ) , to the alcohol ( 2 1 ~ Hydrolysis of the latter affords the aldehyde (22). Finally, reduction with sodium borohydride and ozonolysis provide (S)-frontalin in 84 - 88% optical purity. On the other hand, if the order of addition of the reagents (18) and (19) to the ester (17) is reversed, a way is opened to @)-frontalin via the carbinol (21b). In this case [ ( I S ) + (ZOb)],the observed diastereoselectivity is even higher, and @)-(I) is obtained with an enantiomeric excess of 100% in a chemical yield of 40 -47%.

(234

(S)-(l)

In a rather similar synthesis of frontalin, Whitesell and Buchanan [16] started with the chiral pyruvate ester of 8-phenylmenthol (23a) rather than the aminal ester (17). Here again, a highly diastereoselectiveaddition of a Grignard reagent is the key step. Subsequent reduction with lithium aluminium hydride followed by

ozonolysis affords (S)-frontalin in 100% enantiomeric excess. Exchanging the residues in the ketoester (23a) and the Grignard component =CH2 instead of CH3 [i.e. CH2CH2CH2C(CH3) and CH3MgBr instead of BrMg-CH2CH2CH2C(CH3)= CH2] permits the synthesis of (R)frontalin as well. Another approach with an obvious relationship to Mukaiyama’s synthesis has been described by Eliel and Ohwa [17], who replaced the chiral keto aminal (20b) with the keto-1,3oxathiane (23b), thus obtaining @)-frontalin with 96% enantiomeric purity. As in many other cases, the Sharpless method for enantioselective epoxidation of allylic alcohols also opens the way to highly effective syntheses of the pheromone (1) [l8-201. Lee, whose approach is outlined in Scheme 3 [18a], chose as starting material the acetal (24) from the commercially available 6-methyl-5-hepten2-one. Oxidation leads to allylic alcohol (25a), which serves as substrate for the subsequent Sharpless reaction. Mediation with ( -)-diethy1 tartrate provides as expected epoxide (26)in at least 95% optical purity. Regioselective cleavage of the oxiran ring by reduction and subsequent treatment with acid affords (S)-frontalin. Similarly ( +)-diethy1 tartrate leads to the formation of (R)-frontalin. The chemical yield in this process is a remakable 67%. More recent syntheses of (R)- and ( S ) - ( l )utilize allylic alcohols (25b) [19] and (25c) [20] as

1) HF 2) PCC

OSi(iPr),

72% 1) HO(CH 21 NCS. A

5) Chromatography

a%

k 0

341

Frontalin Scheme 3 Frontalin synthesis according to Lee.

H3CKCH. H3CO

q

t-Bu-OOH Ti(O-iPr)4

O

H

1

S O p . t-Bu-OOH

H3C,

lCH3

(-)-diethy1 tartrate

OH

(254 LiAIH4

substrates for the Sharpless method, further underscoring the great value of this procedure. A new method for the creation of chiral tertiary carbinol centers [such as C-I in (I)] relies on the principle of "self-reproduction of a center of chirality", as elaborated by Seebach and coworkers [21]. Thus, readily available a-hydroxy- or a-aminocarboxylic acids with a single Ti(O-iPr)4, fBuOOH (-)-Diethyltartrate

L

O

H

A 44%

Ti(O-iPr)4, tBuDOH (+)-Diisopropyltartrate %

1) LiAIH4 12) HQ

Li,CuCI,

68%

(R)-(7)

asymmetric carbon atom can be converted via their enolates into a-alkylated and a-heterosubstituted carboxylic acid derivatives without invoking any additional chiral auxiliaries.

PdCI? CuCl

' 3 ' S C H 3

OH

2sJ \1

irr

& ' OH

0

< 02

X = OH; NH,

342

Individual Natural Products

Scheme 4 Frontalin synthesis according to Naef and Seebach.

The (R)-frontalin synthesis outlined in Scheme 4 [22] is a good example of this method. The inexpensive starting material (S)-lactic acid is treated with pivalaldehyde to give the acetals (27u)and (27b)in a ratio of 4: 1. The cisisomer (27u) can be isolated in pure form by recrystallization, whereas hydrolysis of the cis/ trans mixture remaining in the mother liquor permits recovery of the starting materials. Once the asymmetric C-atom of lactic acid has successfully “induced” the stereoselective formation of a second chiral center C* it is sub-

sequently converted into a prochiral unit by generation of the corresponding enolate (28).In the next step, the temporary asymmetric carbon atom C* assumes responsibility for the diastereoselectivity, which is associated with alkylation of the enolate (28).Treatment of (28)with the iodide (29)results in the diastereomerically pure product (30). The bulky tert-butyl group apparently prevents the electrophile from approaching the Si-face of the substrate. Reduction of the heterocyclic product (30) and subsequent treatment with acid leads to (R)-fron-

Frontalin

talin in an overall yield of 73%. @)-lactic acid has also recently taken its place among the inexpensive chiral reagents, so “self-reproduction of a center of chirality” now constitutes viable approach to the enantiomeric ($)-frontalin as well.

References [I] J. P. VitP and W. Francke, Chem. unserer &it 19, 11 (1985); J. P. VitP, R. F. Billings, C.W. Ware, and K. Mori, Naturwissenschaften 72,99 (1985). [2] G. W. Kinzer, A. F. Fentiman, T. F. Page, R. L. Foltz, J. P. VitP, and G. B. Pitman, Nature 221, 477 (1969). [3] T. L. Payner et al., J. Chem. Ecol. 3,657 (1977); R. M. Silverstein et al., J. Chem. Ecol. 3, 27 (1977). [4] According to the studies of Payne et al., racemic frontalin does not impair the effect of the “naturally occuring” (-)-enantiomer: J. Chem. Ecol. 8, 873 (1982). [5] T. D. J. D’Silva and D. W.Peck, J . Org. Chem. 37, 1828 (1972). [6] T. Sato, H. Kaneko, and S. Ymaguchi, J. Org. Chem. 45, 3778 (1980). [7] P.-E.Sum and L. Weiler, Can. J. Chem. 57,1475 (1979); N. N. Joshi, V. R. Mamdapur, and M. S. Chadha, J. Chem. SOC.Perkin Trans. I 1983, 2963; cf. references in [9] and [151. [8] H. Hagiwara and U. Hisashi, J. Chem. SOC.,Perkin Trans. I 1985, 283. [9] E. P. Serebryakov and G. D. Gamalevich, Izv. Akad. Nauk. SSSR, Ser. Khim. 1985, 1890; Chem. Abstr. 105, 13355113 (1986).

343

[lo] R. A. Micheli et al.. J. Org. Chem. 40,675 (1975). [ll] K. Mori, Tetrahedron 31, 1381 (1975). [I21 a) D. R. Hicks and B. Fraser-Reid, J. Chem. SOC.,Chem. Commun. 1976, 869. b) H. Ohrui and S. Emoto, Agric. Biol. Chem. 40, 2267 (1 976). [I31 M.-C. Trinh, J.-C. Florent, and C. Monneret, Tetrahedron 44, 6633 (1988). [14] P. Magnus and G. Roy, J. Chem. SOC.,Chem. Commun. 1978, 297; cf. R. Burner and J. Hiibscher, Helv. Chim. Acta 66, 880 (1983). [IS] Y.Sakito and T. Mukaiyama, Chem. Lett. 1979, 1027. [16] J. K. Whitesell and C. M. Buchanan, J. Org. Chem. 51, 5443 (1986). [I71 M. Ohwa and E. L. Eliel, Chem. Lett. 1987, 41. [IS] a) A. M. W. Lee, J. Chem. SOC.,Chem. Commun. 1984, 578. b) B. D. Johnston and A. C. Oehlschlager, Can. J. Chem. 62, 2148 (1984). c) C. H. Meister and H. D. Scharf; Liebigs Ann. Chem. 1983, 913. [I91 T. Hosokawa, Y. Makabe, T.Shinohara, and S.I. Murahashi, Chem. Lett. 1985, 1529. [20] J. S. Yadav,B. V.Joshi, and A. B. Sahasrabudhe, Synth. Commun. 15, 797 (1985). [21] D. Seebach and R. Naef; Helv. Chim. Acta 64, 2704 (1981); D. Seebach, M. Boes, R. Naef; and W. B. Schweizer, J. Am. Chem. SOC.105, 5390 (1983); D. Seebach, R. Naef, and G. Calderari, Tetrahedron 40,1313 (1983);D. Seebach and T. Weber, Helv. Chim. Acta 67, 1650 (1984); D. Seebach, J. D. Aebi, R. Naef, and T. Weber, Helv. Chim. Acta 68, 144 (1985). [22] R. Naefand D. Seebach, Liebigs Ann. Chem. 1983, 1930. [23] Fuganti has described a frontalin synthesis in which enzyme catalysis is involved in the key step; cf. this book, page 221.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Milbemycin b3

t

Milbemycins were first isolated in Japan in 1975 from a culture of streptomyces (B-41-146) [l]. The structural features shared by the 18 siblings belonging to this new family include a central 16-membered lactone ring, a spiroacetal unit in the “northeastern hemisphere” and a conjugated diene in the “southwest”, together with a six-membered ring - often aromatic to the south. One offspring of the family is milbemycin b3 (f), the synthesis of which is described here. HO

(2)

Avermectin B,,

I

R = HO Me0

tins have no antibacterial effect. The great commercial interest in the total synthesis of these compounds is a result of their remarkable pesThere is a close structural relationship be- ticide and antiparasitic activity. Milbemycin tween the milbemycins and the avermectins, testing so far suggests a lack of phytotoxicity, isolated in 1981 by Merck Sharp & Dohme but avermectins are effective against helminths from Streptomyces auermitilis [2]. The latter and arthropods in doses as low as 10 pg/kg. It display minor modifications within the spiroac- is assumed that rather than inhibiting protein eta1 part of the molecule and, more important, synthesis they interfere with invertebrate neuthey feature two sugar units connected to (2-13. rotransmission. The first four total syntheses of the relatively Avermectin Bla, for instance, has structure (2). Whereas milbemycins share with most ma- simple milbemycin p3(f) are analyzed retrosyncrolides certain antibiotic properties, avermec- thetically in Fig. 1. In each case, lactone (I) was

4

Milbemycin

8,

345

0 ’

H

OSiPh,tBu

a (3)

>,\\)L

(+)-Glycerinaldehyde

(-)-Citronella1

Fig. I Retrosynthesis of milbemycin

a (5)

8, according

(-)-Citronello1

to Smith (a), Williams ( b ) . Baker ( c ) , and Kocienski (d).

dissected into three building blocks, the broken bonds always lying in very similar positions. A comparison of the strategies employed by Smith I11 [3] (bonds a), Williams [4] (bonds b), Baker [ S ] (bonds c), and Kocienski [6] (bonds d) discloses that the final lactone ring closure was uniformly rather successful, that the precursor diene unit was always generated in similar ways, and that connection of the spiroacetal block to the “northwest” fragment was usually effected by comparable means. Furthermore, the construction of the spiroacetal moiety follows the same pattern in three of the synthetic pathways. Whereas route a (A. B. Smith) provides a racemic mixture of ( I ) , routes b to d are classical examples of ex-chiral-pool syntheses, where the correct absolute configuration of the building blocks is assured with the aid of more or less inexpensive natural products available

as pure enantiomers. Since the synthetic strategies are so strikingly alike, their principal features can be understood by examining the Williams route (b), which combines fragments (3), (4,and (5) into (1)(Fig. 1). Preparation of the spiroacetal aldehyde (5) begins with (-)-citronello1 (6) (Fig. 2). This is transformed into lactone (8) by stereoselective iodolactonization (trans:cis = 15:1) of hexenic acid (3,obtained by dehydration and oxidation. Thus, two of the six stereogenic centers required for (f) have already been correctly established. Williams derives the five missing carbon atoms of fragment (5) from the chiral sulfoxide (if). No details are provided for synthesis of the latter from D-mannitol(9), but the process involves the ( + )-glyceraldehyde derivative (10) (cf. this book, p. 243 ff.). The carbanion generated from (if) adds to lactone (8) to form

346

Individual Natural Products

0 (7)

Pt

H

’

O

d /

toluene, 110%

:

(

75%H 0 cat.

”,&’

93%

(13)

0

LDA THF

ouz I

1. CISiPh.pu

2. LiOH

HJoJ 0‘

(75)

OH

/U

wOH 1. PCC : POH

5:1

(COCI)?, NEt3, - 50% 92%

2. NaBH., 70%

J

Ar

I Ar

HuO0

(5)

0 ’

OSiPhztBu

Fig. 2 Preparation of fragment ( 5 ) according to Williams [ 4 ] .

ketone (12) as a mixture of two diastereomers. Acid-catalyzed acetalization yields the crucial intermediate (13).The configuration of the spiro center is established by thermodynamic control, because anomeric effects dictate axial placement of the ether oxygens relative to the pyran rings. Although the sulfoxide group simultaneously undergoes partial equilibration this is

of no consequence, as in the following step this group is removed by pyrolysis. The “trifling” modifications necessary to transform benzoate (14) into aldehyde (5) required considerable effort. Although chlorohydrin formation from (14) is regioselective, the absence of stereoselectivity must still be corrected. This is attended to by reductive dehal-

Milbemycin fl,

76%

OTHP

(3)

THP =

0

; Cp =

0

Fig. 3 Synthesis of building block (3).

Fig. 4 Connection of fragments (3) and ( 5 ) to intermediate (23).

347

348

Individual Natural Products

ogenation to (15) followed by oxidation of the predominant isomer with pyridinium chlorochromate (PCC) and subsequent reduction (NaBH,). The desired p-isomer of (15) is thus made accessible in an awkward but nonetheless satisfactory way. Protective group manipulations and Swern oxidation of the primary alcohol result in the key fragment (5), which now contains five of the required asymmetric centers of (1)in the correct configuration. Fragment (3)is also derived from an optically active terpene derivative. (-)-Citronella1 (16) reacts with dibromo methyllithium to yield a

vinylbromide (Fig. 3). Ozonolysis of the trisubstituted double bond gives aldehyde (17),which is then transformed into an enamine. Selenylation at low temperature affords (18), and this is reduced and subsequently oxidized without epimerization at the methyl group to yield after elimination the allylic alcohol (19). Having completed its function as a latent acetylene, the vinylbromide unit is now transformed by treatment with methyllithium, giving (20).A key step in the overall synthesis is a zirconocene dichloride catalyzed, cis-stereoselective methyl alumination by the Negishi method. Treatment of

I-1 * Swern oxidation

95%

- 78% 74%

1. NaH THF

4 2 1-BuLi.

0O , Me

- 78%

0O , Me

I

2. Nal, acetone

Milbemycin p3

Fig. 5 Completion of the synthesis of milbemycin /13 ( 1 ) .

Milbemycin

the aluminum intermediate with iodine leaves the olefin geometry unchanged, and the product is a vinyliodide with the desired E configuration. The alcohol function of the latter must now be protected before the next set of steps can be carried out. These consist of an iodine lithium exchange in (3) and addition of the intermediate to the spiroacetal aldehyde (5)(Fig. 4). Apparently, removal of the superfluous hydroxyl group in (21) was not easy, but it was nevertheless accomplished by formation of a xanthogenate which was in turn converted directly to (22)by [3,3]sigmatropic rearrangement. Reduction with tributyl tin hydride stereoselectively restores the double bond to its original position. Deprotection of the alcohol function provides (23), a compound well-suited to the remaining decisive steps: connection of the “southern hemisphere”. Aldehyde (24), prepared by Swern oxidation (no details given), together with the dianion (25) generated from (4), gave the six-membered lactone (26) in good yield (Fig. 5). The E,E-diene carboxylic acid (27) was obtained by desilylation within the spiroketal portion and base-induced fragmentation of the lactone. Milbemycin p3 is finally obtained after macrolactonization by means of a carbodiimide derivative and cleavage of the methoxymethyl group. In view of the complexity of the molecules involved, these steps were all accomplished with remarkably good yields. This stereoselective synthesis of optically active (1) has been described in great detail in order to provide a sense of the effort required as well as the number of problems that must have been encountered along the way (although these are only briefly mentioned by the authors). Virtually all of the steps in the Williams route, and in the other routes mentioned, make use of known chemistry; nevertheless, they have been combined in a very impressive way, with little material wasted in the form of undesired stereoisomers. Williams’s group achieved a surprisingly high overall yield of 4% (based on

p3

349

citronellol). Taking into account the parallel path required to prepare fragment (23) one arrives at a total of 25 steps in the course of the longest linear route. It remains doubtful whether any commercial use can be made of these milbemycin [7] and avermectin [S] syntheses, however admirable they are. At the present time, fermentation is the only practical approach to these compounds in significant quantities. Hydrogenation of avermectin provides the veterinary drug “Ivermectin”, which is currently being tested in Africa as a potential treatment for humans suffering from “river blindness”. Moreover, “Ivermectin’s” insecticidal activity seems to be so strong that even feces from treated animals are restistent to normal degradation by dung fauna [9]. There may be important environmental consequences - so far not examined - for pasture land should antiparasitic drugs with such unprecedented potency come into widespread use.

References [l] H . Mishima, M . Kurabayashi, C . Tamura, S. Sato, H. Kuwano, and A. Saito, Tetrahedron Lett. 1975, 711. [2] G. Albers-Schonberg,B. H . Arison. J. C . Chabala, A. W . Douglas, P. Eskola, M. H. Fisher, A. Lusi, H . Mrozik, J. L. Smith, and R. L. Tolman, J. Am. Chem. SOC. 103,4216 (1981). [3] A. B. Smith III, S. R. Schow, . I D. .Bloom, A. S . Thompson, and K. N. Winzenberg,J. Am. Chem. SOC. 104,4015 (1982);S. R. Schow, J. D. Bloom, A. S. Thompson, K. N. Winzenberg, and A. B. Smith 111, J. Am. Chem. SOC. 108, 2664 (1986). [4] D. R. Williams, B. A. Barner, K. Nishitani, and J. G. Phillips, J. Am. Chem. SOC. 104, 4708 (1982). [S] R. Baker, M. J. OMahony, and C . J. Swain, J. Chem. SOC. Chem. Commun. 1985, 1326; J. Chem. SOC. Perkin Trans. I, 1987, 1623. [6] S. D. A. Street, C . Yeates, P . Kocienski, and S. F. Campbell, J. Chem. SOC. Chem. Commun. 1985,1386,1388; P. J. Kocienski, S. D. A. Street, C . Yeates, and S. F. Campbell, J. Chem. SOC. Perkin Trans. I, 1987,2171, 2183,2189.

350

Individual Natural Products

[7] For further (formal) syntheses of milbemycin ps see: a) S. V.Attwood, A. G. M. Barrett, R. A. E. Carr, and G. Richardson, J. Chem. SOC.Chem. Commun. 1986,479; A. G. M. Barrett, R. A. E. Carr, S. V. Attwood, G. Richardson, and N. D. A. Walshe, J. Org. Chem. 51,4840 (1986); b) M.

T. Crimmins, D. M. Bankaitis-Davis, and W . G. Hollis, Jr., J. Org. Chem. 53, 652 (1988). [8] For the first total synthesis of (+)-avermectin B,, see: S. Hanessian, A. Ugolini, D. Dubt, P. J. Hodges, and C . Andrt, J. Am. Chem. SOC.106, 2777 (1986). [9] R. Wall and L. Strong, Nature 327, 418 (1987).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Daunosamine

Antibiotics are an abundant source of amino sugars, which are present in the form of glycosides. L-Daunosamine (3-amino-2,3,6-trideoxy-L-Iyxo-hexose) ( I ) is a case in point in that it serves as the carbohydrate moiety in the anthracycline antibiotics. The most prominent of the anthracyclines, daunomycin ( 2 4 and adriamycin (2b), are well established, clinically proven drugs in use for almost two decades in the treatment of childhood leukemia and several types of solid tumors [l].

I NHz

HO

ically pure L-daunosamine (I)and its analogues in order to provide sufficient material for pharmaceutical structure-activity studies. Whereas all the early syntheses started with “common”, more or less inexpensive sugars [3,4], more recent strategies have focussed on non-carbohydrate precursors. As an example of the first type, consider the synthesis achieved by Horton and Weckerle [3]. A comparison of the starting material (3) (D-mannose) with the target molecule makes the essential reaction steps immediately obvious: deoxygenation at carbon atoms 2 and 6, epimerization at position 5, and substitution (with inversion) of the 3hydroxyl group by an amino group.

(1)

Since modification of the carbohydrate moiety can have a significant effect on the biological activity of this type of antibiotic [2], especially with respect to the suppression of undesired toxic side effects, considerable interest has been shown in developing syntheses of enantiomer0

OH

0

( 2 b ) : R = OH

The realization of this strategy is outlined in Scheme 1. By introduction of acetal protective groups, ct-D-mannopyranoside (4a) is converted into the mixture of epimers (4b), which is then transformed further without purification. The elegant method of Klemer [5] is next applied in order to deoxygenate carbon atom 2: treatment of the pyranoside (4b) with butyllithium leads to ketone (Sb). The observed regioselectivity with respect to cleavage of the dioxolane

352

Individual Natural Products

Scheme 1 Synthesis of daunosamine by Horton and Weckerle.

CH,OH

Ph

PhCH(OMe)2

HO @OCH3

(4d

'

J ph
-6 H30@

@ P -(h-

0 - OCH,

*

OLi

f5a)

f5b) 0 -CH,

0 -CH,

P h < o p

OCH, +

~~
NHAc

(7a) 87% CH, Hg: Pd

1. AgF

k

%ziT

HO HO@CH, NHAc

HL? .OCH, H,C - Li. I C3H7

O@0 OCH3

NH20H

0 -CH,

0

(4b)

0 -CH,

Ph

v %

ONHAc C H

3

'

(i'b) 12% CH,Br

PhC - 0O O C H 3 NHAc

t8)

HOP

O

H

NH3CI (1)

'

HCI

ring can be plausibly explained by assuming complexation with the butyllithium and subsequent abstraction of the axial proton at POsition 3. This generates lithium enolate (h), the precursor of ketone (Sb), together with benzaldehyde. Introduction of the amino group is accomplished by reduction of the oxime (6),giv-

ing predominantly (74. Small amounts of the epimeric product (7b) can be removed by recrystallization. In order to effect deoxygenation at carbon atom 6, the dioxane ring is cleaved by treatment with N-bromosuccinimide using the method introduced by Hanessian [6], thereby providing bromide (8). Elimination of

Daunosamine

hydrogen bromide, cleavage of the benzoate, catalytic hydrogenation (fortunately in a stereoselective manner), and hydrolysis of the amide moiety finally results in L-daunosamine hydrochloride (I) HCl, which is isolated in crystalline form as the a-anomer. The authors claim to have achieved an overall yield of 40%; but this result could not be reproduced by another research group [7a]. A second carbohydrate-based synthesis of daunosamine [S] features as its key step iodocyclization of imidate ester (IOU) to give iodooxazoline (fob) in 90% yield. Subsequent dehalogenation, hydrolysis, and acylation produces N-acetyldaunosamine. In order to obtain imidate ester (IOa),the hydroxyl group of enepyranoside (9),itself available from L-rhamnose [8,9] must first be inverted by the method of Mitsunobu. The overall yield of N-acetyldaunosamine based on (9) amounts to 55%. In all the carbohydrate-based syntheses of daunosamine (I),stereocontrol is achieved in 1) PhCO4l

Ems-

N= N - C O g t

2) HOo Ph3P

Ho@oMe

>

89 %

dicollidine perchlorate

/@OMe

0 CCI,

I

(lob) 90% 1) B u p H 2) TsOH. pyridine. H . p 3) Ac20, pyridine

VMe

HO NHAc

ClOl.

Dyong and coworkers [7] chose (E)4-hexenal as their acyclic starting material, a substance that contains the complete carbon skeleton of daunosamine (1) (see Scheme 2). The "only" task that remains is the introduction of functional groups with the appropriate relative and absolute configurations. First, aldehyde (f 1)is converted into the tartaric acid-derived acetal (12), the intent being to use this chiral auxiliary group to functionalize carbon atoms 3, 4, and 5 stereoselectively. Unfortunately, the very first step - introduction of the amino group - produces only a low diastereomeric excess with respect to the N-sulfinylsulfonamide (13). Nevertheless, cleavage with methoxide followed by recrystallization gives the principle stereoisomer (14) in pure form in 23% yield. Subsequent cis-hydroxylation of the double bond, induced by silver acetate and N-bromoacetamide, is effectively directed by the tosylamido group and gives mainly acetate (f5a). The mixture of epimers (154 and (1%) is then converted into the pyranosides (16a)/(16b).Column chromatography results in enantiomerically pure N-tosyldaunosamine (164, which is thus made available in 10 g scale. Stereoselective coupling of achiral C2 and chiral C4 units also opens the way to highly effective syntheses of L-daunosamine (1).Three different research groups selected the aldehyde (17) as their C4fragment, a compound available either from L-tartrate [ll] of from D-threonine [12]. Another approach to aldehyde (f 7) relies

lNaH C13CCN

iodonium

the classical way; that is, the corresponding manipulations rely on the presence of a cyclic pyranoside or furanoside framework. Syntheses that avoid sugars as starting materials are competetive only when acyclic stereocontrol is possible. Furthermore, the choice of an appropriate chiral starting material and effective "asymmetric induction" are prerequisites to success with this approach. Needless to say, only a synthesis that delivers the target molecule in enantiomerically pure form is really sufficient

aoMe

HO

QoMe

"YNH CCI,

f W

353

354

Individual Natural Products

b<:

Scheme 2 Synthesis qf daunosamine by H3C

I

(1 1 )

TosN=S=NTos

I

NHTos

TOS

\

(14) 23% from (12)

(73)

CH3CONHBr AgOAc

(754 R, R’ = H, Ac

I

NHTos

(156) R, R’ = H, Ac

1. NaOCH3 2. HCI/CH@H 3. HOAclHfl

HO@OH

NHTos

(16a) 14% from (14)

on a baker’s yeast-mediated acetoin condensation of benzaldehyde and acetaldehyde to give diol (19) [13]. Aldehyde (18), available from alkene (19) by ozonolysis, is subject to H

- N - SNHTOS

CH3

+

NHTos

(16b)4% from (14)

base-catalyzed isomerization, giving (2R,3S)( 17 4 . Fuganti and coworkers [14] were able to synthesize L-daunosamine (1)in a straightforward manner starting with aldehyde (174. Diallylzinc adds to sulfenimine (20) with excellent stereoselectivity,and subsequent hydrolysis and benzoylation result almost exclusively in diastereomer (21). Finally, ozonolysis gives Nbenzoyldaunosamine (22). In the key step, the organometallic reagent attacks the carbon-nitrogen double bond of sulfenimine (20)from the desired Si-face. This stereochemical result is in accordance with the Felkin-Anh model; i.e.,

Daunosamine C02Et HO

H*oH

H

C02Et

J

J

\1

d d

CHS

b/

(77a): R1/R2 = (CH3),C

(17b): R1/R2 = (CH2)& PhCHO

+

CH3CH0

yeast

(19) 25-30%

I

0

NC%Ph (24)

NSPh

(7 7a)

(20) 75% 2. %O" 3. PhCOCl

OH NHCOPh

hCOPh

(22) 85%

I

transition state (23a),which leads to the formation of ( 2 f ) ,should be favored relative to (23b) because the approach of the nucleophile is hindered in the latter by the dioxolane ring ~151. The enolate of dimethyl acetamide adds to benzylimine (24) stereoselectively upon treatment with zinc bromide, giving almost exclusively the diastereomer (25). This is converted into L-daunosamine (f) by conventional methods. The precursor of benzylimine (24) [16] is obviously once again aldehyde (f 7b).

--+ Ph

CH3

355

(21) 80%

R-Yet

(251 50%

Another derivative of aldehyde ( 1 7 4 nitrone (26a), is also subject to highly stereoselective

attack, this time by silyl ketene acetal (26b)in the presence of zinc iodide [17]. DeShong and coworkers [18] chose the 1,3 dipolar cycloaddition of ethyl vinyl ether to nitrone (27) as the key step in their synthesis (cf. this book, p. 48). It turns out that isoxazolidine (28) is the only product formed in this reaction (see Scheme 3). Subsequent catalytic hydrogenation leads immediately to daunosamine glycoside (29).The overall yield in this elegant and straightforward synthesis is 58%. In view of the fact that two chiral centers are created in the key step, one might have anticipated the formation of a mixture of four diastereomers. An endo-like transition state (30) would explain in a plausible way the observed anti-configuration (C*) of isoxazolidine (28).Furthermore, it is apparent that the ethyl vinyl ether is only able to

356

Individual Natural Products

Scheme 3 Synthesis of daunosamine by DeShong

H HO

H3C

H3C o / Z V P h

0

0

(1 7a)

-

0

CH3

f2W

OMe

PhCHPHOH

/Zniz

OSiMegEu

Hobo t--3) AcOH

NHCOPh

H3C&

.

C0,Me

I

(27) 84% in 2 steps

(28) 93% 1. H2; Pd(OH)z

HCI/CHsOH 2. Ac,O. pyridine

DIBAH

OH

HO NHCOPh

H

NHAc

68%

approach one of the two diastereotopic faces of nitrone (27).Here again, the Felkin-Anh model offers a reasonable explanation: given the two conformations (31a) and (31b), the former should be the more reactive, since only in this orientation is steric hindrance by the dioxolane ring avoided. An intramolecular 1,3-dipolar cycloaddition (cf. this book, p. 79ff.) with the chiral nitrone (32) sets the stage for a synthesis of 4-epi-daunosamine, also known as acosamine (35). The chiral phenylethyl substituent is responsible for an “asymmetric induction”, so that an 82:18 ratio of diastereomeric products (334 and (33b) is observed. In this case, the nitrone oxygen atom in not linked with the oxygen-substituted carbon atom of the enol ether moiety, in contrast to the corresponding intermolecular reaction (see above). This kind of regioselectivity is apparently a result of the fact that the ester group acts as a “clamp”. The major product

‘OD

PhH,C’

H

H3C , N y P h t-BuMe,SiO CH, 96%

03%

I

-

a

(1 7 4

(29) 74%

L

EtO’

EtO’

O

(543

(334 can be converted into lactone (34) by reductive cleavage of the nitrogen-oxygen bond. The final transformation into acosamine (35)is accomplished by conventional methods [191. Yet another approacb to daunosamine (1)relies on the successive addition of three fragments: C3 C2 C1 [20]. First, 0-protected

+

+

351

Daunosarnine

, .

OdN

HO

i

NHBoc

2) i - B u y H

(38)

Zn/HOAc

HO'

KO- t -Bu

cle

phs;qoq

(39)

d$

0

(34) 89%

\

L

HO O

L

OH OCH, H , C I I I W O NH3C1

. .

H

HO.

( I ) . HC1 24% from L lactic acid

NH2

I

NHBOC

NHBW

(35)

L-lactate is coupled with isonitrile (36) to give the oxazole (37). Hydrolysis of the heterocyclic ring and simultaneous cleavage of the hydroxyl protective group leads to the formation of lactone (38).Catalytic hydrogenation of this cyclic intermediate occurs, as expected, in a stereospecific manner. Finally, reduction to the hemiacetal and homologization with the Wittig reagent (39)gives L-daunosamine (f) in 24% overall yield based on L-lactic acid. In another approach [21], 0-benzylated lactaldehyde (40) serves as a chiral C2 building block suitable for combination with 3-nitropropionate (41). When this reaction is mediated with neutral alumina, thermodynamic control dictates formation largely of the ribo-adduct

>- A'2°3

H&

1

OH

I

H3C& HO NHCOPh

-<

(42) 62%

l p NHCOPh

358

Individual Natural Products

[5] A. Klemer and G. Rodemeyer, Chem. Ber. 107, 2612 (1974). [6] S. Hanessian, Carbohydr. Res. 2, 86 (1966). [7] a) I. Dyong and R. Wiemann, Chem. Ber. 113, 2666 (1980); b) I. Dyong, H. Friege, and T. zu Hone, Chem. Ber. 115,256 (1982). [8] H. W. Paub and B. Fraser-Reid, Carbohydr. Res. 150, 111 (1986); cf.: H. W. Pauls and B. Fraser-Reid, J. Chem. SOC.Chem. Commun. 1983,1031;G. Cardillo, M. Orena, S. Sandri, and C. Tomasini, J. Org. Chem. 49, 3951 (1984). [9] For a synthesis of enepyranoside (9) from (17a) see: S. Servi, J. Org. Chem. 50, 5865 (1985). [lo] Daunosamine by resolution: F. M. Hauser, R. (35) P . Rhee, and S. R. Ellenberger, J . Org. Chem. 49,2236 (1984); rac. daunosamine: S. J. DanishThe past decade has witnessed the synthesis efsky and C. J. Maring, J . Am. Chem. SOC.107, of numerous derivatives of daunosamine, all 1269 (1985). prepared in the hope of improving the effectiv- [11] G. Fronza, C. Fuganti, P. Grasselli, and G. Marinoni, Tetrahedron Lett. 1979, 3883. enes of the anthracyclines. For example, if dauFuganti, P. Grasselli, and G. Pedrocchi-Fannosamine (1)is replaced by acosamine (35)or [12] C. toni, Tetrahedron Lett. 1981, 4017. by 4-deoxydaunosamine (44) [22], the corre- [13] G. Fronza, C. Fuganti, and P. Grasselli, J. Chem. spondingly modified anthracyclines show deSOC.Chem. Commun. 1980,442;earlier publications cited therein. Cf. this book, p. 221. creased toxicity [2] relative to the natural products (2). The morpholino sugar (45) [23], with [I41 C. Fuganti, P. Grasselli, and G. Pedrocchi-Fantoni, J. Org. Chem. 48, 910 (1983). a glycosidic anthracycline linkage, displays dra- [l5] M. ChPrest, H. Felkin, and N. Prudent, Tetramatically enhanced cancerostatic activity in hedron Lett. 1968, 2199; N. T. Anh and 0. Eisenstein, Nouv. J. Chim. 1, 61 (1977). Cf. this comparison with daunomycin (24 and adriabook, p. 3ff. mycin (2b). [36] T. Mukaiyama, Y. Goto, and S. Shoda, Chem. Lett. 1983,671; for a similar synthesis of L-acosamine see: T. Hiyama, K. Nishide, and K. KoReferences bayashi, Tetrahedron Lett. 25, 569 (1984). [17] Y. Kita, F. Itoh, 0. Tamura, Y. Y. Ke, and Y. Tamura, Tetrahedron Lett. 28, 1431 (1987). [I] F. Arcamone: Doxorubicin, Academic Press, [I81 P. DeShong and J. M. Leginus, J. Am. Chem. New York 1981. SOC.105,1686 (1983);P. DeShong, C. M. Dicken, [2] H. S. El Khadem (Ed.): Anthracycline AntibiotJ. M. Leginus, and R. R. Whittle, J. Am. Chem. ics. Academic Press, New York 1982. SOC.106, 5598 (1984). [3] D. Horton and W. Weckerle, Carbohydr. Res. [I91 P. M. Wovkulichand M. R. UskokoviC,J. Am. 44, 227 (1975). Chem. SOC.103, 3956 (1981). [4] J. P. Marsh, C. W.Mosher, E. M. Acton, and L. Goodman, J. Chem. SOC.Chem. Commun. 1967, [20] Y. Hamada, A. Kawai, and T. Shioiri, Tetrahedron Lett. 25, 5409 (1984). 973; T. Yamaguchi and M. Kojima, Carbohydr. Res. 59, 343 (1977); G. Grethe, T. Mitt, T. H. [21] S. Hanessian and J. Kloss, Tetrahedron Lett. 26, 1261 (1985). Williams, and M. R. UskokoviC, J. Org. Chem. 48,5309 (1983); A. C. Richardson, J . Chem. SOC. [22] Cf.: L. F. Tietze and E. VoJ, Tetrahedron Lett. 27, 6181 (1986). Chem. Commun. 1965,627; H. H. Baer, K. C‘apek, and M. C. Cook, Can. J. Chem. 47, 89 [23] E. M. Acton, G. L. Tong, C. W. Mosher, and R. L. Wolgemuth, J . Med. Chem. 27, 638 (1984). (1969); M . K. Gurjar and S. M. Pawar, Tetrahedron Lett. 28, 1327 (1987).

(42),which can be isolated as a pure, crystalline product. Five more steps, including an inversion of the configuration at carbon atom 5, result in lyxo-lactone (43), which has been previously converted [13] into L-daunosamine (1).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Two Strategies, One Target: Swainsonine

Some years ago, the trihydroxylated indolizidine alkaloide swainsonine ( I ) was isolated from the plants Swainsona canescens [I] and Astralagus lentiginosa [2] and, somewhat later, from a fungus called Rhizoctonia leguminicola [3]. The relative stereochemistry of ( I ) was determined by X-ray crystallography [4], whereas its absolute configuration was postulated on the basis of biosynthetic considerations [S].

&H

a

lllOH

(1) Swainsonine

Several groups [6 - 91 confirmed this structure in 1984 by preparing swainsonine from optically active compounds with known configurations. Owing to the three hydroxy groups, sugars are ideal precursors for ( I ) - indeed, various "ex-chiral-pool" syntheses all start from D-mannose derivatives. This common feature is readily explained by retrosynthetic analysis: ( I ) can be broken down into a C6 synthon possessing the D-mannose configuration and equipped with three acceptor positions; the two remaining synthons offer no particularly striking features with respect to stereochemistry or polarity pattern. Thus, the problem of swainsonine synthesis is reduced to one of adequate activation of positions l, 4, and 6 of D-mannose in order to

introduce the N and C2 building blocks required to form the bicyclic compound ( I ) , all the while maintaining the configuration at C-4. Skilful use of protecting groups is required with respect to the hydroxyl functions at C-2, C-3, and C-5. The most elegant approach is that of Fleet and coworkers [S], who obtained ( I ) in a remarkable overall yield (ca. 16%). As shown in Figure 1, a-D-mannose (2) was first provided with a variety of protecting groups designed to allow selective deblocking. Temporary inversion of the configuration at C-4 in (3),leading to the D-talose derivative (4), was achieved by oxidation with pyridinium chlorochromate (PCC) and reduction of the resulting ketone. The D-mannOSe configuration was then restored by activation of this 4-hydroxyl group as the triflate, followed by SN2substitution with sodium azide. The nitrogen synthon has thus

360

Individual Natural Products G \ , , O H

OH

0 4 1. P h C H p H HCI, 50%

2. CISiPhlCBu. imidazole 3. MefiO(H@)

OH OH CHO

Mefi(OMe)p

D-mannose

72%

O+

'

, HO

I

0

OSiPh2-t-Bu 1. PCC molecular sieves 88% 2.NaBH4 EtOH

O+

HgPd, MeC02H

4 3 days

H (9)

(7) 07% with respect to

(6)

16% overall yield with respect to (2)

Fig. 1 Ex-chiral-pool synthesis of swainsonine ( 1 ) according to Fleet et al. [ 8 ] .

been successfully introduced into (5) with the correct stereochemistry. Generation of a aldehyde group at C-6 permitted a chain extension by two C atoms via the Wittig reaction, providing (6), the key compound of the Fleet route. Swainsonine derivative (10)was obtained with almost incredible efficiency (87%) following two hydrogenation steps. First, the double bond was saturated, and

then the azido function was transformed into an amino group. Reductive amination to (7) resulted in the desired piperidine ring. The benzyl ether moiety initially remained intact, but this could also be cleaved under somewhat more vigorous conditions, and the resulting lactol(8) was then opened to furnish aldehyde (9).A second reductive amination (9) -+ (10)completed the indolizidine framework. Deprotection pro-

Swainsonine

vided swainsonine (1)as the result of an impressive 13-step synthesis from D-mannose. In addition, the key intermediate (5) allows the preparation of other polyhydroxylated pyrrolidine derivatives. The remaining “ex-chiral-pool” syntheses of (1)are similar in concept, although they involve more steps, are tedious, and much less effective than Fleet’s route [6, 7, 9, 101. Interesting new chemistry appears in the work by the Fujisawa Pharmaceutical group, specifically in the ring closure to form indolizidines (10) and (14) (Fig. 2). The chirality of the required intermediate (13)is again derived from D-mannose, via compounds (11) and (12). The new feature here is a sodium borohydride reduction in ethanolltrifluoroethanol as solvent, which saturates the double bond in (13) and releases the amino group. The latter opens the epoxide ring and also reacts with the ester function to form a mixture of bicyclic lactams. Subsequent reduction provides the final products of this reaction cascade, swainsonine derivative (10) and its isomer (14). The only drawback of this nicely planned double cyclization is the fact that in-

tramolecular attack of the primary amine is not regioselective, providing instead two bicyclic isomers. A second strategy for swainsonine synthesis starts from “normal” achiral chemicals, reaching the desired destination by means of enantioselective reactions [ll]. The Sharpless oxidation of allyl alcohols is the logical method of choice for preparing polyhydroxylated compounds such as (1).Figure 3 presents the synthesis developed by the MIT group: starting from trans-l,4-dichloro-2-butene, allyl alcohol (15) is obtained in 68% overall yield in three steps. The future swainsonine nitrogen has already been incorporated in the form of an Nbenzyl-p-toluene sulfonamide unit. Proper choice of protective groups for the amino function is crucial in this route to (25): they must not prevent enantioselective epoxidation and must be both stable to a variety of reagents and at the same time easily removable. Epoxidation of (15) is achieved under the standard Sharpless oxidation conditions resulting in an enantiomeric excess of 95%. Thus, the optically active auxiliary (-)-tartaric acid diisopropylester, in-

+ + + 1. C r 0 3 . pyridine 2. Ph3P=CH-C02Et

10 eq. NaBH4 C2H@H/CF3CHflH 10 : 1

Et0,C COCF,

(7 3)

Fig. 2 Swainsonine by double cyclization [ l o ] .

361

362

Individual Natural Products CI

3 steps

68%

CI

HO

Bn = Benzyl Bn

@

=

91%

(-)-tartaric acid diisopropyl ester, Ti(O-i-Prop)d, f-BuOp, CH2C12,

" : s o -2 ~

95%

ee

- 20 OC. 2,5 h

Ho',fl 71%

(1 7)

NaOH. I-BuOH 85 oc

HO (16)

1. NaH,

quant.

1. M e S O

1. Ac,O lutidine 2. LiAIHq

OtSPh

M 9) BnO,,

.,OBn

BnO,

H

o

d

>

(21)

93%

(-)-tartaric acid diisopropyl ester Ti(O-i-Prop)+ t-BuO# CHfi12 - 20°C, 21 h

93% 99% ee

BnO,,

HO

Et02C

- 78% (22)

,OBn

4

1. OMSO C6HI1-N=C=N-C6H11 pyridiniurn M a l e

2. Ph3P=CHCO+t 89%

Q

BnO,

3 Et0,C-

I

(24)

85%

K0,C- N = N - COZK pyridine AcOH, 40 %. 40 h

BnO,,

t-BuMe2Si0 K B : B n

Fig. 3

pen

HC=CH

(23)

EtO,C

-,OBn

4

HAl(i-Bu),

-

111

I

Bn

7 DME. - 60 "C 2. t-BuMe$iOSOfiF3 NEt3 CH2Clp 0 %

68%

Et02C

'I

.'=OBn Bn (25)

Swainsonine

1

MeO,A

J

v

0 1 Bn

363

exchange resin 84%

(27)

7% overall yield

Fig. 3 Enantioselectiue synthesis of ( 1 ) according to Sharpless et al. [li] (continued).

troduced in stoichiometric amount, ensures epoxidation of ally1 alcohol (15) predominantly from the “front face” to yield stereoisomer (16) c121. The next steps in the swainsonine preparation follow familiar patterns developed by Sharpless and Masamune in their hexose syntheses. Payne rearrangement to form (17) and opening of this compound with thiophenolate to (18), followed by protection of the hydroxyl groups and oxidation, yields the sulfoxide (19). Subsequent Pummerer reaction to an intermediate 0,s-acetal, reduction to alcohol (20), Swern oxidation, and Horner olefination afford olefin (21).All that remains is a DIBAL reduction to give (22),setting the stage for the second act of this total synthesis. Epoxidation is once again effected with the aid of (-)-tartrate, this time on (22),and oxygen again approaches from the “front”. Steps (15) -+ (16) and (22)+ (23) illustrate nicely the way the stereochemical consequences of Sharpless oxidations can be predicted and planned, independent of other functional groups and additional asymmetric centers. The preparation of ( I ) requires chain extension by two C atoms in this case as well (see Fig. 3 (23) -+ (25)).Next comes activation of the sulfonamide group to this point a rather lethargic entity. Reductive N-S-cleavage within (25),intramolecular attack of the resulting N-anion on the epoxide, and a silylation reaction complete the synthesis of the intermediate (26) which contains all four asym-

metric centers of (1) in their correct configurations. The remaining steps to swainsonine (shown in Figure 3) are straightforward. Although the sequence (24)+ (27) requires a greater number of individual steps than the very similar onepot procedure (13)+ (10), it guarantees regioselective formation of the bicyclic compound from the C8N chain. Comparing the two strategies for preparation of swainsonine, the “ex-chiral-pool” method [13] of Fleet merits by far the highest marks. The starting material, D-mannose, is an inexpensive, tailor-made educt. Few syntheses of this type benefit from so much structural similarity between the starting material and the product; normally, one is obligated to invest more effort in a greater number of steps. It should be emphasized that one great advantage of Sharpless’ enantioselective route is that any of the 16 stereoisomers of (1)should in principle be attainable. One need only start with cis-1,4dichloro-2-butene, change the stereochemistry of the tartaric acid ester for the steps (15) + (16) and/or (22)-+ ( 2 4 , or modify the epoxide openings. Syntheses of “g1uco”- and “ga1acto”swainsonine isomers are in fact mentioned in a footnote [Il, 141. Before concluding, it is worth explaining why swainsonine has attracted so much interest and recent synthetic effort. Swainsonine as well as some of its stereoisomers and other polyhydroxylated pyrrolidines are characterized by

364

Individual Natural Products

significant biological activity, including strong enzyme inhibition. Thus, swainsonine can interrupt the hydrolysis of mannopyranosides by inhibiting the mannosidases. This in turn leads to pronounced physiologic effects in mammals feeding on plants containing (f) (serious nerve disturbances and fatal effects on muscle coordination), with symptoms similar to those found in persons suffering from the inherited disease mannosidosis. Fleet has postulated [I 51 that protonated swainsonine (28) inhibits the enzymatic cleavage of D-mannose (29)as a consequence of its structural similarity to D-mannose glycosides protonated adjacent to the endocyclic acetal oxygen. It has also been claimed that compounds like swainsonine offer some potential for stimulation of immune responses and for prevention of cancer metastatis [16].

[3] M. J. Schneider, F. S. Ungemach, H. P. Broquist, and T. M. Harris, Tetrahedron 39, 29 (1983). [4] B. W. Skelton and A. H. White, Aust. J. Chem. 33, 435 (1980). [5] M . J. Schneider, F. S. Ungemach, H. P. Broquist, and T. M. Harris, J. Am. Chem. SOC.104, 6863 (1983). [6] M. H. Ali, L. Hough, and A. C. Richardson, J . Chem. SOC.Chem. Commun. 1984, 447; Carbohydr. Res. 136, 225 (1985). [7] T. Suami, K. Tadano, and Y.Zmura, Chem. Lett. 1984, 513; Carbohydr. Res. 136, 67 (1985). [8] G. W. J. Fleet, M . J. Gough, and P. W. Smith, Tetrahedron Lett. 25,1853 (1984);B. P. Bashyal, G. W. J. Fleet, M. J. Gough, and P. W . Smith, Tetrahedron 43, 3083 (1987). [9] N. Yasuda, H. Tsutsumi, and T. Takaya, Chem. Lett. 1984, 1201. [lo] H. Setoi, H. Takeno, and M. Hashimoto, J. Org. Chem. 50, 3948 (1985). [11] C. E. Adams, F. J. Walker, and K.B. Sharpless, J. Org. Chem. 50, 420 (1985). [12] For the catalytic version of the epoxidation see: R. M. Hanson and K.B. Sharpless, J. Org. Chem. 51, 1922 (1986). [13] For more recent “ex-chiral-pool” syntheses of swainsonine see: N. Zkota and A. Hanaki, Chem. Pharm. Bull. 35, 2140 (1987) (starting with glutaminic acid); J. M . Dener, D. J. Hart, and S. Ramesh, J. Org. Chem. 53, 6022 (1988) (starting with tartaric acid); R. B. Benett ZZZ, J.-R. Choi, W .D. Montgomery, and J. K.Cha, J. Am. Chem. SOC.111, 2580 (1989) (starting with erythrose). [14] Biological activity: A. D. Elbein, T. Szumilo, B. A. Sanford, K. B. Sharpless, and C. E. Adams, Biochemistry 26, 2502 (1987). [l5] G. W.J. Fleet, Tetrahedron Lett. 26, 5073 (1985). [I61 G. W.J. Fleet, J. C. Son, D. S. C. Green, I. Cenci di Bello, and B. Winchester, Tetrahedron 44, 2649 (1988).

woH /OH

OH

H

OH

-. .

OH

H

(29)

References [l] S. M. Colegate, P. R. Dorling, and C. R. Huxtable, Aust. J. Chem. 32, 2257 (1979). [2] R. J. Molyneux and L. F. James, Science 216, 190 (1982).

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

C. Synthesis of Non-Natural Target Compounds

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Syntheses of Statine

Statine ( l a ) is an unusual P-hydroxy-y-amino acid and an essential component of pepstatin [l], an inhibitor of proteolytic enzymes such as renin.

Based on the hypothesis that the inhibitory effect of pepstatin [2] depends on a structural similarity between the statine unit and the tetrahedryl transition state in enzymatic hydrolysis of a peptide bond, an intensive search was begun years ago for synthetic peptides containing statine or side-chain-modified analogues that might function as renin inhibitors and offer new therapeutic possibilities for the treatment of high blood pressure [3]. This concept has proven very effective, in part because of the intensive application of molecular modeling, and it has led to the development of a number of potent and promising renin inhibitors. Hence, there is increased interest in straightforward, stereocontrolled syntheses of statine systems (1) bearing the requisite (3S,4S)-stereochemistry and suitable for large-scale implementation. Most of the early attempts [4] to synthesize ( l a ) started from an optically active a-aminoaldehyde protected with a t-butoxycarbonyl (Boc) group (24, a substance that was then reacted with an achiral acetate enolate.

0

Boc;,,,+ R

0

H -

eCH2!OR*

(2)

However, it was soon found that this approach does not lead to significant diastereoselectivity, and that it is difficult to separate the resulting diastereoisomers (3) and (4) [ S ] . On the other hand, Danishefsky observed a promising degree of threolerythro selectivity [ 6 ] on cyclocondensation of (24 with "his" diene (5). Cycloadduct (6) was found to predominate, with an isomer ratio of 9:1, and after HPLC separation (6) could be converted to N-Boc-statine (3a).

+ Boc-(~~) 2. H202

366

Individual Natural Products

In theory it would also be possible to carry out a diastereoselective aldol reaction leading to (3)by invoking a chiral enolate to control the addition to (2). Since the established boronenolate aldol strategy of Evans is known to give high selectivities only in the case of a-substituted acetic acid derivatives, the synthesis of statine requires use of systems such as (7),where the a-substituent can be removed again after diastereoselective addition has been performed c71.

Meanwhile, Braun has succeeded in carrying out efficient diastereoselective aldol reactions in cases involving unsubstituted acetate enolates [8]. Application of this method to a variety of protected a-aminoaldehydes now makes statine analogues accessible with selectivities of 9: 1 and above [9]. In general, the route to statine systems from N-Boc-protected a-aminoaldehydes suffers from a notorious tendency toward racemization. It is thus all the more remarkable that Reetz [lo] found the equally accessible dibenzyl-protected a-aminoaldehydes (9)to be more stable, adding even to ester enolates without racemization in a nonchelate-controlled reaction. Unfortunately, the principal product (de > 80%) is the undesired erythro-product (10).

An attempt to reverse the diastereoselectivity using enol silanes and TiCl, did not allow the reaction to be interrupted at the stage of the aldol adduct. Under these conditions water was eliminated, leading to the corresponding unsaturated system. However, in the case of the ally1 anion equivalent allyltrimethylsilane, and in the presence of SnCb, chelate control can be induced to yield (If)(de > 80%). Such adducts should lend themselves to statine syntheses upon oxidative cleavage of the double bond.

There is yet another possibility for avoiding stereochemically labile Boc-protected a-aminoaldehydes (2) in the synthesis of statine systems: ester enolates can be added to the more stable Boc-protected amino acid derivatives (12),with subsequent reduction of the P-keto esters (13).The first step poses no problems in the case of suitably activated amino acids, but stereochemical control of the reduction has proven difficult. The usual reducing agents provide only moderate threo selectivity, and a maximum selectivity of 6: 1 resulted from reduction with a chirally modified LiBH, [ l l , 121. Preliminary attempts at enzymatic reduction of the pketo ester (13)with baker's yeast also failed to show much promise, with yields of 30 to 50% and a maximum de of 60%. Since the behaviour of baker's yeast tends to be a function of biological origin and strain, efforts were also made to improve the stereoselectivity by employing pure cultures of particular yeast strains [13]. It was found that of the 14 yeasts tested only five were able to effect complete reduction of the pketo ester (13)(R = CH,Ph). Four strains pro-

statine

duced (3S,4S)-diastereoisomers,while one yeast generated (3R,4S)-diastereoisomers. Even after scaling up to large quantities of substrate (50 to loo0 g), careful optimization of the enzymatic reaction resulted in almost complete conversion with a selectivity of 23: 1. Twofold recrystallization permitted the diastereoisomeric excess to be raised to > 99%. All the prerequisites thus appear to be fulfilled for the commercial production of this statine system: a short diastereoselective route starting from easily accessible educts that avoids both low-temperature organometallic reactions and chromatographic separations.

dioxide. The critical step is the preparation of (15). This can only be accomplished by in situ

activation of the protected amino acid (12)with isopropenyl chloroformate in the presence of 4-N,N-dimethylaminopyridine.Highly stereospecific reduction of (16) to (17)is possible either with NaBH4 at acidic pH or by catalytic hydrogenation. The NMR spectrum of the product provides no evidence for the formation of diastereoisomers. Regioselective hydrolysis or methanolysis allows conversion of (17) into a stereochemically appropriate precursor to the statine system (3).

H BocN ,, (

(19)

I

( 1 7)

The only competing approach that seems to be viable is a method [14] that also introduces the chiral alcohol via a reduction step. However, in this case the process occurs on a fivemembered ring system, so the existing asymmetric center from the amino acid can be easily exploited for optimal stereocontrol. The key cyclic derivative (I@, a chiral tetramic acid derivative, is surprisingly easy to prepare by simple reflux in acetonitrile or ethyl acetate of the condensation product (15 ) from an amino acid with Meldrum's acid. The driving force for this reaction is the elimination of acetone and carbon

1. R e d 4 THF. 0 %

R

Boc

367

OH

2. Pt, o2

Boc-(1)

NsHC03. H20

In addition to the methods already discussed, other possibilities also exist for stereocontrolled construction of the vicinal amino alcohol unit characteristic of the statine system [15 - 181. For instance, Kogen [lS] has shown that one can employ a diastereoselective epoxidation to introduce the required hydroxyl function. Reaction of the allylic alcohol (18) with m-chloroperbenzoic acid gives primarily epoxide (19), which can be opened regioselectively with bis(2methoxyethoxy)aluminum h ydride (Red-Al) and then transformed into the corresponding protected statine derivative (3) by selective oxidation of the primary hydroxyl group. Whereas this synthesis presupposes the availability of Z-configurated allylic system (18), prepared from (2) by cis-selective Wittig-Horner olefination followed by reduction, another route [16] employs the E-configurated olefin (20). The key step here is an intramolecular SN2'type substitution. Starting from (20),the cyclic

368

-

Individual Natural Products

I

H

t-BuSiOpCN ,,,f\\/'c, I R

AQF

Pd(ll)-cat.

References

[l] H. Umezawa, T. Aoyagi, H. Morishima, M. Matsuzaki, M. Hamada, and T. Takeuchi, J. Antibiotics 23, 259 (1970). [2] D. H. Rich, J. Med. Chem. 28,262 (1985). 3 steps [3] G. J. Hanson, J. S. Baran, T. Lindberg, G. M. Walsh, S. E. Papioannou, M . Babler, Biochem. Biophys. Res. Commun. 132, 155 (1985). [4] Cf. the references cited in Ref. [14]. [5] a) W.-S.Liu and G. I. Glover, J. Org. Chem. 43, carbamate (21) can be prepared with a se754 (1978); W. S. Liu, S. C. Smith, and G. I. lectivity of 15: 1 using silver fluoride and Glover, J. Med. Chem. 22, 577 (1979); b) D. H . Rich, E. T. Sun, and A. S. Boparei, J. Org. Chem. allylpalladium(II) chloride dimer as catalyst; 43, 3624 (1978); c) K. E. Little, C. 8'. Homnik, G. three additional steps suffice to convert this S. Ponticello, and B. E. Evans, J. Org. Chem. 47, compound into statine. 3016 (1982). [6] S. Danishefsky, S. Kobayashi, and J. F. Kerwin, J. Org. Chem. 47, 1981 (1982). [7] P. W. K. Woo,Tetrahedron Lett. 1985, 2973. [8] M. Braun and R. Devant, Tetrahedron Lett. THF. / \ 1984, 5031; M. Braun, Angew. Chem. 99, 24 (1987);Angew. Chem. Int. Ed.Engl. 26,24 (1987). [9] R. M. Devant and H.-E. Radunz, Tetrahedron Lett. 29, 2307 (1988). [lo] M . T. Reetz, M. W . Drewes, and A. Schmitz, Angew. Chem. 99, 1186 (1987); Angew. Chem. Int. Ed. Engl. 26, 1141 (1987). [Ill M. N. Dufour, B. Castro, P. Jouin, J. Poncet, and A. Pantaloni, J. Chem. SOC.Perkin Trans. I (24) (23) 1986, 1895. Finally, there is one other interesting method [I21 B. D. Harris, K. L. Bhat, and M . M . Joullik, Tetrahedron Lett. 1987,2837; B. D. Harris and that should be mentioned, one in which a pM. M. Joullii, Tetrahedron 44, 3489 (1988). amino alcohol system is simply transformed [13] P. Raddatz, H.-E. Radunz, G. Schneider, and H. from one diastereoisomer into another that Schwartz, Angew. Chem. 100, 414 (1988); Ancontains an inverted alcohol function [17]. Bagew. Chem. Int. Ed. Engl. 27, 426 (1988). sic conditions permit the carbobenzoxypro- [14] P. Jouin, B. Castro, and D. Nisato, J. Chem. SOC. Perkin Trans. I 1987, 1177. tected system (22)to be converted into the cyclic carbamate (24)with retention of configuration. [IS] H. Kogen and T. Nishi, J. Chem. SOC.Chem. Commun. 1987, 311. Thionyl chloride, on the other hand, produces 1161 M . Sakaitani and Y. Ohfune, Tetrahedron Lett. the diastereoisomer (23).This makes it possible 28, 3987 (1987). in a statine synthesis to convert the "wrong" [I71 S. Kano, T. Yokomatsu,H. Iwasawa, and S. Shibuya, Tetrahedron Lett. 28, 6331 (1987). diastereoisomer, resulting from reduction of the appropriate ketone with Et3SiH (22) (R1= i- [IS] R. G. Andrew, R. E. Conrow, W.S. Johnson, and S. Ramezani, Tetrahedron Lett. 28,6535 (1987). Bu, R2 = CH2CH=CH),into the product (23) [I91 New routes have recently been described, e.g., with the desired configuration - though obJ. Mulzer, B. Biittelmann, and W. Munch, Lieviously at the expense of additional steps. bigs Ann. Chem. 1988, 445; G. Bringmann, G. Kiinkel, T. Geuder, Synlett 1990, 253; P. G. M. Our conclusion: there are many routes [19] Wuts, S. R. Putt, Synthesis 1989, 951. that lead to statine but only a few are likely to

be suitable for large-scale application.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Fenestranes - A Look at “Structural Pathologies”

Fenestranes (also called stauranes or windowpanes [l]) are tetracyclic compounds in which a central carbon atom is common to all four rings. The name is derived from the Latin word “fenestra”, and its aptness can be appreciated without long explanations by examining the structure of C4.4.4.41fenestrane ( I ) [lc]. The monograph by Greenberg and Liebman [2] on “Strained Organic Molecules” describes this class of compounds with some irony in the chapter entitled “A potpouri of pathologies”. However, the structural principle is not really so exotic, as can be seen in molecules like hemin, chlorophyll or vitamin BI2.To be sure, the central atom in these particular systems is a metal, but laurenene (2)is a naturally occurring [5.5.5.7]fenestrane devoid of metal atoms [3]. The problem of fenestrane synthesis is closely related to the question of how far the tetrahedral structure of an sp3hybridized carbon atom can be flattened [4, 51. In the nomenclature of fenestranes, the number of bridge atoms is simply inserted in square brackets directly in front of the name (i.e., [m.n.p.q]fenestrane). This even permits the derivation of a general nomenclature of cyclic compounds, so that the “broken” window (3) might be called [4.4.4]fenestrane, and cyclohexane would be [6]fenestrane. (For general treatments of the nomenclature of analogous polycyclic compounds see ref. 1b, 5). Much progress has been made in recent years in the synthesis of the previously unknown parent structures (for an early review see ref. 4a).

H [4.4.4.4]Fenestrane 1 Laurenene (2). a [5,5,5,7]fenestrane

[4,4,41Fenestrane (3)

What where the synthetic strategies and methods that led to success in the preparation of these strained molecules? The synthesis of the unsubstituted skeleton of all-cis-[5.5.5.5]fenestrane (8) was accomplished by Luyten and Keese [8] using two different routes, as shown in Scheme 1. A key step in the first route was palladiumcatalyzed decarboxylation of the lactone (?, a newly discovered reaction of quite general importance. Interesting chemistry also contributed to the preparation of the starting material (7) from cycloocta-1,5-diene (4) [la]. Thus, trichloromethyl substituted oxotriquinane was prepared in a Lewis acid-catalyzed reaction of (4) with chloral, and then converted in seven further steps into the diester (5) [9]. The subsequent Dieckmann condensation followed by decarboxylation to (6) proved surprisingly facile. Finally, the ring system was converted to

312

Non-Natural Target Compounds

that of fenestrane (7) by a transannular carbene insertion. The requisite carbene was generated photolytically from a phenylsulfonyl hydrazide derived from (6). With a ring system arranged somewhat differently as in (9),only the conditions of the Ziegler -Thorpe condensation, and Scheme I Synthesis of all-cis-[5.5.5.5]fenestrane ( 8 ) by Keese et al. [ l a , 81. 1. CC13CH0, AIC1~)(-50%)

2. 7 steps

H3coi?:

>

Scheme 2a Synthesis of a partially unsaturated all-cis[5.5.5.5]fenestrane derivative (14) according to Mani and Keese [ l o ] .

(4)

COCH,

W

H 3 C 0 2 C A

1. Base

Ref. [l]

-TGz&G? (55%)

1. pTsNHNH2

not those of Dieckmann, permitted conversion to the eight-membered ketone (10). Moreover, the planned carbene insertion of the corresponding hydrazone (10) failed to yield (8).Surprisingly, however, fenestrane (8) could be obtained directly from (10)in the presence of palladium and small amounts of hydrogen (Scheme 1). In another investigation by the same group, the partially unsaturated compound (14) was prepared as shown in scheme 2a [lo].

(6)

,@

2. KH. hv

Pd-C/H2

d

-

(310OC);

(-17%)

H H

1. KOH. CH30H;

90%

A

3. CH2NZ. 0 OC

(7)

Ref. pa]

43%

(13)

(7 4)

Pd-C/NZ. H2 320 %, 5 h

Ref. [8b]

0

1. Ziegler-Thorpe 51%

CH3

This case involved use of the meta-cycloaddition of olefins to aromatic compounds previously investigated by other authors [ll]. It is not surprising that irradiation was required to disrupt the aromatic system of (11).The dotted lines in (11)indicate the formation of new bonds to afford (12), one of several products isolated, which already contains three of the rings of the target molecule (14)! Addition to the double

Fenestranes

bond occurs upon treatment of the diazoketone (13), derived from (12),with trifluoroacetic acid (Scheme 2a). The target molecule (14) is presumably formed via cationic intermediates in a process very reminiscent of similar cascade reactions in terpene chemistry. More recently, direct synthesis of a substituted [5.5.5.5]fenestrane has been achieved by intramolecular arene-olefin photocycloaddition [loa] (Scheme 2b).

373

Scheme 3 Synthesis of all-cis-[5.5.5.5ffenestrane (19)

according to Cook et al. (121.

Scheme 26 Direct formation of [5.5.5.5ffenestrane

(14c) by meta-cycloaddition [10a f.

OMe

+ OH

Three photoproducts were isolated after irradiation of the 7-methoxyindane (14a).The major product was (14b)(23%), derived from a [2 + 21 cycloaddition, but the [5.5.5.5]fenestrane (14c) (ca. 4%) was also formed by intramolecular rneta-cycloaddition of the double bond to the aromatic system. Cook et al. [12] arrived at the four-fold unsaturated, highly symmetric [5.5.5.5]fenestratetraene (19)by a totally different route, skillfully exploiting the high symmetry of the molecule through use of “symmetric” reaction steps. Double addition of acetone dicarboxylic ester to a-ketoaldehydes such as (15) was accomplished under almost physiological conditions. This Weiss reaction [13b] was followed by decarboxylation to afford the diketone (16). Other related compounds have also been prepared via this reaction [13a]. The diacid (17a) can be obtained in good yield from (16)by cis-hydroxylation and Jonesoxidation, and it undergoes a facile cyclization to the [5.5.5.5]fenestrantetrone (18). By contrast, treatment of the corresponding aldehyde

HOAc. H @ room temp.

(17b) affords a tetracyclic diacetate (20) with a very different skeleton. The desired target seemed to be very close at hand with compound ( l a ) , which was already known from an earlier synthesis [14] but several years passed before tetraketone (18)was successfully converted into the fenestrene (19).The P-diketone is subject to rapid ring opening by nucleophiles on account

374

Non-Natural Target Compounds

of the considerable ring strain present in the system. All attempts at reduction failed as well, because the intermediate P-hydroxy ketones also opened via a retroaldol reaction. As is often the case, the solution proved to be very simple: reduction with diborane! According to the authors, the retro-aldol reaction is avoided here due to the high energy of activation for the cleavage of an 0 - B bond in (21)with concurrent elimination of BH: to (22) [12a]. The stereoisomeric alcohols obtained upon diborane reduction can be dehydrated by heating in HMPA solution to afford the all-cis-fenestratetraene (19) in 80% yield. The parent system (8) is of course also available through hydrogenation of (19) [l5].

(21 )

(22)

Strained polycyclic systems very often show an increase in stability upon condensation with aromatic rings. The synthesis of such systems can be facilitated by drawing upon the repertoire of aromatic chemistry, has been skillfully demonstrated by Kuck and Bogge [16] in their synthesis of octacycle (26), fenestrindane. Starting material (23)is easily prepared according to a literature procedure [17] by double Michael addition of 1,3-indandione to dibenzalacetone, as shown in Scheme 4a. The stereoisomericalcohols obtained by aluminum hydride reduction of (23)are cyclized to the C5.5.5.61fenestrane derivative (24)in a single step, albeit under drastic conditions (H3P04, 2 h reflux in xylene). Interestingly, milder reaction conditions with similar systems leads only to open-chain unsaturated aldehydes [l 81. Ring contraction using the conditions of Favorskii, followed by decarboxylation, affords the olefin (25).The fourth six-membered ring is now introduced in a Diels-Alder reaction of (25)

Scheme 4a Synthesis of fenestrindane by Kuck and Bogge [16].

1. LiAIH4

2. H3P04/xylene reflux (80%)

3. KOH 4. Cu/Quinollne. A

2. Na/tert-BuOH,

A

with tetrachlorosulfolane. Elimination of hydrogen chloride and reductive exchange of the chlorine atoms for hydrogen by reaction with sodium metal concludes the synthesis of (26). Very recently, fenestrindane (26) served as the starting point for the synthesis of a facinating new molecule: centrohexindane (26b) [16al (see Scheme 4b). In this centropolyquinane, six cyclopentane rings are anullated around a central carbon atom common to all the rings. The molecule is also of interest with respect to graph theory, but from the fenestrane point of view

375

Fenestranes

structure (26b) is significant because it contains three fenestrindanes, and it is the first fenestrane in which all four bridgeheads are substituted. The synthesis of (26b) is surprisingly easy. Fenestrindane (26) is first brominated to the tetrabromo derivative (26a). Heating (26a) with four equivalents of AlBr3 in benzene affords (26b) as colorless needles in 50% yield [16a].

Scheme 5 Synthesis of [4.4.5.5]fenestrane derivatives by Dauben and Walker 1191. 0

67)

0

(28)

Scheme 4b Centrohexindane (26b) from fenestrindane (26) [16a].

H (29a): X = H, (296): X = CHOH (29c): X = N,

1. NaH, HCO@

3. hv (Pyrex) (61%)

Even more pronounced flattening of the central carbon atom can be expected in fenestranes that contain four-membered rings. The synthesis of such systems has been attempted many times, but the parent system has still not been prepared. It is logical to invoke [2 23 cycloaddition in the construction of four-membered rings, but it is even more tempting to try to generate two rings at the same time. Dauben and Walker [19] took advantage of this possibility in the photolysis of the bicyclooctene (28),available from (27) by intramolecular olefination, as depicted in Scheme 5. The quaternary center and the last two fenestrane rings were generated simultaneously. The derivative (29) can of course be reduced to the hydrocarbon [4.5.5.5]fenestrane, but ring contraction to (30) appears to present more of a challenge. The required diazoketone (29c)was

+

obtained by formylation of (29a) to (29b) followed by treatment with tosyl azide. Photolysis of (29c) then led via a Wolf€rearrangement to the epimeric esters (30) in 61% yield. Dauben offered with respect to this remarkable reaction the laconic observation: “the fenestrane does not appear to have any unusual instability” ~191. Crimmins et al. [20] in their model investigations aimed at the synthesis of laurenene (2) also utilited a photocyclization of (31) to (32) (Scheme 6). The divergent behaviours of the unsubstituted system (314 and of the methyl substituted compound (31b) constituted an important finding here. Compound (31a) could be cyclized by irradiation at room temperature, whereas heating to 110°C was necessary in the case of the methylated compound (31b).Incidentally, (32b) is the first known fenestrane with substituents

376

Non-Natural Target Compounds

Scheme 6 Synthesis of the first fenestrane (32b) with substituents at opposite bridgeheads [ZO].

Scheme 7 Synthesis of a [4.4.4.5]fenestrane according to Agosta et al. [21].

““2”\1

1

CH3’

(3la): R = H 131b): R = CH,

(32aj: R = H (326): R = CH,

at positions, opposite to each other. (For a review of intramolecular enone-olefin photocycloadditions see ref. [20a].) Applying the same principle of high-temperature photoreaction to a more highly functionalized starting material, Crimmins and Gould recently achieved the first total synthesis of (+)laurenene (2) [20a]. The seven-membered ring of (2) was formed via fragmentation of the cyclobutane ring. Tow other syntheses of this unique, naturally occurring fenestrane were also recently reported [20b, 20cl. Agosta et al. [21] also invoked photocyclization with (33).However, in this case the tricyclic system (34) with two four-membered rings is formed first, as illustrated in Scheme 7. The diazoketone (35)can be prepared in four steps from (34). Cyclization with C-H insertion to the fenestrane (36) occurs via a ketocarbene generated with the aid of rhodium catalysis [22]. The carbonyl groups can be reductively removed to give the corresponding parent molecule, but again a more challenging goal was ring contraction. Initial attempts involving acetal ketone (36) were unsuccessful, but success was eventually achieved through reactions based on a monoketone, which was converted to the diazoketone (37) in a sequence similar to that shown in Scheme 5. This resulted in the smallest known fenestrane, the C4.4.4.5lfenestrane derivative (38), which was isolated in 20% yield as a 3:l mixture of isomers (Scheme 7). (See ref. 21d for recently discovered thermal and photochemical reactions of C4.4.4.5lfenestranes.)

CH, (34) Isomers

(33)

1. Ketal formation 2. (COCI)*

3. C H g 2

>

m? 1. Red

1 CH3

(37)

(38)

What can now be said about the degree of planarity around the central carbon atom of the above mentioned fenestranes? It will not have escaped the alert reader’s attention that in each case it was the all-cis-configuration that was synthesized. In fact, according to MNDO calculations [la] the introduction of trans-connected rings into (8)would increase the energy by about 762 kJ mol-’ compared to (8) itself. Extended calculations on a large number of analogous systems [l, 4, 21bl have revealed that an approximately tetrahedral arrangement is always highly favored energetically relative to planarity. However, the tetrahedral angle is subject to enlargement, in some cases by a considerable ‘amount. The angles 01 and p in (39)

Fenestranes

377

[9] H . Fritz, C. D.Weis,and T. Winkler,Helv. Chim. Acta 58, 1345 (1975). [lo] J. Mani and R. Keese, Tetrahedron 41, 5697 (1985); a) J. Mani, S. Schiittel, C. Zhang, P. Bigler, C. Miiller, and R. Keese, Helv. Chim. Acta 72, 487 (1989). [ll] a) Review: A. Gilbert and P. Yianni,Tetrahedron 37, 3275 (1981); b) cf. P. A. Wender and G. B. Dreyer, J . Am. Chem. SOC.104, 5805 (1982). a [l2] a) M. N. Deshpande, M . Jawdosiuk, G. Kubiak, n M. Venkatachalam, U. Weiss, and J. M. Cook, J. Am. Chem. SOC.107, 4786 (1985); b) J. M. (39) Cook et al., Tetrahedron 42, 1597 (1986). [13] a) M. N. Deshpande, S. Wehrli, M. Jawdosiuk, J. B T. Guy, jr., D. W. Bennett, J. M. Cook, M. R. The synthesis of these callenging targets has Depp. and U. Weiss, J . Org. Chem. 51, 2436 (1986); b) See also this book, page 121 ff. greatly enriched synthetic methodology generally. However, much work remains to be done [14] R. Mitschka, J. Oehldrich, K. Takahashi, U. Weiss, J. V. Silverton, and J. M. Cook, Tetrato fill in the blank areas on the map of the hedron 37,4521 (1981). fenestranes. [IS] M. Venkatachalam, G. Kubiak, J. M. Cook, and U. Weiss, Tetrahedron Lett. 27, 4863 (1985). [16] D. Kuck and H. Biigge, J. Am. Chem. SOC.108, References 8107 (1986);a) D. Kuck and A. Schuster, Angew. Chem. 100, 1222 (1988);Angew. Chem. Int. Ed. Engl. 27, 1192 (1988). [l] For nomenklature compare: a) A. Pfenninger, A. Roesle, and R. Keese, Helv. Chim. Acta. 68,493 [17] W. Ten Hoeue and H . Wynberg, J. Org. Chem. 44, 1508 (1979). (1985); b) P. Grund and T. M. Grund, J. Am. Chem. SOC.103,4456 (1981);c) V.Georgian and [18] D. Kuck, Angew. Chem. 96, 515 (1984);Angew. Chem. Int. Ed. Engl. 23, 508 (1984). M. Saltzman, Tetrahedron Lett. 1972, 4315; d) The history of naming is beautifully de- [19] W. G. Dauben and D. M. Walker, Tetrahedron scribed in: A. Nickon and E. F. Silversmith, OrLett. 23, 711 (1982). ganic Chemistry - The Name Game, Perga- [20] M. T. Crimmins, S. W. Mascarella, and L. D. Bredon, Tetrahedron Lett. 26, 977 (1985);a) M. mon Press, New York 1987. [2] A. Greenberg and J. F. Liebman: "Strained OrT. Crimmins, Chem. Rev. 88, 1453 (1988);b) M. ganic Molecules". Academic Press, New York T. Crimmins and L. D. Gould, J. Am. Chem. SOC. 1978, p. 369. 109, 6199 (1987); c) L. A. Paquette, M. E. Okazaki, and J.-C. Caille, J. Org. Chem. 53, 477 [3] R. E. Corbett, C. M. Couldwell, D. R. Lauren, (1988);d) G. Metha and K. S. Rao, J . Org. Chem. and R. T. Weavers, J. Chem. Sac. Perkin 1,1978, 1791. 53, 425 (1988). [4] For an introduction to the problem see: a) R. [21] a) V. B. Rao, S. WoVJ and W. C. Agosta, J. Chem. SOC.Chem. Commun. 1984, 293; b) V. Keese, Nachr. Chem. Tech. Lab. 30,844 (1982); b) Pure Appl, Chem. 1987,43; c) W. Ten Hoeve B. Rao, C. F. George, S. WoVJ and W. C. Agosta, J. Am. Chem. SOC.107, 5732 (1985); and H. Wynberg,J . Org. Chem. 45, 2925, 2930 (1980). c) V. B. Rao. S. WoVJ and W . C. Agosta, Tetrahedron 42, 1549 (1986); d) S. WoVJ B. R. [5] B. R. Venepalli and W. C. Agosta, Chem. Rev. 87, 399 (1987). Venepalli, C. F. George, and W. C. Agosta, J. [6] F. A. Cotton and M. Millar, J . Am. Chem. SOC. Am. Chem. SOC.110, 6785 (1988). 99, 7886 (1977). [22] For a review of insertions of diazo carbonyl compounds see: S. D. Burke and P. A. Grieco, [7] J. B. Collins, J. D. Dill, E. D. Jemmis, Y.Apeloig, P. von R. Schleyer, R. Seeger, and J. A. Pople. Org. React. 26, 361 (1979). [23] J. Chandrasekhar, E.-U. Wiirthwein, and P. von J. Am. Chem. SOC.93, 5419 (1976). R. Schleyer, Tetrahedron 37, 921 (1981). [a] a) M. Luyten and R. Keese, Angew. Chem. 96, 358 (1984);Angew. Chem. Int. Ed. Engl. 23,390 [24] R. Keese and W.LueJ Helv. Chim. Acta, 70, 543 (1984);b) Helv. Chim. Acta 76, 2242 (1984). (1 987).

provide a measure of the degree of flattening. These correspond to 128' and 129" for derivative (38), and similar values can be assumed for other small fenestranes [I, 41. The widening of the angles is less dramatic (116.5') for C5.5.5.5lfenestranes [16]. (For a more detailed discussion see ref. 4b, 5, 24.)

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

“Starburst Dendrimers” and “Arborols”

In winter one can’t help but admire the starlike frost patterns with crystrals that the mineralogists call dendrites (from the Greek dendron = tree). In this contribution it is my pleasure to provide the reader with a discussion of organic compounds whose molecular architecture is reminiscent of such crystals - or of the “Christmas stars” - as suggested by the twodimensional illustration of the “dendrimer” (I).

The term “starburst dendrimer”, coined by Tomalia et al. [l], is borrowed from “star polymers”, and it implies a star-shaped growth with radial symmetry; the expression “starburst” also conjures up an explosive expansion of molecular chains. For a review see ref. [la]. The tree-like nature of these cascade molecules is aptly summarized in the term “arborols” (Latin arbor = tree), coined independently by Newkome et al. [Z]. By way of contrast, the term “cauliflower polymers” employed by de Gennes [3] sounds rather prosaic, but the similarity between a cauliflower and the space-filling hemispherical or Corey-Pauling models of such molecules can scarcely be overlooked. The poly-

meric nature of these substances is also implicit in the term “dendrimer”. We thus find ourselves departing from our normal preoccupation with relatively small molecules and individual functional groups, moving toward an appreciation for molecular interactions (e.g., “guest-host chemistry”).The relevance of this trend was signalled by the award of the Nobel prize to Cram, Lehn and Pedersen in 1987. Cram’s [4] “spheres” (“spherands”), with molecular structures such as (2), incorporate more or less rigidly prefabricated cavities in which guest molecules may reside, and they are in some ways analogous to the dendrimers discussed below. On the other hand, molecules such as Pedersen’s [S] crown ethers (corands) (3) or even Lehn’s [ 6 ] cryptands (4) develop their cavities only during the course of a dynamic process. Crown ethers and cryptands are cyclic analogs of Vogtle’s and Weber’s [7, 81 open-chair “octopus molecules” (5), and the concept underlying their construction is similar to that behind such starburst dendrimers as (I),at least with respect to the first branching step. The same is also true of Suckling’s [9] ”tentacle molecules” (4, or the enzyme model (7) of Murakkami et al. [lo]. Of course, each of these molecules was conceived for a rather different purpose, and there are no new branches at the ends of their chains from which true dendrimers could arise. De Gennes et al. [3] and Maciejewski [11] published a rather comprehensive theoretical study

Starburst Dendrimers and Arborols

319

successfully, including the maximum number of generations, and the structure of the resulting cavities (see below). The first synthesis of molecules in this topological class was realized in the laboratories of the Allied Corporation by Denkewalter et al. [12]. Macromolecular species were synthesized by stepwise linkage of u,w-protected diamino acids such as lysine or H2NCH2CH(NH2)COOH using standard peptide chemistry.

BHA Lys Lys2 Lys4

+++ Polymer

(9)

-CH

6 (4)

(3)

Corands (3) 5, and Cryptands (4) 6, (from ref 4):

RO-C

R

R

CO-R

R = OH R = Cl R = O(CH2),,Br

+

R = O(CH2),,NC5H5

(6)

(7)

of starburst molecules almost simultaneously with their successful synthesis [19]. As later comparison with experiment showed, many of the observed Dronerties were Dredicted auite

,CH2CH2CHZCH2-Z \

Z

Z

= functional

terminal group

(10)

Once the first branched molecule (8) is obtained, expansion to the next generation (9)results in four terminal lysine residues. The growing polymers thus display branching of the type indicated in (lo),and they fulfil Maciejewski's [11] criteria, but their chains are of varying length so the structures lack ideal radial symmetry [13]. As a result, the Denkewalter molecules fail to exhibit some of the properties predicted by de Gennes [3]. Thus, the branched, polymeric lysines are characterized by a linear relationship between molecular weight and volume; for starburst dendrimers with ideal radial symmetry, on the other hand, interesting deviations disrupt this relationship, and one is forced to conclude that cavities exist within the molecules [13]. Molecules with ideal symmetry and a large number of repetitive sequences (generations) were first synthesized by the Tomalia team at Dow Chemical, and methods drawn from polymer-chemistry were then used to thoroughly investigate their properties [l, 13- 151. The basic chemistry involved is actually mite simple.

380

Non-Natural Target Compounds

Scheme 1 ,,Starburst-Dendrimers" according to Tomalia et al. [ l , 13- IS] Initiator Surbnnch Con Oligoma

Starbum Oligomen

A

"

We begin by considering the general principle, presented in the form of an overview. The synthetic starting point is a trivalent "initiator core", which is extended by adding chains that in turn provide trivalent end groups on which new branching is possible. The resulting shells leading from one branch to the next are arranged in layers around the core, and they are referred to as "generations". Following Tomalia et al. [I41 the chemical development of the generations occurs in two stages. Michael addition of acrylic ester to ammonia first yields the triester (11).An exhaustive aminolysis with ethylenediamine then provides the amide (12), the terminal amino groups of which permit the reaction sequences a and b to be repeated, leading to a new generation in the form of (13).Since the goal is to synthesize molecules that are as symmetric as possible, incomplete Michael reactions or aminolyses must be avoided. This is achieved by using enormous excesses of reagent. These excesses increase from generation to generation, and may ultimately reach a thousand times the stoichiometric amount. It is also essential to prevent competing phenomena such as retro-Michael reactions, intramolecular linkage, and ester saponification, and this is accomplished by careful control of the reaction conditions. As predicted by de Gennes [3], once radial symmetry is achieved the extent to which the

Dandrinwn"

"1st Generation" "2nd Generation"

reaction sequence can be repeated is limited, because the volume change from generation to generation increases linearly, which the number of terminal functional groups increases exponentially. Therefore, depending upon the type of system involved, increasingly dense packing at the surface of the dendrimer will lead to a last generation in which an ideal degree of stoichiometric branching is present. The number of end groups Z in a given dendrimer can be calculated precisely using the formula Z = N c f l - ' , where N, is the multiplicity of the in

Starburst Dendrimers and Arborols

itiator core, N, is the multiplicity of the repeating subunit, and G is the number of generations. (Consider as an example the specific case (13) in the sixth generation: N, = 3; N, = 2; G = 6: Z = 3 x 26-1 = 96). These figures may be easily verified by consulting Scheme 1. A different chemical structure, (18), also developed by Tomalia’s [16] team and by Hall et al., is based on (tetrabromomethy1)methane ( I d ) ,which is converted into (16)using (1.9,the potassium salt of a protected pentaerythritol. The structure of the generation that results from hydrolysis, tosylation, and repeated alkylation is readily apparent. In this case, an attempt to produce more than four generations with radial-symmetrical symmetry is “forbidden” [16] due to the short chain length and the high multiplicities associated with N, and N,.

KOCH-@

C(CH2Br)4

(14)

(75)

r

o

1. Hydrolysis 2. Tosylation

rO-HCZO>

repeat

----3

Polymer

Dendrimers differ from classical polymers by their high symmetry, extensive branching, and maximal functionalization on a spherical surface. In addition, the products are often monodisperse polymers that deviate very little from the theoretical molecular weight, as can be confirmed by various analytical methods including laser light scattering and electron microscopy. Electron microscopic analysis is simplified by the fact that the terminal functional groups can be coordinated with monovalent cations of the first main group elements. Results show that individual dendrimer molecules are relatively

381

uniform in size. Higher aggregates are occasionally observed, held together by either covalent bonding or electrostatic interaction. These new structures have many unusual properties. Perhaps most noteworthy is the presence of sterically induced cavities that may be regarded as “covalently fixed micelles. Corey-Pauling scale models make it possible to estimate diameters for three-dimensionally expanded or contracted systems. Very recently, molecular mechanics simulations have provided information about shape in the presence of internal guests [16a]. Hydrodynamic measurements of the size of the dendrimer molecules with 1 - 5 generations give values lying between those calculated for contracted and expanded structures. Moreover, the diameter increases more rapidly than the number of generations. From this one concludes that the excess volume is either occupied by solvent or that there exist sterically determined cavities like those predicted by de Gennes [3]. The latter premise appears to be correct, and this sets up the analogy to the Cram spheres described above. Numerous possible applications follow, such as the metered release of active ingredients. The immunological properties of these new types of materials are also certain to catch the attention of pharmacologists. Newkome et al. [2] pursued other chemical paths in their independent investigations of cascade molecules. In Newkome’s first publication [2] the analogy to “tree structures” is especially relevant since the “initiator core” retains a kind of stem. Alanate reduction of the triester (17) gave only ally1 alcohol (18),so a cross Cannizzaro reaction starting with the aldehyde (19) was used for synthesizing the trio1 (20),which serves as the core. Steric hindrance prevented direct extension of the chain (and simultaneous branching) in the case of a tosylate derived from (20); consequently, it was necessary first to lengthen the chain by alkylation with chloroacetic acid followed by esterification and alanate reduction, producing (21). Repeated to-

382

Non-Natural Target Compounds

sylation, alkylation with NaC(C02Et)3, and aminolysis with triethanolamine produces (in 43% yield) compound (22),which is designated as [27]-arbor01 (i.e., 27 terminal OH groups). The shortness of the chains and the extensive branching (Z = 3) bring a relatively quick end to undisturbed radial-symmetrical growth.

a diameter of approximately 200 A. A pronounced tendency to form micelles is also confirmed by light-scattering measurements; with micelle formation occurring above a critical concentration of 2.02 mM [17].

kr

1. NaC(C02Et),

NaC(C02Et),

R-Br

R-C.

/

>

RC(C02Et)3

IAH

+

( 1 7)

CH,OH

I

Br

v

,

2. H~NC(CH~OH),

(23)

(18) CH2 C2HsOH/OH-

CH3(CH2>,CH,CHO

HCHO (60%)

/

CH20H

> R-C-CHZOH \

NH

(20) CH20H

(19)

(-OH

1. TosCI/B2. CLCH;COOH

o;

1. TosCI/B2. NaC(C02Et),

/\OH

3. H2N(CH20H), 43%

3. CH30H. H+’ 4. LAH

(21 )

ct

CONHC(CHzOH)3 CONHC(CH20H)3

CONHC(CH20H)j

R = NHC(CH20H)3

‘COR

(22)

Another study employed trisbromomethylbenzene (23) as the initiator that led to “ben~ene[9]~-arborol” [17]. For the use of tris(2-cyanoethy1)nitromethane see ref. [17a]. The reduced steric hindrance in this case, permits direct alkylation with NaC(C02Et)3,and chain extension by aminolysis results in the beautifully symmetrical structure of arborol (24). Transmission electron micrographs reveal an aggregation of monomers into micelles with

(R = identically branched groups)

In contrast to the Denkewalter structures, Newkome’s molecules have radially symmetric branches. They differ from the Tomalia dendrimers in that the chains vary chemically and in the number of atoms they contain, so it is not strictly appropriate to speak here of “generations”. The future will reveal what effect such differences have on the properties of the materials, a subject which is still under investigations.

References [I] D. A. Tomalia, H. Baker, J. Dewala, M. Hall, G.

Kallos, S. Martin, J. Roeck, J. Ryder, and P. Smith, Polmer Journal 17, 117 (1985);a) D.A. Tomalia, A. M. Naylor, and W.A. Goddard III, Angew. Chem. 102, 119 (1990);Angew. Chem. Int. Ed. Engl. 29, 138 (1990). [2] G. R. Newkome, 2. Yao, G. R. Baker, and V.K. Gupta, J. Org. Chem. 50, 2003 (1985). [3] P.-G. de Gennes and H. Hervet, J. Phys. Lett. 44, 351 (1983). -r41- D. J. Cram, Angew. Chem. 98.1041 (1986);Angew. Chem. In; Ed. Engl. 25, 1039 (1986):

Starburst Dendrimers and Arborols [5] C. J. Pedersen and H. K. Frensdorff; Angew. Chem. 84, 16 (1972); Angew. Chem. Int. Ed. Engl. 11, 241 (1972). [6] J.-M. Lehn, Angew. Chem. 86, 670 (1974); Angew. Chem. Int. Ed. Engl. 13, 611 (1974). [7] E. Weber and F. Viigtle, Kontakte (Darmstadt) 1980 (2), 36; E. Weber, Kontakte (Darmstadt) 1981 (I), 24; 1982 (1); 24; 1983 (I), 38; 1984 (I), 26. [S] F. Viigtle and E. Weber, Angew. Chem. 86, 896 (1974); Angew. Chem. Int. Ed. Engl. 13, 814 (1974); for further reading see also ref. 2). [9] C. J. Suckling, J . Chem. SOC.,Chem. Commun. 1982, 661. [lo] Y. Murakkami, A. Nakano, K. Akiyoski,and K. Fukuya, J. Chem. SOC.,Perkin Trans 1 1981, 2800. [11] M. Maciejewski, Macromol. Sci., Chem. A. 17, 689 (1982). [12] R. G. Denkewalter, J. F. Kolc, and W. J. Lukasavage, US Patent 4410688,1983; Chem. Abstr. 100, 10397013 (1984).

383

[13] D. A. Tomalia, M. Hall, and D. M. Hedstrand, J. Am. Chem. SOC.109, 1601 (1987). [14] D. A. Tomalia et al., Macromolecules, 19, 2466 (1986). [IS] D. A. Tomalia, V. Berry, M. Hall, and D. M. Redstrand, Macromolecules 20, 1167 (1967). [16] D. A. Tomalia, lecture on the Biirgerstock, May 1987; a) A. M . Naylor, W.A. Goddard 1119G. E. Kiefer, and D. A. Tomalia, J. Am. Chem. SOC. 111, 2339 (1989). [17] G. R. Newkome, Z. Yao, G. R. Baker, V. K . Gupta, P. S. Russo, and M. J. Saanders, J . Am. Chem. SOC.108, 849 (1986); a) G. R. Newkome, C. N . Moorefield, and K. J. Theriot, J . Org. Chem. 53, 5552 (1988). [18] H. Hall, A. Padias, R. McConnel, and D. A. Tomalia, J. Org. Chem. 52, 5305 (1981). [I91 Starburst dendrimers were first synthesized and reported in the Dow Laboratories in 1981.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Author Index

Abd el Hafez, F.A. 3 Agosta, W.C. 376 Ali, M.B. 57 Anh, N. 4 Aumann, R. 188 Baggiolini, E.G. 84 Baker, R. 345 Barnett, W.E. 158 Bartlett, P A . 162, 230, 258 Beak, P. 46, 47, 101 Benezra, C. 75 Berson, J.A. 169 Bickelhaupt, E 192 Binger, P. 97, 98 Bir, G. 62 Boche, G. 47 Boeckman, R.K. 271, 273 Bogge, H. 374 Bougault, M.J. 158 Braun, M. 366 Breslow, R. 61, 71 Bringmann, G. 183, 273 Brooks, D.W. 219 Brown, A.G. 309 Brown, E.J. 169 Brown, H.C. 33, 37 Brown, R. 46 Buchanan, C.M. 340 Buchi, G. 105, 235 Buch, M. 97 Burgi, B. 4, 5 Bunce, R.A. 101 Burke, S.D. 135

Calas, S . 132 Cane, D.E. 145 Carceller, E. 142 Chamberlin, A.R. 268 Chapuis, C. 68 Charlton, J.L. 60 Chenard, B.L. 139 Chieffi, G. 105 Clive, D.L.J. 321 Cohen, N. 212 Confalone, P.N. 90, 91 Cook, J.M. 121, 373 Corey, E.J. 31, 160, 161, 162, 236f Cornforth, J.W. 3, 4 Cram, D.J. 3, 4, 6, 378 Crimmins, M.T. 375 Curran, D.P. 90 Danheiser, R.L. 100 Danishefsky, S . 34, 63, 67, 117, 142, 161, 323, 327, 365 Dauben, W.G. 286, 375 Davis, EA. 40, 41, 42 Deana, A.A. 313 de Gennes, P.-G. 378,379, 380 de Meijere, A. 146 Demuth, M. 21, 329, 330 Denkewalter, R.G. 379 Denmark, S.E. 113, 138 DeShong, P. 355, 356 Dotz, K.H. 186 D’Silva, D.T. 335 Dunitz, J. 4 Dyong, I. 52, 353f

386

Author Index

Edwards, J.M. 121 Effenberger, F. 228 Eilbracht, P. 97 Eisch, J.J. 196 Eliel, E.L. 340 Enders, D. 42, 303 Endo,A. 309 Evans, B.E. 366 Evans, D.A. 11, 36, 41, 51, 56, 192, 302, 304 Falck, J.R. 315, 317 Felkin, H. 3, 4, 5 Ferrier, R.J. 255 Fischer, E. 246,251 Fischer, E.O. 188 Fischer, H.O.L. 243ff Fittig, R. 158 Fleet, G.W.J. 359, 363, 364 Franck, R.W. 60 Fraser-Reid, B. 258, 337 Fuganti, C . 6, 221, 354 Funk, R.L. 117 Genet, J.P. 302 Gennari, C . 51, 304 Giese, B. 129, 258 Gilman, H. 167 Gotthardt, H. 109 Gould, L.D. 376 Graham, R.S. 33 Grieco, P.A. 14, 15, 60, 71, 72, 73, 316, 318 Grubbs, R.H. 192, 194 Gschwend, H.W. 168 Gutman, A.L. 228 Haner, R. 48 Hall, M. 381 Hanessian, S. 255, 352 Harris, T.M. 235 Hart, D.J. 129, 267 Hayashi, T. 302 Heathcock, C.H. 5, 274, 316, 319 Heck, R.E 174, 175, 176

Helmchen, G. 54, 56 Hirama, M. 311, 312, 313 Hoffmann, R.W. 34, 37, 217 Holmes, A.B. 155 Hoppe, D. 289 Horton, D. 351, 352 Hosomi, A. 132 Houk, K.N. 4, 5, 55 Hoye, T.R. 146 Hua,D.H. 17 Hudlicky, T. 229 Huisgen, R. 77 Hull, K. 134 Ikegami, S. 324, 325 Ireland, R.E. 116, 193 Iriuchijima, S. 295 Ito,Y. 60, 302 Jadhav, P.K. 37 Jager,V. 86, 88, 90 Johnson, W.S. 21, 135, 232 Jones, W.E. 46 Julia, M. 298 Jung, M.E. 294 Jurczak, J. 68 Kachensky, D.F. 321 Kallmerten, J. 118 Karabatsos 3 Katagiri, N. 58 Kato,T. 288 Katzenellenbogen, J.A. 162 Kaufmann, D. 62 Kaufmann, T. 101 Keck, G.E. 321 Keese, R. 371, 372 Kellog, R.M. 23 Kelly,T.R. 58, 68 Kinzer, G.W. 335 Kishi,Y. 147 Kitahara, M. 245 Klemer, A. 351 Klibanov, A.M. 227, 228, 296

Author Index

Knight, D.W. 117 Kochetkow, N.K. 278 Kochi, J.K. 327 Kocienski, P. 153, 345 Koga, K. 61, 66 Kogen, H. 367 Koizumi, T. 59 Kokko, G.J. 46, 47 Koreeda, M. 325, 326, 327 Kozikowski, A.P. 90, 91, 92, 93, 313 Kraus, G.A. 93, 94 Kreiser, W. 296 Kuck, D. 374 Kuehne, M.E. 274 Kiindig, E.P. 172 Kunz, H. 278, 303 Kurozumi, S. 210 Kurth, M.J. 114 Kuwajima, I. 134 Kuzuhara, H. 256 Larock, R.C. 179 Lee, A.M.W. 341 Lehn, J.-M. 378 Lehr, E. 25 Lemieux, R.U. 279 Lenfers, J.B. 259 Lenz,W. 109 Leuenberger, H.G. 213 Ley, S.V. 152 Lichtenthaler, E W. 251 Li, C.-S. 313 Liebeskind, L.S. 97 Little, R.D. 98 Lubineau, A. 61 Luche, J.-L. 75, 76 Luyten, M. 371, 372 Maasbol, A. 188 Macdonald, T.L.M. 292 Maciejewski, M. 378 Magnus, P. 142, 271, 326, 327, 338 Majetich, G. 133, 134 Mani, J. 372

387

Marshall, J.A. 289, 290 Masamune, S. 36, 59, 290 Masamune, T. 152 Matsui, T. 245 Matsumoto, K. 25 Matsumoto, T. 325 Mattay, J. 57 Matteson, D.S. 37, 38 Maurer, K. 251 Mc Gamey, G. 9, 10 Mehta, G. 332 Meinhart, J.D. 194 Meyers, A.I. 12, 168, 169, 183, 271 Midland, M.M. 33 Mikolajczyk, M. 16 Mirza, S. 30 Miyano, M. 210, 211 Mori, K. 216, 245, 336 Mukaiyama, L.T. 297 Mukaiyama, T. 6, 45, 73, 153, 339 Mulzer, J. 9 Murakkami, Y. 378 Musso, H. 234 Naef, R. 342 Nagasaka, K. 67, 68 Nakai, H. 112 Nazarov, N.I. 137 Negishi, E. 96, 101, 179 Neuberg, C. 212, 221 Newkome, G.R. 381 Nicolaou, K.C. 147, 153, 155 Ninamiya, I. 263 Noyori, R. 21, 237 Ochiai, M. 102 Ohno, M. 222 Ohrui, K. 256 Ohwa, M. 340 Oku,A. 22 Oppolzer, W. 51, 54, 55, 62, 82, 263, 266, 271, 304 Overman, L.E. 135, 154

388

Author Index

Paquette, L.A. 146, 152 Paterno, E. 105 Paterson, I. 149 Paulsen, H. 279, 284 Pearson, W.H. 49 Peck, D.W. 335 Pedersen, C.J. 378 Prugh, J.D. 313 Quast, H. 123 Queneau,Y. 61 Rajan Babu, T.V. 258 Rebek, J. 263 Redlich, H. 258, 259 Reetz, M.T. 66, 69, 292, 366 Regitz, M. 48 Rideout, D.C. 71 Robinson, J.A. 149 Rosen,T. 316 Roush, W.R. 81, 290 Roy, G. 338 Sahakura, T. 50 Sakito, Y. 339 Sakurai, H. 107, 132 Sato,T. 335 Saucy, G. 212 Scharf, H.-D. 109 Schenk, (3.0.107 Schinzer, D. 133 Schmid, M. 213 Schmidt, R.R. 280, 282 Schollkopf, U. 11, 300, 301 Schopf, C. 232 Schreiber, S.L. 23, 107, 143, 148, 153 Schuda, P.E 328 Schultz, R.G. 230 Seebach, D. 10, 13, 14, 20, 23, 25, 27, 28, 48, 57, 63, 67, 217, 227, 300, 301, 342 Semmelhack, M.E 171, 188 Sharpless, K.B. 363 Sher, P.M. 128 Shono,T. 199

Sih, C.J. 210, 211, 222, 226, 228, 310 Simmons, H.E. 146 Smith, 111, A.B. 89, 345 Snieckus,V. 167, 182 SolladiC, G. 15, 16, 297 Speckamp, W.N. 266ff, 269 Steglich, W. 303 Stille, J.K. 138, 178 Stille, J.R. 194 Still, W.C. 147, 148, 288 Stobbe, H. 158 Stork, G. 127, 244 Suami,T. 256 Suckling, C.J. 378 Tadano, K. 256 Tanaka, M. 50 Tatsuta, K. 323, 331 Tebbe, EN. 192 Terashima, S . 20, 163 Tietze, L.F. 60 Tius, M.A. 290 Tolbert, M. 57 Tomalia, D.A. 378, 379f Trimble, L.A. 11 Trost, B.M. 49, 58, 97, 99, 142, 330, 331 Tsai, Y.-M. 129 Tsuchihashi, G. 14 Tufariello, J.J. 83 Uemura, M. 172 Ugi, I. 303 Vassella, A. 30, 257, 258, 259 Vedejs, E. 147 Vederas, J.C. 11, 51, 304 Vogtle, F. 378 Wagner, H.U. 47 Walborsky, H.M. 57, 58 Waldmann, H. 57 Walker, D.M. 375 Wasserman, H.H. 270, 271 Watanabe, K. 69

Author Index

Watanabe, M. 167 Weber, E. 378 Weckerle, W. 351, 352 Weinges, K. 303, 327 Weiss, U. 121 Welch, J.T. 114 Welch, S,C. 101 Welzel, P. 54, 294 Wender, P.A. 287, 332, 333 Westley, J.W. 145 Wettlaufer, D.G. 169 Whitesell, J.K. 225, 340 Whitesides, G.M. 295, 296 Wilcox, C.S. 258

Williams, D.R. 345, 346 Williams, R.M. 302 Wittig, G . 167 Woodward, R.B. 263 Wovkulich, P.M. 80, 82 Wulff, W.P. 190 Yamamoto, Y. 303 Yamomoto, H. 57, 58, 62, 67, 69 Zack,A. 171 Zamojski, A. 107 Zaretskaya, 1.1. 137 Zell, R. 213

389

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig OVCH Verlagsgesellschaft mbH, 1991

Subject Zndex

acetal 10, 23 chiral 20 - cyclic 19, 20 - a-Keto 19 0,N-acetals - electrochemical preparation 199 2-acetamido-2-deoxyglucose 278 acetobromoglucose 61 a-D-acetobromoghcose 277 acetone 69 acetoxy-butadiene 58, 68 (acetoxymethyl)-3-trimethyl-silyl-propene 99 acetyl cholinesterase 227 N-acetyldaunosamine 353 acosamine 80, 82, 356 acrolein 61 acrylate - 8-phenylmenthyl 98 acrylic esters 55, 71, 77 actinobolin 61 acyclic stereocontrol 288 acyclic stereoselection 162 acyl chlorides - a,P-unsaturated 138 acyl iminium ions - amidoalkylation 201 acyl migration 295, 296 acylation - enzymatic 213 acylglycerides - enzymatic hydrolysis 295 acyliminium cyclizations 267 -

acylsilanes 100 addition - 1,3-dipolar 77-95 - nitrone-olefin 79-85 - organometallic 6 adriamycin 78, 351 Agelas oroides 234 AlC13 57 alcohol - alkynyl 33 - allylic 112, 138, 149 - amino 78, 82ff, 92 - homoallylic 34, 37, 75 - homopropargyl 36 - optically active 21 - tert 10 aldehyde 9, 11, 22, 25, 26 - a-chiral 6 - dialkoxy 8 - enzymatic reduction 228 - a-hydroxy 42 - keto 12, 29 - a,b-unsaturated 23 aldol addition 25; 36, 73, 75 - aldolase-catalyzed 228 aldol condensation - by Mukaiyama 153 aldol reactions - diastereoselective 366 aldolase - specificity 228 aldols - anti 107

392

Subject Index

aldose

- l-deoxy-l-nitro 30 aldoses

- chain elongation 246

aldoxime 30 AlEtCl, 57, 68 alkaloids - aspidosperma 269 - axially chiral 273 - biomimetic synthesis 274 - bridged macrolactam 270 - by electrochemical means 203 - macrocyclic 271 - naphthylisoquinoline type 272 - synthesis 263ff alkanes - chlorination 105 alkene-carbonyl metathesis 106 alkenes - intramolecular addition of radicals 126 - see also olefins alkinyllithium compounds 152 2-alkoxyoxetanes - ring opening 106 3-alkoxyoxetanes - ring opening 106 alkoxytosylates 114 alkylating reagents 23 alkylation 12 - 0- 25 - C- 25 - mono 10 l-O-alkylation 282 alkylglycerophosphorylcholines 292 3-alkylidene oxepan 135 alkyllithium 21, 47 alkylsilanes 21 alkynes - addition of radicals 127 - cobalt complexes 143 - cocyclization with Cr carbene complexes 186 alkynyl carbene complexes - cycloadditions 190

allenes - highly substituted 194 - nucleophilic addition of allyl alcohols 112 - phosphoryl-activated 113 allenylphosphoramidates 113 a-allokainic acid 93, 94 allyl boranes 303 allyl vinyl ethers - a$-unsaturated 112 - P,y-unsaturated 112 allylic alcohols 138 - asymmetric oxidation 149 - vinylation 112 allylic carbamate - titanium substituted 289 allylic ester enolates - Claisen rearrangement 111, 116 allylic ketene acetals - Claisen rearrangement 111 allyloxycarbonyl group - in sugar chemistry 278 allylpalladium(I1) chloride 368 allylsilanes - cis-configured 133 - cyclization 131ff - optically active 132 allylstannanes - syn-selectivity 289 allyltrimethylsilane 366 aluminiumhydrides 22 aluminum amalgam 315 amides - a,a’-dimethoxylated 202 - anodic oxidation 199 - a-methoxylated 203 amidoalkylation 199ff aminal 12 amination - electrophilic 45, 48, 50, 51 - reductive 29 amines 45 - alkynyl 47 - anodic oxidation 199 - a-hydroxy 52

Subject Index

- methoxy 46 - primary 46, 48 secondary 46 amino-alcohols - y 78, 82, 85, 86, 92 2-cis-amino-2-deoxyglycosides 279 amino-diketones - cyclization 274 (R)-amino-p-hydroxybutyricacid 244 amino acid - N-t-Boc-protected 303 amino acid synthons - electrophilic 302 amino acids 11, 48 - p 52 - aromatic 255 - substituting in a-position 300 a-amino acids 20, 50, 72 - asymmetric synthesis 300ff - four-component condensation 303 - stereo-selective alkylation 301 a-amino esters 50, 51 amino phosphates - anodic oxidation 199 amino sugars 351 a-aminoaldehydes - protected 366 aminodiol 12 aminomethylation 73 aminonitriles - from N-methyl pyrrolidine 199 6-aminopenicillanic acid 213 amphotericine B 10, 282 amphoteronolide B 282 anamarine 255 anchimeric effect 12 (-)-ancistrocladine 272 anellation - [3+3] 202 anguidine 218 anhydroserricornine 218 anion - sulfinyl 17 -

anisol

- metallation 167

anisomelic acid 286, 289 anodic oxidation 199ff anthracyclines 351, 358 anthracyclinones 20, 78, 188 antibiotics - anthracycline 351 - by fermentation 213 - glycosidic 253, 283 - ionophoric 147 - polyether ionophoric 145 L-arabinose 294 arborols 378ff arene-olefin cycloaddition 332 arene-olefin photocycloaddition - intramolecular 373 arenes - 1,2-disubstituted 167 aromatic aldehydes - ortho alkylation 168 aromatic substitution 167ff (S)-artemisia alcohol 37 aryl coupling 181ff aryl halides - palladium-catalyzed stannylation 182 4-aryldihyropyridine - chirality transfer 170 aryloxypropanolamines 244, 292 arylsuifonazides 304 L-ascorbic acid 294 ascorbic acid - Reichstein’s synthesis 212 asperdiol 286, 288 asteltoxin 107f - racemic 109 Astralagus lentiginosa 359 asymmetric induction 356 - internal 111 - relative 111 asymmetric synthesis - C3 components 292 - enzymatic 295f aureolic complex 283

393

394

Subject Index

aurovertines 150 auxiliary 41 - chiral 51, 54,55, 58, 59, 60 - (S)-proline 339 - (-)-tartaric acid diisopropylester 361 avermectin Al 63 avermectin B1, 344 avermectins 344 axial attack 12 axial chirality 67 azide 31, 48 - trifluoro methanesulfonyl 49 - trimethylsilyl 49 - trimethylsilyl methyl 49 - vinyl 50 a-midoacetic acids 304 azidocarboxylic acids 304 aziridine - siloxy 50 aziridinium ion 52 azo-bis-isobutyronitrile 126 azoester - a 51 azomethine ylide 93, 94 B -3-pinanyl-9-borabicyclo[3.3.llnonane 33 bacteria - thermophilic 217 Baeyer-Villiger degradation 332 Baeyer-Villiger oxidation 155 baker’s yeast - in enantioselective reduction 216 - reductions 297 Barbier reaction 76 9-BBN 91 Beckmann reaction 92 benzalacetone 99 benzaldehyde 73 - Paterno-Biichi Reaction 105 benzannulation reactions 186ff cis-benzene glycol 229 benzyl-amine 72 benzyl-ammonium tnfluoroacetate 74

benzyl ethers

- as protecting groups 279 benzyldiethyl-phosphonoacetate 47

3-benzylox ypropanal - photocycloaddition 107

BF3 58, 62, 66 biaryl system - axially chiral 183ff bicyclo[3.3.0]-octanedionetetraesters 121 bicyclo[3.3.0]octanediones 123 2,2’-binapthol 67, 69 biomimetic syntheses 145, 232ff biotin - commercial synthesis 226 a-bisabolol 58 Bischler-Napieralsky reaction 274 bislactim ether 12 bislactim ether method 300 bis(2-methoxyethoxy)aluminum hydride 367 (-)-bissetone 253 2,5-bistetrahydrofurandiyl systems 146 blastmycinone 90, 91 P-blocker 292, 294 borane - acyloxy 62 - chiral 34 boron-enolate aldol strategy 366 boron - enolate 36 boron compounds 131 boronates - ally1 34, 35, 36, 37 - a-chloro 37, 38 - crotyl 35, 36, 37, 38 brefeldinA 245, 256 brevetoxin A 151 brevetoxin fragments 155f brevicomin 221 3-bromo-cyclooctene 90 2-bromo-2-deoxyglycosylbromides 283 5-bromohexene - cyclization 126 bromolactonization 20, 159 - selective 163

Subject Index

Burgi-Dunitz trajectory 4, 5 BuzSnO 297 n-Bu3SnH 156 butadiene - 1,Zdimethyl 62 di-tert butyl-azodicarboxylic ester 11, 51 butyl-lithium 26, 37 y-butyrolactone systems - lipase-catalyzed lactonization 228 C-C bond - stereoselective formation

116 C-C connection - asymmetric 221 - enzymatic 212, 221, 228 - radical reactions 126 C-H-acidity 16 C2 building block - chiral 357 camphanic acid chloride 297 camphor 41, 54, 55 camphorsulfonic acid 149 Cannizzaro reaction 381 A(9~'2)-capnellene 140, 194f carbacyclin derivatives - asymmetric syntheses 211 carbamate group - ortho directing effect 167 carbamates - anodic oxidation 199 - a-methoxylated 203 carbanion 14, 45 - stabilized 46, 271 carbaprostacyclin 123 carbene complexes - Schrock-type 192 - a$-unsaturated 188 carbene insertion - transannular 372 carbenium ion 73 carbenoid 47 carbethoxy-formo-nitrile oxide 88 carbinols - phenylglyoxylic esters 109

carbinomycin 78 carbocycles - from carbohydrates 255 carbohydrate precursors - radical cyclization 258 carbohydrates - as renewable raw materials 251 - conversion to carbocycles 255 - overfunctionalization 251 carbonates - methylenation 193 carbonyl - a-hydroxy 40, 41 - a$-unsaturated 98 carbonyl compounds - y,&unsaturated 111 carbonyl reduction - microbial 211, 217 carboxamides - ortho lithiation 167 L-carnitine hydrochloride 216f (-)-carpetimycin 222 carpetimycin A 222 carvone 287 catalytic hydrogenation 20 cembranoids 286 cembranolides 286, 289 cembrene 286f centrohexindane 374f centropolyquinane 374 chaenorhine 271 chanoclavine 82 chelate complex 55 chelate control 9 chelate cram model 6 chelate formation 68 chelation 13 chiral auxiliary 19, 20, 21, 23, 162 - pyrrolidine 301 - see also auxiliary chiral methyl branching 218 chirality - axial 272 chirality transfer 2, 170

395

396

Subject Index

3-chloro-2-diethyl-phosphoryloxy-l-prope-

ne 101 chloroamine 45, 52 chlorolactic acid 296 chlorophyll 371 chloropyruvic acid 296 0-chlorosilanes - HC1-elimination 131 cholesterol - biosynthesis 309 chorisminic acid 230 chromanes 16, 169 chromium - arene tricarbonyl complexes 170 chromium carbene complexes - cocyclization with alkynes 186 chromium hexacarbonyl - recovery 188 chromium(I1)allyl 6 cis-chrysanthemic acid 117 cinchonine 336 (-)-citronella1 348 (-)-citronello1 345 citrulline 235 Claisen-Ireland rearrangement 88 Claisen rearrangement 2 - alicyclic 117 - ally1 vinyl ethers 111 - allylic ester enolates 116 - allylic ketene acetals 111 - aza 114, 269 - carbanion-accelerated 113 - catalysis 112 - 1,3-chirality transfer 117 - diastereoselective lllff - phenol-catalyzed 112 - starting materials 193 - stereochemical control 116 cobalt alkyne complexes 143 cobyric acid 85 cocaine 83 CO(CO)~ 142 compactin 14, 15, 309ff (+)-compactin 310ff, 318ff

complexation 58 conformation - antiperiplanar 26, 55 - cisoid 55 - fixed 22 - gauche 28 - reactive 5, 21 - transoidal 22, 55 copper - for aryl coupling 181 corands 378 Corey-Pauling model 378 Corey-Pauling scale models 381 Corey lactone aldehyde 160 coriolin 142, 323ff - optically active 329 Coriolus consors 323 corticoids - anti-phlogistic effect 207 - anti-rheumatic effect 207 covalent model 9, 12 Crammodel 4 - Cram-cyclic model 26 Cram’s rule 3, 8 crotonamide 68 crotonic ester 55 crown ethers 378 cryptands 378 cuprate-addition 6 cuprates - alkynyl 47 - dialkyl 21 Curtin-Hammett principle 3 tris(2-cyanoethy1)nitromethane 382 cyanohydrin 47 - alkylation 287 cyclic ethers - medium-ring 153 - stereocontrolled anellation 156 - with exocyclic double bonds 135 cyclic systems - Heck reaction 178 cyclization - acetal-initiated 135

Subject Index

arene-olefin 332, 373 C-C 153 C - 0 152 cationic 134 10-endo-dig 85 initiation 134 nitrileoxide-olefin 90-92 nitrone-olefin 69, 83, 84 polyepoxides 145 radical 103 zirconium-catalyzed 96 cycloaddition 2 - [2+2] 20, 105 - [3+2] 97-104 - [3+2]-Pd-catal. 99 - [4+1] 96-97 - [4+2] 30, 71 - Diels-Alder 54ff - 1,3-dipolar 77-95 - meta 373 [2+21-cycloaddition 105 [3 +21-cycloaddition - intramolecular 259 cyclohexadienones - heteroannulated 189 cyclohexanones 257 1,lO-cyclohexanotriquinacene 125 cyclohexenone 12 cyclopenta-1,3-diones - microbial reduction 218 cyclopentadiene 55, 57, 61, 62, 63, 66, 67, 71, 72 cyclopentane rings - fusion 323 cyclopentanoid systems 140 cyclopentenone 98, 99 - one-pot-synthesis 141 cyclopropane 19 cyclopropanoic ester - l-amino 48 cycloreversion - rhodium-catalyzed 106 L-cysteine 84

397

cytocalasin 61 cytostatic agents 188 d-biotin 84, 90, 91 Danishefsky diene 67, 246, 321 daunomycin 78, 351 daunosamine 78, 80, 351ff L-daunosamine 357 daunosamine glycoside 355 L-daunosamine hydrochloride 353 De Mayo reaction 21 decasaccharides 284 deepoxyasperdiol 290 (+)-deepoxyasperdiol 291 dehydroamino acids 300 dehydroestrone 63 16-dehydropregnenolone 208 dehydroserine 213 Dendroctonus brevicomis 335 Dendroctonus frontalis 335 deoxy compounds - by anionic cyclization 257 6-deoxy sugars 253 ll-deoxydaunomycinone 172 4-deoxydaunosamine 358 deoxyfrenolicine 188 deoxygenation 17 2-deoxyglycosides 283 P-2-deoxyglycosides 283 2-deoxypentose derivatives 246 (S)-deplancheine 271 di-l-menthyl-(acet0xymethyiene)-malonate 58 1,3-diacetoxy systems - enantioselective hydrolysis 227 diallylzinc 6, 354 diazo-transfer 48 diazonium salt 50 DIBAL 16, 82, 84 dibenzoyltartaric acid 298 dibenzyl-peroxo-dicarbonate 40 diborane 33, 62 dibromo methyllithium 348 3,3'-dibromobinaphthol 67

398

Subject Index

dibromophakellin 234 1,2-dicarbonyl compounds - Weiss reaction 123 1,2-dichloro-3-acetoxypropane295 truns-l,4-dichloro-2-butene 361 dichloro-dicyclopentadienyl zirconium 96 dichloro-methylboronate 37 dichloro-methyllithium 37 dichloroacetone 101 2,3-dichloropropanol 296 dicobalt octacarbonyl 97, 141 Dieckmann condensation 371 Diels-Alder reaction 2, 6, 14, 27, 33, 54, 55, 56, 57, 59, 60, 61, 62, 63, 66, 67, 68, 71, 77, 79, 86, 94, 97 - aza- 61, 74, 267 - combination with halolactonization 162 - hetero 71 - intramolecular 193, 265, 271f diene - chiral 60 diene in situ 6 - electron-rich 67 dienophile 27, 54 - chiral 60 diesters - enantiodifferentiating hydrolysis 222 diethyl-tartrate 19, 67 dihydro-azines 11, 12 dihydroagarofuran 127 dihydrocompactin 135, 309 (+)-dihydrocompactin 317 dihydromevinolin 309 dihydrooroidine 235 dihydropyranones - substituted 251 dihy dropyrans - from glucal derivatives 252 dihydropyridines 169 dihydropyrimidinone 271 dihydroxyacetone phosphate 228 dihydroxycompounds 21 diisopropylidene - glycol cleavage 293

1,Zdiketones

- cyclic 121 diketones

- symmetric 121 1,4-dimethoxy naphthalene 172 dimethyl-zinc 69 0,O-dimethyl phosphorodithioic acid 283 dimethyl sulfide 298 L-dimethyl tartrate 294 1,lO-dimethyl triquinacene 125 4-dimethylaminopyridine 196 3,Qdimethylfuran - photocycloaddition 107 cis-dimethyloxocene 154 1,l'-dimethylstannocene 297 dinoflagellates 151 1,3-diones - microbial reduction 218 diosgenine - degradation 208 1,3-dioxane 22 dioxanone 23 dioxinones 20 1,3-dioxolane 10 dioxolanone 21, 23 dioxygen 40 dioxygenase 229 3,3'-diphenyl-binaphthol 68 a,P-diphenyl-P-hydroxy-ethanol43 dipolar model 3 1,3-dipoles 77-95 diradical - 1,3, 97 diterpenes 286 divinyl ketones - acid-catalyzed cyclization 137 - silyl-substituted 139 - synthesis 138 divinyl silanes - unsymmetrically substituted 138 divinylketones - silyl substituted 138 DMPU 26

Subject Index

Dotz reaction - intramoleular

186f 188

L-dopa 213 double asymmetric induction 43 double stereodifferentiation 6, 63, 66 Dreierdiastereoselektivitat 9 effect - antiperiplanar - steric 10

4, 6

eicosanoids 236 elaeokanine B 267 electrophilic amination - enolates 304 electrophilic azide transfer 304 elfamycin - total synthesis 147 e1imin ation - pyrolytic 14 - reductive 102 ellipticine 168 emodine 235 enamine 28 - chiral 29 enantiotopic ester groups 296 ene-carboxylic acids - polycyclic 160 - unsymmetrically substituted 158 ene-reaction 66 enol ethers - photocycloadditions 106 enol silanes 366 enolacetates 50 enolates 6, 9, 10, 11, 12, 13, 16, 40, 41 - boron 36, 69 - chiral 41, 69 - chiral glycolate 21 - chiral imide 41 - deoxybenzoin 43 - electrophilic amination 304 - ester 45, 48, 51 - ketoester 43 enolether 22, 23, 38 - silyl 43, 45, 51, 69, 75, 76

enterobacteriae 280 enterobacterial corum antigen 280 enzymatic catalysis 207 - membrane-enclosed 224 enzyme reactions - in organic solvents 224, 227 enzymes - enantioselectivity 226 - in nonaqueous solvents 224, 227 EPC-synthesis 14, 16, 17 ephedrine 48, 212 L-ephedrine 213 (+)-epi-widdrol 134 epimerization 27, 90 epoxidation - asymmetric 298 - see also Sharpless reaction epoxide ally1 alcohol rearrangement 142 epoxides 11 - diaxial opening 161 epoxy alcohols - hydrolyses of esters 295 equatorial attack 12 equilibration 15, 16 ergolines 92, 263 D-erythro-C18-sphingosine 281 erythronolide B 161 L-erythrulose 294 Eschenmoser fragmentation 86 ester enolate - Claisen rearrangement 116ff ester hydrolysis - by hydrolases 224f - Lipase-catalyzed 211 esterases 295 esterification - enantioselective 227 - lipase-catalyzed 228 esters - P-hydroxy 16 - methylenation 193 estrone - total synthesis 209, 210 estrone methyl ether 210

399

400

Subject Index

Et2AlCI 57, 58 ether lipids 292 etheromycin 149 ethers - macrocyclic 151ff ethyl vinyl ether 78 ethylaluminum dichloride - intramolecular Sakurai reaction ethylenation 194 europium shift reagents 33, 67 Evans reagent 50 ex-chiral-pool strategy 337 ex-chiral-pool synthesis - swainsonine 360 5-exo-tet-reaction 146 Felkin-Anh model 4ff, 354, 356 fenestranes 371ff [4.4.4.4]fenestrane 371 [4.5.5.5]fenestrane 375 [5.5.5.5]fenestrane 124, 373 [5.5.5.7]fenestrane 371 all-cis[5.5.5]fenestranes 373 [5.5.5.5]fenestratetraene 373 [5.5.5.5]fenestratetrone 373 fenestrindane 374 fermentation 207 Ferrier rearrangement 255 ferrocenylphosphine ligand - chiral 302 Finkelstein reaction 313 Fischer-Kiliani reaction 246 Fischer carbene complexes 186ff - synthesis 188 formaldehyde 71 formylbutadiene - synthetic equivalent 109 Forssman antigen 279 fosfomycin 213 frenolicin 171 Fries rearrangement - anionic ortho 168 frontalin 11, 335ff (-) -frontalin 221

133

(R)-frontalin 340, 342 (S)-frontalin 340 Fujimoto-Belleau reaction 257 fumarate - dimethyl 56 furan - methoxy 59 furanes - Paterno-Buchi reactions 107 furochromones 188 ~-galactono-1,4-lactone 294 galbanum resin 127 Gaucher’s disease 281 geranyl acetate - allylic oxidation 149 geranylfarnesoyl chloride - cyclization 287 geranylgeranoyl chloride - cationic cyclization 286 gestagens - physiological activity 209 gibberellic acid GA3 160 glucal - tri-O-acetyl 14 glycal esters - epoxidation 251 glycals - as glycosyl donors 281 L-glyceraldehyde 294 glyceraldehydes - protected 292 glycerides - enantiomerically pure 292 glycerol - 2-O-protected 297 glycerol derivatives - optically active 292, 295, 297f - protected 293 - unsymmetrically substituted 292, 293 glycidic esters - from serine 295 glycidol - racemic 298

Subject Index

(R)-glycidyl butyrate 295 glycine synthons 302 glycoconjugates 277 glycolipids 292 O-glycoproteins 279 glycosidase inhibitors 228 glycosides 78 - complex 282f - 5,6-unsaturated 255 cis-glycosides - from mannose 252 O-glycosides 277ff P-trans-glycosides 280 1,2-trans-glycosides 278 glycosyl donors 277 grandisol 21 Grignard addition 6, 8, 17 Grignard coupling - palladium-catalyzed asymmetric 132 Grignard reagents 21, 46, 48, 50 Grob fragmentation 316, 332 guanidinium-chloride 71 guest-host chemistry 378 gymnomitrol 123 H-D-exchange 14 a-halo-sugars 279 P-halo-sugars 279 halo sugars 277 halolactonization 158ff (-)-hastanecine 268 Heavy-metal salts - glycoside synthesis 277 Heck reaction 97, 174ff - intramolecular 179 Helferich catalyst 279 (+)-heliotridine 268, 269 hemin 371 Henry reaction 25, 26 12(R)-HETE 41 heteroaryls - coupling 182 heterocycles - Heck reaction 178

401

heterocyclic systems

- by benzannulation reactions 189 E-Chexenal 353 hexose derivatives - approach to 246 HMG-CoA reductase 309 HMPA 26, 40, 43 Hofmann elimination 88 homoallylic alcohols - chiral 132 Horner-Wadsworth-Emmons reaction 289f, 312, 316, 363 Houk’s model 4, 6 Hiinig base 69 hydrazines 48 hydrazino-acids 11 hydrazino-esters - a 51 a-hydrazinocarboxylic acids 304 hydrazono-ester 50 hydride-transfer 33 trans-hydrindan 134 hydroboration 6 - oxetane 107 hydrogenations - asymmetric 300 P- hydroxy - carboxylic acids 90 - nitriles 90 hydroxy-amination 52 p-hydroxy-a-amino acids 302 hydroxy-carbonyl - p 34 (S)-P-hydroxy-isobutyric acid 92 9-hydroxy-methyl-anthracene 71 3-hydroxy-3-methylglutaryl-CoA 309 (S)-3-hydroxy-2-methylpropionic acid 218 (S)-2-hydroxy-1,2,2-triphenylethylacetate (HYTRA) 315 a-hydroxy acids 11, 20, 228 3-hydroxy butyrate 20, 23 a-hydroxy carboxylic acids 228 2-hydroxy glucal esters - hydroxyl aminolysis 252

402

Subject Index

(R)-3-hydroxybutyrates 217 (S)-P-hydroxybutyric acid 216 a-hydroxycarboxylic acid - asymmetric synthesis 163 hydroxylactonization 162 hydroxylamine 45, 52 - 2,4-dinitro-phenyl 46 - O-diphosphonyl-N,N-dimethyl 47 - lithiated 47 - O-mesitylenesulfonyl 46 - O-sulfonic acid 45 hydroxylamine-benzyl 83 hydroxylation - a 40, 45 - enzymatic 229 iBu2A1C1 57 imidazolidinones - diastereomerically pure 301 1,3-imidazolidin-one 10 imine 52 iminium - ion 72, 74 - salt 71 a-imino esters - addition of carbon nucleophiles 303 iminoalkylation 47 in situ anomerization 279 1,3-indandione 374 indanes 169 indole derivatives 188 induction - 1,2- 3 inoc-reaction 92 insertion - CO 96-97 iodine lithium exchange 349 2-iodo-a-glycosides 283 6-iodo sugars - reduction 253 iodocyclization 353 iodolactonization 159, 161, 283, 312 - diastereofacial selectivity 162 - stereoselective 345

N-iodosuccinimide method 283 (+)-ipsdienol 132 Ireland-Claisen rearrangement 117 isoascorbic acid 295 isobutyric acid - microbial hydroxylation 218 isocamphenyl-haloborane 62 isocomene 123 isolariciresinol 60 isoprenoids 218 - cationic cyclization 145 isopropenyl chloroformate 367 isopropyl-phenylcarbinol 59 (R)-2,3-isopropylidene glyceraldehyde 243ff, 292, 313 - preparation 248 isoquinoline alkaloids - biomimetic syntheses 236 isoretronecanol 129 a-~-isosaccharino-l,4-lactone 337 isovanillin 271 isoxazole 85 isoxazolidine 78 isoxazolines 85, 88, 259 ivermectin 349 Jones oxidation 327, 373 juglone 58, 68 kainic acid 94 (-)-kainic acid 117 ketal - spiro 22, 23 ketene-N, O-acetals - Claisen rearrangement 111 keteneacetals 50 - vinyl 61 a-keto-acetal 19 P-ketoesters - microbial reduction 217 - a-phenylselenyl-substituted 152 ketones 26, 29 - acetylenic 152 - alkinyl 33

Subject index

- alkynyl 22, 33 a-amino 50 enzymatic reductions 228 methylenation 193 prochiral 296 - a$-unsaturated 75 kinetic acidity 14 kjellmanianone 43 Kochi decarboxylation 219 Konigs-Knorr reaction 253, 277, 280 Kumada-Negishi cross-coupling 182 -

lactaldehyde

- 0-benzylated 357

lactam 12 - bicyclic 12 - macrocyclic 29 lactate dehydrogenase 228, 296 L-lactic acid 10 lactic acid 56 (S)-lactic acid 342 trans-lactone moiety 289 lactones -P 9 - y 31, 76 - a,a’-disubstituted 153 - bicyclic 156 - butyro 10 - conversion to cyclic ethers 154f - iodo 57 - macrocyclic 29 - medium-ring 154 - methylenation 193 lactonic acid - racemic 336 lactonization - enzymatic 228 lanosterol - biomimetic synthesis 232 1asalocidA 117, 193 laurencin 151, 152 laurenene 371, 375 Lawesson’s reagent 156 LDA 16, 23, 41, 81, 91, 101

lead tetra-acetate 43 Lemieux oxidation 331 Lewis-acidity 8 Lewis acid 19, 22, 23 - catalyzed 21, 45, 54, 55, 57, 73 - chiral 66, 67, 69 LiA1H4 - binaphthol complex 238 lignans 272 (R)-linalool 337 linalool - silyl-protected 338 lipases 295 - selectivity 226 liquid crystals 181 lithium - alkyls 27, 45, 47 - aryls 45, 47 lithium alkylphosphonates - in sugar chemistry 257 lithium chloride 71 lithium diisopropylamide 116 - see also LDA lithium dimethylcuprate 253, 316 lithium dimsylate 113 lithium methoxide 315 D-lividosamine 86, 88 loganine - 0-methyl 56 LSD 263 lycopodine 274, 275 lycorine 271, 273 lysergic acid 263 lysergine 265 macrocyclization 286 macrodithionolactone - reductive coupling 155 macrolactonization 349 maleate - dimethyl 71 L-malic acid 294 malingolide 129 mandelate ester 58

403

404

Subject Index

(S)-(-)-mandelic acid 301 mandelonitrile lyase 229 Mannich reaction 72f, 76 - intramolecular 274 L-mannitol 294 D-mannitol - double protection 294 - glycol cleavage 243 - synthesis of glycerols 293 a-D-manno-glycoside 278 p-manno-glycosides 279 a-D-manno-halo sugars 278 p-D-manno-oligosaccharides 253 a-D-mannopyranoside 351 Mannose - nitro 30 McMurry reaction 155 mCPBA 43, 81, 83 Meenvein aryl coupling 126 Meerwein salt 188, 300 Meerwein’s reagent 58 Meldrum’s acid 367 MEM-ether 33 menthol 54 - 8-Phenyl 59 menthone 20 menthyl - ester 58 - oxyaluminium dichloride 62 menthyl ether 66 menthyl phenylglyoxylate - photocycloaddition 109 meso-diester - enantioselective hydrolysis 225f metallacyclobutanes 192 metallation 35, 45, 48 methacrolein 61, 62, 66 4-methoxy-benzaldehyde 47 (methoxy-ethoxy)methyl ethers 135 7-methoxyindane - irradiation 373 3-methyl-butenal 37 6-methyl-5-hepten-2-one 340 O-methyl-tetradehydrotriphyophylline 236

methyl-vinyl-ketone 71 methyl alumination 348 methyl trifluoromethanesulfonate 114 methylenations - Tebbe-Grubbs-reagents 192ff methylene-cyclopropane 98 N-methylhydroxyl-amine 259 methylrhamnoside 283 mevalonic acid 309 mevinolin 309 (+)-mevinolin 311 mevinolin 312ff Michael acceptor - addition 17, 20, 51, 93, 98, 100, 101, 102 Michael reactions - retro 380 microbial hydroxylation 207 milbemycin 344 milbemycin p3 344ff mitomycin 178, 188 mitramycin 283 modhephene 123 molecular mechanics 381 molecular modeling 365 monensin 117, 145f monoclonal antibodies - as catalysts 230 monosaccharide synthesis 245 morpholino-cyclohexene 28 miinchnones 94 mukulol 286 a-multistriatin 162 muscaflavin 233 muscarine 7 mussettamycin 283 NADH 297 naphthoquinones - selective construction 188 naphthylisoquinoline alkaloids 183f natural products - aromatic 235 - cyclopentanoid 137 Nazarov reaction 137ff

Subject Index

Nef reaction 25 Nicholas reaction 143 nickel-ally1 complex 23 nickel complexes - for aryl coupling 181 Ni(COD)2 23 nicotinic acid derivatives - metallation 169 nitration 48 nitrile oxides 85-94 nitro-alkane 25, 30, 31 nitro-ethylene 93 nitro-ketone 28, 29 2-nitro-1,3-propane-diols28 nitro-styrene 28f 2-nitroallyl esters 227 nitrodiene 30 nitronate 25, 26, 30, 31 nitrones 77-85 - N-glycosyl 30 nitroolefin 27, 28 nitrophenyl-pivalate 27 norbornenone 55 D-norgestrel - total synthesis 209 19-norsteroids - via Birch reduction 210 nucleosides 226 octopus molecules 378 olefin metathesis 192 olefins - arylation 174ff - meta-cycloaddition 372 - vinylation 174ff - see also alkenes oligonucleosides - synthesis 277 oligopeptides - electrochemical modification 203 oligosaccharide syntheses - catalytic systems 279 oligotetrahydrofuran systems 146 Oppenauer oxidation 275

organic semiconductors 181 organo-copper reagents 22 organoaluminium reagents 22 organoborane 33 organomercury compounds 255 organopalladium reagents 174 oroidine 234 ortho esters - opening 277 osmium tetroxide 52 osmylation 6 oxazepane-dione 60 oxaziridine 42 1,3-oxazolidine 10 oxazolidones - N-acyl (Evans reagent) 50 - aryloxy 56 - N-crotyloxy 56 oxazolines - alkylation 114 - chiral 169 1,3-oxazolines - converted to glycosides 278 oxetane - hydroboration 107 5-0x0-hexanoic acid 12 oxobicycles 155 oxocanes - 2,8-substituted 155 o-oxocarboxylate derivatives 200 oxocenone system 152 3-oxoglutarate - Weiss reaction 123 oxopolycycles 155 oxotriquinane - trichloromethyl substituted 371 oxy-Cope rearrangement 287 oxygen heterocycles - with chiral side chains 117 p-nitro-benzaldehyde 69 paliclavine 92 palladium - r-ally1 177

405

406

Subject Index

diary1 182 - stannylation of aryl halides 182 palladium-catalysis 23, 96, 98, 101 - [3+2]-cycloadd. 99 palladium-catalyst - chiral 302 palladium complexes - as catalysts in Claisen rearrangement 112 palladium compounds - for aryl coupling 181 (-)-palythazine 253 pantolactone 58 R-(-)-pantolactone 118 [2,2]-paracyclophanes 177 parazoanthoxanthin A 235 Paterno-Biichi reaction 105ff Pauson-Khand reaction 96, 137ff, 327 Payne rearrangement 363 penicillin acylase 213 penicillins - bacterial resistance 213 pentaerythritol - protected 381 pentalene 17, 123 pentalenolactone 17 pepstatin renin 365 peptides - coupling to sugars 283 - synthesis 277 - synthetic 365 perhydro-histrionicotoxin 267 perhydrotriquinane system 142 Perilla aldehyde 219 Perkow reaction 101 peroxide - bis-(diphenyl-phosphinyl) 47 pestalotin 33, 34 Phakellia flabellata 234 phase transfer catalysis 48 phenol - Ullmann condensation 271 phenols - coupling to alkens 178 - coupling to alkynes 178 -

- enzymatic C-C coupling 213 phenyl-alanine 11 phenyl-glyoxal 72 8-phenyl-menthone 21 phenylacetate - ethyl 41 phenylisocyanate 85, 93 8-phenylmenthol - substitutes for 225 8-phenylmenthylphenyl-glyoxylate 109 pheromones 335 phosphaarenes 189 phosphin-imine 31 phospholipids 292 phosphonate 16 photoaddition - aldehydes to furane 107 photocycloaddition - aldehydes 105 - alkenes 105 - ketones 105 photoreaction - metal-catalyzed 335 (+)-phyllantocine 218, 220 pinene - a 33, 34 piperidine 73 - dihydroxy 73 Pitzer strain 151 pivalaldehyde 20, 342 0-pivaloylgalactose 304 platelet activating factor 292 polybutadienes - epoxidized 146 polycycles - cis-linked 155 - trans-linked 155 polyene mycotoxins - biosynthesis 150 polyenes - cyclization 233 polyepoxide cyclization - biomimetic 147

Subject Index

polyepoxides

- cyclization 145 polyether ionophore systems 146 polyether macrolides 117 polyether toxins 151 polyh ydroxybutyrate - acid-catalyzed depolymerization 217 polypropionates 218 polyquinane systems 258 porcine-liver esterase 28, 226 - enantiodifferentiating effect 222 - ester hydrolyses 225 porcine pancreatic lipase 295 potassium - tert-butoxyde 11, 23 potassium dimsylate 114 Prelog-Djerassi lactone 117 prephenic acid 230 progesterone - microbial hydroxylation 207 (S)-proline benzyl ester 57 propanediol - 1,3- 22, 23 propargyl ethers - cobalt complexes 143 propargyl systems - alkoxysubstituted 153 [3.3.x]propellanes 121 propiolate esters - nucleophilic addition 112 prostaglandin - biomimetic synthesis 236, 238 - biosynthesis 236 - halolactonization 160 - industrial synthesis 161 - microbial transformations 211 - PGEl 210, 244 - PGF, 160 prostaglandin B1 methyl ester 177 protecting group techniques - glycoside synthesis 277 pseudo sugars 256 pseudonucleosides 226 ptilocauline 81

407

(R)-pulegone 217 (+)-pumiliotoxin A 135 Pummerer reaction 109, 363 pyridinium chlorochromate (PCC) 348, 359 pyridinium p-toluenesulfonate (PPTS) 282 pyridylalanine 234 pyroglutamate 42 pyrone units - in natural product syntheses 253 pyrrolidines - polyhydroxylated 363 pyrrolizidine alkaloids 129, 268 quinine 263, 336 quinodimethide - ortho 60 racemization 14, 56 radical chemistry - selective 126 radical cyclizations - scope 128 radical reaction - intermolecular 129 RAMP 42 Raney-nickel 27, 90, 91 rearrangement - Claisen 2 - selfimmolative 2 - sigmatropic 2 - 2,3-sigmatropic 15 red tide 151 Reichstein’s S-17-acetate - microbial hydroxylation 207 resorcinol dimethyl ether 170 retro-aldol reaction 374 retro-Claisen reactions 124 retro-diene addition 63 L-rhamnose 353 Rhizoctonia leguminicola 359 rifamycin S 162 ring-closure reactions 151 ring-expansion 29

408

Subject Index

Robinson annulation proline-catalyzed 210 Robinson spiro-annelation 218 Robinson-Schopf condensation 152

-

Sakurai allylation 83 Sakurai reaction 132,143 - in terpene chemistry 134 SAMP 42 P-santalene 55 Schlosser-Fouquet coupling 212 sedridine 78 self-reproduction of chirality 10 semibullvalene structure 124 L-serine 294 Seyfarth-Fleming ylid 133 Shapiro reaction 138,310 Sharpless-Masamune method 246 Sharpless epoxidation 146,147,149,298,

327 - microbial analogon 213 Sharpless oxidation 225 Sharpless reagent 52 - epoxidation 68 shikimate

- methyl 30

methyl-5-epi 59 shikimic acid 255 - optically active 256 Si-C bond 131 sigmatropic rearrangement 230 -

-

3, 111

silanes - alkyl 21 - allenyl 100 - allyl 69,74,76,131ff silicon-carbon compounds 131 silicon reagents 131 siloxydiene 67 silver tetrafluoroborate 134 silver triflate 283 silyl-acetylene 21 silyl-cyanides 21 silyl-enolethers 21

silyl-ethers 21 silyl-ketene acetals 21 silyl-migration 101 a-silyl epoxides 338 Simmons-Smith reaction 19 sitosterol - microbial degradation 209

SN2’ 22

SnC14 30 Sn(1V) alkoxides 297 sodium hydride 29 D-sorbitol 294 spherands 378 spiroallene 133 spiroannulation - Reformatsky-type 265 spirocyclic compounds 133

(S,S)-1,4-dibenzyl-oxy-2,3-butandiol68

x-stacking 58,60 stannanes - allyl 289 stannylation - of aryl halides 182 starburst dendrimers 378ff statine 365ff stauranes 124,371 (2S)-stegobinone 217 steroid hydroxylation 207 steroids - biomimetic synthesis 135,233 - cationic cyclization 145 - enantiomerically pure 233 - enzymatic hydroxylation 207 stigmasterol - microbial degradation 209 Stille reaction 139f Strecker synthesis 303 Streptomyces avermitilis 344 streptovaricine D 49 strychnine 263 sugar - selective protection 256 (S)-sulcatol 216 sulfenate 14

Subject Index

sulfenate allyl 14 sulfinate menthyl ester 15 sulfinyl-acetate 16 sulfinyl-methyl ester 17 sulfonamides - anodic oxidation 199 sulfonylallenes 113 sulfoxide - alkenyl 59 - allyl 17 - chiral 14, 16 - P-keto 16 - vinyl 17 sulprostone 211 sultam 55 surface antigens 280 Swainsona canescens 359 swainsonine 359ff - biological activity 364 Swern oxidation 348, 349, 363 sydnones 94 t-butyl azodicarboxylate 304 tandem metallation 167 tartaric acid 20, 36, 62 D,L-tartaric acids 295 tartramide 22, 58 Tebbe reagent 154f, 192ff tentacle molecules 378 terpenes - biomimetic synthesis 135 - cationic cyclization 145 tetraacetylglucose 281 (tetrabromomethy1)methane 381 tetrabutyl-ammoniumfluoride 25 tetrahydro furan 73 tetrahydrofuran 26 tetrahydroquinolines - from aniline derivatives 199 te traphen y1 cyclopentadiene - anion 52 - oxime 52 thienamycin 222

thioester

- P-hydroxy 36 thioether addition of alkyllithium 155 homolytic cleavage 155 thiolactones 155 three-carbon fragment - chiral 247 threonine 61 thromboxane B2 161 XC14 55, 57, 58, 68, 100, 132, 134 TiC12(OiPr)2 57 tin chelate ligands 297 tin triflate 302 tin(I1)allyls 6 tirandamycin 117 titanacyclobutanes - synthetic applications 194 titanacyclobutenes 194 titanates - trialkoxy 4 titanium - alkoxy 68 titanium complex 66 titanium enolate 193 titanocene dichloride 192 TMM-complexes 98 TMM-systems 99 a-tocopherol - asymmetric synthesis 211f N-tosyldaunosamine 353 trajectory 4 transacylation - enzymatic 222 transannular interactions 151 transesterification - enzymatic 227, 296 transition metals - for aryl coupling 181 transmetallation - ortho 182 tri-n-butyl-tin hydride 29, 126, 283, 349 triaryl phosphanes 174 tributyrin 296 -

409

410

Subject Index

trichloroacetimidates 280f trichloroimidate method 280 trichothecene 219 trichothecene derivatives 218 tricyclo[6.3.0.02.6]undecane 140 triene-triepoxide biosynthesis 145 triethylamine 85 triethylborane 315 1-trimethyl-siloxy-cyclohexene 73, 75 trimethylene-methane (TMM) 97, 98 trimethylethylene - Paterno-Biichi Reaction 105 trime th ylsilyl - chloride 23 - cyanide 69 - triflate 19, 281 2-(trimethylsily1)-methacrolein 99 bis-trimethylsilyl-peroxide 40 trimethylsilyl triflate 281 trioxahomobarrelene 146 trioxatrishomocubane 146 triquinacene 125 triquinane skeleton 323 triquinanes - angularly condensed 142 trisbromomethyl-benzene 382 tropinone - biomimetically 232 L-tyrosine 213 Ullmann coupling reaction Umpolung 40, 45 valine 11 Vedejs reagent 40, 41 vindoline 274 vindorosine 269 vinyl ethers 59 vinyl iodides 138 vinyl lithium 16 vinyl radicals - cyclization 127 vinyl tnflates 139 - Heck reaction 177 vinylation reaction 177

181, 271

vinylmagnesium compounds 138 vinylsilanes - cyclization 131ff vinyltriazene 50 vitamin BI2 371 vitamin E 188 vitamin K 188 vitamin Kl(zo) 187f Wacker oxidation 142, 325 Wagner-Meenvein rearrangement - undesirable 134 Weiss reaction 121ff, 373 whole-cell system 229 Wilkinson’s catalyst 179 Williamson ether synthesis - intramolecular 288 window-panes 371 Wittig-Horner reaction see Horner-EmmonsWadsworth Wittig condensation 88 Wittig cyclopropanation 247 Wittig homologation 155 Wittig reaction 360 Wittig reagents 192 Wittig rearrangement 288 Wolff rearrangement 375 yernomenine

- racemic 161 ylides from a-silyl onium salts 131 ynamines 112

-

(Z)/(E)-isomerization 28 Ziegler-Thorpe Condensation 372 zinc 75 zinc borohydride 253 zinc diallyl 6, 354 zinc dichloride 58 zincophorine 63 zipper reaction 233, 271 zirconocene dichloride 348 Zoogloea ramigera 217

Organic Synthesis Highlights I1 Edited by Herbert Waldmann

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Further Titles of Interest Drauz, K. /Waldmann, H. (eds.) Enzyme Catalysis in Organic Synthesis. A Comprehensive Handbook Two Volumes. ISBN 3-527-28479-6 Fuhrhop, J. /Penzlin, G. Organic Synthesis. Concepts, Methods, Starting Materials Hardcover. ISBN 3-527-29086-9 Softcover. ISBN 3-527-29074-5 Mulzer, J. /Altenbach, H.-J. /Braun, M. / Krohn, K. /Reissig, H.-U. Organic Synthesis Highlights ISBN 3-527-27955-5 Nicolaou, K. C ./Soremen, E . Classics in Total Synthesis Hardcover. ISBN 3-527-29231-4 Softcover. ISBN 3-527-29284-5 Nogradi, M. Stereoselective Synthesis. A Practical Approach Second, Thoroughly Revised and Updated Edition Hardcover. ISBN 3-527-29242-X Softcover. ISBN 3-527-29243-8

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Organic Synthesis Highlights I1 Edited by Herbert Waldmann

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Professor Dr. Herbert Waldmann Institut fur Organische Chemie der Universitat Richard-Willstatter-Allee2 D-76128 Karlsruhe Germany This book was carefully produced. Nevertheless, authors, editors and publishers do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadventently be inaccurate. Published jointly by VCH Verlagsgesellschaft, Weinheim (Federal Republic of Germany) VCH Publishers, NewYork, NY (USA) Editorial Director: Dr. Ute Anton Production Manager: Dip1.-Wirt.-Ing. (FH) Bernd Riedel The cover illustration shows the polycyclic ring system of morphine, surrounded by the primary rings. Strategic bonds determined in a retrosynthetic analysis are highlighted (see p. 358). Library of Congress Card No. applied for

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Organic synthesis highlights / ed. by Herbert Waldmann. Weinheim ; New York ;Base1 ; Cambridge ;Tokyo : VCH, 2. (1995) ISBN 3-527-29200-4 [Geb. Ausg.] ISBN 3-527-29378-7 [Kart. Ausg.] NE: Waldmann, Herbert [Hrsg.]

0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1995

Printed on acid-free and chlorine-free paper All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition: Mittenveger Werksatz GmbH, D-68723 Plankstadt Printing: Strauss Offsetdruck GmbH, D-69509 Morlenbach Bookbinding: J. Schaffer GmbH & Co. KG., D-67269 Griinstadt Cover design: Graphik & Text Studio Zettlmeier-Kammerer, D-93164 Laaber-Waldetzenberg Printed in the Federal Republic of Germany

Preface

Organic synthesis is a powerful art, which has a strong impact on numerous branches of science. Its methodology can be applied to the construction of manifold compounds. Thus, it opens up new avenues of research in medicinal chemistry for developing alternate and better drugs. It fuels research in biology, biochemistry and bioorganic chemistry by making substrates and inhibitors of enzymes and ligands for receptors accessible. Also, without the possibility of preparing tailormade compounds with a predesigned molecular architecture, the development of new materials and all the challenges which may be loosely described by the phrase “molecular recognition” could not be addressed appropriately. This impact is based on the continuous improvement of the methods of organic synthesis, which must prove their efficiency in the construction of target compounds of an everincreasing complexity. Like its congener (Organic Synthesis Highlights, J. Mulzer et al. VCH, Weinheim 1990), Organic Synthesis Highlights 11 presents a collection of forty articles which provide an overview of the most recent and important accomplishments in organic synthesis. They are based on contributions made from 1988 to 1993 by a team of young authors from universities and industry to the short review section “Synthese im Blickpunkt” (“Focus on Synthesis”) of the Nachrichten aus Chemie, Technik und Laboratorium, the members’ journal of the Gesellschaft Deutscher Chemiker (German Chemical Society). For their publication in this book, all articles were updated and revised. The selection of the individual topics

reflects to a certain extent the points of view of the authors, concerning “important” and “less important” developments, and - of course - their own interests. However, the fact that a total of ten scientists, working in different areas of organic chemistry, have contributed to the book, guarantees the desired diversity. Organic Synthesis Highlights 11 is subdivided into two parts. Part I describes the development of new methods and reagents and covers, for instance, new results from the fields of asymmetric synthesis, organometallic chemistry and biocatalysis. Part I1 details the application of such techniques in the development of new routes to different classes of natural products and to individual target compounds, for instance, calicheamicin y,’ and rapamycin. The short reviews found in this book provide valuable and up to date information for researchers active in organic chemistry. The articles cover the most recent trends in the field, give short introductions to new areas of research and they contain a good collection of references, which suggest alternate solutions to prevailing problems or lead deeper into specific topics. In addition, it is my personal experience with the congener of the book (vide supra) which makes me recommend Organic Synthesis Highlights 11 to my colleagues who are involved in the education of advanced students, and, of course, to the students themselves, as a rich source for the preparation of seminars and lectures. Karlsruhe, March 1995

Herbert Waldmann

Contents

Part I. New Methods and Reagents for Organic Synthesis A. Asymmetric Synthesis The Sharpless Epoxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Schinzer Enantioselective cis-Dihydroxylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Enantioselective Deprotonation and Protonation . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Carbohydrate Complexes in Enantioselective Carbon-Carbon Bond Formation. . . . . . K. H. Dotz Asymmetric ha-Diels-Alder Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann C,-Symmetric Amines as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann

3 9 19 29

37 49

B. Organometallic Reagents in Organic Synthesis Iron $-Complexes in Organic Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Schinzer Rhodium-Catalyzed Carbenoid Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . K. H . Dotz Nickel-Activated C1-Synthons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . K. H . Dotz Aminocarbene Complexes in Ligand- and Metal-Centered Carbon-Carbon Bond Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . K . H . Dotz Organolanthanides in Reduction and Nucleophilic Addition Methodology . . . . . . . . . K. H.Dotz Carbon-Carbon Bond Formation with Group Four Metallocenes . . . . . . . . . . . . . . . M. Maier Aluminum Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann

59

65 75

83 91 99

115

VIII

Contents

C. Silicon in Organic Synthesis Selective Transformations with Pentacoordinate Silicon Compounds . . . . . . . . . . . . . D. Schinzer Oxidative Cleavage of Silicon-Carbon Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Schinzer Temporary Silicon Connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M . Maier

123 129 135

D. Enzymes in Organic Synthesis Enzymatic Carbon-Carbon Bond Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Enzymatic Synthesis of 0-Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann

147 157

E. Cyclization Reactions Electrophilic Cyclizations to Heterocycles: Iminium Systems . . . . . . . . . . . . . . . . . . D. Schinzer Electrophilic Cyclizations to Heterocycles : Oxonium Systems . . . . . . . . . . . . . . . . . D. Schinzer Electrophilic Cyclizations to Heterocycles: Sulfonium Systems. . . . . . . . . . . . . . . . . D . Schinzer Polycyclization as a Strategy in the Synthesis of Complex Alkaloids . . . . . . . . . . . . . D . Schinzer

167 173 181 187

F. General Methods and Reagents for Organic Synthesis Domino Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Group Selective Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M . Maier Hypervalent Iodine Reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Furan as a Building Block in Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M . Maier Fluorine in Organic Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R . Bohlmann

193 203 223 231 243

Contents

IX

Part 11. Applications in Total Synthesis A. Synthetic Routes to Different Classes of Natural Products and Analogs Thereof Synthesis of Hydroxyethylene Isosteric Dipeptides . . . . . . . . . . . . . . . . . . . . . . . . R. Henning Synthesis of Natural Products for Plant Protection. . . . . . . . . . . . . . . . . . . . . . . . . H . -l? Fischer Penems : A New Generation of PLactam Antibiotics . . . . . . . . . . . . . . . . . . . . . . . G. Sedelmeier Synthesis of 0-Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Carbacyclines: Stable Analogs of Prostacyclines . . . . . . . . . . . . . . . . . . . . . . . . . . D. Schinzer Synthesis of Mitomycins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Waldmann Syntheses of Ergot Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7:Brumby Enantioselective Synthesis of Piperidine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . l? Hamrnann Taxanes: An Unusual Class of Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . D. Schinzer

251 261 277 289 301 309 315 323 335

B. Synthesis of Individual Natural Products CC-1065: One of the Most Powerful Anti-Tumor Compounds . . . . . . . . . . . . . . . . . D. Schinzer Syntheses of Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M . Maier Synthesis of Calicheamicin y; . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Waldmann Total Synthesis of Rapamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M . Maier

349 357 371 381

List of Contributors

Dr. R. Bohlmann Institut fiir Arzneimittelchemie Pharmazeutische Chemie I11 Schering AG Postfach 65 03 11 D-13342 Berlin (Germany)

Dr. R. Henning Bayer AG Pharma Research Chemistry Science Labs PH-FE F CWL D-42096 Wuppertal (Germany)

Dr. T. Brumby Schering AG Pharma Forschung Postfach 65 03 11 D-13342 Berlin (Germany)

Prof. Dr. M. Maier Institut fiir Organische Chemie Martin-Luther-Universitat Halle-Wittenberg Weinbergweg 16 D-06120 Halle/Saale (Germany)

Prof. Dr. K.H.DOtz Institut fiu Organische Chemie und Biochemie der Universitat Gerhard-Domagk-Str.1 D-53121 Bonn (Germany) Dr. H. P. Fischer Ciba-Geigy Ltd. Research Relations, PP 2.201 R-1047.3.26 CH-4002 Basle (Switzerland) Dr. P. Hammann Hoechst AG Allgemeine Pharma Forschung Lead Discovery Gruppe H 780 Postfach 80 03 20 D-65926 Frankfurtmain (Germany)

Prof. Dr. D .Schinzer Institut f i r Organische Chemie der Technischen Universitat Postfach 33 29 D-38023 Braunschweig (Germany) Dr. G. Sedelmeier Ciba-Geigy Ltd. Verfahrensforschung K-684.233 CH-4002 Basle (Switzerland) Prof. Dr. H. Waldmann Institut f i r Organische Chemie Universitat Karlsruhe Richard-Willstatter-Allee2 D-76128 Karlsruhe (Germany)

List of Abbreviations

AIBN APA BINAP Boc BTMSA COD CP mCPBA CSA CSI DABCO DAST DBU DCC DCPE DEPC DET DIBAH DMAD EPC FMOC HMPTA LDA MOM NBS NMO TBAF TBS, TBDMS TBSOTf TMS TOSMIC

azobisisobutyronitrile aminopenicillanic acid

2,2'-bisdiphenylphosphino-1,l'-binaphthyl tert-butoxycarbonyl bis(trimethylsily1)acetylene 1,5-cyclooctadiene cyclopentadienyl rn-chloroperbenzoic acid camphorsulfonic acid chlorosulfonylisocyanate diazabicyclo[2.2 .%]octane (diethy1amino)sulfurtrifluoride l,&diazabicyclo[5.4.01undec-7-ene dicyclohexylcarbodiimide bis(dicyclohexy1phosphino)ethane diethyl phosphorcyanidate diethyl tartrate diisobutylaluminium hydride dimethyl acetylenedicarboxylate enantiomerically pure compound 9-fluorenylmethoxycarbonyl hexamethyl phosphoric acid triamide lithium diisopropylamide methoxymethyl N-bromosuccinimide N-methylmorpholine-N-oxide tetrabutyl ammonium fluoride tert-butyldimethylsilyl tert-butyldimethylsilyl triflate trimethy lsilyl tosylmethyl isocyanide

Part I. New Methods and Reagents for Organic Synthesis

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

A. Asymmetric Synthesis The Sharpless Epoxidation Dieter Schinzer

The synthesis of enantiomerically pure comCOOC2H5 COOC2H5 pounds is one of the most important goals in H-C-OH HO-C-H I I organic synthesis and is a major target in HO-I;-H H-C-OH industrial syntheses of physiologically active COOC~H, COOC2Hs compounds. Even more important are asymD - (-) - Diethyl tartrate metric transformations under catalytic condi- L - (+) - Diethyl tartrate [L - (+) - DET] I D - (+) - DET] tions and high turn over rates because fewer (natural) (unnatural) by-products are obtained, which are in many cases a problem for the environment. This chapter will only focus on one particular reaction, which is available under catalytic conditions and is also used industrially: the Sharpless epoxidation. In 1980 K. B. Sharpless and T. Katsuki published the first paper on this important reaction. [l]The reaction can be operated under simple conditions and all components v required for the in situ preparation of the Scheme 1 active catalyst are commercially available: The catalyst is probably obtained by two titanium tetraisopropoxide, diethyl tartrate exchange reactions of isopropoxide with DET (DET), and t-butyl hydroperoxide as the oxiand in solution is dimeric (I) (Scheme 2). dizing agent. Two characteristics are important about these reactions: 1)Many substrates give very high asymmetric induction ; 2) The chirality obtained depends only on the chirality of the diethyltartrate. The oxygen will be transfered only from one enantiotopic face of the allylic alcohol, independent of the structure of the substrate. Therefore, the absolute configuration of the product can always be predicted (Scheme 1). [2, 31

OC2%

Scheme 2

(1)

4

A . AsymmetricSynthesis

In a cyclic process the allylic alcohol is As early as 1981 Sharpless et al. described fixed, and the oxygen is transfered to the dou- an important extension of the epoxidation: the so-called kinetic resolution of secondary ble bond (Scheme 3). allylic alcohols. [4] This type of alcohol is an important building block in many complex Oi-C,H, syntheses. The enantioselective differentiaOi-C,H, tion of the two antipodes is based on the difference of the relative rate constants. Starting from a racemate, one enantiomer is epoxidized faster, which means that the other enantiomer remains as the allylic alcohol. Even small differences in relative rate constant provide quite high enantiomeric excess. This effect can be used for many problems in synthesis and yields extremely high enantiomeric excess (99.999999 % ee) for secondary allylic alcohols. A very good example was published by Overman et al. in their synthesis of pumiliotoxine C. [5] (S)-(-)-2-Methylpentene-3-01(2) ,used as starting material, was obtained after a kinetic resolution in a purity >98% ee. Therefore, it is basically available in unlimited amounts! After benScheme 3 zylation of the alcohol and ozonolysis of the double bond, (3) is diastereoselectively transThe reaction is completely chemoselective formed into the allylic alcohol by addition of and only allylic double bonds are epoxidized vinyl magnesium bromide. In situ addition of (Scheme 4). propionic acid chloride yields the desired ester (4). After deprotonation at low temperature L - (+)-DEr, with LDA, the kinetic enolate is quenched with t-butyldimethylsilyl chloride to give the silylenol ether (5). Compound (5) is rearranged via an Ireland-Claisen rearrangement 77%; 95% ee [6] to (6). In this sequence a trisubstituted double bond is constructed via a chair-like transition state. The ester group is reduced to the aldehyde and finally transformed into a triple bond using the Corey-Fuchs procedure. [7] Compound (8) represents the key intermediate for the coupling with the cyclic fragment, which is based on the amino acid proline (Scheme 5). [5] Greene et al. published an enantioselective synthesis of the side chain of taxol (9). [8, 91 Starting with allylic alcohol (lo), which was epoxidized under standard conditions, the Scheme 4

fl0"

The Sharpless Epoxidation

0

3.

5

(4)

so3-pr Scheme 6

Scheme 5

required alcohol was obtained with the correct configuration.The alcohol was oxidized to the acid and addition of diazomethane gave ester (11). Regio- and stereoselective opening of the epoxide with trimethylsilyl azide in the presence of ZnClz yielded the desired acyclic a i d e (12). The azido benzoate (13) was directly reduced to give the taxol side chain (14) (Scheme 6). The first practicable total synthesis of leucotriene B5(by E. J. Corey et al.) also used an symmetric epoxidation as the key step. [lo, 11) Lactone (IS) was used as starting

material and was transformed in five steps to the aldehyde (17). First, a reduction was carried out, followed by a base-catalyzed double bond shift ((15) -+ (16)], hydrolysis, hydrogenation, and subsequent oxidation to (17) (Scheme 7).

Scheme 7

( 1 7)

A. AsymmetricSynthesis

6

f On

ni I

In a sequence of steps the acyclic part (23) was synthesized from octa-2,5-diine-l-ol (18). In the first step the iodide is synthesized from the alcohol. It is coupled in a copper-catalyzed reaction to give (20). Reduction with LAH provided the starting material for the Sharpless epoxidation. Hydrogenation with Lindlar catalyst followed by Collins oxidation provided (22), which was transformed into (23). The final step is the coupling of the subunits (17) and (23) to give (24)).Hydrolysis of (24) yielded leucotriene B5(Scheme 8). In connection with their studies of cycloadditions Jager et al. described asymmetric epoxidation of divinyl carbinols (25). [121 Indeed, (25) was diastereoselectivley epoxidized with (+)-diethy1 tartrate. Opening of (26), tosylation, and acetonide formation yields crystalline (27) as a pure diastereomer (Scheme 9).

PH,P. Imidazole,: I

I

Scheme 9

Ph,P.

\

Imidazole, I,

1. Ph3P

COOH Leukotriene B,

Scheme 8

(27)

A related reaction was described by Schmidt et al. in an efficient synthesis of desoxyhexoses. [13] Starting with racemic or meso-diglycols a kinetic resolution was used to obtain (28). The starting material for this elegant transformation can be obtained by a reductive dimerization of crotonaldehyde. The epoxide (28) was treated with sodium hydridobis(2-methoxyethoxy)aluminate (RedAl) to give trio1 (29) in a regioselective manner. The ozonolysis yielded 4,6-desoxy-~-xylohexose (30) in only five steps (Scheme 10). All the reactions presented so far are stoichiometric processes, that is, stoichiometric amounts of the titanium-tartrate reagent must

7

The Sharpless Epoxidation

catalyst:

99 %ee

Scheme 12

Recently, Jacobsen et. al. published an be used. In the presence of molecular sieves asymmetric epoxidation of cis-olefins with a the titanium reagent can be applied in cata- manganese catalyst (Scheme 13). [17] lytic amounts, which makes the whole process even more attractive (Scheme 11).[14, 151 5 MoC% Ti(0-CPr),,

C L O H

7.3MoC% w(+)-DET. t-BuOOH, 4 A-molecular sieve

A

+OH

nx*

93% ee 5 MoC% Ti(O-i-Pr)4, 7.4 MoC% &(+)-DET,

w

SBuOOH. 4 A-rnol&ular sieve

Scheme 13

In this account only a few aspects of this beautiful chemistry could be covered. The Scheme I1 number of examples and applications in synthesis could be extended to an enormous The best selectivity can be obtained by the amount. The high and even very high selectivuse of diisopropyltartrate. The only drawback ities obtained indicate high potential for this to this beautiful reaction is the limitation to reaction in the future. The catalytic variation allylic alcohols as substrates. in particular will be of great interest. No other Highly enantioselective oxidations of trans- reaction in organic synthesis with such an olefins have been achieved in a fairly general impact on chemistry has been found in the last sense via osmium-catalyzed asymmetric decade. dihydroxylation by Sharpless et al. [16] They have used a procedure based on a cinchona alkaloid catalyst (Scheme 12). 95x' ee. 91%

8

A . Asymmetric Synthesis

References (11 T.Katsuki, K.B. Sharpless, J. Am. Chem. SOC. [ll] E. J. Corey, P.B. Hopkins, J.E. Munroe, 1980,102,5974. [2] B.E. Rossiter in J.D. Morrison (Ed.): Asymmetric Synthesis, 5 . Academic Press, 1985. [3] A. Pfenninger, Synthesis 1986, 89. [4] V.S. Martin, S. S. Woodard, T.Katsuki, Y.Yamada, M.Ikeda, K.B. Sharpless, J. Am. Chem. SOC. 1981,103, 6237. [5] L.E. Overman, N.-H. Lin, J. Org. Chem. 1985,50,3669. [6] R. E. Ireland, R.H. Muller, A.K. Willard, J. Am. Chem. SOC. 1976 98,2868. [7] E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769. [8] J.-N. Denis, A.E. Greene, A.A. Serra, M.-J. Luche, J. Org. Chem. 1986,51,46. [9] D. Schinzer, Nachr. Chem. Tech. Lab. 1989,37, 172. [lo] E. J. Corey, S. G. Pyne, W. Su, Tetrahedron Lett. 1983,4883.

A.Marfat, SHashimoto, J. Am. Chem. SOC. P%O, 102,7986. [12] B. Hafele, D. Schroter, V. Jager, Angew. Chem. 1986, 98, 89. Angew. Chem. Int. Ed. Engl. 1986,25, 87. [13] U.Kufner, R.R. Schmidt,Angew. Chem. 1986, 98, 90. Angew. Chem. Int. Ed. Engl. 1986,25, 89. [14] R.M. Hanson, K. B. Sharpless, J. Org. Chem. 1986,51, 1922. [15] Y.Gao, R.M. Hanson, J.M. Klunder, S.Y. KO, H.Masamune, K.B. Sharpless, J. Am. Chem. SOC. 1981,109,5765. [16] H.L. Kwong, C.Sorato, Yogino, H.Chen, K.B. Sharpless, Tetrahedron Lett. 1990, 31, 2999. [17] E. N. Jacobsen, W. Zang, A. R. Muci, J. R. Ecker, L.Deng, J. Am. Chem. SOC. 1991,113, 7063.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Enantioselective cis-Dihydroxylation Herbert Waldrnann

Methods for the stereoselective oxidation of olefins are of great interest to organic synthesis since the epoxides and alcohols generated thereby are valuable intermediates for further syntheses. Allylic alcohols can be converted to the corresponding oxiranes by means of the Sharpless epoxidation [l]and improved methods are also being developed for the analogous transformation of simple unfunctionalized 1) 1.1 equhr. -0, 1.1 eouiv 141

alkenes. [2] In addition, effective reagents for the highly enantioselective cis-dihydroxylation were recently introduced. The addition of Os04 to double bonds to give vicinal diols belongs to the standard methodology of organic synthesis. Based on the finding [3] that pyridine accelerates this transformation several research groups investigated chiral nitrogen ligands of osmium in

1) 1.1 equiv. OSO, 1.1 emiu i21

45 - 03 % t?e

48

- 02 %ee

I\

(6)

x=o,s

3)A/H0

56 - 63 %, 2 90% ee

Scheme 1. Enantioselectivecis-dihydroxylationemploying 0-acetylated dihydrocinchona alkaloids as chiral ligands according to Sharpless et al. [4].

10

A . Asymmetric Synthesis

order to develop enantioselective dihydroxylations. Thus, Sharpless et al. [4] found that the olefins (I) are converted to the diols (3) and (5) with moderate ee values in the presence of the dihydroquinidine acetate (2) and the dihydroquinine acetate (4), respectively (Scheme 1). If the acetals (6) of cinnamic aldehyde are used the enantiomeric excess even exceeds 90 % . [5]The cinchona alkaloids

(7)

90 % ee

(2) and (4) are diastereomers; however, in these transformations they display a quasi enantiomeric behavior. Narasaka et al. [6] introduced the chiral diamine (8) derived from tartaric acid as a stereodifferentiating ligand of osmium. In the presence of this mediator cis-dihydroxylation of the phenyl substituted olefins (7) proceeds with an enantiomeric excess of 35-90%

45-95%

60 % ee

55 % ee

66 % ee

35%ee

I

(94 Old) Scheme 2. Enantioselective cis-dihydroxylation employing the diamines

according to Narasaka et al. [6] and Snyder et al. [7].

(8) and (10) as chiral ligands

Enantioselective cis-Dihydroxylation

(Scheme 2). In the absence of an aromatic substituent the enantioselectivity remains low. The C, symmetric diamine (10) was investigated by Snyder et al. [7] Amine (10)makes the alcohols (11) available with 34-86% ee. The influence of the C2symmetry [8] incorporated in suitable ligands is more pronounced if the diamines (12), (18) and (19) are employed. According to Tomioka et al. [9] in the presence of the bis(diphenylpyrrolidine) (12) monosubstituted and E-configured disubstituted olefins are converted into vicinal diols with uniformly high enantioselectivity. For

11

alkenes carrying three substituents, for example, (14),the ee value is lower. The reaction sequence has proved its efficiency, for instance, in the synthesis of anthracyclin antibiotics. [9a,c,f] Thus, the ketone (16), obtained by selective deoxygenation of the diol (15), was transformed into 4demethoxydaunomycine (17) by means of well-established techniques. To explain the stereoselectivity of the hydroxylation step the authors assume that the reaction proceeds as a [2+2]-cycloaddition leading to the metallacycle (13) which then rearranges to the respec-

1.1 equk

pPTq 1 equiv. mot

J2/

R3

R'

TW,

- 110°C

(5)

R3 = H, R', R2 = Me, Et, Ph, C02Me: 67-85%, 90-99% ee (14)

OMe

0

0

OMe

0

OMe

2) SO, I pyridine

OMe

OMe

(15)a2 % ee

(171

(16)

1.1 equiv. -0,

acetone or CyCl,,

L

R1

R'. R2 = CH3 Et, Pr,

koH

HO

R2

Bu, Ph,

COOMe, COOEl

A ,q

lrsl

OH

R2

79-86 %

neohevl

Scheme 3. Enantioselective cis-dihydroxylation employing the C2-symmetricdiamine ligands (12) and (18) according to Tomioka et al. [9] and Hirama et al. [lo].

12

A. Asymmetric Synthesis

tive osmate ester. [Sc, el In (13) the substituents R1 to R3 occupy the sterically most advantageous positions. This model also accounts for the unexpected result that the sense of the asymmetric induction in some cases is reversed if 3,5-xylyl substituents are present in (12) instead of the phenyl groups. [9d] Hirama et al. [lo] employed the bispyrrolidine (IS) as mediator of chirality in the cis-dihydroxylation of monosubstituted and E-configured alkenes (Scheme 3). The respective reactions proceed with high stereoisomeric excess, which is also influenced by the solvent used. Olefins that are conjugated with an aromatic ring give the best results in toluene, in the other cases the use of dichloromethane is recommended. The addition of OsO, to E-alkenes also proceeds with high enantioselectivity if the chiral

A' (20)

\tlHM. HO

R'

*

R2 OH

75-90 %, 82-98 % ee R', R2 = H, CH3, El, pMeO-C6H,, C,&, MeOOC, (CHdflTBDPS, ~-BuO-C(O)- NH -CH2-

Scheme 4. Enantioselective cis-dihydroxylationem ploying the diamine ligand (19) according to Corey et al. [ll].

diamine (19) which was developed by Corey et al. [ll]is used as the stereodirecting ligand of the metal atom (Scheme 4). It causes a substantial acceleration of the osmylation and, like the amines (12) and ( I S ) , it can be recovered in high yield. Corey et al. assume that the cis-dihydroxylationproceeds in the sense of a [3+2]-cycloaddition in which the C2symmetric complex (20) determines the stereoselection. In this complex the amino groups of the diamine ligand occupy equatorial positions, with the phenyl and the neighbouring mesityl groups in an anti-orientation. The nitrogen atoms donate electrons to the cr* orbitals of the trans-0s-0 bonds and, thereby, the equatorial oxygen atoms become more nucleophilic than the corresponding oxygen atoms occupying axial positions. Consequently, one equatorially and one axially oriented oxygen behave as reacting centers in the cycloaddition. The olefin is then coordinatively bound to one of the edges of the octahedron in such a way that the steric interactions between R', R2 and the mesityl substituents are minimized. Due to the C2-symmetry of (20) the edges of the octahedral complex are identical. The notion that a nucleophilic and an electrophilic oxygen are involved in the process also explains the observed acceleration of the dihydroxylation by the amine ligand. Although the processes described above proceed with excellent stereoselectivity and although the chiral auxiliary reagents can be recovered, they make the use of equimolar amounts of the volatile, toxic, and expensive OsO, necessary. For applications on a larger scale, therefore, similarly effective, but catalytic, methods must be developed. Sharpless et al. [12-141 succeeded in reaching this goal for the reagent system originally developed by this group (see above, Scheme 1). First, they found that the cis-dihydroxylation in the presence of the nitrogen bases (2) and (4) can be carried out with catalytic amounts of OsO, if N-methylmorpholine-N-oxide (NMO) is

Enantioselective cis-Dihydroxylation

employed for the reoxidation of the consumed osmium. [12a] In this process the chiral amine accelerates the oxidation reaction (“ligand accelerated catalysis”). If the olefin is added slowly, the disturbing influence of an undesired competing catalytic cycle, which proceeds only with low enantioselectivity, is reduced and the ee values reach levels that are otherwise only accessible in the presence of equimolar amounts of the cinchona alkaloid. [12c] However, the decisive breakthrough was achieved by the findings that a) the undesired second catalytic cycle is eliminated completely if K3Fe(CN)6is used together with K2C03for the reoxidation of OS(VI)in a two-phase system composed of tert-butanol and water; that b) the volatile Os04 can be replaced by the H)4 solid, non-volatile K 2 0 ~ ( ~ ~ ) 0 2 ( O (potassiumosmate &hydrate); and that c) under these conditions the dihydroxylation proceeds at 0-25°C and without slow addition of the

13

olefin with higher selectivity than with subsequent addition of the alkene and reoxidation by means of NMO. In conclusion, in the catalytic cycle thereby developed (Scheme 5) Os( VZ) (21) is oxidized in the aqueous phase to Os(VZZZ) (22) which then passes into the organic phase as OsO, to form a complex with the ligand. The latter then converts the olefin to the monoglycol ester (23) which is hydrolyzed rapidly. The diol and the ligand thereby released remain in the organic phase, whereas Os( VZ) passes into the aqueous phase where it is reoxidized to Os(VZZZ). The most important features of this catalytic process are the rapid hydrolysis of the ester (23) (in the case of tetrasubstituted, trisubstituted or 1,2-disubstituted olefins the hydrolysis of the intermediary osmate ester is improved by the addition of methanesulfonamide) and the separation of the hydroxylation step and the reoxidation step into two phases. In a homogeneous

organic phase

.I o;;

-0

/

0s04

I

2 OH’

aqueous phase

2 OH2 Fe(CN)e3-

2 H2O 2 Fe(CN)e‘-

Scheme 5. The catalytic cycle of the enantioselectively catalyzed cis-dihydroxylation according to Sharpless et al. [12].

14

A . Asymmetric Synthesis

I

Top (p)- attack

otr

HO

1

/=-

I

wo

I OH'

I Bottom (abattack I

84

97 77

R R S

97

S S

-

70

R

-

80

Scheme 6. Enantioselective cis-dihydroxylation of various olefins employing phthalazine-derived ligands according to Sharpless et al. [13d].

Enantioselective cis-Dihydroxylation

medium in the presence of NMO the hydrolysis is only slow and thereby provides an entrance into the second, less efficient catalytic cycle. Based on these optimized reaction conditions, a conveniently applicable and in the meantime also commercially available reagent mixture (AD-mix) was formulated in which all inorganic ingredients and the respective ligand (quinine ligand: AD-mix a, quinidine ligand: AD-mix p, see Scheme 6) are blended. This reagent mixture is dissolved in tert-butanol/HzO and the olefin is simply added. Finally, Sharpless et al. varied the substituents attached to the OH-group of the cinchona alkaloids in a wide range and thereby discovered specific ligands that give optimized enantioselectivity for the respective classes of olefins (Scheme 6). They found that four out of the six olefin classes can be converted to the cis-diols and with high enantiomeric excess if the phthalazine-derived ligands (DHQD)zPHAL (24) and (DHQ),-PHAL, (25) (PHALclass, see Scheme 7) are used (Schemes 6 and 7). [13d, el For cis-disubstituted olefins the highest, albeit still moderate, ee values are recorded if indolinylcarbamoyl groups are attached to the alkaloids (IND-class, see

Preferred ligand

Scheme 7), [13fl and for tetrasubstituted alkenes the best results are obtained if pyrimidine-based ligands are employed (PYRclass, see Scheme 7). [Bg] Finally, for terminal olefins, an improvement in the stereoselectivity was achieved if the OCH3 group in the quinoline moieties of the PHAL ligands was replaced by OR groups carrying longer alkyl chains. [13h] Under the reaction conditions given and employing the ligands mentioned above a variety of alkenes can be converted to the corresponding vicinal diols with high ee values. Typically these reactions are run at 0-25°C using 1-5 mole% of the ligand and 0.2-1 mole% of the inorganic osmate. [13d, f, g] With the development of this methodology the enantioselective cis-dihydroxylation has reached a high level of practicality and efficiency. It has not only been applied to simple unfunctionalized olefins, but also, for instance, a , bunsaturated carbonyl compounds [13i, k] and -acetals, [131] enol ethers [13m] and a-hetero-substituted styrene derivatives [13n] have been investigated. Particularly remarkable is the kinetic resolution of the chiral fullerene C76[130] and the respective asymmetric bisosmylation of C , [13p]

+-r

=

A i

ii

PYR PHAL

PHAL

IND

PHAL

70-97% ee

20-80% ee

90-99.846 ee

ee range 80-9746 ee

I

Ph PYR-class

15

iV

Vi

PHAL

90-99% ee

PYR PHAL

20-97% ee

OAlk' PHAL-class

IND-cIass

Scheme 7. Ligand preference in enantioselective dihydroxylation as a function of olefin substitution pattern.

16

A . Asymmetric Synthesis

carried out recently. Despite intensive efforts Sharpless et al. could not devise a mechanistic model to rationalize the enantioselectivity observed in the cinchona alkaloid-mediated oxidations. They could only devise a mnemonic device that allows prediction of the sense and the approximate level of the enantioselectivity. [13c] This guide is based on the experience gained in the osmylation of ca. 90 different olefins. On the other hand, Corey et al. proposed to apply the model developed for the ligand (19) (see above) [llb] to the transformations in the presence of the ligands containing one cinchona alkaloid. In addition, they presented an analogous mechanistic scheme for the PHAL ligands carrying two alkaloid moieties. [13q] Corey et al. assume that in these cases p-0x0-bridged bis-Os04 species (26a) and (26b) are formed from two Os04molecules and the chiral ligands. Due to the electron donation of the nitrogen atoms

into the a*-orbitals of the trans-oriented 0 s - 0 bonds the equatorial and the axial oxygen atoms once more become non-equivalent, so that the observed phenomenon of "ligandaccelerated catalysis" can be explained. How-

OH conduritol C

(35)

&: OH

conduritol E

(36)

PH OH "'OH

condutitol F Derythtose

L-ribonalactone

(37)

Scheme 8. Biocatalytic oxidation of aromatic compounds to the cis-dihydrodiols (28) and synthesis of natural products employing the chiral dienes (28) according to Hudlicky et al. [16].

Enantioselective cis-Dihydroxylation

17

ever, Sharpless et al. [ 13r] recently presented [4] S. G. Hentges, K.B. Sharpless, J. Am. Chem. SOC. l980,102,4263. kinetic data and related observations that do [5] R. Annunziata, M. Cinquini, F. Cozzi, L. Rainot support this notion. mondi, S. Stefanelli, Tetrahedron Lett. 1987, As for other classical chemical enantioselec28, 3139. tive reactions biocatalytic transformations [6] T. Yamada, K. Narasaka, Chem. Lett. 1986, have provided a competing methodology to 131. the osmium mediated cis-dihydroxylation. [7] M. Tokles, J. K. Snyder, Tetrahedron Lett. 1986, Particularly interesting is the conversion of 27, 3951. aromatic compounds (27) to cis-diols (28) car- (81 Short review: H.Waldmann, Nachr. Chem. ried out with high enantioselectivityby PseudoTech. Lab. l99l,39, 1124. moms putidu (Scheme 8). [15] In the mean- [9] a) K. Tomioka, M. Nakajima, K. Kogra, J. Am. Chem. SOC. 1987, 109, 6213; b) K.Tomioka, time the alcohols (28) have become commerM. Nakajima, Y. Iitaka, K. Koga, Tetrahedron cially available and have been used by several Lett. 1988, 29, 573, c) K.Tomioka, M.Nakagroups as advantageous intermediates for the jima, K.Koga, J. Chem. SOC., Chem. Comsynthesis of various natural products. In parmun. 1989,1921; d) K. Tomioka, M. Nakajima, ticular, Hudlicky et a1 [16] demonstrated the K.Koga, Tetrahedron Lett. 1990, 31, 1741; e) viability of the dienes (28) as chiral building M.Nakajima, K.Tomioka, Y.Iitaka, K. Koga, blocks. Thus, for instance (28) (R = CHJ was Tetrahedron 1993, 49, 10793; f) M.Nakajima, transformed into prostaglandin PGEz (29), K. Tomioka, K. Koga, Tetrahedron 1993, 49, [ 16a] and the analogous vinyl derivative (28) 10807. (R = CH = CH,) served as starting material [lo] a) T. Oishi, M.Hirama, J. Org. Chem. 1989,54, 5834; b) M.Hirama, T.0ishi and S.Ito, J. for the synthesis of the plant metabolite (-)Chem. SOC. Chem., Commun. 1989, 665; c) zeylena (30). [16b] From the chloroT. Oishi, K. Iida, M. Hirama, Tetrahedron Lett. substituted diene (28) (R = Cl) Hudlicky et 1993,34, 3573; d) 0.Sato, M. Hirama, Synlett al. built up the alkaloid trihydroxyheliotriW2,705. dane (31), [16c] the carbohydrates L-ribo- [ll] a) E. J. Corey, P. DaSilva Jardine, S. Virgil, P.nolactone (32) [16d] and D-erythrose (33), W.Yuen, R.D. Connell, J. Am. Chem. SOC. [16e] as well as the polyols (+)-phito1 (341, 1989,111,9243; b) E. J. Corey, G.I. Lotto, Tet[16f] conduritol C (35), [16g] conduritol E rahedron Lett. 1990,31,2665. [I21 a) E.N. Jacobsen, I.Mark6, W. S. Mungall, (36) [16h] and conduritol F (37). [16h] G.SchrOder, K.B. Sharpless, J. Am. Chem.

SOC. 1988, 110, 1968, b) E.N. Jacobsen,

References Reviews: a) D.Schinzer, Nachr. Chem. Tech. Lab. 1989, 37, 1294; b) R.A. Johnson and K. B. Sharpless in Catalytic Asymmetric Synthesis (Ed. : I. Ojima), VCH, Weinheim, 1993, p. 103. a) Review: E. N. Jacobsen in Catalytic Asymmetric Synthesis (Ed.: I.Ojima), VCH, Weinheim, 1993, p.159; b) E.N. Jacobsen, W.Zhang, A. R. Muci, J.R. Ecker, L.Decker, J. Am. Chem. SOC. 1991,113,7063. a) R.CriegCe, Liebigs Ann. Chem. 1936,522, 75; b) CriegCe, B. Marchand, H. Wannowius, Liebigs Ann. Chem. 1942,550, 99.

I.Mark6, M.B. France, J.S. Svendsen, K.B. Sharpless, J. Am. Chem. SOC.1989,111,737; c) J. S. Wai, I. Mark6, J. S. Svendsen, M. G. Finn, E.N. Jacobsen, K.B. Sharpless, J. Am. Chem. SOC. 1989, 111, 1123; d) J.S. Svendsen, I.Mark6, E.N. Jacobsen, C.Pulla Rao, S.Bott, K.B. Sharpless, J. Org. Chem. 1989, 54, 2263; e) B.M. Kim, K.B. Sharpless, Tefrahedron Lett. 1990, 31, 3003; f) B.B. Lohray, T. H. Kalantar, B. M. Kim, C. Y. Park, T. Shibata, J. S. Wai, K. B. Sharpless, Tetrahedron Lett. 1989, 30, 2041. For recent reviews see: g) B.B. Lohray, Tetrahedron:Asymmetry W 2 , 3 , 1317; h) R.A. Johnson, K.B. Sharpless in Catalytic Asymmetric Synthesis (Ed. : I. Ojima), VCH, Weinheim, 1993,p. 227.

18

A . Asymmetric Synthesis

[13] a) H.Kwong, C.Sorato, Yogino, H.Chen, K.B. Sharpless, Tetrahedron Lett. 1990, 31, 2999; b) Y. Ogino, H.Chen, H.-L. Kwong, K.B. Sharpless, Tetrahedron Lett. 1991, 32, 3965; c) K.B. Sharpless, W.Amberg, M.Be1ler, H. Chen, J.Hartung, Y. Kawanami, D. Lilbben, E. Manoury, Y. Ogino, T. Shibata, T. Ukita, J. Org. Chem. 1991,56,4585; d) K. B. Sharpless, W.Amberg, Y.L. Bennani, G.A. Crispino, J. Hartung, K.-S. Jeong, H.L. Kwong, K. Morikawa, Z.-M. Wang, D. Xu, X.-L.Zhang, J. Org. Chem. PH2,57,2768; e) W.Arnberg, Y.L. Bennani, R.J. Chadha, G. A. Crispino, W.D. Davis, J.Hartung, K.S. Jeong, Y. Ogino,T. Shibata, K. B. Sharpless, J . Org. Chem. l9!J3,59,844; f ) L. Wang, K.B. Sharpless, J. Am. Chem. SOC. 1992,114,7568; g) K. Morikawa, J. Park, P. G. Andersson, T. Hashiyama, K.B. Sharpless, J. Am. Chem. SOC. 1993,115, 8463; h) M.P. Amngton, Y.L. Bennani, T. Gobel, P.Walsh, S.-H. Zhao, K. B. Sharpless, Tetrahedron Lett. 1993, 34, 7375; i) K. Morikawa, K.B. Sharpless, Tetrahedron Lett. 1993, 34, 5575; k) P.J. Walsh, K.B. Sharpless, Synlett 199;3, 605; 1) R.Oi, K.B. Sharpless, Tetrahedron Lett. 1992,33,2095; m) T.Hashiyama, K. Morikawa, K.B. Sharpless, J. Org. Chem. 1992,57,5067; n) Z.-M. Wang, K.B. Sharpless, Synlett 1993, 603; 0) J.M Hawkins, A.Meyer, Science 1993,260,1918;p) J.M. Hawkins, A.Meyer, M.Nambu, J. Am.

Chem. SOC. 1993, 115, 9844; q) E.J. Corey, M.C. Noe, S.Sarshar, J. Am. Chem. SOC. 1993, 115,3828; r) H. C. Kolb, P. G. Andersson, Y.L. Bennani, G.A. Crispino, K.-S.Jcong, H.L.Kwong, K.B. Sharpless, J. Am. Chem. SOC. 1993,115, 12226. [14] a) T. Shibata, D. C. Gilheany, B. K. Blackburn, K.B. Sharpless, Tetrahedron Lett. 1990, 31, 3817; b) Y. Ogino, H. Chen, E.Manoury, T. Shibata, M. Beller, D. Liibben, K. B. Sharpless, Tetrahedron Lett. 1991,32, 5761. [15] a) D. T. Gibson, M. Hensley, H. Yoshika, R. Mabry, Biochemistry 1970, 9, 1626, b) For a review see: H.L. Holland: Organic Synthesis with Oxidative Enzymes, VCH, Weinheim, 1992. [16] a) T. Hudlicky, H. Luna, G. Barbien, L. D. Kwart, J. Am, Chem. SOC. 1988, 110, 4735; b) T. Hudlicky, G. Seoane, T. Pettus, J. Org. Chem. 1989,54,4239; c) T.Hudlicky, H. Luna, J.D. Price, F.Rulin, J. Org. Chem. 1990,55, 4683; d) T. Hudlicky, J. Price, Synlett 1990,159; e) T.Hudlicky, H. Lunn, J. D. Price, F. Rulin, Tetrahedron Lett. 1989,30,4053; f ) T. Hudlicky, J.Price, ERulin, T.Tsunoda, J. Am. Chem. SOC. 1990, 112, 9439; g) T.Hudlicky, J.D. Price, H. Luna, C. M. Andersen, Synlett, 1990, 309; h) T.Hudlicky, H.Luna, H.F. Olivo, C.Andersen, T.Nugent, J. D. Price, J. Chem. SOC.,Perkin Trans.11991,2907.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Enantioselective Deprotonation and Protonation Herbert Waldmann

can, for instance be transformed to various functionalized cyclic ketones and dicarboxylic acids. [2, 31 Accordingly, cryptone (7) was synthesized with 67 % ee and used for the synthesis of the marine metabolite (+)-brasilenol (8). [4] By application of this methodology also symmetric disubstituted ketones like (9) [3] and (15) [2b, 51 can be enolized enantioselectively. In the case of the 2,6-dimethylcyclohexanone (9) the highest stereoisomeric excess is achieved with the bornylamines (10) and (11). For the monoacetal(15) of bicyclo[3.3.0]octene-3,17-dionethe use of (2) and (16), which differ from (4) only by the achiral N-substituent, is most advantageous. The steric outcome of these deprotonations is identical to the result obtained for the 4alkylcyclohexanones. The silylenol ethers (12), (17) and (19) are also versatile intermediDeprotonation of meso-Ketones ates for the construction of natural products Koga et al. [2] and Simpkins et al. [3] indepen- and physiologically active compounds. For instance, the lactones aeginetolide (13) dently used chiral lithium amides for the asymmetric deprotonation of cyclic meso- and dihydroactinidiolide (14) were obtained ketones and for the resolution of racemic 2- from (12),[6] and (17)provides a rapid access alkylcyclohexanones. [2c] For instance, the 4- to the carbacyclin precursor (18). Although alkylketones (1) were converted into the silyl- Koga et al. and Simpkins et al. studied the enol ethers (3) and (6) by means of the chiral deprotonation of meso-ketones in detail, they bases (2), [2a] (4) [2a] and (5) (Scheme l), could not offer a rationalization for the [3a, b] Whereas (2), which contains an addi- observed stereoselection. It is, however, striktional coordination site, induces the preferred ing that bases that carry additional heteroformation of the (R)-enantiomer (3), the (S) atoms, for examples (2), induce high enanenantiomer (6) is formed predominantly if (4) tiomeric excess only after addition of and (5) are employed. The silylenol ethers HMPTA, whereas lithium amides of type (4) The development of asymmetric transformations belongs to the major goals of organic synthesis. In addition to diastereoselective syntheses that have already been developed to high efficiency, enantioselective methods are gaining increasing attention. In particular, the enantiodifferentiatingtransfer of protons is of special interest, [l] since this process may provide elegant routes for the conversion of racemic substances into pure enantiomers (“deracemization”) or for the generation of optically active intermediates from prochiral meso compounds. Due to the low steric demand of the proton the realization of these processes with high stereoselectivity is considered to be particularly demanding.

20

A . Asymmetric Synthesis

1'

6'

M%(acac):! C& f-B~OOH R

*

60 96

= C&

R

(3) R = iPr: 66 % ee R = t-Bu: 97 % ee

x

A (7) (R)-(-)-cryptone

i

TMS = (H&)$i HMPTA = (Mefi)3P(0)

(8)

(+)-brasilenol

Scheme I. Enantioselective deprotonation of 4-alkylcylohexanones according to Koga et al. [2] and Simpkins et al. [3]. v

are most effective in the absence of this strongly complexing reagent.

1

(la)

h IHF, -40%

2)Acfl

68%

74% eo

Opening of meso-Epoxides (9)

For the highly selective rearrangement of epoxides (20) to allylic alcohols (23) and (24) N,N-disubstituted aminomethylpyrrolidines, in particular (21), which were used first by Asami [7] for this purpose, show the most advantageous properties. The highest selectivity is recorded for cyclohexene oxide; other HJ$ cyclic and acyclic oxiranes react with lower ee. ("I 83x: ee In these cases the addition of bases like DBU results in a marked improvement of the enantiodifferentiation. Asami et al. assume that the cis-coordinated five-membered chelates

*lkYA

-- P 35%

Enantioselective Deprotonation and Protonation

21

for the construction of prostaglandins and other cyclopentanoid natural products.

Elimination of Proton Acids HX Duhamel et al. [ll] and Sakai et al. [12] describe the elimination of HC1 from the symmetrical @halogen-substituted carboxylic acids (30) and (31) and the elimination of triflic acid from the meso-triflate (33). In the first case the adamantylmethyl-substituted phenylethylamide (32) shows the highest stereoselectivity. [ ll] If the size of the sterically demanding alkyl group is reduced, lower ee values are obtained; however, the size of the 4-substituent of the carboxylic acid is not important. Interestingly, the prochiral ciscarboxylic acid (30) and the corresponding trans-compound (31) deliver opposite enantiomers on deprotonation. This observation proves that the amide in both prochiral carboxylic acids abstracts the same enantiotopic H-atom. For the elimination of triflic acid from (33) N, N-dimethylphenyiethylamine(34) is clearly superior to other bases. [12]To achieve a high (22) are the decisive intermediates in the selectivity in this case, the carbonyl group deprotonations. In these arrangements the must be converted into an acetal, which second alkyl group does not undergo unfavor- shields the concave face of the molecule. able steric interactions with the pyrrolidine Bicyclo[3.3.0] oct-2-ene (35) is obtained with substituent of the base. Compound (21) is also >90% ee. It can be employed as a valuable effective for more complex epoxides, for starting material for the construction of variexample, the cis-oxiranes (26) are converted ous natural products, for example, coriolin, with high selectivity to the functionalized cyc- loganin, etc. lopentenediols (27), [8] and the em-epoxide (28) delivers the bicyclic allylic alcohol (29) with 58 % enantiomeric excess. [9] The allylic alcohols, also, can be employed as central Deprotonation intermediates in further syntheses. Thus, from of Akylcarbamates (S)-cyclohexene-1-01 (24) (n = 2) two diastereomers of the nor leukotriene D4 analogue Hoppe et al. succeeded in the highly enantio(25) were constructed. [lo] From (27) both selective deprotonation of achiral and racemic enantiomers of 4-hydroxycyclopentenol and N,N-dialkyl-allyl- and -alkylcarbamates such of 2-oxabicyclo[3.3.0]oct-6-eneare accessible, as (36), (40) and (41) [13] (Scheme 2 ) . On [8] which are versatile building blocks treatment of the urethanes with sec-BuLi in

22

6

A . Asymmetric Synthesis

Qf)

benzene. 4 “C

A

,

OR

(27)

(26)

R = TBDMS: SOX w, 92% R =nip: 89% W, 77x

and

0

(20) (28)

(22)

___I,

(2s)

58% ea

CH31). [13d] In (36) and (40) the chiral nitrogen base differentiates between two enantio92Yo ee topic protons, in the case of the racemic allylic 58% ee carbamate (41)in the presence of 0.5 equiva720/.ee lents of sparteine one of the two enantiomers 600/0 ee is preferred with high selectivity. After stanthe presence of the nearly C,-symmetric alkal- nylation at the 3-position of the allylic system oid (-)-sparteine (37) the chiral lithium alkyls and transmetallationwith ‘IiC1, the homoaldol (38) and (42) are formed, which remain config- (43) is obtained with 82 % ee. [13c] The two urationally stable due to complexation with possible anions formed by deprotonation of the urethane carbonyl oxygen. The anions can the allylic carbamate (40) are in rapid equilibbe trapped in high yield and with high selectiv- rium, but fortunately only one of the two diasity by various electrophiles (C1SnMe3, COz, tereomeric complexes (42) (R = H) crystal(25)

R’ = CHz: R, R’ = (CH2)2: R, R’ = (CH& R = R’ = H: R = R’ = Et:

41 Yoee

Enantioselective Deprotonation and Protonation

I

23

10 eq. (34)

A ether, -70 "C

-

(34)

R Me: 80% ee R = t-Bu: 82% M me

me

Protonation of Enolates lizes from the solution under the particular reaction conditions. [13b] Here, too, transmetallation to the analogous titanium compound opens a route to highly enantioselective transformations. From the protected homoallylic alcohols natural products like the querus lactone A (44) are advantageously available.

Duhamel et al. studied in detail the protonation of the enolates (45) generated from aromatic imines of amino acid esters. [14] The chiral proton source of choice in particular is the (2R,3R)-bis-pivaloyltartaric acid (46). The size of the amino acid side chain does not show a significant influence on the efficiency of the stereoselection, but the electronic prop-

52-86%

H&+pj R=%:

'

~3 (40)~R = H j (41) R = CH3

CH3

1) Reu,sna 2) Tia,

ether. -78°C

j

3) R'-CHO

A

:

~

R = H

2) 1) Ti(OAPr), R'-CH)

(i-Pr)*N

Scheme 2. Enantioselective deprotonation of N,N-dialkylcarbamates according to Hoppe et al. [131.

24

A . Asymmetric Synthesis

4

The same model can also be applied if instead of the imines a-hydroxyketones like benzoin (48) are used. [15] After deprotonation with KH to give the enediolate (49) and protonation with (46) (S)-benzoin is obtained with an enantiomer ratio of 90: 10. Of particular interest is the finding that the protonation of (49) to give the enediol is fast and that the stereoselectivity is established in the subsequent relatively slow keto-enol tautomerization.

-50 "C

I

X

R = Ph. base = LDA, X = H. 50% ee A = Ph. base = LDA, X = OMe, 70% ee

R = Ph, base = (47J X = H. 70% ee

Ph

HO H

(S) ;(R) = 90 ; 10

erties of the substituents in the aromatic ring of the Schiff's base and the structure of the base used for deprotonation are of particular importance. [14b-d] Suitable chiral lithium amides, for example, (47) induce a significant increase in the optical yield as compared with the use of lithium diisopropylamide (LDA). [14b] In all cases the (2R, 3R)-configuredproton source (46) preferably attacks the Re face of the enolates (45), which are stabilized by complexation. In these cases, therefore, the sense of the stereoselection seems to be predictable with a high probability. [14c]

Hiinig et al. used the conformationally fixed cyclic ester enolates (50) as model compounds to study enantiodifferentiating protonations. [16] a-Hydroxy carboxylic acid esters such as (51) and (52) proved to be efficient proton sources; 0-acyl tartaric acids, for example, (45), C,-symmetric diols and different carbohydrates induced only lower ee values. Whereas the secondary amine used for the deprotonation does not seem to be involved in the protonation of (50), the cations play a decisive role. Thus, in the protonation of (50) by (51) the ee value drops to ca. 2% if NaHMDS or KHMDS is used. However, after generation of an ate complex by means of 13(OiPr)4 it rises to 61 %. The authors conclude from these findings that a tight ion pair

25

Enantioselective Deprotonation and Protonation

must be formed to achieve an efficient stereoselection. This is attacked at the cation by the carbonyl group of the chiral a-hydroxy ester. Thereby the proton would be transferred perpendicular to the double blond to the acarbon of the enolate. Rebek et al. investigated the tricyclic lactams (53) and (54), which can be obtained from Kemp's triacid and chiral alkylarylamines by diastereomer separation, as proton sources in this transformation. [171 For aromatic a-hydroxycarboxylic acid esters only unreproducible results were obtained, but the alkylsubstituted intermediates (50) were protonated with high selectivity. To account for the observation that the enantiomeric excess increases with increasing steric demand of the "R'group, the authors propose the transition state model (55). In the latter the lithium ion is complexed by two oxygen atoms and the

H3c' Ar l-CioH7

(54)

Ph: 42% ee (S) (52), R P h 53% ee (S) (53). R = MU: 72% ee (R) (54), R =

H3C'

(55)

MU: 91%

Ph:

1

Ar = CeH5

--

(54), R

r

H3C'

(53) (St), R

alkyl group remains outside the cage structure. Fehr et al. described the stereoselective protonation of an acyclic ketoenolate without additional complexation site. [18] To construct (-)-damascone (59) from the ketene (56) the magnesium enolate (57) was generated by addition of allylmagnesium chloride. Compound (57) was then converted to a 1:1Li-Mg complex by treatment with the lithium alkoxide (58) (X = Li). Protonation of this intermediate with the respective alcohol (58) (X = H) proceeds with virtually complete enantioselectivity (ee >98 %). (-)-Damascone is formed by isomerization of the double bond. By analogy its enantiomer may be obtained from the easily accessible ent-(58).

OX ee

(3

3) 4203

(59) : (-)-Damascone

According to Pracejus et al., ketenes like (60) (R = H) can be protonated enantioselectively by achiral alcohols in the presence of catalytic amounts of chiral bases, for example, acylated cinchona alkaloids, to give esters like (61). [191 Whereas the analogous transformations employing exclusively chiral alcohols display only a low selectivity, [20] in these cases the addition of an achiral base causes a significant increase in the diastereomeric excess. Thus, Ruchardt et al. demonstrated that the ester (63) is formed from (60) and (S)phenylethyl alcohol in the presence of pyridine with nearly 80% de. [21] The authors propose that in the reaction an intermediary

26

A . Asymmetric Synthesis

phd Me

OMe

(6 1) toluene -iio"C

T

R=

offers, for example, a very practical method for the highly stereoselective generation of optically active arylpropionic acids (65) from their racemates. Those compounds are of particular interest since they are widely used as non-steroidal anti-inflammatory drugs.

76% ee

H

1 moC%

acetyC quinine

1

R-iBu 3 equiv. NMe,

M q V P h

toluene. - 78 "C

I

Me

-

0 Me

(a

76% de

H+ or OH-

H

R

enolbetaine (62) is protonated by the alcohol from below and is converted to the ester with simultaneous loss of pyridine. In similar transformations Larsen and Corley et al. [22] recorded a dramatic increase of the stereoselectivity by employing a-hydroxycarboxylic acid esters as chiral proton sources. Lactic acid esters like (64) induced ca. 90% de and with pantolactone (52) the (R)-enantiomer was formed even with 99% de. This process,

References [l] a) Reviews: L.Duhame1, P.Duhame1, J.C. Launay, J.-C. Plaquevent, Bull. SOC. Chim. Fr. 19&1,11-421;b) N.S. Simpkins, Chem. Znd. 1988, 387; c) P.C. COC,N. S. Simpkins, Tetrahedron: Asymmetry l9!?l,2, 1. [2] a) R.Shirai, M.Tanaka, K.Koga, J. Am. Chem. SOC. 1986,108,543; b) H.Izawa, R.Shirai, H.Kawasaki, H.Kim, K.Koga, Tetrahedron Lett. 1989,30, 7221; c) H. Kim, H. Kawasaki, M. Nakajima, K. Koga, Tetrahedron Lett. 1989,30,6537. [3] a) N. S. Simpkins, Chem. Rev. 1990,19,335; b) C.M. Cain, R.P. Cousins, G.Coumbarides, N.S. Simpkins, Tetrahedron 1990, 46, 523; c) N.S. Simpkins, J . Chem. SOC., Chem. Commun. 1986,88;see also lc). [4] A. E. Greene, A. A. Serra, E. J. Barreiro, P. R. Costa, J . Am. Chem. SOC. 1987,52, 1169. [S] J. Leonard, J.D. Hewitt, D. Ouali, S. K. Rahman, S.J. Simpson, R.F. Newton, Tetrahedron: Asymmetry 1990 I, 699. [6] M.C. Cain, N.S. Simpkins, Tetrahedron Lett. 1987,28,3723. [7] a) M.Asami, Chem. Lett. 1984, 829, b) M.Asami, Bull. Chem. SOC. Japan. 1990, 63, 721. [8] M. Asami, Tetrahedron Lett. 1985,26, 5803. [9] J.Leonard, J.D. Hewitt, D. Ouali, S. J. Simpson, R.F. Newton, Tetrahedron Lett. 1990, 46, 6703. [lo] J.S. Sabol, R.J. Cregge, Tetrahedron Lett. 1989,30,3377. 111 a) L. Duhamel, A. Ravard, J.-C. Plaquevent, Tetrahedron: Asymmetry 1990, I, 347; b) L. Duhamel, A. Ravard, J.-C. Plaquevent, D. Davoust, Tetrahedron. Lett. 1987,28, 5517. 121 H. Kashibara, H. Suemune, T. Kawahara, K. Sakai, Tetrahedron Lett. 1987,28, 6489.

Enantioselective Deprotonation and Protonation 1131 a) D. Hoppe, T. Kramer, J.-R. Schwark, 0. Zschage, Pure Appl. Chem. 1990, 62, 1999; b) D.Hoppe, O.Zaschge, Angew. Chem. 1989, 101, 67; Angew. Chem. Int. Ed. Engl. 1989,28, 69; c) O.Zschage, J.-R.Schwark, D.Hoppe, Angew. Chem. 1990, 102, 336; Angew. Chem. Int. Ed. Engl. 1990, 29, 296; d) D.Hoppe, EHintze, P. Tebben, Angew. Chem. 1990,102, 1457; Angew. Chem. Int. Ed. Engl. 1990 29, 1422. For experimental details and further references see: 0.Zschage, J.-R. Schwark, T. Warner, D. Hoppe, Tetrahedron 199t, 48, 8377 and 0.Zschage, D.Hoppe, Tetrahedron 48, 8389. [14] a) L.Duhame1, J.-C.Plaquevent, J. Am. Chem. SOC.1978,100, 7415; b) L. Duhamel, J.C. Plaquevent, Tetrahedron Lett. 1980, 21, 2521; c) L. Duhamel, J.-C.Plaquevent, Bull. SOC. Chim. Fr. W82, 11-75, d) L.Duhame1, P. Duhamel, S. Fouquay, J. J. Eddine, 0.Peschard, J.-C. Plaquevent, A. Ravard, R. Solliard, J.-Y.Valnot, H. Vincens, Tetrahedron 1988, 44, 5495.

27

1151 L. Duhamel, J.-C. Launay, Tetrahedron Lett. 1983,24,4209. [16] U.Gerlach, S.Hiinig, Angew. Chem. 19zn,99, 1323; Angew. Chem. Znt. Ed. Engl. 1987,26, 1283. [17] D.Potin, K. Williams, J. Rebek, Jr., Angew. Chem. 1990,102, 1485;Angew.Chem. Int. Ed. Engl. 1990,29, 1420. [18] C.Fehr, J.Galindo, J. Am. Chem. SOC. 1988, 110,6909. [19] a) H. Pracejus, Liebigs Ann. Chem. 1960, 634, 9; b) H.Pracejus, G.Koh1, Liebigs Ann. Chem. 1969,722,l. [20] E.Anders, E.Ruch, I.Ugi, Angew. Chem. 1973, 85, 16; Angew. Chem. Int. Ed. Engl. 1973,12,25. [21] a) J. Jahne, C. Riichardt, Angew. Chern. 1981, 93,919;Angew. Chem. lnt. Ed. Engl. 1981,20, 885; b) U. Salz, C.Riichardt, Tetrahedron Lett. 1982,23,4017. [22] R.D. Larsen, E.G. Corley, P.Davis, P. J. Reider, E.J. Grabowski, J. Am. Chem. SOC. 1989,111, 7650.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Carbohydrate Complexes in Enantioselective Carbon-Carbon Bond Formation Karl Heinz Dotz

The remarkable progress that has been achieved in stereoselective carbon-carbon bond formation is mostly due to the development of novel organometallic reagents. An already classical example is provided by organotitanium compounds, the synthetic potential of which was recognized in the early 1980s. [ 11 In comparison with Grignard and organolithium compounds from which they are generated by a simple in-situ transmetalation, the titanium reagents exhibit an often dramatically improved chemo- and diastereoselectivity, as shown by the addition to aldehydes and ketones. [2] Whereas methyl lithium (la)cannot differentiate between benzaldehyde and acetophenone the methyl titanium reagent (Ib) is perfectly aldehyde selective (Scheme 1). Equally impressive is the diustereoselectivity that - in favor of the Cram product (3u) - is observed in the addition of (1b) to chiral aldehydes such as (2). In contrast, powerful enuntioselective methods have been restricted to a few examples for a long time (e.g. (4) -+ (5) [3]). Obviously, the incorporation of chelating ligands into compounds of type (6u) is not necessarily associated with a sufficient stability of configuration. This goal, however, is achieved if a pentuhupto cyclopentadienyl ligand is incorporated into the reagent. Coordination of chiral coligands (two unidentate coligands X or one bidentate coligand with C2-symmetryto avoid the generation of an undesired metal stereo-

center) leads to compounds of type (6b). Carbohydrates turned out to be especially effective in reagents that allow high asymmetric induction both in the nucleophilic addition to aldehydes and in aldol reactions. [4] A potent allyl transfer reagent is complex (10) which can be prepared in a 1OOg scale from the chloro precursor (9) following a twostep sequence from cyclopentadienyltitanium trichloride (7) and diacetone glucose (DAGOH) (8). [5] Complex 10 prefers addition to the re--face of aldehydes, thereby affording homoallyl alcohols (11) in good chemical yields (50-90%) and very good enantioselectivity (86-95 % ee). The selectivity depends only to a minor extent on the temperature, as shown in the addition of (10) to benzaldehyde: The ee value drops from 90 % to 80% when the temperature is raised from -74°C to 0°C. Controlled hydrolysis of the reaction mixture affords undefined titanate species that are transformed to the trichloride (7). Thus, both the metal component and the released chiral auxiliary can be recovered (Scheme 2). The enantioselectivity of the allyl transfer depends markedly on the combination of the coligands: It is essential that two carbohydrate ligands are attached to the metal center together with one allyl group. The ee value of the allylation of benzaldehyde decreases to 46 % and 21 %, respectively, if the bis(diacetone glucose) complex CpTiC1(ODAG)2 (20)

30

A . Asymmetric Synthesis

(60)

Scheme 1. Diastereoselective and enantioselective C-C bond formation using lithium and titanium organo-

metallics.

is replaced by its diallyl(0DAG) and allyl chloro ODAG analogues. However, the enantioselectivity is unaffected (but only in this example) by increasing bulk and donor capacity of the cyclopentadienylligand, as shown by trimethylsilyl or pentamethyl substitution. [6] Upon reaction with complex (10) chiral racemic aldehydes such as (12) afford the stereoisomeric homoallyl alcohols (13)-(16). The pair of diastereomers (13)/(14) arises from (R)-(12),while (S)-(12)leads to (15)/(16). The only moderate enantiomeric differentiation (2.5:l) and the fact that the more reactive enantiomer reveals the better diastereoselectivity [97 % de, for (R)-(12)]may be rational-

ized in terms of a Cram selectivity that is overruled by the enantiofacial differentiation [71% de for (S)-(12)]. Furthermore, allyl complex (10) exhibits the well-known chemoselectivity of titanium reagents: At -74 "C no reaction occurs with ketones; at O"C, however, aryl ketones give tertiary homoallyl alcohols (albeit with induction reduced to 50 % ee). A complementary allyl transfer to the siface of aldehydes occurs with complexes containing threitol ligands. The ligand of choice is the diphenyl derivative (R, R)-(17),accessible from natural tartaric acid in 88 % yield. Upon reaction with CpTiC13it forms a stable chloro chelate (R, R)-(18),which serves as precursor

Carbohydrate Complexes in Enantioselective Carbon-Carbon Bond Formation

31

-

DAGOH

(8)

(CpTiO,OH),

+ DAGOH' +- R

1)

OH (11)

R = Ph

t-Bu

/-74oc

2,

yield

e.e.

85%

90% 862

61%

i-Pr

wi

67%

58%

0 I

5

DAGo/Ti*t+~*oDAc

(10)

902

88%

Scheme 2. Ally1 transfer reactions with the bis(DAG0)titanium reagent (10).

71

1

24

for the allyl complex (R,R)-(19). This compound adds to the si-face of aldehydes producing the homoallyl alcohols (20) with excellent enantioselectivity combined with very good chemical yields. Similarly successful is the allyl transfer to a-chiral aldehydes. Since reagent (19) is accessible both as (R,R)- and (S, S)-enantiomer, depending on the configuration of the tartaric acid precursor, the Lserinal derivative (21) [7] allows the formation

4

of both diastereomers (224 and (22b). The diastereoselective potential of the titanium complexes becomes evident in comparison with well-established boron reagents, for example, diisopinocampheny(ally1)borane , [8] as demonstrated for 2-phenyl-butanal(23). Complexes of type (10) and (19) are also well-suited for the transfer of substituted allyl groups. Independent on whether the titanium reagent is generated from the organometallic

32

A . Asymmetric Synthesis

methodology syn-crotyl adducts also have been obtained. [lo] Whereas the cyclopentadienyl complexes si (10) and (29) are efficient allyl transfer reagents, their alkyl analogues are unreactive in alkyl transfer reactions. Taking advantage of the increasing Lewis acidity encountered in complexes containing the higher homologues of titanium this drawback can be overcome by yield e.e. switching to zirconium or hafnium. Thus, the 93% 95% R = Ph pentamethylcyclopentadienyl complexes of 83% 87% i-Pr zirconium(1v) and hafnium(rv), accessible t-Bu 67% 97% from their chloro precursors (27) and methyl lithium or methyl magnesium bromide, undergo a highly enantioselective methyl E-or 2-ally1 precursor the anti-products (26) transfer to aromatic aldehydes. [6, 111In conare formed exclusively. Obviously, the ql-allyl trast to the trisalkoxy titanium compounds titanium species (25) undergoes a rapid equiMeTi (OR*),, the ee values are independent libration in which the trans-isomer containing the metal coordinated to the sterically unshielded allyl terminus prevails. A similar trans-preference was observed earlier for crotyl titanium reagents. [9] Using the boron

d BOC

8,

Ph

R

-

: 97 X d.e.. 98 X 98% d.e., 98 X SiMes : 98 X d.r, 98 X Me

Ph

:

0.0. 0.0. 0.0.

Carbohydrate Complexes in Enantioselective Carbon-Carbon Bond Formation

33

OLi

A 0 -t-Bu

I 2) Ph

Phuu

Ph

-78 oc

y,,,

(27)

(28)

R-

M

8.0.

kMgBr kLi MeMgBr MeU

Zr Zr

98%

Hf

96.5X

BUU

Zr

68X

BuLi

Hf

65X

m

97.5X 97.5%

of the metal used for transmetalation. However, the enantioselectivity distinctly decreases if benzaldehyde is replaced by nonaromatic aldehydes and if longer or branched alkyl groups are transferred. [4a] Carbohydrate titanium complexes have also been successfully applied in aldol reactions. This is demonstrated for acetate enolates, which have caused problems in aldol reactions until recently. [12] The titanium enolate (30), prepared in situ from lithium enolate (29) and the chloro complex (9), reacts with aldehydes to give /3-hydroxy esters (32). [13] This route is particularly interesting for a,@unsaturated aldehydes, since their aldols cannot be obtained from Eketo esters by enantioselective hydrogenation. [141 Unfortunately, the reaction of the threitol complex (32) obtained from (R,R)-(28) is not similarly selective, as demonstrated for isovaleraldehyde. [6] Another difference between the DAGO and threitol reagents arises from the temperature dependence of the enantioselectivity: The ee value observed for the DAGO complex (30) remains unchanged between -78 "C and ambient temperature, whereas for the threitol derivative (32) the induction decreases distinctly with increasing temperature. A major advantage of these aldol reactions is that they can be easily scaled up. For

I" (33)

(3 1) yield

e.e.

R = n-Pr 51% 94% i-Bu 81 X Ph

94%

69X 95X

temp.

yield

e.e.

- 7 8 0 ~ 8 0 % 78%

0OC

54 x

instance, the insect pheromone (-)-(S)ipsenol (35) has been synthesized on a 50 g scale. [15] Starting from tert-butyl acetate and CpTiC13the /l-hydroxy ester (34) was obtained via the titanium enolate (30); subsequent elaboration (8 steps, mainly protectioddeprotection procedures) afforded the diene alcohol (35) in 13% overall yield.

34

A. Asymmetric Synthesis

i,8,

-78%

xon,

R

R

R7

:

0Ar

(37)

(39)

(40)

81 - 9 7 7. d.e.

89-977. d.e.

81 -90 % d.e.

91 -97

X

e.e.

Ar =

94-98 % e.e.

F

Scheme 3. Formation of syn- and anti-aldols from a common titanium enolate precursor.

An extension of these studies in propionate aldol reactions involves the lithium enolate (36) which has been used by Heathcook in a diastereoselective access to anti-phydroxy-amethyl carboxylic esters (37). [161 Transme-

43-70

x

I." -78

*c

OH

R+C02R ~

talation at -78°C to give titanium enolate (38a) followed by addition of the aldehyde, however, affords the syn-aldol products (39) with comparable de values. [4, 6,171The reaction is temperature-dependent : At -30 "C the

H

80%

D -(43) 96-98 % d.e.

B 8 7~ - 9 8~% e.e.

R

-

L 44)

Et : 8 1 % 0.e.

t-Bu:

9 4 % e.e.

1" -78

oc

&C02R

NHBoc

Scheme 4. Synthesis of D- and L-hydroxy amino acid esters from glycine ester enolates.

Carbohydrate Complexes in Enantioselective Carbon-Carbon Bond Formation

35

E-enolate undergoes a rearrangement (proba- [2] Reviews: a) D.Seebach, B. Weidmann, L. Widler in Modern Synthetic Methods, (Ed. : bly to give the 2-isomer 38b); as a conseR. Scheffold), Vol. 3, Salle, Frankfurmain quence, the anti-esters are again obtained, as and Sauerlander, Aarau, 1983;b) M.T. Reetz, known for the lithium enolate series. Thus, Organotitanium Reagents in Organic Synthesis, both epimers (39) and (40) are accessible from Springer, Berlin, 1986. the same precursor (38u) with good diastereo- [3] a) A. G. Olivero, B. Weidmann, D . Seebach, selectivity. In both cases the titanium enolate Helv. Chim. Acta 1981, 64, 2485; b) D.Seeadds to the re-face of the aldehyde as previbach, A. K. Beck, R.Imwinkelried, S. Roggo, ously observed for the ally1 transfer using the A. Wonnacott, Helv. Chim. Acta 1987,70,954. DAGO reagent (10) (Scheme 3). [4] Reviews: a) R. 0. Duthaler, A. Hafner, Chem. Rev. 1992, 92, 807; b) R.O. Duthaler, A.HafFinally, carbohydrate-modified titanium ner, M.Riediker, Pure Appl. Chem. 1990, 62, reagents can be used in the functionalization 631. of amino acids. [18] Transmetalation of the [5] a) M. Riediker, R. 0. Duthaler, Angew. Chem. lithium enolate of the N-protected glycine 1989,101, 488; Angew. Chem. Int. Ed. Engl. ester (41) generates the DAGO titanium enol1989, 28, 494; b) A.Hafner, R.O. Duthaler, ate (42), which attacks the re-face of an aldeR. Marti, G. Rihs, P. Rothe-Streit, F. Schwarhyde and thus affords the D-syn-Phydroxy-azenbach, J. Am. Chem. SOC. 1992,114, 2321. amino acid ester (43). In a complementary [6] R. 0. Duthaler, A. Hafner, M. Riediker in fashion, the threitol complex (44), obtained Advances in Organic Synthesis via Organomefrom the same lithium enolate by transmetalatallics, (Eds.: R.W. Hoffmann and K.H. Dotz), Vieweg, Wiesbaden, 1991,p. 285. tion using (R,R)-(18), adds to the si-face of butyraldehyde and thus leads to the L-amino [7] P. Gamer, J.M. Park. J. Org. Chem. 1987,52, 2361. acid ester ~44.5)(Scheme 4). H.C. Brown, K.S. Bhat, R.S. Randad, J. [8] To rationalize the attack at complementary Org. Chem. l989,54, 1570. faces of the aldehyde by the DAGO and threi[9] M.T. Reetz, M.Sauerwald, J. Org. Chem. to1 complexes X-ray studies have been per1984,49,2292. formed for the chloro complexes (9) and [lo] R. W. Hoffmann, Pure Appl. Chem. 1988,60, (R,R)-(18). [6, 191The major difference in the 123. molecular structure of both compounds is a [ll] R.O. Duthaler, A.Hafner, P.L. Alsters, pair of Ti-0-C angles that differ by 7 and 10O, R. Rothe-Streit, G. Rhis, Pure Appl. Chem. l992,64, 1897. respectively, for the re- and si-side. It is tempting to make this enantiomeric distortion [12] a) M.T.Reetz, EKunisch, P.Heitmann, Tetrahedron Lett. 1986,27, 4721; b) S.Masamune, responsible for the efficient chiral induction T.Sato, B.-M.Kim, T.A. Wollmann, J. Am. that - in fact - is the opposite of that for reaChem. SOC. 1986, 108, 8279; c) Review: gents derived from (9) (re-side attack) and M.Braun, Angew. Chem. 1987,99,24;Angew. (R,R)-(18) (si-side attack). Chem. Int. Ed. Engl. 1987,26,24.

References [l] a) M.T. Reetz, R. Steinbach, J. Westermann, R.Peter, Angew. Chem. 1980,92,1044;Angew. Chem. Int. Ed. Engl. l980, 19, 1011; b) B. Weidmann, D. Seebach, Helv. Chim. Acta 1980,63,2451.

[13] R. 0. Duthaler, P.Herold, W.Lottenbach, K.Oertle, M.Riediker, Angew. Chem. 1989, 101, 490; Angew. Chem. Int. Ed. Engl. 1989, 28, 495. [14] R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Kumobayashi, S.Akutagawa, J. Am. Chem. SOC. 1987,109,5856. [W] K.Oertle, H.Beyeler, R.O. Duthaler, W.Lottenbach, M. Riediker, E. Steiner, Helv. Chim. Acta l990,73,353.

36

A . Asymmetric Synthesis

[16] C.H. Heathcock, M. C. Pirrung, S.H. Montgomery, J.Lampe, Tetrahedron 1981,37,4087. [17] R. 0. Duthaler, P.Herold, S. Wyler-Helfer, M. Riediker, Helv. Chim. Actu 1990, 73,659.

[18] G.Bold, R.O. Duthaler, M.Riediker,Angew. Chem. 1989,101, 491; Angew. Chem. Int. Ed. Engl. 1989,28,497. [19] M. Riediker, A.Hafner, U.Piantini, G. Rihs, A.Togni, Angew. Chem. 1989, 101, 493; Angew. Chem. Int. Ed. Engl. 1989,28, 499.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Asymmetric Aza-Diels-Alder Reactions Herbert Waldmann

Hetero-Diels-Alder reactions with azasubstituted dienes or dienophiles are powerful methods for the regio- and stereoselective synthesis of nitrogen heterocycles [l] and can play pivotal roles in the construction of many natural products and biologically active compounds. Therefore, the development of methods that allow these transformations to be carried out asymmetrically is of particular interest to organic synthesis. In contrast to the asymmetric carbo-Diels-Alder reaction the analogous cycloadditions with ma-substituted dienes and dienophiles have gained much less attention, and only recently have several efficient asymmetric aza-Diels-Alder processes been developed.

analogous cycloadditions employing acyclic derivatives of butadiene give rise to substituted pipecolic acid esters (6), from which the auxiliary can be easily removed by hydrogenolysis, and that are interesting intermediates for the construction of thrombin inhibitors such as (7). The presence of small amounts of water is absolutely necessary to effect the cycloadditions, which do not proceed in dry DMF. The authors therefore propose the iminium ion (3) to be the reactive intermediate, which, for steric reasons, is attacked predominantly from the si-side. If the imine (3) is generated from racemic phenylethyl amine the respective cycloadditions proceed in dichloromethane and in the presence of BF3 OEt2 with complete facial selectivity. [2b] In contrast, to the N-phenylethylsubstituted Schiffs base (24, the Nsulfonyldienophiles (2b-2fl, carrying a chiral Imino Dienophiles and Dienes auxiliary in the ester function [2c, d] in purely Whereas simple, non-activated Schiff’s bases thermal, uncatalyzed cycloadditionswith varidisplay only a low reactivity in hetero- ous dienes induce a diastereomeric excess of Diels-Alder reactions, C- or N-acylimines only 20-30%. [2a, el However, a significant prove to be more efficient dienophiles. Thus, improvement is recorded for (2e) and ( 2 f ) if the imine (2a), derived from (R)- the cycloadditions are promoted by a Lewis phenylethylamine and glyoxylic acid ester (1) acid. [2d] N-Acyl imines are the reactive interreacts even at room temperature with cyclic mediates in the Lewis acid mediated reaction dienes in DMF as solvent and in the presence of the lactam (8) with the diene (9) [3a] and in of equimolar amounts of trifluoroacetic acid the reaction of the enamine (14) with the aas well as catalytic amounts of water to yield bromo substituted amino acid ester (12) [3b] the bicyclic amino acid esters (4) and (5) with (Scheme 2). On treatment with ZnClz (8) elihigh diastereoselectivity [2a] (Scheme 1).The minates acetic acid and the N-acyl imine

-

38

A. Asymmetric Synthesis

0E N @ Me

(24 YO

oEN-Tos

(2b) R' I (-)menth9 (Zc) R' = (-)bomyl (Zd) R' = (-)phenylrnenthyl (2e) R' = (+ethyl lactate (2)R' = (R)pantdactone

(6a) R' = H: 44 %, de 62 %

(6b) R' = Me:, 69%, de 68%

b HC 0 , (7)

n I 1 : 8 2 % ; e x o : e n d o n 9 7 : 3 ; d e e x o I 8 9 % ; deendo>99% n = 2: 31 %; exo: endo = 92: 8; deexo = 84%; deendo > 99%

Scheme 1. Asymmetric ma-Diels-Alder reactions with the chiral C-acyl imhe (24.

thereby formed delivers the carbacephem (10) from which the carbapenem (11) can be formed. In the presence of NEt3the ester (12) eliminates HBr to generate the chiral hetero diene (13) which reacts with the chiral enamine (14) to give the cycloadduct (15). After hydrolysis, the amino acid ester (16) is obtained from (15) with complete stereoselectivity and in quantitative yield. [3b] Recently, a highly efficient asymmetric intramolecular cycloaddition with an azo compound generated in situ by oxidation of a proline derived hydrazide has been reported. [3c] In the cycloadditions mentioned above the C=N group is activated by an electron-withdrawing C- or N-acyl substituent. This goal can also be reached by protonation of the heteroanalogous carbonyl function or, in general, by its

complexation with a Lewis acid. For instance, the imine (17) reacts with the electron-rich Brassards diene (18) in the presence of an aluminum Lewis acid in a highly stereocontrolled manner to give the cycloadduct (19) which is converted on hydrolysis to the a& unsaturated amine (20) (Scheme 3). [4a] For such Lewis acid-mediated aza-DielsAlder reactions with the Brassard diene valine tert-butyl ester has proven to be an efficient mediator of selectivity. [4b, c] The imines (21), obtained from this primary amine and aliphatic, aromatic and further functionalized aldehydes, react with diene (18) to give the addition products (23) with high diastereomeric excess (Scheme 3). In these cases, the primary adducts (23), which can be addressed as orthoesters, can not be isolated. Rather, on

Asymmetric Aza-Diels-Alder Reactions TBDMSO

39

TBDMSO

H

TBDMSO

TBDMSO %OTBDMS

2- 1W'C

0 0 HNKPh

(16)

quantitative, de = ee > 99.9 %

(15)

hydrolytic workup they are converted into the amides (24) and the esters (25), which, however, can easily be subsequently cyclized to the lactams (24). For the removal of the chiral auxiliary from (24) the amino acid acarbon is converted into an acetal center by means of a Curtius rearrangement. Cleavage of the intermediate urethanes thereby generated leads to the desired heterocycles, for example (26), in good yield (Scheme 3). This reaction sequence is most advantageously carried out as a one-pot reaction. To explain the steric course of the reactions between the imines (22) and the diene ( I @ , the Diels-Alder

Scheme 2. Asymmetric aza-Diels-Alder reactions with chiral N-acyl imines.

type transition state (22) was proposed, in which the diene attacks the si-side of the imine double bond. In this arrangement the amino acid ester adopts an anti-Felkin-Anh type conformation to minimize unfavourable steric interactions between the voluminous substituents on C-1 of the diene and the sterically demanding amino acid side chain. However, a stepwise reaction consisting of the formation of the esters (25) and their subsequent cyclization to the lactams (24) could not be rigorously ruled out. Such a pathway may also be involved in the reactions of the electron rich silyloxydienes

40

A . Asymmetric Synthesis

only one diastereomer

,I

(25)

(26) 62 % overall yield

4

I

C ~ C O O Htoluene l

w

C

0

O

M

H

R = alkyl, aryl 57-84% diastereomer ratio 93 : 7 to 97.5 : 2.5

e

OMe

(27) MeO

Me

(31) OMe diastereomer ratio > 99 : 1

Me 0

facial selectivity > 99 : 1 endo : ex0 = 4 : 1

Scheme 3. Lewis acid mediated aza-Diels-Alder reactions with non-activated Schiff's bases.

(28) and (30) with the imine (27) derived from tryptophan. [4d] These cyclizations proceed with high stereoselectivity to give the polycyclic compounds (29) and (31) (Scheme 3), which may be interesting congeners to alka-

loids. However, a cycloaddition and not a stepwise process clearly occurs if the carbohydrate-derived imines (32) are treated with alkyl-substituted butadienes (33) in the presence of ZnClz to give the dehydropiperidi-

Asymmetric Aza-Diels-Alder Reactions

41

Protonated imines are the reactive heterodienophiles in ma-Diels-Alder reactions in aqueous solution. [7] Under conditions that are otherwise typical for Mannich reactions, ammonium salts (35) and aldehydes, in partico-zo*c ular formaldehyde, form iminium intermediates (36) in situ that undergo cycloadditions * ; ) with various dienes (Scheme 4). If (S)phenylethylamine is used as mediator of chirality in the Diels-Alder reaction with cycloR pentadiene, the diastereomers (37) and (38) 90-95 x are formed in a ratio of 80:20. [7a] However, R =Aryl. R', R" = H. CH3 in this reaction the stereoselectivity is rather diastereomer ratio: sensitive to the steric bulk and the electronic 70 :30 to 90 : 10 properties of the chiral auxiliary. Thus, with the respective 4-bromophenyl or the 4-N02nes (34) with appreciable diastereomeric phenyl analogue and (S)-1-phenylpropylamine the diastereomers are formed in a ratio ratios. [5] Recently, highly diastereoselective Lewis of ca. 1:l. [7g] If amino acid esters are acid mediated ma-Diels-Alder cycloadditions employed as mediators of selectivity isomer with chiral imines and dienes carrying a chiral ratios up to 93:7 are reached (Scheme 4). auxiliary have also been reported. [6] In these [ 7 k ] This enhanced level of stereodiscrimprocesses 2-amino-1,3-butadienes embodying ination can be explained by the assumption 2-(methoxymethy1)pyrrolidine as mediator of that in these cases in the aqueous medium highly ordered transition states (40), with minchirality were employed with great success.

I

Scheme 4. Asymmetric aza-Diels-Alder reactions with iminium salts generated in situ in aqueous solution.

R = iBu 57%; 93:7 R = Ph 90%; W:20

42

A. Asymmetric Synthesis

imized hydrophobic surfaces, are passed in which the diene attacks the iminium intermediates from the direction opposite to the amino acid side chain. The chiral auxiliary is easily removed from the phenylethylamine and the phenylglycine derivatives obtained from these transformations by hydrogenation. Thereby enantiomerically pure nitrogen heterocycles, for example (43), become available, which can be advantageously employed in the construction of alkaloids. For instance, the terpene alkaloid (-)-GN-normethylskantine (39) was constructed from (38) making use of a [3,3]-sigmatropic rearrangement as the key step. [7fl

A 2-aza-1,3-butadiene that is activated via N-arylation is present in the isoquinolinium salt (44). [ S ] This heterodiene undergoes asymmetric cycloadditions with chiral enol ethers. The cycloadducts (45) formed initially are further converted by the solvent methanol into the tetralines (46) and (47). It is striking that the most advantageous chiral auxiliaries for this process contain aromatic groups but a rationalization of the observed direction of stereoselection is not at hand. If tetrabenzyl glucose is employed as source of chirality, its removal can readily be affected by a threestep sequence.

[&

OR*]

(45)

4

p+.

u.oH

Me0

MeOyOMe

+ \

L

J

77%

one diastereomer

OMe

OR*

\

NHDNP (46)

NHDNP (47)

Ph

91 X; (46):(47)< 5 : 9 5

,O-Bzl

7 0 % (46):(47)> 9 5 : 5

one diastereomer

Asymmetric Aza-Diels-Alder Reactions

43

N-Sulfinyl Dienophiles N-Sulfinyl compounds are heterodienophiles that already under mild conditions react with various dienes to give dehydrothiazine oxides. The N-sulfinyl carbamates (48) and (51) carrying 8-phenylmenthol or a camphor derivative react with open-chain butadiene derivatives and cyclohexadiene in the presence of SnC4 and Tic&,respectively, to give, for instance, the cycloadducts (50) and (53) in a ratio 298:2. [9] The heterocycles obtained in these transformations can be transformed into various synthetically useful derivatives, for example, homoallylamines, by well established techniques. In both cases the steric course of the cycloaddition is rationalized by assuming that endo transition states (49) and (52) are involved in which one diastereotopic face of the dienophile is efficiently shielded by the chiral auxiliary.

CI Q & HPN

fsoa!

Nitroso Dienophiles and Dienes N-Acyl- and a-chloronitroso compounds are very reactive heterodienophiles that undergo hetero-Diels-Alder reactions with various dienes at low temperature. Thus, the 17-chloro17-nitrosoepiandrosteronederivative (54) and the 1-chloro-1-nitrosomannose(55) in alcoholic solution react with cyclohexadiene to give the expected cycloadducts (56a) and (56b) (Scheme 5). The latter are in equilibrium with the iminium salts (57) that immediately release the chiral auxiliary on solvolysis. By this procedure the dihydrooxazines (58) and (59) are obtained with an enantiomeric excess of 2 9 6 % [lo] (the absolute configura-

(59)

(58)

(60) + (52)

(sob)

*

(W

(Sod)

(60e)

ee 2 94%

hOAC 0 NHp CIo

1)

zn/m

2)&0 82%

(61)

OAc

NHAc ,,OAc

()""OAc OAc

(62)

Scheme 5. Asymmetric hetero-Diels-Alder reactions with chiral a-chloro-a-nitroso compounds.

tion initially [loa-c] assigned to (58) and (59) was subsequently corrected [lod]). The observed sense of asymmetric induction is explained by the involvement of an exo-attack of the diene on the sterically more accessible face of the nitroso dienophiles (Scheme 5).

44

A . Asymmetric Synthesis

The mannosyl dienophile (55) also undergoes highly enantioselective cycloadditions with the substituted cyclohexadienes (60u-c) [lOd-f] and the butadiene derivatives (60d) and (60e). [lOc] The dihydrooxazines are valuable precursors for the construction of inosamines. For instance, the cycloadduct (61) obtained from (60b) can be readily converted to the tetraacetate (62) of conduramine A 1by reductive cleavage of the N-0 bond and subsequent acetylation (Scheme 5). [loe] The use of chiral N-acylnitroso compounds in asymmetric hetero-Diels-Alder reactions has been investigated thoroughly. [ll] These studies

Et.N"lO,e,

HFi ' HO

MeOH

revealed that simple derivatives of mandelic acid and proline [lla-i] are only ineffective auxiliary groups in this process. However, high levels of asymmetric induction are attained if C2-symmetric amines [12] are employed as mediators of chirality. [11k-n] In general, the chiral hetero dienophiles (64) are generated in situ from the corresponding hydroxamic acids (63) by oxidation with periodate. They subsequently react with various dienes, for example, cyclohexadiene, to deliver the desired heterocycles (65) with high yield and virtually complete stereoselectivity. [ l l e , m] If 2-azabutadienes are employed in this process, an interesting and highly stereoselective route to amino acids is opened up. [ l l n ] The stereochemical course of these hetero Diels-Alder cycloadditions can be understood by assuming an endo-attack of the respective diene on the S-&-conformer (64) of the dienophile. In addition to the pyrrolidine derivatives, the nitroso compounds (66) [llo] and (67) [ l l p ] which are derived from camphor, proved to be highly stereodirecting chiral heterodienophiles that render the desired cycloadducts available with high isomer ratios.

(64) R' = CHg. R2 = H: 81 %, de 98% R' = CHzOMe, R2 = H: 88 X , de > 99 X R', R2 = \ FH2*bPh

t-0'

02

(66)

n = 1: 91 X . d e > 9 8 % d e n = 2: 94X, d e > 9 8 % d e

90 X , de > 99 X

62-94 X . de

,

I '

> 95 % COOEt

I

Asymmetric Aza-Diels-Alder Reactions

HO/i

R'

A!

I

65% diastereomer ratio

38 % diastereomer ratio

94 : 6

88: 12

52 % diastereomer ratio

54% diastereomer ratio

> 95:5

79 : 21

t P h Ph

o<;.o

4

C02Me

L

(72) Cya2,

- 78°C

II

= 1,2

TC12(OiPr),

LA

C02Me

(73)

n=2

toluene

0

\1 H 94%, ee > 9 8 %

(75)

n = 1.2

Scheme 6. Asymmetric hetero-Diels-Alder reactions with nitroso- and nitroalkenes.

45

46

A . Asymmetric Synthesis

Hetero-Diels-Alder reactions with inverse electron demand in which the nitroso group is part of the hetero diene system are observed if chiral enol ethers react with nitrosoalkenes, for example, (68), generated in situ (Scheme 6). In these transformations a camphor derivative and diacetone glucose have been identified as advantageous chiral auxiliaries. [13] If the heterodiene (68) is treated with EIZ-mixtures of enol ethers (69) derived from these mediators of chirality, the Eisomers react not only faster but also with higher selectivity to give the truns-1,2-oxazines (70) with high diastereomeric excess. However, the cis-configured heterocycles (71) are also obtained from the 2-enol ethers with appreciable results. Similar to nitrosoalkenes nitroalkenes also undergo hetero-Diels-Alder reactions with inverse electron demand. Thus, (72) reacts with chiral enol ethers in the presence of TiC12(OiPr)2already at low temperature to give nitronates (73), which, on warming to ambient temperature ( n = 1) or after heating ( n = 2) undergo a spontaneous [3+2]cycloaddition to the nitroso acetals (74) and (75). [14] Both steps proceed in a highly stereoselective manner. The sense of the diastereoselection can be reversed by using the aluminum catalyst (76) instead of a titanium Lewis acid. In conclusion, despite the great potential that aza-Diels-Alder reactions hold for the synthesis of heterocycles, in particular physiologically active compounds, natural products and analogs thereof, only a very limited number of efficient chiral auxiliaries has been introduced for these processes. Therefore, research directed at the development of new methods for the highly stereoselective execution of these cycloadditions is worthwile and rewarding.

References [l] Review on asymmetric hetero Diels-Alder reactions: H. Waldmann, Synthesis l994, 535; general reviews on hetero Diels-Alder reactions: a) D.L. Boger, S.M. Weinreb, Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press, San Diego, 1987; b) S.M. Weinreb in Comprehensive Organic Synthesis, Vol. 5 (Ed. : L. A. Paquette), Pergamon Press, Oxford 1991,p. 401; c) D. L. Boger in Comprehensive Organic Synthesis, Vol. 5 (Ed.: L. A. Paquette), Pergamon Press, Oxford, 1991, p. 451; d) S. M. Weinreb, R. R. Staib, Tetrahedron 1982, 38, 3087; e) D.Boger, Chem. Rev. 1986,86,781. [2] a) P.D. Bailey, G. R. Brown, F. Korber, A. Reed, R. D. Wilson, Tetrahedron: Asymmetry 1991,2, 1263; b) L.Stella, H.Abraham, J. Feneau-Dupont, B. Bnant, J. P. Declercq, Tetrahedron Lett. 1990, 31, 2603; c) M.Maggini, M.Prato, G.Scorrano, Tetrahedron Lett. 1990, 31, 6243; d) P.Hamley, G.Helmchen, A.B. Holmes, D. R. Marshall, J. W.M. MacKinnon, D.E Smith, J.W. Ziller, J. Chem. SOC., Chem. Commun. 1992,786. [3] a) A. I. Meyers, T. J. Sowin, S. Scholz, Y. Ueda, Tetrahedron Lett. 1987,28, 5103; b) R.Kober, K. Papadopoulos, W. Miltz, D. Enders, W. Steglich, Tetrahedron 1985, 41, 1693; c) T.Sheradsky, J. Milvitskaya, I. E. Pollak, Tetrahedron Lett. 1991,32, 133. [4] a) M. Midland, J. Mcbughlin, Tetrahedron Lett. 1988, 29, 4653; b) H.Waldmann, M. Braun, M. Drager, Angew. Chem. 1990,102, 1445; Angew. Chem. Int. Ed. Engl. 1990,29, 1468; c) H. Waldmann, M. Braun, M. Drager, Tetrahedron: Asymmetry, 1991, 2 , 1231; d) S. Danishefsky, M. Langer, C. Vogel, Tetrahedron Lett. 1985,26, 5983. [5] W. Pfrengle, H. Kunz, J. Org. Chem. 1989,54, 4261. [6] J. Barluenga, F. Aznar, C. Valdes, A. Martin, S. Garcia-Granda, E. Martin, J. Am. Chem. SOC. 1993,115,4403. [7] a) S.D. Larsen, P.A. Grieco, J. Am. Chem. SOC. 1985, 107, 1768; b) P.A. Grieco, A.Bahsas, J. Org. Chem. 1987,52, 5746; c) H. Waldmann, Angew. Chem. 1988, 100, 307; Angew. Chem. Int. Ed. Engl. 1988, 27, 307; d)

AsymmetricAza-Diels-Alder Reactions H. Waldmann, Liebigs Ann. Chem. 1989,231 ; e) H. Waldmann, M. Braun, Liebigs Ann. Chem. 1991,1045; f ) M. M. Cid, U. Eggenauer, H. P. Weber, E. Pombo-Villar, Tetrahedron Len. 1991, 32, 7233; g) E. Pombo-War, J.Boelsterli, M.M. Cid, J.France, B.Fuchs, M.Walkinshaw, H.-RWeber, Helv. Chim. Acta 1993, 76, 1203. [8] A.Choudhury, R. W. Franck, R.B. Gupta, Tetrahedron Lett. 1989,30,4921. [9] a) J. K. Whitesell, D. James, J.F. Carpenter, J. Chem. Soc., Chem. Commun. 1985, 1449; b) S. W. Remiszewski, J. Yang, S. M. Weinreb, Tetrahedron Lett. M, 27, 1853. [lo] a) M. Sabuni, G. Kresze, H. Braun, Tetrahedron Lett. 1984, 25, 5377; b) H.Felber, G. Kresze, H. Braun, A. Vasella, Tetrahedron Lett. 1984, 25, 5381; c) H.Felber, G. Kresze, R.Prewo, A. Vasella, Helv. Chim. Acta 1986, 69, 1137; d) H.Braun, R. Charles, G.Kresze, M. Sabuni, J. Winkler, Liebigs Ann. Chem. 1987, 1129; e) O.Werbitzky, K.Klier, H.Felber, Liebigs Ann. Chem. 1990, 267; f ) K. Schiirrle, B. Baier, W. Piepersberg, J. Chem. SOC.,Chem. Commun. 1991, 2407; g) Very recently, an efficient nitrosodienophile that is easily accessible from ribose has been developed: H.Braun, H.Felber, G.Kresze, F.P. Schmidtchen, R.Prewo, A. Vasella, Liebigs Ann. Chem. 1993, 261. [ l l l a) A.Miller, T.M. Paterson, G. Procter, Synlett 1989,32; b) A.Miller, G.Procter, Tetrahedron

47

Lett. 1990, 31, 1041 ; c) A. Miller, G. Procter, Tetrahedron Lett. 1990, 31, 1043; d) A.D. Morley, D.M. Hollinshead, G. Procter, Tetrahedron Len. 1990, 31, 1047; e) G.W. Kirby, M.Nazeer, Tetrahedron Lett. 1988,29, 6173; f) A. Defoin, H. Fritz, C. Schmidlin, J. Streith, Helv. Chim. Acta W , 70, 554; g) A. Brouillard-Poichet, A. Defoin, J. Streith, Tetrahedron Lett. 1990,30, 7061; h) A.Defoin, J.Pires, J. Streith, Synlett 1991, 417; i) A. Defoin, A. Brouillard-Poichet, J. Streith, Helv. Chim. Acta 1992, 75, 109; k) A.Defoin, J. Pies, I. 'Iissot, T. Tschamber, D. Bur, M. Zehnder, J. Streith, Tetrahedron: Asymmetry 1991,2, 1209; 1) A.Defoin, A.Broui1lard-Poichet, J. Streith, Helv. Chim. Acta 1991, 74, 103; m) YGouverneur, L.Ghosez, Tetrahedron: Asymmetry1990,1,363; n) V. Gouverneur, L.Ghosez, Tetrahedron Lett. 1991, 32, 5349; 0) V. Gouverneur, L. Ghosez, Tetrahedron: Asymmetry1991,2, 1172; p) S.F. Martin, M. Hartmann, J. A. Josey, Tetrahedron Lett. 1992,33,3583. [12] Short review: H.Waldmann, Nachr. Chem. Tech. Lab. 1991,39, 1142. [13] a) T.Arnold, H.-U.Reissig, Synlett 1990, 514; b) T. Arnold, B. Orschel, H.-U. Reissig, Angew. Chem. 1992, 104, 1084; Angew. Chem. lnt. Ed. Engl. 1992,31, 1033. [14] a) S. E. Denmark, C. Senananyake, G.-D. Ho, Tetrahedron 1990, 46,4857; b) S. E. Denmark, M.E. Schnute, J. Org. Chem. 1991,58,1859.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

C2-SymmetricAmines as Chiral Auxiliaries Herbert Waldmann

The use of chiral auxiliary groups derived from natural products like terpenes, amino acids and carbohydrates to direct the steric course of asymmetric transformationsbelongs to the most powerful methods of stereoselective synthesis. The majority of the most efficient auxiliaries that are often employed for this purpose do not display striking symmetry elements. However, it has recently been demonstrated that the concept of using C2symmetric chiral auxiliary groups like the amines (1)-(5) and their enantiomers, as mediators of the stereochemical information, is particularly viable. [l] The introduction of this symmetry element may have three consequences: (1) both faces of the auxiliary become equivalent, (2) the number of the competing diastereomeric transition states is reduced significantly, (3) the atoms which are located on the C,-axis become chirotopic but not stereogenic, [l, 21 i.e., no new stereocenters are formed that would additionally complicate the situation. In addition to the use of diols [3] the application of the amines and diamines (1)-(5) turned out to be particularly rewarding. In a strict sense, due to the sp3hybridization of the N-atoms in the ground state, (1)-(3) are not C,-symmetrical. However, reactions carried out on derivatives of these chiral auxiliary groups proceed as if this condition was fulfilled. To characterize this, the term “functional C,-symmetry” was coined. [4] [To achieve a uniform and thereby better

understandable presentation, in the following paragraphs the results in some cases are presented for the enantiomer of (1)-(5) which actually was not used by the authors in their original work. This is marked in the text with an (*)-I The pyrrolidines (2) prove to be particularly effective chiral auxiliary groups. Thus, the alkylation of the enamine (6)(*)with different alkyl halides delivers the cyclohexanones (7)

(20) R = CH3

(2b) R = CH20CH20CH3 (CH20MOM) (2c) R

Ph

H

(24

-

CH20CH3

BtlO

OBzl

(3)

Bzl = -CHz-Ph Phy!H

R R CH3 (4) R = SOpCFj (40)

9

Ph 4

TH R

(5) R

SO$’

’

50

A . Asymmetric Synthesis

(9) 40 - 69 % diastereomeric ratio >95:5

(8)

-70

0°C

+

(1 1)

1) TMSCl - 70%

JN?

(12)

CYLo s

86 % 93% ee

94- 97% ee

0-c-tau (14)

hv, - 35°C

d 55 %

diastereomenc ratio 14 : 1

(18):

4

(19):

....)I11

Scheme 1. Use of the 2,5-dimethylpyrrolidine(2a) as chiral auxiliary.

(18): (19) = 12: 1

C2-SymmetricAmines as Chiral Auxiliaries

with optical purities of 82-95 % [ S ] , and after deprotonation the vinylogous urethane (10) reacts with aldehydes [6a] and acid chlorides [6b] (*) with high diastereoselectivity to give the adducts (11) and (12) (Scheme 1). The (2R, 5R)-dimethylpyrrolidine ( 2 4 furthermore turned out to be an efficient auxiliary group in asymmetric intermolecular radical reactions. In a series of papers [7] Giese et al. and Porter et al. demonstrated that reactions of amide radicals that embody (2a) proceed with high stereoselectivity (Scheme 1). Thus, on irradiation the acrylamide (13) and the ferfbutyl radical donor (14) form the chiral radical (15), which reacts further with the thiocarbonyl group of (14). [7c] Alternatively, for instance, from the bromoamide (16) the chiral radical (17) can be generated, which even at 80 "C reacts with acrylic acid ethyl ester to give the products (18) and (19) in a ratio of 12:l. [7d] In a similar but photochemically-induced reaction this value rises even to 36:l. [7d] In earlier studies [7a, b, el (*) the authors had already demonstrated that the addition of chiral radicals to amides of fumaric acid and alkylidene malonic acids derived from (2a) proceeds with high selectivity. Finally, the radical transformations of the enamine (6) to give the cis-disubstituted cyclohexanes (9) display cis/ trans and diastereomer ratios of >95:5, respectively. [8] In the reactions compiled in Scheme 1 the C,-symmetric auxiliary causes the educts to preferably adopt one out of a multitude of possible conformations. Consequently, the steric course of the nucleophilic and radical transformations carried out with (6) is explained by the fact that the conformation shown for (6) in Scheme l is particularly low in energy end directs the attack to the reside. The amide radicals (15) and (17) most probably are present as 2-conformers and are attacked predominantly anti with respect to the neighbouring methyl group of the dimethylpyrrolidine. The doubly alkoxy-substituted pyrrolidine (2b) was used by Katsuki et al. in a variety of

51

organometallic syntheses (Scheme 2). The enolates generated from (20) undergo alkylations [9 a, c, f] (*), acylations [9b] and aldol reactions 19el with excellent stereoselectivity. The Pketoamides (21) are converted to the hydroxyamides (22) or (23) by employing suitable reducing reagents. [9b, d] Alternatively, (22) and (23) would have to be formed by synor anti-selective aldol reactions. Furthermore, (2b) proves to be efficient in Wittig rearrangements [9g] [Scheme 2, (24) + (25)] and reductions of a-keto amides [9h] (*). The use of the MOM protecting group on the one hand causes a supporting chelation of the involved metal ions. On the other hand this acetal is easily hydrolyzed and thereby liberates OH groups, which support the hydrolytic removal of the amide auxiliary in refluxing 1~ HC1. The enantiomer of the methoxy-substituted auxiliary (2c) induces high stereoselectivity in Diels-Alder reactions, hetero Diels-Alder reactions and iodolactonizations. For instance, after activation by TBDMS triflate the acrylamide (26) reacts at low temperature with the bis-(si1yloxy)-substituted cyclohexadiene (27) to give the endo- and ex0 isomers (28) and (29) with high de values [loa] (Scheme 3). In the presence of the europium salt Eu(fodX at 80°C in toluene the ex0 compound (29) is formed with an isomer ratio 95: 5. Similarly, the carbamoynitroso dienophile (30) is converted to the corresponding cycloadducts with a selectivity of 87-98 % . [lob] If the tetrasubstituted pyrrolidine (2d) is used as chiral auxiliary in the hetero DielsAlder reaction with cyclohexadiene the diastereomeric excess even exceeds 99 % . [lOc] As already pointed out above for the radical reactions with (2a), the functional C,symmetry of the auxiliaries in these latter cases, too, causes the dienophiles to adopt preferred conformations that are attacked from the more accessible sides (Scheme 3). In the course of the enantioselective iodolactonization of (31) the trans-lactone (33) is pro-

52

A . Asymmetric Synthesis

,OMOM OH 0

R;

R'

Nc+N?

,OMOM 5

R'-X

OMOM

,OMOM

80-90% de

R, R' = alkyl X = Br, I

,OMOM 1) LDA, -78'C

- 20%

A"-% - 20'C 73-92%

R' El, i - P r , W , Ph diasteriomeric ratio > 100 : 1 threo: eiythythn, > 1M): 1

OMOM

R = CN 1) BUM,

R = CH3

'?fN? 0 120) . .

OMOM

2) 70 R'-X - 78 %

OMOM

diasteriomeric ratio > 100: 1

1) Buli

-7wc

R = alkyi, PhCH2O

2 ) R'COCI

,OMOM 0

R' = alkyi, Ph, alkenyl X = Br, I

0

=

KBE!,H

R ' = alkyl, Ph, alkenyl

94-99%

d

,OMOM

,OMOM

syn : anti > 97 : 3 - 99 : 1

syn : anti > 99 : 1

,OMOM

,OMOM BuU TW.

- 1M)"C

OH

a

0

OMOM

(25) 96 % de

Scheme 2. Use of the 2,5-dialkoxymethylpyrrolidine(2b) as chiral auxiliary.

duced with high enantiomeric excess and a cisisomer is not isolated. [lOd] Here the presence of the C2-symmetric auxiliary makes a differentiation between the E- and the Zconformer unnecessary. Its influence is responsible for the fact that the hypothetical transition state (32) is energetically lower than three competing arrangements. If the enantio-

mer of (2a) [lla] or the piperidine derivative (3) [4]are employed similar observations are made. Furthermore (3) [4] and (1) [llb] prove to be efficient stereodirecting groups in aldol reactions. Effenberger et al. [12] could carry out an intermolecular electrophilic addition that proceeds with practically complete diastereoselectivity. In the reaction of the amide

AN5 +

C2-SymmetricAmines as Chiral Auxiliaries toluene, - 60°C

+~iC-Tl.

6046, e n d 0 : m = 87:13 de endo > 98%

0

I 1 U N 5 O M S

0

:

(28) "endo"

- ? O O?+ 9

53

'OMe

(27)

Me02 (26)

Eu(fod),, toluene, 80°C 98 % endo: em = 0: 100 deem=90%

'50&O

t

N

-Si-

\

(29)

"exo"

OMe

70-83% 87-98% de

(30)

Scheme 3. Use of the auxiliary (2c) in Diels-Alder reactions.

(33) 91 % ee COOMe

COOMe (34)

CWZ

-,",":

CI

COOMe

(35) > 95% de

Scheme 4. Diastereoselective iodolactonizations and electrophilic additions to amides of C,-symmetric pyrrolidines.

(34) with a sulfur electrophile only the achloroamide (35) was formed (Scheme 4). The examples highlighted above demonstrate that by employing the amines (1)-(3) very high diastereomeric excesses can be achieved in various reactions. However, these

auxiliaries are often only available by multistep syntheses and, in particular, their removal from the reaction products in the majority of the cases can be effected only under drastic conditions. The difficulty mentioned last does not have

54

A . Asymmetric Synthesis

(38)

(37)

(R) : (S)= 95 : 5

4

x = c y

diastereornenc ratio

:EOc

S

sK s

(36)

U

9o:io - 99:l

diastereomenc ratio

90: 10 - 99: 1

0.1 N HCI

81-88%

88 - 100 %

1) R,Cuti / Et,O 0°C

COOMe

R = Me, Bu, COOEt

80 - 90%

Ph,

R

90-96% ee

(41)

1) A,Culi I Et,O 2) H,O+

,

72 - 98 %

R 1) 4LiBr

e

i

96-98% ee R = RBU, i-Bu

R

%) e

(43)

Scheme 5. Use of the cyclohexanediamine ( 4 4 as chiral auxiliary group in diastereoselective syntheses.

C2-SymmetricAmines as Chiral Auxiliaries

to be met in the applications of the diamine (4a) shown in Scheme 5. Hanessian et al. [13a] used this cyclohexane derivative and its enantiomer for the synthesis of axially dissymmetric and optically active olefins via Horner olefination. The potassium salt of the phosphonamide (36) obtained from (4), for instance, reacts with 4-tert-butylcyclohexanone to give the olefins (37) and (38) in a 95 :5 ratio. Furthermore, the chiral auxiliary proves its efficiency in the alkylation of the respective a-nitrogen-substituted [13c] phosphonic acid amide (36). After mildy acidic hydrolysis the a-chloro- and a-aminophosphonic acids (39)and (40) are obtained in high yield. Such compounds are, for instance, of interest as building blocks for peptidomimetics. Alexakis et al. used the enantiomer of (4a) and converted aromatic aldehydes into the aminals (41)-(43). The addition of cuprates to the cinnamic acid derivative (41) [14a] and to the carbonyl compound (42) [14b] in both cases proceeds with high diastereomer differentiation. Also the reaction of the aryl lithium compound, which is generated from (43), to aliphatic aldehydes displays a marked selectivity [14c] (*). The possibility to reach high isomer ratios in the transformations carried out with the aminals (41)-(43) can be attributed to a large extent to the fact that the acetalic C-atoms due to the C,-symmetry of the chiral auxiliary (4a) do not become new stereocenters (see above). The enantioselective addition of zinc alkyls to carbonyl compounds can be steered efficiently with the sulfonamide (4b). Yoshioka et al. [15] demonstrated that catalytic amounts of (46) together with titanium tetraisopropylate catalyze the highly enantiodifferentiating addition of these organometallic reagents to aldehydes. The authors propose that complexes (44) are formed as intermediates. In (44) the sulfonamide groups enhance the Lewis acidity of the metal and thereby set up an efficient catalysis, which proceeds with turnover numbers up to 2000. Corey et al. also

55

n (46)

";9"

Tf = S0,CFS

R ' R oo 92 99 X

-

used the activating influence of sulfonic acid moieties in the development of the complexes (45), (49) and (53), which are derived from the stilbene diamine derivative (5), as reagents for enantioselective syntheses (Scheme 6 ) . Already at low temperature (45) catalyzes the Diels-Alder reaction between the oxazolidinone (46) and the dienes (47), in which the cycloadducts (48) are formed with 95 % ee. [16a]. Highly enantiodifferentiating aldol reactions can be carried out by means of boron enolates, which are generated from the bromoboranes (49) and (53) [16 a , d, el Compound (49), for instance, proves to be efficient in the synthesis of the pheromone sitophilur (SO), whereas (53), is a particularly advantageous reagent for transformations involving ester enolates. If phenylthio esters are used in the respective reactions, syn aldols like (54) are the major products, but on the other hand from tert.-butyl esters the anti isomers (55) are

56

A . Asymmetric Synthesis

91-94%, >95% ee

(47)

TosN,

,NTos B I

R

R'-CW

TOS

Ph

Ph%J R-Snm3s CY&

R =

w

phH cYa2 ?Br -

TosN, ,NTos

(kPr),NI 78°C

-78°C

JJ M8

(50) >98% ee O,BRi 4 S P h

(kPr),Et

- 40°C

(53)

Ftl-CHO

-7B"c 93 %

OH 0 P h v S P h Me (54)

>95% ee

syn : anti = 99 : 1

Fo+

\

hmdtoluene 2:1

- 78°C

93-97% ee

syn : anti

Scheme 6. Use of the stilbenediamine (5) in enantioselective transformations.

obtained with high isomer ratios. Furthermore, ester enolates derived from (53) allow highly stereoselective Mannich reactions [16g] and Ireland-Claisen rearrangements [16h] to be carried out. From (49) and allyl-, allenyl-

2 : 98

or propargylstannanes in situ excellent reagents for nucleophilic additions to aldehydes are generated. [16b, c] They make the carbinols (52) available with an enantiomeric excess of 95-99 % and in high yield.

C2-SymmetricAmines as Chiral Auxiliaries

2*

R’

COOMe

(57)

In addition to these transformations, the N,N’-dialkyl stilbenediamine (56) was found to be a highly stereodirecting ligand in Os04mediated cis-hydroxylations of different olefins. [16f] In these processes the diols (57) are formed with uniformly high ee values exceeding 92 %,

References [l] J.K. Whitesell, Chem. Rev. 1989,89, 1581. [2] R.Breslow, J. Siegel, J . Am. Chem. SOC. 1984, 106, 3319. [3] a) H.-J.Altenbach, Nachr. Chem. Tech. Lab. 1988, 36, 1212; b) A.Alexakis, P.Mangeney, Tetrahedr0n:Asymmetry 1990,477. [4] a) S.Najdi, M.Kurth, Tetrahedron Left. 1990, 31, 3279; b) S. Najdi, D. Reichlin, M. J. Kurth, J. Org. Chem. 1990,55, 6241. [5] J. K. Whitesell, S. W. Felman, J. Org. Chem. W ,42, 1663. [6] a) R.H. Schlessinger, E.J. Iwanowitz, J.K. Springer, J . Org. Chem. 1986,51, 3070; b) R. Schlessinger, J.R. Tata, J.P. Springer, J . Org. Chem. 1987,52,708. [7] a) N.A. Porter, D.M. Scott, B. Lacher, B.Giese, H.G. Zeitz, H.J. Lindner, J . Am. Chem. SOC. 1989, 111, 8311; b) D.M. Scott, A. T. McPhail, N. A. Porter, Tetrahedron Lett. 1990, 31, 1679; c) B.Giese, M.Zehnder, M.Roth. H.G. Zeitz, J . Am. Chem. SOC. 1990, 112, 6741; d) N. A, Porter, E. Swann, J. Nally,

57

A.McPhai1, J . Am. Chem. SOC. 1990, 112, 6740; e) N.A. Porter, D.M. Scott, I. J. Rosenstein, B.Giese, A.Veit, H.G. Zeitz, J . Am. Chem. Soc. 1991,113, 1791. [8] P. Renaud, S. Schubert, Synlett 1990,624. [9] a) Y. Kawanamaki, Y. Ito, T. Kitagawa, Y. Taniguchi, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1984,25, 857; b) Y. Ito, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1984,25, 6015; c) M. Enomoto, Y. Ito, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1985, 26, 1343; d) Y.Ito, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1985, 26, 4643; e) T.Katsuki, M.Yamaguchi, Tetrahedron Lett. 1985,26, 5807; f ) T.Hanamozo, T. Katsuki and M. Yamaguchi, Tetrahedron Lett. 1986,27, 2463; g) M.Uchikawa, T. Hanamoto, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1986,27, 4577; h) Y.Kawanami, LFujita, S. Asahara, T. Katsuki, M. Yamaguchi, Bull. Chem. SOC.Japan 1989,62,3598. [lo] a) H. Lamy-Schelkens, L. Ghosez, Tetrahedron Lett. 1989,30,5891;b) V.Gouverneur, L. Ghosez, Tetrahedron: Asymmetry 1990,1, 363; c) A. Defoin, A. Brouillard-Poichet, J. Streith, Helv. Chem. Acta. 1991, 74, 103; d) K. Fuji, M. Node, Y. Naniwa, T. Kawabata, Tetrahedron Lett. 1990,31,3175. 1111 a) D. J. Hart, H. C. Huang, R. Krishnamurthy, T. Schwartz, J . Am. Chem. SOC. 1989, 111, 7507; b) D. Tanner, C. Birgersson, Tetrahedron Lett. 1991,32,2533. [12] F. Effenberger, H. Isak, Chem. Ber. 1989,122, 545. [13] a) S. Hanessian, D. Delorme, S. Beaudoin, Y. Leblanc, J . Am. Chem. SOC. 1984, 106, 5754; b) S. Hanessian, Y. L. Bennai and D. Delorme, Tetrahedron Lett. 1990,31, 6461; c) S. Hanessian, Y. L. Bennai, Tetrahedron Lett. 1990,31, 6465. [14] a) A. Alexakis, R. Sedrani, P. Mangeney, J. F. Nornant, Tetrahedron Lett. M , 29, 4411; b) A. Alexakis, R. Sedrani, J. F. Normant, P. Mangeney, Tetrahedron: Asymmetry 1990,1, 283; c) M. Commercon, P. Mangeney, T. Tejero, A, Alexakis, Tetrahedron: Asymmetry 1990,1,287. [15] a) M. Yoshioka, T. Kawakita, M. Ohno, Tetrahedron Lett. 1989,30,1657; b) H. Takahashi, T. Kawakita, M. Yoshioka, S. Kobayashi, M. Ohno, Tetrahedron Lett. 1989,30,7095.

58

A. AsymmetricSynthesis

[16] a) E. J. Corey, R. Imwinkelried, S. Pikul, Y. B. Xiang, J. Am. Chem. SOC. 1989,111, 5493; b) E. J. Corey, C.-M. Yu, S. S. Kim, J . Am. Chem. SOC.1989,111,5495; c) E. J. Corey, C.M. Yu, D.-H. Lee, J. Am. Chem. SOC. 1990, 112,878; d) E. J. Corey, S. S. Kim, Tetrahedron Lett., 1990,31, 3715; e ) E. J. Corey, S. S. Kim, J. Am. Chem. SOC. 1990, 112, 4976; f) E. J .

Corey, P. DaSilva Jardine, S. Virgil, P.-W. Yuen, R. D. Connel, J. Am. Chem. SOC.1989, 111,9243; g) E. J. Corey, C. P. Decicco, R. C. Newbold, Tetrahedron Lett. 1991,32, 5287; h) E. J. Corey, D.-H. Lee, J. Am. Chem. SOC. 1991,113, 4026; i) Review: E. J. Corey, Pure Appl. Chem. 1990, 62, 1209.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

B. Organometallic Reagents in Organic Synthesis Iron $-Complexes in Organic Synthesis Dieter Schinzer Metal-mediated C-C bond formations are becoming more and more important in organic synthesis. The following chapter will draw attention to a small but growing part of the field: C-C bond formation with iron $-complexes. As early as 1960 E. 0. Fischer et al. carried out pioneering work and complexed 1,3cyclohexadiene with iron pentacarbonyl to obtain the desired q4-complex(2). [l]Hydride abstraction of (2) in the presence of trityl cation yielded the $-complex and triphenyl methane. But it took almost 8 years before the potential was recognized in organic synthesis (Scheme 1). Most of the starting materials for this type of chemistry can be synthesized from aromatic precursors using the Birch reduction. [2] Therefore it was evident that this particular research group started projects with $-iron complexes. The interesting question of the regioselectivity of the hydride abstraction was also studied first by Birch et al., who showed that hydride abstraction from (I) (R=OMe) is completely regioselective in favor of (4).

"0

F-))a,A

(CO)3F*y) (2)

(1)

(3)

Scheme 1

R = H

The latter is formally the more unstable compound. The effect can be understood by HOMO-LUMO interactions of the cation and orbitals of the iron. The orbitals of the cation (4) are energetically closer to those of the iron atom, which favors overlap and therefore stabilization of this particular cation. Cation (5) cannot have this stabilization because the energy of the ally1 cation is too low relative to that of the metal (Scheme 2). [3] @e(CO), /

PhJCe

BF*8

(1)

(5) 6%

> &,(co)3

BF,'

(4) 94%

R

= OMe

Scheme 2

The real potential for these compounds in synthesis is reactions with nucleophiles. This preparatively very important area was been started by Pearson's research group. [4] In general, soft nucleophiles, like alcohols, amines, enolates, and other stabilized anions, can be applied. The stereochemical course of these reactions mostly leads diastereoselectively to the so-called em-products (6), relative to the metal (Scheme 3). The metal will be removed oxidatively under very mild conditions with various reagents to give (7). In particular, metal salts

60

B. Organometallic Reagents in Organic Synthesis R F~(co),

(41

R = OMe

Scheme 3

(Fe3+,Cu2+)and trimethylamine N-oxide have been used most successfully (Scheme 4).

(6)

(7)

Scheme4

A smooth reaction is obtained if alkoxides and amines are used as nucleophiles (Scheme 5). [5]

R

-

OMe

(12)

Scheme 6

dihydro benzofuran derivative (16). As reagent for the oxidative cyclization MnO, was used (Scheme 7 ) . (4)

R = OMe

0

(9)

Scheme 5

Reactions with enolates [6], enamines [7] and allylic silanes [8] in particular should be pointed out, because all these transformations can be done with high chemical yield. No additional Lewis acid is required for reactions with ally1 silanes, which demonstrates the high reactivity of these complexes (Scheme 6). More important for synthesis are combined processes in which two bonds are closed. The first example of this type was published by Birch et al. [9] An oxidative cyclization is followed a C-C bond formation with an activated 1,3-dicarbonyl compound yielding a

A useful sequence of reactions can be realized by the use of acetone, as shown by Pearson et al. [lo] The authors obtained a cyclic ether (18)+(19), which was cleaved under acidic conditions to yield a second $complex, which reacted with an external nucleophile. The overall result was the stereose-

Iron $-Complexes in Organic Synthesis

lective introduction of two substituents “em”

?Me

(4) 1. Et&-

2. &uo 5. H f l e

711%

>

k

COzMe

(28)

Scheme 8

(20)

(2 7)

Another important task in organic synthesis is the introduction of quaternary centers, which is always a good testing ground for new synthetic methods. Again, Pearson et al. were

$”’ \

R (24

6 R

R’

1.u.

~

2. T@H. A 3. FO(CO)~A

(x+o)3 /

R

Scheme 10

successful in establishing such a method. [ll] Substituted aromatic compounds of type (22) can be transformed into iron complexes after Birch reduction. Cation (24) can be obtained by the use of trityl cation, and subsequent reaction with a soft nucleophile yields compounds of type (25). The cation (24) represents a synthon for compound (25a) (Scheme 9). A spiro-cyclization was realized by this technique in two steps. In addition to the problems involved in the synthesis of quaternary centers, now a spiro ring had to be constructed. The only drawback in this sequence was the use of only “soft” nucleophiles, which limits the general scope of transformations with these complex cations. The method was demonstrated by the synthesis of spiroundecane (28) (Scheme 10). [12]

(23)

[61

(24)

(254

Scheme 9

61

Scheme 11

62

R

B. Organornetallic Reagents in Organic Synthesis

(34)

Scheme 12

= HC(C02Me)2

A useful extension of this concept was the synthesis of aza-systems. Again Pearson has synthesized several spiro-piperidines and -pyrrolidines. [13] The complex cation (29) was transformed with benzylamine to (30) via an in situ substitution with the tosylate and subsequent ring closure to (30). The spiropiperidines in particular are important precursors for the biologically active histrionicotoxine [14] framework (Scheme 11).

75)’

Starting from bicyclic compounds like (32) angular substituents can be introduced. The complex cation (32) can be treated with nucleophiles to obtain - after oxidative demetalation - enones of type (34) (Scheme 12). [15] Very elegant combinations of the concepts presented have been done by Knolker et al. These authors have already synthesized all the known and biologically active carbazomycines. [16, 171 Knolker used a combination of aromatic substitution and oxidative cyclization to synthesize the carbazomycine skeleton. Starting with complex cation (4), addition of the aromatic amine (35) yielded (36). Oxidative cyclization to (37) followed by demetalation with MnOz gave directly the natural product (38) (Scheme 13).

+

82 oc

2. KOH. EWH. 25%

/A 1

Scheme 13

H (45)

Scheme 14

Iron $-Complexes in Organic Synthesis

By the use of the same strategy carbazomycine A and B could be synthesized starting from aromatic precursors. Knolker started with the commercially available phenol (39), which was transformed in a short sequence of steps into the required amine (43) : acylation, followed by methylation of the phenol; the missing oxygen atom was introduced by a Baeyer-Villiger reaction. Finally, regioselective nitration and subsequent reduction gave (43). Key reaction in this synthesis was an electrophilic aromatic substitution with (4) yielding hexasubstituted aromatic compound (44) ! This demonstrates again the high reactivity of these complexes. The synthesis was fin-

OR

R-X:

(49)

dcl

w

ished by oxidative cyclization and final demetalation to give the natural product (45) (Scheme 14). Finally, an iron-mediated diastereoselective spiro-annulation will be presented. In contrast to the method described by Pearson et al. [ 131 this process, reported by Knolker et al., is a one-pot procedure in which both the C-C and the C-N bonds are formed. [18] The desired iron complex was synthesized in four steps. After oxygen-functionalization and hydride abstraction complex cation (49) was obtained. Addition of p-anisidine gave directly the spiro-cycle (50), via aromatic substitution reaction followed by in situ substitution of the benzoate (Scheme 15). The last examples presented in particular show the high potential of this technique in constructing various ring skeletons. The whole concept is very much extended by recent findings from Knolker’s laboratories in which the complexation of the required dienes with 1aza-1,3-butadiene can be carried out as a high yield catalytic process. [19, 201

References

\OR

OH

63

Scheme 15

[l] E.O. Fischer, R . D . Fischer, Angew. Chem. 1960,72,919. [2] See textbooks on organic chemistry. [3] A. J. Pearson, in: Comprehensive Organometallic Chemistry. Vol 8, 939, Pergamon Press, 1982. [4] A. J. Pearson: Metallo-Organic Chemistry, Wiley, 1985. [5] A. J. Birch, B. E. Cross, J.Lewis, D. A. White, S.B. Wild, J. Chem. SOC. (A) 1968,332. [6] A.J. Birch, K.B. Chamberlain, M . A . Haas, D. J. Thompson, J . Chem. SOC. Perkin Trans.I 1973, 1882. [7] R.E. Ireland, G.G. Brown, Jr., R.H. Stanford, Jr., T.C. McKenzie, J . Org. Chem. 1974, 39, 51. [8] L.F. Kelly, A . S. Narula, A. J . Birch, Tetrahedron Lett. 1980,21, 871. [9] A. J. Birch, K.B. Chamberlain, D. J. Thompson, J . Chem. SOC.Perkin Trans.I EV3,1900.

64

B. Organometallic Reagents in Organic Synthesis

[lo] A. J. Pearson, J. Chem. SOC. Chem. Commun. 1980,488. [ l l ] A.J. Pearson, J. Chem. SOC. Perkin Trans.Z 1979, 1255. [12] A.J. Pearson, J. Chem. SOC. Perkin Trans.Z 1980,400. [13] A. J. Pearson, P.Ham, D. C. Rees, Tetrahedron Lett. 1980,21,4637. [14] E. J. Corey, J.F. Arnelt, G.N. Widiger, J . Am. Chem. SOC. 1975,97,430. [15] A.J. Pearson, J. Chem. SOC. Perkin Trans.1 1978,495.

[16] H.-J. Knolker, M. Bauermeister, D. Blaser, R. Boese, J.-B. Pannek, Angew. Chem. 1989, 101, 225. Angew. Chem. Int. Ed. Engl. 1989,28, 223. [17] H.-J. Knolker, M. Bauermeister,J. Chem. SOC. Chem. Commun., 1989,1468, [18] H.-J. Knolker, R. Boese, K. Hartmann, Angew. Chem. 1989,101, 1745. Angew. Chem. Int. Ed. Engl. 1989,28, 1678. [19] H.-J. Knolker, P. Gonser, Synlett, 1992,517. [20] H.-J. Knolker, P. Gonser, P. G. Jones, Synlett 19Qq, 405.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Rhodium-Catalyzed Carbenoid Cyclizations Karl Heinz Dotz

Diazo reagents serve as an example for a class of compounds on which interest has focussed again after a rather quiet period of some decades. The copper-catalyzed decomposition of diazo ketones and diazo acetate represents a long-known standard method for carbene transfer reactions. [l]In these processes carbenoids containing a metal-coordinated electrophilic carbene are supposed to be the reactive intermediates. [2] The second generation of catalysts, represented by dinuclear rhodium carboxylates, has led to a significantly improved methodology. [3] These compounds are characterized by a dimetal unit strongly hold together by four bridging carboxylate ligands; this results in a compact and stable skeleton that resists substitution in the equatorial positions. The axial position, however, is readily accessible for carbene coordination. Rhodium (11) acetate is often used as catalyst, generating a carbenoid of type (I). Since rhodium carboxylates are inert towards redox reactions with diazo compounds, only low concentrations of the catalysts are required, for example, 0.05 mol% for the cyclopropanation of methoxycyclohexene (2). The catalytic cycle (Scheme 1) suggests that the activity of the catalyst A depends on the degree of coordinative unsaturation of the metal center. The catalyst acts as an electrophile and adds the diazo compound to give complex B, which undergoes elimination of N2 affording the carbenoid C. The final steps

B

R

0.05 mol % Rh,(OAc), -N2

XI 80 %

X

SC( Y

S

c

‘

Scheme I. Catalytic cycle for the cyclopropanation of an olefinic substrate S with the carbenoid C using rhodium carboxylate A as catalyst.

66

B. Organornetallic Reagents in Organic Synthesis

of the catalytic cycle involve carbene transfer to the substrate S combined with the regeneration of the catalyst. In catalytic reactions no direct evidence for carbenoid C has been provided so far. However, support for the involvement of a carbenoid intermediate comes from the observation that alkenes undergo enantioselective cyclopropanation in the presence of optically active catalysts; [2, 41 moreover, a linear reactivity/selectivity correlation exists for a wide range of olefins between the Rh,(OAc),-catalyzed cyclopropanation with phenyldiazomethane and the stoichiometric cyclopropanation using the isolable and well-characterized benzylidene tungsten complex (CO),W=CHPh. [5] Synthetically useful applications involve cycloaddition of carbenoids to aromatic C-C bonds, as demonstrated by fury1 diazo ketones, which are modified to give acyl vinyl cycloalkenones. Previously, copper sulfate in boiling cyclohexane has served as catalyst ; [6] using rhodium acetate in dichloromethane, however, the transformation (3)+(4) occurs with improved yield even at ambient temperature. [7] Whereas the reaction is compatible with a variety of substitution patterns in the furan ring, the length of the diazo ketone chain is crucial: C4 and C5 side chains readily undergo ring-closure to give five- and sixmembered enones. In contrast, the furfuryl diazo ketone (3c) leads to a complex mixture of products under identical conditions. If benzene is used as a solvent instead of dichloromethane, the intermolecular cycloaddition prevails to give cycloheptatriene (5) via a norcaradiene intermediate. This primary cycloaddition product can be isolated in the benzofuran series : the tetracyclic product (6) is obtained, which allows subsequent acidcatalyzed modification to give ketone (7) or a thermal rearrangement to isomer (8). The cycloadditiodcycloreversion sequence has been exploited in a novel access to compounds of the pionone series. [8] The diazo ketone (9), accessible in several steps from 2-

(3)

0 R n yield

(4)

(34,(4a): H 1 86 % (3b), (4b): H 2 07 %

I

(7)

88 x

0 (8) 82 x

Rhodium-Catalyzed Carbenoid Cyclizations

67

methylfuran, undergoes concomitant deamination and cyclization in the presence of rhodium acetate to give (Z)-0x0-pionone (lo), which has been modified to the (E)isomer (11) under iodine catalysis. Cycloaddition to the benzene ring affords a direct and efficient access to the hydroazulene skeleton. This strategy has been exploited in the key steps of a confertin synthesis: Under rhodium mandelate catalysis diazo ketone (12) is transformed quantitatively to hydroazulenone (13b),which exists in a rapid equilibrium with its valence tautomer (13a). [9]

for intramolecular reactions : Starting from acyclic diazo compounds such as (14), fivemembered rings are the preferred products; trans-cyclopentanones (15) are formed diastereoselectively suggesting a six-membered chair-like transition state. [ll] Cyclic diazo precursors, for example, (16), however, lead to the formation of six-membered rings, for example (17). [12] Given a favorable geometry of the transition state, C-H insertion can compete successfully with cycloaddition ; for instance, the unsaturated diazo ketoester (18) affords the trans-cyclopentanone (19). [ 131

The development of the rhodium catalysts had a significant impact on the carbene insertion in carbon hydrogen bonds. Based on the electrophilic character of the carbenoid, the selectivity increases in the order of primary, secondary and tertiary C-H bonds. [lo] Whereas in ethers a-C-H insertion is favored, phenyl, vinyl and ester groups lead to a deactivation of a-C-H bonds. In addition to electronic factors the conformation plays an important role. This is particularly important

The selectivity of the C-H insertion depends on the catalyst used. The diazo acetate (20) is not able to discriminate between primary and tertiary C-H bonds in the presence of rhodium acetate; if rhodium acetamide is used as catalyst, however, only the tertiary C-H insertion product (21) is formed. [14] Selective insertion in N-a-C-H bonds of diazo acetoacetamides occurs even though they are deactivated by an N-carboalkoxyethyl substituent, as demonstrated for (23). [151 Apparently, in this example the influence of electronic factors is over-compensated by a

68

B. Organometallic Reagents in Organic Synthesis

favored conformation of the carbenoid intermediate (24), adopted as a consequence of the bulky N-tert-butyl group, and the trans-p lactam (25) is formed exclusively. Evidence for this argument comes from the observation that the reaction becomes unselective if the tert-butyl substituent is replaced by an n-butyl group, which - concerning its steric demand is comparable with the Epropionate side chain. The a-C-H bond of the carboalkoxy group and the pC-H bond of the n-butyl substituent compete for the insertion; the E lactam (27) and the y-lactam (28) are formed in a 1:9 ratio along with the seven-membered ring (29),which arises from the carbonyl ylide intermediate (30). The influence of the conformation exerted on the stereoselectivity is obvious from the cyclization of amidoacetate (31). Using rhodium perfluorobutyrate FU ~ ~ ( p f bas ) ~ catalyst the plactam (33) is obtained in a diastereoselective cyclization, as anticipated from the preferred conformation of intermediate (32).

q=+

N2HC

(20)

(2 7) W

4

Rh, (OAC)~ Rh, (acamL

yield 81 % 96 o%

A breakthrough in the synthesis of bicyclic Elactams has been achieved by the carbene insertion in N-H bonds of 2-acetidinones. This strategy has become the standard method for access to derivatives of the carbapenem and the carbacephem series. An elegant example is provided by the synthesis of thienamycin (37) [16]. The key step of this sequence is the rhodium acetate-catalyzed cyclization of a-diazo-Eketoester (35), which is readily accessible from pketoester (34). The cyclization is remarkable in two aspects: First, it proceeds quantitatively via Nl-C2 ring closure, and, second, is leads exclusively to the more stable em-carbapenam isomer (36), which may be rationalized in terms of a facile epimerization at C2 via an enol intermediate. A similar reaction path - starting from a simple plactam precursor (38) via diazo ketoester (39) - leads to homothienamycin (41),a compound with a carbacephem skeleton. [17] The insertion of carbenes into N-H bonds can be further exploited for the synthesis of p lactam analogues. Standard diazo transfer to hydrazides using tosyl azide affords the diazo derivatives (42) in variable yields ; subsequent rhodium carbenoid induced cyclization in boiling benzene leads to 1,Zdiazetidinones (43). [18] Similarly, the diazo precursors (44) are well-suited for the construction of 1,3bridged “anti-Bredt”-plactams (45). The methyl derivative ( 4 5 ~ )decomposes in solution (decomposition in CHC13: = 1 h); the isopropyl analogue (45b), however, is stable under these conditions. The reason for this is that sterically demanding substituents in the 3position block the addition of nucleophiles,

96 %

Rhodium-Catalyzed Carbenoid Cyclizations

r

1

69

70

B . Organometallic Reagents in Organic Synthesis

which can occur only from the @lactam face opposite the bridge and which is responsible for the decomposition. [19] YHR? 7-h

Et02C/KNR'

0

Et02 2::#

0

(42)

(45a) :

(45b):

R'

R2

Ph

-CH,Ph

-CH,CO,Et

-C02CH2Ph

Ri Me iPr

Rz H H

yield 87

x

93 %

superior to the copper-catalyzed decomposition of diazo carbonyl compounds. [20] In the presence of rhodium acetate (1) diazo sulfide (47), which is accessible from the thiolactone (46) and lithiodiazoacetate with subsequent in-situ alkylation, is modified into the cyclic sulfonium ylide (48). This type of intermediate can be isolated in some cases; it may undergo a 1,2-Stevens rearrangement, for example, to give (49), or a 2,3-sigmatropic rearrangement, for example, to afford (50). [21] PElimination has been only observed if exo-cyclic phydrogen atoms are present; in this case, a ready fragmentation leads to derivatives of type (51). In contrast, endo-cyclic hydrogen atoms do not take part in p elimination. This methodology can be extended to the generation of stable five- and six-membered sulfoxonium ylides such as (52) or (53), although side reactions involving deoxygenation may occur. [22] An interesting application is provided by a synthetic approach to pyrroli-

yield

64%

50% 20%

attractive The rhodium access to carbenoid ylides, which route provides offers ana useful alternative to the base-induced standard methodology. Moreover, in comparison with methods based on the thermal or photochemical generation of carbenes, it is significantly more selective and - due to its scope and its mild conditions - it is generally also

) . A 86%

F

2

E

t

03..

Ph

(M)

(50)

71

Rhodium-Catalyzed Carbenoid Cyclizations

dimethyl acetylenedicarboxylate (DMAD). [24] The cycloaddition is regioselective : The carbonyl ylide intermediate generated from 1diazo-2,5-pentandione (59) adds to benzaldehyde with exclusive formation of acetal (60), while addition to methyl propiolate affords the regioisomer (61a) in a 15:l preference over (61b). [25] Starting from ally1 aryl diazopentandione (62) no intermolecular cycloaddition occurs even in the presence of an activated dipolarophile such as DMAD. In this example - in contrast to the oxygen-stabilized carbonyl ylide (56) - no efficient resonance stabiliza-

Ph

6%

58 X

zidine alkaloids, which involves cyclic sulfonium ylides in the key step. [23] offers The acarbene simple direct transfer routetotocarbonyl 1,3-dipoles groups that can be subsequently either trapped in cycloaddition reactions or that may undergo rearrangement leading to modified 1,3-dipoles (Scheme 2). Often, the diazo carbonyl precursors are easily accessible. For example, the ring-opening of phthalic acid anhydride by 3-methyl-3-buten-1-01 followed by diazotation affords ester (55), which under Rh2(OAc)r catalysis undergoes ring closure to give the carbonyl ylide (56). The 1,3-dipole can be either trapped intramolecularly leading to the tetracyclic skeleton (57) or it can be exploited in an intermolecular [3 2lcycloaddition with

+

Scheme 2. Generation of 1,3-dipolesvia carbene transfer to carbonyl groups.

q+@-+ I

(55)

Y

-Y-

(56)

R

R

(58)

65 X

72

B. Organometallic Reagents in Organic Synthesis n

< 10%

tion of the intermediate 1,3-dipole by an aheteroatom can be provided. As a consequence, the resulting carbonyl ylide is shortlived and the bimolecular reaction can no longer successfully compete with the intramolecular cycloadditionleading to the formation of (63)*

(63)

The scope of the formation of carbonyl ylide intermediates is further extended by a "dipole cascade'' sequence. The reaction of Nacetylpyrrolidine (64) with DMAD affords only small amounts of the carbonyl ylide cycloaddition product (65). Instead the dihydropyrrolizine (67) is obtained as the major product, which is obviously formed via a carbonyl ylide-azomethine ylide isomerization followed by addition to the dipolarophile to give (66) and by a final 1,3-alkoxy migration. [26] Calculations indicate that the carbonyl ylide (69) derived from (68) is more stable than the azomethine ylide intermediate (70). Experimental evidence for this result has been provided

(67)

90 x

by the exclusive formation of the N , 0-acetal (71) from the reaction of (68) with DMAD. The scope of synthetic applications of diazo ketoamides is demonstrated by the aliphatic analogue (72). In this example, instead of a direct cycloaddition, the carbonyl ylide (73) prefers isomerization to give the N , 0-acetal (74),which then adds to the dipolarophile and finally affords the spiro compound (75). [27] In summary, it should be pointed out that the carbenoid intermediate faces a general competition of ylide formation and insertion reaction. The example (76) demonstrates that the formation of the ylide is especially favored

Rhodium-Catalyzed Carbenoid Cyclizations

73

0

(71) 90 x

&y

COzEt

in the presence of an easily polarizable group such as a sulfur atom. [28] Based on the broad synthetic scope of catalyzed carbene reactions and the mild reaction conditions required rhodium carbenoids have become well-established. So far, rhodium acetate has been used as catalyst almost exclusively. It can be anticipated that both scope and selectivity can be further improved by a more elaborated “fine-tuning” of the rhodium ligand sphere.

References [1] W. Kirmse Carbene Chemistry, Academic Press, New York, l97l. [2] H.Nozaki, S. Moriuti, H. Takaya, R. Noyori, Tetrahedron Lett. 1966,5239. [3] Reviews: a) A. J. Hubert, A.F. Noels, A. J. Anciaux, P.TeyssiC, Synthesis 1976, 600; b) G .Maas, Top. Curr. Chem., 1987 137, 7 5 ; c) M.P. Doyle, Chem. Rev. 1989, 86, 919; d) J.Adams, D.M. Spero, Tetrahedron 1991, 47, 1765; e) A.Padwa, K.E. Krumpe, Tetrahedron m,48,5385. [4] T. Aratani, Y. Yoneyoshi, T. Nagase, Tetrahedron Lett. 1982,23,685. [5] M.P. Doyle, J.H. Griffin, VBagheri, R.L. Dorow, Organometallics W,3, 53.

74

B. Organometallic Reagents in Organic Synthesis

[6] M.N. Nwaji, 0.0. Onyiriuka, Tetrahedron Lett. 1974, 2255. [7] A.Padwa, T. J. Wisnieff, E. J. Walsh, J. Org. Chem. 1989,54,299. [8] E. Wenkert, R. Decorzant, F. Naf, Helv. Chim. Acta 1989,72, 756. [9] M.Kennedy, M.A. McKervey, J. Chem. SOC. Chem. Commun. 1988,1028. [lo] A. Demonceaux, A. F. Noels, A. J. Hubert, P. TeyssiC, Bull. SOC. Chim. Belg. 1984,93,945. [ll] D. F. Taber, R. E. Ruckle, Jr., J. Am. Chem. SOC. 1986,108, 7686. [12] D. E. Cane, P. J. Thomas, J. Am. Chem. SOC. 1984,106,5295. [13] P. Ceccherelli, M. Curini, M. C. Marcotullio, 0.Rosati, E. Wenkert, J. Org. Chem. 1990,55, 311. [14] M. P. Doyle, V. Bagheri, M. M. Pearson, J. D. Edwards, Tetrahedron Lett. 1989,30, 7001. [15] M.P. Doyle, J.Taunton, H.Q. Pho, Tetrahedron Lett. 1989,30, 5397. [16] T. N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F.A. Bouffard, J. Am. Chem. SOC. 1980,102,6161.

[17] T.N. Salzmann, R. W. Ratcliffe, and B. G. Christensen, Tetrahedron Lett. 1980,21, 1193. [18] G. Lawton, C.J. Moody, C.J. Pearson, J . Chem. SOC. Perkin I1987, 899. [19] R.M. Williams, B.H. Lee, M.M. Miller, O.P. Anderson, J. Am. Chem. SOC. 1989,111,1073. [20] E.Vedejs, Acc. Chem. Res. 1984,17, 358. [21] C.J. Moody, R.J. Taylor, Tetrahedron Lett. 1988,29,6005. [22] C.J. Moody, A.M.Z. Slawin, R.J. Taylor, D.J. Williams, Tetrahedron Lett. 1988, 29, 6009. [23] T. Kametani, H. Yukawa, T. Honda, J. Chem. SOC. Perkin 11988,833. [24] A. Padwa, S. P. Carter, H. Nimmesgern, P. D. Stull, J. Am. Chem. SOC. 1988,110, 2894. [25] A.Padwa, G. E. Fryxell, L.Zhi, J. Org. Chem. 1988,53,2875. [26] A.Padwa, D.C. Dean, L. Zhi, J. Am. Chem. SOC. 1989,111,6451. [27] A.Padwa, L.Zhi, J. Am. Chem. SOC. 1990, 112,2037. [28] A.Padwa, S.F. Hornbuckle, G.E. Fryxell, P.D. Stull, J. Org. Chem. l989,54,817.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Nickel-Activated C1-Synthons Karl Heinz Dotz

Transition metals can be used to activate substrates by coordination and couple them under stereoelectronic control by the coordination sphere of the metal. A classical example of this type of reaction is provided by a “naked” nickel template, which mediates the cyclooligomerization of unsaturated hydrocarbons. [l]This methodology is similarly attractive for carbon-carbon bond formation using C,synthons. In this respect, interest has focused almost exclusively on carbon monoxide, as demonstrated in industrial processes such as hydroformylation and the Monsanto acetic acid process. The use of carbon dioxide, however, has been limited so far to less spectacular applications - in spite of its ubiquitous natural occurrence. Nevertheless, the synthetic potential of carbon dioxide [2] and its heterocumulene analogues, the isocyanates, [3] can be widely extended in combination with an appropriate transition metal. Carbon dioxide combines the properties of a Lewis acid (at carbon) and a Lewis base (at oxygen). These properties result in various modes of coordination that - in general - can be traced back to complexes ( I ) and (2), which have both been structurally characterized by X-ray analysis. [4, 51 Compounds of type (I) are particularly interesting for the synthetic organic chemist: They are supposed to be key intermediates in the transition metal-assisted coupling of C 0 2 with unsaturated substrates such as alkenes and alkynes,

although direct experimental support is still missing. Instead, metalalactones (4) have been observed, the formation of which may be rationalized in terms of an oxidative coupling of coordinated COz with the alkene ligand via intermediate (3). Low-valent “late” transition metals turned out to be efficient templates: Among them, nickel(o) stabilized by amine or phosphine ligands plays a key role. [2, 3, 61

(4)

L = arnine, phosphine

76

B. Organometallic Reagents in Organic Synthesis

Stability and reactivity of the metalacycles depend on the nature of the coligands. Wellbalanced properties are observed for the 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) complex (5), [7] which is accessible from bis(cyc1ooctadiene)nickel (Scheme 1). It is stable at ambient temperature and its structure is well-characterized by X-ray analysis. Its synthetic potential is focused on the nickel carbon bond, which is prone to insertion by nsystems. This reaction is particularly useful for monofunctionalized alkenes or allene, which afford monocarboxylic acids (6) and (7) after insertion followed by hydrolysis; butadiene, however, gives only disappointingly low yields of alkenoic acids (84 and (Sb). The selectivity is controlled both by the metal and the coligands. This fact is demonstrated by the ferra-

I

L=DCPE: L = PMe,:

yield

(10) : (11)

49%

10 : 1 1 : 400

60%

lactone (9), an iron analogue of (5), which undergoes insertion of excess C 0 2 into the Fe-C bond. [8] In the presence of the sterically demanding bis(dicyclohexy1phosphino)ethane (DCPE) dimethylsuccinate (10)is obtained as the main product after hydrolysis and esterification. On the other hand, the methylmalonic acid derivative (11) is formed nearly exclusively, if DCPE is substituted for trimethylphosphine. Metalalactones (4) serve as potential C,carboxyl synthons and can be exploited in the homologization of alkyl halides, as exemplified in the modification of the D-ring side chain in steroids. Usually, cross-coupling of the bispyridyl nickel complex (12) with the steroid halide (13) is hampered by undesired side reactions. For instance, the oxidative

80%

I

Scheme I. Influence of coligands on the reactivity of metalalactones.

Nickel-Activated C,-Synthons

addition product of (13) undergoes Phydride elimination and finally gives the propenyl steroid (14)in low yield. Using MnIz and ultrasound conditions, however, C-C coupling occurs readily and the carboxylic acid (15) is formed in 80 % yield. [9] The cross-coupling is chemoselective : Enone functionalities in ring A remain unchanged.

In analogy to alkenes, alkynes can also be coupled with carbon dioxide to give unsaturated metalalactones (16). These compounds are involved in the synthesis of a-pyrones formed by [2+2+2]cycloaddition: [lo] The insertion of another alkyne leads to the sevenmembered metalacycle (17),which undergoes reductive elimination to a-pyrone (18). It is important for synthetic applications that competing reaction paths such as alkyne cyclotrimerization to give arene (20) via metalacyclopentadiene (19) can be slowed down efficiently by appropriate catalysts. An efficient system is Ni(COD),/PEt, (1 :2), which is used in acetonitrile in amounts of 0.1 equivalents

77

and which shows a a-pyrone selectivity of 96 %. [9b, lob] More recent studies demonstrate that this type of reaction can be extended to functionalized alkynes (e.g., ethoxyethyne [ll]) and diynes. [12] Again, the choice of coligands attached to the nickel center is crucial : Terminally disubstituted diynes require unidentate phosphine ligands whereas 8N-chelating systems should be used if unsubstituted diynes are involved. Furthermore, the coligands control the regioselectivity of the CO,/diyne coupling: In the presence of the 8N-chelating ligand (21) the silyldiyne (22) is predominantly cyclocarboxylated to give the 7-silyl derivative (23); if, however, trin-octylphosphine is used as coligand, the regi-

"&: Et

Et

F&;

L 0

"L,,Ni'

E%c Et

78

B. Organometallic Reagents in Organic Synthesis

R = n-Pr

R’ = n-Qct: S-Bu:

P(n-Oct)a :

*/.

(25) 93%

25%

( E / Z = 93/7)

59%

ochemistry is reversed and the 3-silyl isomer (24) is obtained as the only product. Similar catalytic systems allow the addition of aldehydes to alkynes. Application of appropriate coligands, for example tri(noctyl)phosphine, leads in a “hydroacylation reaction” predominantly to E-a,penones (25); [13] more bulky phosphines increase the amount of dienone (26). The mechanism of this reaction is unclear and two alternatives must be discussed: The initial step might involve either oxidative addition of the aldehyde to the zero-valent nickel center (path a) or the formation of a nickelaoxacyclopentene intermediate (path b). So far, the hydroacylation has been applied mainly to symmetric dialkylalkynes. The addition of aldehydes to unsymmetric alkynes suffers from low regioselectivity; a synthetically useful selectivity (27)/(28) requires a-branched alkyne side chains, which, in turn, results in decreased yields. The activation of C 0 2 can be combined with the oligomerization of 1,3-dienes. [l] This strategy leads to the formation of C4,+,carboxylic acids, the chain lengths of which depend again on the coligands present in the nickel catalyst. If a bulky basic diphosphine, for example DCPE, is used, only one diene unit is coupled to carbon dioxide. [141 Unsym-

Rv + 0

Nio/L

1

1

R1-s~’

R = n-Bu:

(27) 19 X

(28) 28 x

t-Bu:

27%

1%

(26) 6% 65 X

Nickel-Activated C,-Synthons

metrical 1,3-dienes such as piperylene afford, after treatment with methanolic hydrogen chloride, two pairs of unsaturated methyl carboxylate isomers (31a, b) and (32a, b), which are derived from the n-ally1 complex intermediates (29) and (30). A pyridine-modified nickel catalyst allows the coupling of C 0 2with two diene moieties to give the G-ester (33) or, at elevated temperature, its C,-dimer (34). [151 A combined diene-trimerization and carboxylation to linear C1,-triene and -tetraene carboxylic esters is effected if pentafluoropyndine (PFP) is used as a coligand (Scheme 2). [I61 The key role of the coligand sphere is further obvious from coupling reactions involving a dimerization of butadiene. In the presence of carbon dioxide a stoichiometric reac-

1

- 30 'C

HCl/MsCm

-R

-

C02Me

tion mediated by the nickelltriphenylphosphine-system affords a 9:l mixture of cyclopentane carboxylic acids (36) and (37). If, however, the less basic tri(isopropy1)phosphite acts as a coligand, exclusively the diene (37) is formed in a Catalytic reaction (30 cycles). [17] Similar catalytic telomerization reactions have been earlier observed with palladium systems. [l8] A more recent example demonstrates the efficiency of cationic palladium(Ir)/triphenylphosphine catalysts. In comparison with other telomers lactone (38) is formed in 96 % chemoselectivity. [19] Similar to carbon dioxide, isocyanates can be incorporated into nickelacycles together with G-n-systems. [20] On reaction with alkynes these heterocumulenes give fivemembered unsaturated metalacycles (39)

kwH

/ -

C02Ms

R=

f

(350)

79

(33)

2OoC:

15

:

1

6OoC:

1

:

10

J, HCI/M~OH

HCI/M.OH

I

C02M6 (34)

Scheme 2. Activation of COz combined with the oligomenzation of 1,3-dienes: Influence of coligands on the formation of carboxylic acids.

80

B. Organometallic Reagents in Organic Synthesis

-

\

1

C02H

+

co2

(36)

CO2H

(37)

pms

do (38)

which subsequently undergo reactions analogous to those already described for their oxa congeners such as metalalactone (16). The cross-coupling with alkyl halides affords acrylic amides (40). Insertion of electrondeficient alkynes into the nickel-carbon bond

followed by hydrolysis leads to diene amides (42) while- reductive elemination from the seven-membered nickelacycle intermediate (41) gives the 2-pyridone (43). [21] These types of nickelacycles have been further used in oxidative degradation reactions. The metalassisted coupling of allene and phenylisocyanate generates a (C,N)-chelate ligand that undergoes dimerization to give the 1,5-diene diamide (45) on oxidation of complex (44) with FeC13. [22]

-.=

+

H ( m m *(nrEDA"

PhN=C=O

Ph

(44)

3

PhH

(45)

To carry out this type of reaction catalytically, a profound knowledge of those steps is required that effect the cleavage of the metal-carbon bond. A key step is the p hydride elimination, which has been studied in the coupling of vinylcyclohexane and phe-

Ph

Nickel-Activated Cl-Synthons

nylisocyanate. [23] A bis(cyc1ooctadiene)nickel/triethylphosphinecatalyst leads to a 1:1 mixture of amides (47) and (48); apparently, in the metalacycle (46), the rates of elimination of the /3- and the P'-€3-atoms are equal. Less basic phosphine ligands, however, allow differentiation: Tri(isopropy1)phosphite favors the PH-elimination [(47)/(48) = 95/51 whereas the even bulkier tri(orthophenylpheny1)phosphite preferentially activates the P' -position [(47)/(48) = 14/86]. The potential of isocyanate C,-synthons in organic synthesis is not restricted to nickel, as demonstrated by two examples referring to

81

the higher homologue palladium. The epoxide (49), accessible from the diene via enantioselective Sharpless epoxidation, reacts with tosylisocyanate in a palladium-catalyzed hydroxyamination with retention of configuration to give oxazolidinone (50), an intermediate in the synthesis of (-)-acosamine (51). [24] It is an attractive feature of this route that independent of the configuration of the epoxide [e.g., (52)] - the cis-oxazolidinone [e.g., (53)]is obtained.

References [l] P. W. Jolly, G. Wilke, The Organic Chemistry of Nickel, Vol.11, Academic Press, New York,

1975.

(49)

(52)

a

(53) from

cis-(52) : 100% tmns452) :

80%

DBA = dibenzalacetone

MeO,

W

[2] Reviews: a) P. Braunstein, D. Matt, D. Nobel, Chem. Rev. 1988, 88, 747; b) A. Behr, Angew. Chem. 1988, 100, 681; Angew. Chem. Int. Ed. Engl. 1988,27, 661. [3] Review: P. Braunstein, D. Nobel, Chem. Rev. 1989,89, 1927. [4] M. Aresta, C. F. Nobile, J . Chem. SOC. Dalton Trans. 19R,708. [5] S. Gambarotta, F. Arena, C. Floriani, P. F. Zanazzi, J . Am. Chem. SOC. 1982,104, 5082. [6] H. Hoberg, in Carbon Dioxide as a Source of Carbon, (Eds.: M. Aresta, G. Forti), Reidel, Dordrecht, 1987. [7] H. Hoberg, Y. Peres, C. Kriiger, Y. H. Tsay, Angew. Chem. 1987, 99, 799; Angew. Chem. Int. Ed. Engl. 1987,26, 771. [8] H. Hoberg, K. Jenni, K. Angermund, C. Kriiger, Angew. Chem. 1987, 99, 141; Angew. Chem. Int. Ed. Engl. 1987,26, 153. [9] a) G. Braunlich, R. Fischer, B. Nestler, D. Waither, Z. Chem. 1989,29,417; b) D. Walther in Advances in Organic Synthesis via Organometallics, (Eds.: R. W. Hoffmann, K. H . Dotz), Vieweg, Wiesbaden, 1991,p. 77. [lo] a) Y. Inoue, Y. Itoh, H. Kazama, H. Hashimoto, Bull. Chem. SOC.Japan 1980,53, 3329; b) D. Walther, H. Schonberg, E. Dinjus, J. Sieler, J . Organomet. Chem. 1981, 334, 377; c) H . Hoberg, D. Schafer, G. Burkhart, C. Kriiger, M. R. Romao, J . Organomet. Chem. 1984,266,203.

82

B. Organometallic Reagents in Organic Synthesis

[ll] T. Tsuda, K. Kunisada, N. Nagahama, S. Morikawa, T. Saegusa, Synth. Commun. 1990,20, 313. [12] T. Tsuda, S. Morikawa, N. Hasegawa, T. Saegusa, J. Org. Chem. 1990,55,2978. [13] T. Tsuda, T. Kiyoi, T. Saegusa, J. Org. Chem. 1990,55,2554. [14] H. Hoberg, D. Schaefer, B. W. Oster, J. Organomet. Chem. 1984,266, 313. [15] H. Hoberg, Y. Peres, A. Milchereit, S. Gross, J. Organomet. Chem. 1988,345, C 17. [16] H. Hoberg, D. Barhausen, J. Organomet. Chem. 1989,379, C 7. [17] H. Hoberg, S. Gross, A. Milchereit, Angew. Chem. 1987, 99, 567; Angew. Chem. Int. Ed. Engl. 1987,26, 571.

[18] a) Y. Inoue, Y. Sasaki, H. Hashimoto, Bull. Chem. SOC. Japan 1978,51,2375; b) A. Behr, K.-H. Juszak, W. Keim, Synthesis 1983,574. [19] P. Braunstein, D. Matt, D. Nobel, J . Am. Chem. SOC.1988,110, 3207. [20] H . Hoberg, J. Organomet. Chem. 1988, 358, 507. [21] H. Hoberg, B. W. Oster, J. Organomet. Chem. 1983,252,359. [22] H. Hoberg, E. Hernandez, K. Siimmermann, J. Organomet. Chem. 1985,295, C 21. [23] H. Hoberg, D. Guhl, Angew. Chem. 1989,101, 1091; Angew. Chem. Int. Ed. Engl. 1989, 28, 1035. [24] B. M. Trost, A. R. Sudhakar, J. Am. Chem. SOC. 1987,109, 3792; J . Am. Chem. SOC. 1988, 110,7933.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Aminocarbene Complexes in Ligand- and Metal-Centered Carbon-Carbon Bond Formation Karl Heinz Dotz

Transition metals have become indispensable tools in organic synthesis. Typical examples involve transmetalation reactions starting from classical organometallic materials such as Grignard or organolithium compounds. These routes allow in situ generation of reagents that - like organotitanium compounds [1] - often exhibit a dramatically improved chemo- and stereoselectivity. In addition, increasing attention has focussed on stable and unambigously characterizable metal complexes provided that they are accessible by a reasonable synthetic effort in medium scale batches. These requirements are met with transition metal carbene complexes : [2] Compounds containing a high-valent metal center (Schrock-type metal carbenes) are used in carbony1 olefination processes - with the Tebbe-Grubbs reagent CpzTi=CH2[3] generated in situ as the most prominent example - or as catalysts in olefin metathesis such as (RF0)2(NR)W=CHtBu. [4] On the other hand, the organic-synthetic interest in lowvalent metal center derived complexes (Fischer type metal carbenes), [5] for example, (CO)&r = C(OR)R', has concentrated on stoichiometric cycloaddition reactions. Initial interest has focussed on Fischer carbene complexes containing alkoxycarbene ligands; [6, 71 more recently, remarkably stereoselective reactions have been reported for arninocarbene complexes. These compounds can be easily prepared from metal carbonyls

either via alkoxy- and acyloxycarbene precursors ( I ) and (2), respectively, or via carbonyl metalates (3) [S, 91 (Scheme 1). The synthetic potential of metal aminocarbenes arises from the conjugate carbene anions as well as from cycloaddition reactions. The intrinsic a-CH-acidity of alkylcarbene complexes ((CO),Cr=C(OMe)Me: pK, = 8 (PPN+ salt in THF; [lo] (CO),Cr=C(NMeJMe: pK, = 20.4 (K' salt in DMSO) [11] has been exploited in aldol reactions. The anions derived from alkoxycarbene complexes ( I ) are more stable and give aldol adducts in synthetically useful yields only if the carbonyl compound is complexed first with a Lewis acid. [12] The deprotonation of aminocarbene complex (4), however, leads to a more reactive conjugate base (5), which rapidly and cleanly adds to aldehydes and ketones without the assistance of a Lewis acid. These reactions proceed with a remarkable diastereofacial selectivity, as shown by the addition of (5) to chiral aldehydes : [131 d,1-2-phenylpropionaldehyde affords an 80% yield of the aldol adduct as a (6a):(6b) = >40:1 (1:u) mixture of diastereomers. A similar stereoselection has been restricted so far to Lewis acidpromoted reactions with silyl enol ethers. [14] With d,l-2-methyl-3-phenylpropionaldehyde the stereoselectivity is reduced to (7a):(7b) = 4.1: 1, but is still competitive with that observed with customary a-unsubstituted enolates. The chromium carbonyl fragment

84

B. Organornetallic Reagents in Organic Synthesis

I

(2)

MI= Na, K

Scheme 1. Synthesis of aminocarbene complexes from alkoxy- or acyloxycarbene precursors and from carbony1 metalates.

can be cleaved by oxidation (e.g., with DMSO or dimethyldioxirane) [15, 161 or by UVirradiation (via carbene CO coupling to give a coordinated ketene intermediate [ 171) and formation of lactone (8) (Scheme 2). The facial selectivity of carbene anions is further expressed in the Michael addition to 'ychiral enones. Presently, the method of choice for such diastereoselective 1,Cadditions is the Lewis acid-mediated addition of enol silanes, [18] which affords a selectivity of up to 30:l. The lowest preference in this series (5: 1) was reported for the TiC14-assistedaddition of the silyl enol ether of 3,3-dimethylbutanone to 1,4-diphenyl-2-penten-l-one.This enone, however, reacts readily at -78 "C with the conjugate base of aminocarbene complex (9) to give ketoaldehyde (11) in a diastereomeric ratio Z:u = 21:l after acidic cleavage of the primary Michael addition product (10). [111 Asymmetric Michael reactions of optically active proline derived carbene ligands with five- and six-membered cyclic enones generally proceed with only moderate enantiomeric excess (60-76% ee). As expected,

steric bulk at the reactive center of the enone increases the selectivity to 95 % ee. The characteristic feature of Fischer type metal carbenes is the electrophilicity of the carbene carbon atom. Since the pentacarbonyl metal fragment is isolobal with an oxygen atom, [19] the reactivity of carbene complexes is expected to correlate with that of their organic carbonyl congeners. In intermolecular Diels-Alder reactions methoxy(viny1)carbene complexes react 2 x lo4 times faster and more regioselectively than their acrylate analogues. [20] Starting materials for the intramolecular version (IMDA) are accessible in a two-step procedure based on subsequent addition of a nucleophile and an electrophile to a carbonyl ligand followed by nucleophilic substitution at the carbene center. As demonstrated in the intermolecular reaction, the metal carbonyl fragment is a strongly electron-withdrawing functional group as powerful as a Lewis acidcoordinated carbonyl oxygen atom. An illustrative example is provided by the following IMDA reaction with inverse electron demand : The (dially1amino)furylcarbene complex (12)

Aminocarbene Complexes in Ligand- and Metal-Centered Carbon-Carbon Bond Formation

0"

Yg Y

n

8

v

+

f I

P I

-91' I 0"

+

85

86

B. Organometallic Reagents in Organic Synthesis

'0If R = H :41%, 64%ee(S) R = M e : 5 1 % , 95%W(S)

obtained from hexacarbonyl tungsten undergoes spontaneous cyclization even under the conditions of its formation at -40 "C. A single diastereomer (13) is observed in which the newly formed five-membered rings are transfused. [21] In comparison, the cyclization of analogous furan carboxylic amides requires reflux conditions in benzene and toluene, respectively, for several hours. Finally, the metal carbene bond can be modified by oxidation to give the lactam (14). Aminocarbene ligands are better donors than their alkoxy counterparts, which results in a more efficient back-bonding from the metal to the carbonyl ligands and has an important consequence for metal-mediated cyclization reactions, for example with alk-

ynes (Scheme 3). While alkoxycarbene ligands in (15)(D = OR) undergo annulation by the alkyne and by a carbonyl ligand via ketene intermediate (16) to give hydroquinone (17),in general, no CO-incorporation is observed with arninocarbene complexes which generate alkyne insertion products in which the resonance form (B) prevails. Instead, a five-membered carbene annulation product (18), in which the less crowded alkyne carbon atom is connected to the carbene carbon atom, is obtained after acidic work-up. [22] Ring formation is regio- and diastereoselective, as demonstrated by the intramolecular example (19)+(20). [23] Only one diastereomer is observed in which the former alkyne substituents in the central five-membered ring are trans and - more remarkably - the benzylic substituent R and the metal carbonyl fragment are bonded to the same face of the tricyclic ring system. A plausible mechanism suggests that the stereochemistry in the central ring is determined by a suprafacial 1,5sigmatropic hydrogen migration (21) + (22). Thus, the carbene annulation methodology allows the formation of coordinated substi-

Aminocarbene Complexes in Ligand- and Metal-Centered Carbon-Carbon Bond Formation

87

Scheme 3. Metal-induced cyclization reactions using alkoxycarbene or aminocarbene complexes.

tuted fused ring systems that can be further functionalized under the stereocontrol exerted by the bulky Cr(C0)3 fragment. [24] Moreover, the versatility of the carbene annulation allows the formation of heterocycles. The iminocarbene ligand in (23),formed by iminolysis from the methoxy precursor, adds to alkynes with the same regioselectivity as discussed above to give pyrrole (24). [25] If the donor ability of the aminocarbene ligand is reduced, the formation of six-membered annulation products is favoured. [26] N Acylation of the benzylaminocarbene complex by (BOC),O occurs with concomitant decarbonylation and affords directly the activated aminocarbene chelate (25). Its annula-

88

B. Organornetallic Reagents in Organic Synthesis 9-t-Bu

(co,5&Raz

c hu

R

Me

Me

Et (26) 11 %

OAc (27)

56 0%

tion by 3-hexyne leads to a 5: 1 preference of the aminonaphthol(27) over the aminoindene (26). The carbene annulation is a thermally induced sequence; it can be explained in terms of a primary decarbonylation of the carbonyl carbene complex followed by coordination of the alkyne and subsequent coupling of the alkyne and carbene ligands. [6] On the other hand, it has been suggested that a direct carbonyl carbene coupling occurs under photochemical conditions. Assisted by metal ligand charge transfer a ketene is formed in the coordination sphere of the metal and can be subsequently trapped by protic nucleophiles or by [2+2] cycloaddition. An interesting application involves the addition of imines which opens up a new diastereoselective route to plactams. [27] Since aminocarbene complexes containing a-hydrogen substituents are accessible via the carbonyl metalate/formamide route and since chiral information can be readily incorporated into the amino group, this strategy is suited for the synthesis of biologically relevant optically active compounds. For instance, the (R)-aminocarbene complex (29), accessible from (R)-phenylglycinol via

the formamide (28), reacts with a series of imines to give plactams (30) in good to excellent diastereoselectivity. It is important that the new chiral center formed next to the carbonyl group has the same absolute configuration as the asymmetric center in the chiral auxiliary. This correlation also holds for the (S)series: The (S)-carbene complex (32) leads to the (S)-lactam (33). The chiral auxiliary is fi-

1) HCI/WH 2) H Z / W H Pd(OH)Z/C

70-923

(30)

>

Aminocarbene Complexes in Ligand- and Metal-Centered Carbon-Carbon Bond Formation

nally cleaved and recovered in a two-step hydrolysishydrogenolysis process, for example (30+(31). The photochemically generated amino ketene intermediates can be further exploited in the synthesis of amino acid derivatives. Irradiation in the presence of water did not afford synthetically useful results. However, if the reaction is carried out in alcoholic solution, the amino acid esters (35) are formed in good yields and interesting diastereoselectivity. [28] It is surprising that, in this case, the newly formed stereocenter has the opposite absolute configuration compared with that of the chiral auxiliary used. Unfortunately, no high-yield synthetic route to the methyl(amino)carbene complexes (34) is available so far. If this problem might be solved, aminocarbene complexes could provide an attractive access to optically natural and unnatural amino acids. An additional avantage arises from the a-CH-acidity in the carbene side chain, which may be used in homologization, as outlined in the formation of (36). The asymmetric protonation leading to the amino acid ester offers an efficient approach to “chiral glycine” [2-*Hl]glycine,an important substance for mechanistic studies in biochemistry. Photolysis of (R) or (S) carbene complex (37) in methanol-dacetonitrile produced the glycine precursor (38) in (R, R ) or

89

(S, S) absolute configuration: Cleavage of the oxazolidine ring afforded the optically active glycine (39) with >97 % monodeuteration, 84 % ee, and 74 % overall chemical yield. [29] A final remark concerns the handling of the carbene complexes described. Their preparation does not require a more sophisticated technique than that used for Grignard and organolithium reagents. Aminocarbene complexes are air-stable in the solid state and can be stored for months. In solution, however, an inert gas atmosphere (nitrogen or argon) should be provided. The uncomplicated handling of metal carbenes has clearly assisted their development from exotic organometallics to customary synthetic reagents.

References (35)

5 93%

Q

(36)

d.e.

[l] M. T. Reetz, Organotitanium Reagents in Organic Synthesis, Springer, Berlin 1986. [2] a) K.H. Dotz, H.Fischer, P. Hofmann, F. R. KreiB1, U. Schubert, K. Weiss, Transition Metal Carbene Complexes, VCH, Weinheim 1983; b) R.R. Schrock in Reactions of Coordinated Ligands, (Ed.: P.S. Braterman), Vol. 1, Plenum Press, New York, 1986,p. 221 ff. ; c) K. H. Dotz, ibid. p. 285 ff. [3] K. A. Brown-Wensley, S. L. Buchwald, L. Cannizzo, L.Clawson, S.Ho, D.Meinhardt, J.R. Stille, D . Straus, R. H. Grubbs, Pure Appl. Chem. 1983,55, 1733.

90

B . Organometallic Reagents in Organic Synthesis

[4] R.R. Schrock, J. Organomet. Chem. 1986, 300, 249. [5] Reviews: a>E. 0.Fischer, Angew. Chem. 1974, 86, 651; b) E.O. Fischer, Adv. Organomet. Chem. 1976,14, 1. [6] Reviews: a) K.H. Dotz, Angew. Chem. 1984, 96,573;Angew. Chem. lnt. Ed. Engl. 1975,14, 644;b) W.D. Wulff in Comprehensive Organic Synthesis, Vo1.5 (Eds.: B.M. Trost, I.Fleming), Pergamon Press, New York, 1991, p. 1065-1113. [7] H.U. ReiBig, in J.Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H . 4 . ReiBig Organic Synthesis Highlights, VCH, Weinheim, 1991, p. 186ff. [8] E. 0. Fischer, J.A. Connor, J. Chem. SOC.A 1967,578. [9] R. Imwinkelried, L. S. Hegedus, Organornetallics 1988,7 , 702. [lo] C.F! Casey, R.L. Anderson, J. Am. Chem. SOC.1974, 96, 1230. [11] B. A. Anderson, W. D. Wulff, A. Rahm, J. Am. Chem. SOC. 1993,115, 4602. [12] W.D. Wulff, S.R. Gilbertson, J. Am. Chem. SOC. 1985,107,503. [13] W.D. Wulff, B.A. Anderson, A.J. Toole, J. Am. Chem. SOC. 1989,111,5485. 1141 C. H. Heathcock, L. A. Flippin, J. Am. Chem. SOC. 1983,105, 1667. [15] C. P. Casey, T. J. Burkhardt, C. A. Bunnell, J.C. Calabrese, J. Am. Chem. SOC. l977,99, 2117. [16] A.-M. Lluch, L. Jordi, F. Sanchez-Baeza,S. Richart, F. Camps, A. Messeguer, J. M. Moreto, Tetrahedron Lett. 1992,33,3021. [17] L. S. Hegedus, G. de Weck, S. D’Andrea, J. Am. Chem. SOC. BtB, 110,2122. [18] C.H. Heathcock, D.E. Uehling, J. Org. Chem. 1986,51,279.

[19] a) R.Hoffmann, Angew. Chem. 1982,94,725; Angew. Chem. Znt. Ed. Engl. 1982,21, 711. b) F.G.A. Stone, Angew. Chem. 1984, 96, 85; Angew. Chem. lnt. Ed. Engl. 1984,23, 89. [20] a) W. D. Wulff, W. E. Bauta, R. W. Kaesler, P. J. Lankford, R.A. Miller, C.K. Murray, D.C. Yang, J. Am. Chem. SOC. 1990,112, 3642; b) W. D. Wulff, T. S. Powers, J. Org. Chem. 1993, 58,2381. 1211 K.H. Dotz, R.Noack, K.Harms, G.Muller, Tetrahedron 1990,46, 1235. [22] a) K.H. Dotz, H.G. Erben, K.Harms, J. Chem. SOC.Chem. Commun. 1989, 692; b) C. Alvarez, A.Parlier, H. Rudler, R. Yefsah, J. C. Daran, C. Knobler, Organometallics 1989, 8, 2253. [23] K.H. Dotz, T. Schafer, K.Harms, Synthesis 1992, 146. [24] a) E.P. Kundig, Pure Appl. Chem. 1985, 57, 1855; b) P. J. Dickens, J. P. Gilday, J. T. Negri, D. A. Widdowson, Pure Appl. Chem. 1990,62, 575. [25] V. Dragisich, C. K. Murray, B.P. Warner, W. D. Wulff, D.C. Yang, J. Am. Chem. SOC. 1990, 112,1251. [26] D.B. Grotjahn, F.E.K. Kroll, T.Schafer, K. Harms, K. H. Dotz, Organometallics 1992, 11, 298. [27] a) L. S. Hegedus, R. Imwinkelried, M. AlaridSargent, D.Dvorak, Y.Satoh, J. Am. Chem. SOC.1990, 112, 1109; b) L.S. Hegedus, L.M. Schultze, J. Toro, C. Yijun, Tetrahedron l985, 41, 5833. [28] L.S. Hegedus, M.A. Schwindt, S. De Lombaert, R.Imwinkelried, J. Am. Chem. SOC. 1990,112,2264. [29] L. S. Hegedus, E.Lastra, YNarukawa, D. C. Snustad, J. Am. Chem. SOC. 1992,114,2991.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Organolanthanides in Reduction and Nucleophilic Addition Methodology Karl Heinz Dotz

The organometallic chemistry of the lanthanides has been a sleeping beauty for quite a long period. This might be due, in part, to the term “rare earth metals”, which is misleading to some extent. These elements are produced in quantities of about 40000 t per year (mainly as oxides), and, for instance, the natural abundance of samarium is twice as high as that of boron. Based on the development of efficient protocols for their preparation and on their structural characterization [11organolanthanides have witnessed an explosive growth from NMR shift reagents to versatile reagents in organic chemistry during the past decade, as documented in recent reviews. [2] Lanthanide cations favor high coordination numbers and are potent oxophilic “hard” Lewis acids; these properties can be exploited in the activation of carbonyl compounds. This report deals with compounds containing divalent samarium and trivalent cerium; these elements are among the less expensive in the lanthanide series. The impetus of organolanthanides in organic synthesis came from compounds containing the metal in oxidation state 11. [3] Due to its electron donor properties ( E , (Sm(II)/ Sm(m) = -1.55 V) samarium was particularly attractive. Starting from the element and 1,2diiodoethane Kagan developed an efficient route to samarium diiodide; [4] this reagent can be stored for months under an inert gas atmosphere and is now commercially available

as a solution in THE Its reactivity resembles that of a Grignard reagent and it is now wellestablished as a soluble one-electron donor in Barbier reactions with alkyl halides. [4, 51The reaction is catalyzed by FeC13 and is most attractive for ketones whereas with aldehydes subsequent Meerwein-Ponndorf-Verley-Oppenauer oxidation is often observed. Illustrative examples are provided by a short route to frontalin ( I ) [6] and by the annulation of five- (but not six-!) membered rings, which occurs with high stereoselectivity [(2a): (2b) = 99.5:0.5]. [7] Alkyl halides can be replaced by acyl chlorides (e.g. a-alkoxy(-acyl)chlorides), which also lead to Barbier-type products (3) via decarbonylation [8]. The reduction potential of samarium diiodide has been widely used for the deoxygenation of epoxides, for pinacol formation from aldehydes and for the coupling of acyl chlorides. [5, 91 More recently, this reagent has been shown to induce stereoselective cyclizations. The reduction of carbonyl com-

92

B. Organometallic Reagents in Organic Synthesis

&-

2 Sml,

80%

'

+HopH

(7)

OH

26o Sml, %

'++o

&^O

(9). The scope of the reaction includes the synthesis of spiro compounds (10); the diastereoselectivity is high to excellent but drops if enolizable substrates (9b) are used. Under similar conditions - and with a diastereoselec-

(3)

pounds by SmI, is expected to generate ketyl intermediates, which can be exploited in the construction of up to 3 adjacent stereocenters. Studies of the reduction of 6-hepten-2-ones indicate that 5-heptenyl radicals (5) are formed that prefer ex0 cyclization to give the primary methylcyclopentyl radical (6) over endo ring closure leading to the cyclohexanol skeleton via the secondary radical (7). [lo] The reaction is not only regioselective, but also diastereoselective, as demonstrated by the formation of cis-1,2-dimethylcyclopentanol (8) as the main product. Besides its reduction potential another interesting aspect of SmI, is its coordination properties. Its propensity to chelate formation can be used in control over the relative configuration of a third adjacent stereocenter. [ll] An illustrative example is provided by the cyclization of the unsaturated Pketoesters

(a) (b)

A

R'

Et

Et

Me H

diastereoselectivity 2oo:i 2O:l

Organolanthanides in Reduction and Nucleophilic Addition Methodology

tivity (220: 1) distinctly superior to that reported for customary procedures [12] - the intramolecular pinacol coupling proceeds [(11)+(12)]. Sometimes problems arise from undesired reduction of carbonyl groups to alcohols [e.g. (13)+(14)] as encountered in a total synthesis of (+)-coriolin; [131 this side reaction can be suppressed in the presence of chelating additives such as HMPA, which favor the aldehyde/alkene coupling to give (15).

93

steroid (17) in high yield under mild conditions. [14] For the reduction of aheterosubstituted ketones this reagent is even the method of choice. [15] The compatibility of SmIz with a wide range of substituents is demonstrated by the lactone (la), which serves as precursor for the A-ring (19) in an enantioselective synthesis of (+)-pillaromycinone. 1161 The scope of this reagent in reductive processes is explained by its ability to undergo two rapid electron transfer steps and thus to avoid an undesirable high stationary concentration of radical intermediates.

80%

(16)

( 1 7)

Kagan's synthesis of SmIz involves a carbenoid intermediate - similar to the Simmons-The electron donor properties of samarium Smith reagent [17] - which looks promising for diiodide facilitate not only radical carbonxar- olefin cyclopropanation. Studies in which the bon bond formation, but have been also used reagent was generated from samarium actiin selective fragmentation reactions, as vated by HgCI2have led to interesting results. demonstrated by two examples aiming at ste- [18] The cycloaddition proceeds with good to roid and anthracycline synthesis. Cleavage of excellent yield and, in comparison with the the xanthate (16) using reductants such as customary Simmons-Smith method (which, in Bu,SnWazaisobutyronitrile leads to complex h mixtures, whereas SmIz affords the 9,lO-seco-

94

B. Organornetallic Reagents in Organic Synthesis

general, requires harsher conditions), with improved stereoselectivity. The major advantage is that only ally1 alcohols but not homoallyl alcohols and non-conjugated or functionalized C-C bonds undergo cyclopropanation. In geraniol(2U) and nerol(21) the CCC7 bond is unaffected. Thus, the Sm1,-method is complementary to the triethylaluminiurddiiodomethane route, which results in methylene transfer to the remote C-C bond. [19]

state and in solution, is still a matter of speculation. Nevertheless, these reagents “RCeX2” are less basic than their organolithium or Grignard precursors and, as a consequence, they add to enolizable substrates, such as (22), whereas deprotonation and subsequent aldol reaction can be suppressed, as demonstrated for cyclopentanone (23). Moreover, with enones (24) 1,6addition is preferred over 1,2addition. [24] (a) CH, MgCl

(b)CH,MgEr/CeC13

(a) LPrMgCI

(23) 4 Srn(HgYICH2U

> (a) 3% (b) 91 %

80 Of0 traces

(a) LPrMgCI

@) LPrMgCVCeCI,

HaC

Another major application of lanthanides in organic chemistry involves transmetalation of Grignard and organolithium compounds. Transmetalation often improves chemoselectivity and concomitantly enhances stereocontrol. Among the d-block elements, organotitanium [20] and organocopper reagents [21] are well-established in synthetic methodology. More recently, attention has focused on organocerium(II1) compounds, [22] which are generated in situ from CeCl, or Ce13 at 0°C in THF. [23] Their structure, both in the solid

>

0 (24)

(a) 12 % (b) 91 “1.

53 “1. 5%

A remarkable observation was made along a reaction sequence aimed at the synthesis of the DEF substructure of the antitumor anti-

Organolanthanides in Reduction and Nucleophilic Addition Methodology

95

biotic nogalamycin. [25] An attempt to add dride cyclopentenol (29) is obtained with a the metalated arene (25) to the chiral ketone selectivity of 97:3, while in the absence of (26) established that the aryllithium com- CeC1, the saturated alcohol (30) is formed pound (25a) produced the desired alcohol exclusively.The reaction proceeds smoothly at (27a) while the lithium-derived organoceriurn ambient temperature, requires neither exclureagent (25b) led to the unnatural epimer sion of air nor moisture and is compatible with (27b). This result might reflect the different a range of functional groups such as esters in coordination abilities of both metal ions: (31) and tosylates. [27] Chiral enones are Whereas in (25b) the cerium cation is sup- reduced stereoselectively, especially at low posed to prefer chelation by the adjacent ben- temperature: Dihydropyrone (33) affords zyloxy group, coordination of the lithium ion exclusively the all-cis allyl alcohol (34). In the by the solvent THF is discussed for (2.5~).Fur- hydride reduction a complimentary stereother studies should aim at the generality of the control similar to the carbon*arbon bond unexpected finding that metal tuning of a formation mentioned above is observed carbanion is a possibility to perform carbonyl depending on whether CeCI, is present or not. addition reactions with opposite stereo- The saturated ketone (35), in which the phoschemistry. phine oxide moiety allows chelation of cerium (111), is reduced by NaBH, to give threo-(36) as the main product. In the presence of CeC13, MOM0 OMOM however, the formation of erythro-(36) prevails [28]. + ' O W + OBn The synthetic application of lanthanides is M * y w e 0 not restricted to stoichiometric reactions. Due to their Lewis acid properties LnX,-type com(26) (250): M = l i (25b) : M = CeC12 OBn MOM0

OMOM

b

THF

0

- -

(270) : R = OH, R' = Me

(276) : R

Bn

-

Me. R'

OH

Benzyl

Another application of organometals containing trivalent lanthanides refers to carbonyl reduction. An established reagent is NaBHJ CeC13 in methanol (Luche reagent), which selectively modifies enones to allyl alcohols. [26] The role of the lanthanide component is obvious from the reduction of cyclopentenone (28): In combination with sodium borohy-

Bn

-

Benzyl

B. Organometallic Reagents in Organic Synthesis

96

(a) NaBH lCeCl 4

3,

(b) Na BH,

In summary, lanthanides exhibit a versatile chemistry and we should be prepared for some more surprises.

References

(Js)

[l] a) H.Schumann, Angew. Chem. 1984, 96,475; Angew. Chem. Znt. Ed. Engl. l984,23,474; b) W. J. Evans, Polyhedron 1987,6, 603; c) Organometallic Chemistry of the f-Elements (Eds. : T.Marks, R. D. Fischer), Reidel, Dordrecht,

1979.

(36) wythm : 85 : 15

thm:

(0):

15

(b):

85

pounds are used as catalysts in aldehydeselective acetalization, [29] in Friedel-Crafts [30] and, most impressively, in hetero DielsAlder reactions. The latter process tolerates a wide range of dienophiles: Highly electrophilic aldehydes as well as unactivated ketones can be employed using Eu(fodX or analogous commercially available NMR shift reagents. [31] Somewhat surprisingly, 1,3dialkoxybutadienes (37) provide dihydropyran cycloadducts (38) resulting from endoaddition of the dienophile even though there are no obvious secondary orbital interactions. A possible explanation is based on steric arguments and arises from a preferred coordination of the lanthanide ion anti to the alkyl group of the aldehyde. On these grounds, the endo-selectivity might be rationalized in terms of the effective size of the alkyl group versus the catalyst-solvent ensemble. [32]

p""

[2] a) H.B. Kagan, J.L. Namy, Tetrahedron 1986, 42, 6573; b) H.B. Kagan, New J. Chem. 1990 14, 453; c) J. A. Soderquist, Aldrichimica Acta 1991,24, 15; d) D. P. Curran, T.L. Fevig, C. P. Jasperse, M. J. Totleben, Synlett, Et2,943; e) G.A. Molander, Chem. Rev. 1992,92,29. [3] D. F. Evans, G. V. Fazakerley, R. F. Philips, J. Chem. SOC. ( A ) l97l,1931. [4] J.L. Namy, P.Girard, H.B. Kagan, Nouv. J. Chim. 19R,1, 5. [5] P.Girard, J.L. Namy, H.B. Kagan, J. Am. Chem. SOC. 1980,102, 2693. [6] T. Imamoto, T. Takeyama, M. Yokoyama, Etrahedron Lett. l984,25,3225. [7] G.A. Molander, J.B. Etter, J. Org. Chem. 1986,51, 1778. [8] M. Sasaki, J. Collin, H. B. Kagan, Tetrahedron Lett. 1988,29, 4847. [9] J.L. Namy, J.Souppe, H.B. Kagan, Tetrahedron Lett. 1983,24, 765. [lo] B. Giese, Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds, Pergamon Press, New York, 1986. [ll] G. M. Molander, C. Kenny, J. Am. Chem. Soc. 1989,111, 8236. [12] E. J. Corey, R.Danheiser, S. Chandrasekaran, J. Org. Chem. 1976,41, 260. [13] T.L. Fevig, R. L. Elliott, D. P. Curran, J. Am. Chem. SOC. 1988,110, 5064. [14] T. P. Anathanarayan, T. Gallagher, P. Magnus, J. Chem. SOC.Chem. Commun. 1982,709. [15] G. A. Molander, G. Hahn, J. Org. Chem. 1986, 51, 1135. [16] J.D. White, E. G. Nolen, Jr., C.H. Miller, J. Org. Chem. 1986,51, 1150. (171 H.E. Simmons, R.D. Smith, J. Am. Chem. SOC. l959,81,4256.

Organolanthanides in Reduction and Nucleophilic Addition Methodology [18] G.A. Molander, L. S. Harring, J. Org. Chem. 1989,54, 3525. [19] K. Maruoka, Y. Fukutani, and H. Yamamoto, J. Org. Chem. 1985,50,4412. [20] M. T. Reetz, Organotitanium Reagents in Organic Synthesis, Springer, Berlin, 1986. [21] G.H. Posner, An Introduction to Synthesis Using Organocopper Reagents, Wiley, New York, 1980. [22] T. Imamoto, Pure Appl. Chem. 1990, 62, 747. [23] T. Imamoto, T. Kusumoto, Y. Tawarayama, Y. Sugiura, T. Mita, Y. Hatanaka, M. Yokoyama, J. Org. Chem. 1984,49, 3904. K. Nakamura, [24] T. Imamoto, N. Takiyama, T.Hatajima, Y.Kamiya, J . Am. Chem. SOC., 1989,111, 4392.

97

[25] M. Kawasaki, F. Matsuda, S. Terashima, Etrahedron Lett. 1985,26, 2693. [26] J.-L. Luche, J. Am. Chem. SOC. 1978, 100, 2226. [27] R. A. Raphael, S. J. Telfer, Tetrahedron Lett. 1985,26,489. [28] J. Elliott, S. Warren, Tetrahedron Lett. 1986, 27,645. [29] R. Baudouy, P. Prince, Tetrahedron 1989, 45, 2067. [30] N. Mine, Y.Fujiwara, H. Taniguchi, Chem. Lett. 1986,357. [31] M.M. Midland, R.S. Graham, J. Am. Chem. SOC. 1984,106,4294. [32] M. Bednarski, S. Danishefsky, J. Am. Chem. SOC. 19a?,105,3716.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Carbon-Carbon Bond Formation with Group Four Metallocenes Martin Maier

In many areas of synthetic organic chemistry, this is due to the fact that very simple and methodological progress and new reactions practical methods could be found to generate are based on the use of transition metals. species of the type “Cp2Zr” or their equivaTransition metals have become almost indis- lents. This fragment represents a 1Celectron pensable, particularly for the formation of compound with a d2-configuration. It possesC-C and C-H bonds. [l] Because they easily ses a free electron pair and, in addition, two form complexes with unsaturated fragments unoccupied valence orbitals. With regard to or undergo insertion reactions, transition reactivity, this zirconium species might best be metals are able to make molecules in their compared with a singlet carbene (e.g. C1,C:); coordination sphere react with each other although the zirconium moiety contains one which would normally not be able to do so. more empty orbital. With the combination of Moreover, transition-metal induced reactions empty orbitals and an occupied orbital, it is can proceed with high selectivity. Finally, with understandable that “Cp2Zr” reacts readily the use of multidentate and chiral ligands, it is with many types of unsaturated compounds possible to prepare catalysts that allow one to with concomitant formation of the correperform enantioselective reactions. [2, 31 sponding metallacycles. For these complexes, Besides being able to activate molecules one can formulate two mesomeric resonance towards certain reactions, transition metals forms (I a) and (Ib), whereby a large amount are also able to stabilize highly reactive species, thereby making them available for selective transformations. In this connection, the chemistry of group four metallocenes has been investigated very intensively, whereby some interesting results have come to light that are the subject of this review. ’

1

Insertion of Unsaturated Species into Zirconium-Carbon Bonds What might be the reason for the renaissance of the group four metallocenes? [4] Primarily,

(2)

d.:C=C 134pm

100

B. Organornetallic Reagents in Organic Synthesis

of x-back bonding from the metal to the organic fragment causes the resulting complexes to behave chemically like metallacyclopropanes (= alkene complexes) or metallacyclopropenes (= alkyne complexes). This is also expressed in the bond lengths found for the alkyne complex (2). [5] Thus, the bond length of 128.6 pm for the original triple bond shows that in the complexed form this bond has a high degree of double bond character. A preparatively very important reaction of the complexes between “Cp2Zr” and unsaturated fragments is the insertion of polar (carbonyl compounds, nitriles) and even unpopular, unsaturated molecules (alkenes, alkynes) into the Zr-C bond with the formation of fivemembered metallacycles, which in turn may be functionalized in many ways (reaction with CO, RNC, H+, I2 etc.). Originally, zirconocene-alkene and alkyne complexes were pre-

pared by reduction of zirconocene dichloride with metals (Mg/HgC12; N a g ) in the presence of an alkene or alkyne, although a significant amount of by products could be formed. A new method by Buchwald et al. relies on the concerted elimination of methane from monoorgano-methyl-zirconocene by p-elimination. [4e] It was also discovered by Buchwald that such complexes can be stabilized with trimethyl phosphine to give 18-electron complexes. For example, he used this method for the regiospecific functionalization of naphthalenes [6] (Scheme 1). In this case, naphtyl bromides such as (3) served as educts, which, after metalation (cf. (4)) react with zirconocene methyl chloride under substitution of chloride to give compounds of type (5). On warming aryne complexes (6) are formed as intermediates, which react with nitriles to give the azametallacycles (7). From these, the acyl-

-CH4 ___)

R’ = BzI, MEM R2 = Awl, Alkyl

(for exp. 4penten-1-yl) Me0

Scheme 1. Insertion of nitriles into aryne-zirconium complexes.

0

Carbon-Carbon Bond Formation with Group Four Metallocenes

naphthalenes (8) can be generated by acid hydrolysis. If the azametallacycles (7) are treated with iodine prior to the hydrolysis, iodoacylnaphthalenes (9) are formed. As can be seen, the acyl substituent is in the metuposition to the OR1-group. That means that by using this method an anti-Friedel-Crafts acylation of aromatic compounds is realized. It should be noted that fundamental studies of aryne-metal complexes were carried out by Erker et al., who succeeded in the first preparation of an aryne-zirconocene complex by elimination of benzene from diphenylzirconocene. [7] Clearly, the simplest procedure for the generation of the fragment “CpzZr” consists of

the reaction of zirconocene dichloride with alkylmetal compounds (Scheme 2). Thus, first the corresponding dialkylzirconocenes (10) are formed, which are converted to alkenezirconocene complexes by 0-hydrogen abstraction and elimination of one molecule of alkane. [8] For example, with n-butyllithium, the 1-butene-zirconocene complex is obtained whereas treatment of zirconocene dichloride with ethylmagnesium bromide or ethyllithium produces the ethene complex. On reaction of these alkene complexes with other olefins, five-membered metallacycles are formed by insertion (e.g. (12) and (16)), which, for example, can be cleaved by hydrolysis. For steric reasons, the alkyl residues are directed

H3cYR Ar

R‘

yield pi&)

Et nHexyl

60

(17)

R’ Ar yield (%) Et Ph 70

65

101

(19) HO

R

R’

R2

yield(%)

H Et

nHeptyl 97 Ph 67

(1.5);R’ = Et Scheme 2. Zirconocene-induced coupling of alkenes with alkenes and aldehydes.

102

B. Organometallic Reagents in Organic Synthesis

to the 3- and 4-positions, providing almost exclusively the trans-isomer (12). [9] Some problems arise if one attempts to couple two different olefins. For example, treatment of Cp,Zr(nBu)2 with one equivalent of 1-octene gives a statistical mixture of homo- and heterocoupling products. If styrene derivatives are used for the second step, then the insertion takes place so that the aryl group occupies the a-position (cf. (16)). In this manner additional stabilization of the partial negative charge next to the zirconium is secured. In both cases these reductive coupling reactions are practically regiospecific. Instead of the second olefin, one can also use aldehydes, whereby hydrolysis of the metallacycle (18) furnishes alcohols of type (19). [lo] In contrast to the coupling of olefins, insertion of the aldehyde takes place into the less substituted Zr-C bond. If one wants to complex alkenes of which a polar organometal compound is not easily available, a variation is offered that

relies on an exchange reaction with complexed isobutene. [ll] Similar studies with mixed dialkyl compounds of zirconocene revealed the relative reactivity of various alkylgroups as phydrogen donors. [12] In general, this reactivity correlates with the degree of substitution at the @enter, whereby the following order is valid: Emethyl > p methylene > pmethine. The Negishi procedure is not only applicable to the preparation of alkene complexes, but can also be exploited in an elegant manner - at least in a formal sense - for the synthesis of intermediate zirconocene-alkyne complexes. Insertion of alkynes into the ethylene zirconocene complex leads first to zirconacyclopentenes (20). From these, in turn, the ethylene can be displaced by other unsaturated fragments; a

R'

R~

Et Et Ph Me Me3Si H

yield(%) 87

84

40

(21) R1= R2 = nPr R3 = I?' = Et (81%)

R

yield (YO)

H

80

Ph

a5

Et

CC5H11

85

75

(22) R1 I R2 = nPr R~ = Me (65%)

(23) I?' = R2 = nPr R3 = Ph (65%) R3 = w e x (52%)

Carbon-Carbon Bond Formation with Group Four Metallocenes

103

result that also indicates a relative weak indeed the case was also demonstrated by C3-C4 bond. Mechanistically, alkyne com- Negishi et al. [14] Coupling of the Grignard plexes, formed by elimination of ethylene, are reagent with the olefin is induced by treatment most likely passed through. Thus, reductive of catalytic amounts of CpzZrClz with two coupling of alkynes with aldehydes, nitriles, equivalents of ethyl magnesium bromide and or other alkynes can be performed by applica- an olefin (in this case 1-decene). The reaction proceeds through the ethene complex (2 a) , tion of this method (cf. (21)-(23)). [13] into which the olefin inserts. An additional advantage is that the reaction proceeds with pair selectivity, that is to say no homoCyclizations with Group Four coupling products are formed. The Grignard Metallocene Catalysts reagent then cleaves the metallacycle (24) regiospecifically via an addition-elimination Although zirconium compounds are toxico- mechanism to give compound (25) from which logically relatively unobjectionable, zircono- the reactive complex ( l a ) is regenerated by cene-induced C-C bond formations that take reductive elimination. place with catalytic amounts of zirconium Using secondary allylic alcohols as coupling would be even more attractive. That this is partners the zirconocene-catalyzed addition of ehtylmagnesium bromide occurs with remarkEtMgBr able stereoselectivity. [15] While the use of / protected allylic alcohols furnishes the antiproducts, on the other hand the free allylic alcohols yield preferentially the syn-isomers. The Grignard reagents (30) formed in this manner can be functionalized in numerous

EtMgBrl\

/

(71%)

+

l2(74%) Ally1 bromide (71 "10) Me1(80 "1)

derivatives

104

B. Organornetallic Reagents in Organic Synthesis

ways; one example is the oxidative formation of 1,3-diols (31). Because of the above mentioned reaction mechanism, this reaction is not, unfortunately, suitable for the direct transfer of methyl groups. With a view to the synthesis of cyclic or polycyclic natural products, intramolecular variants of these reductive coupling reactions

’

(32) 6,

’

(36) s,

ciMrans = 71:29 H30+(94%)

’

(37)’ *)

H30+(87%) I, (76%) :C=O (60%)

;

(34)’7“’

(33)’6’

H30+(6%)

H30+(63%)

(35)‘7a)

cisltrans = 92:8 H30+(71%)

(38) 7c) H30+(79%) one isomer

:c=o (29%)

e3

P

are of particular interest. Indeed, zirconocene-induced cyclization of substrates that contain two unsaturated groups have proven to be very powerful. Under the influence of the species “CpzZr”,the cyclization of diynes, [16] eneynes, [17] and dienes [18] to zirconabicycles can be performed. Normally, these are not isolated, rather transformed into subse-

Dienes:

(39)’7t) H30+(88%) one isomer

HO

Bzl

(40)lab) H30+ (75%)

(44)’8b’

(42)’&)

(41)22’ :c=o (58%) :C=N-k (81%)

H30+(75%)

(43’8”’

Scheme 3. Cyclization of diynes, eneynes, and dienes to give metallacycles.

(43)’8”’ H30+(88%)

Carbon-Carbon Bond Formation with Group Four Metallocenes

quent products. Thus, the treatment of zirconacycles with the vinylcarbene analogues carbon monoxide and isonitriles provides fivemembered ketones or imines, respectively. Work-up with acid or iodine gives products in which the Zr-C bonds are replaced by C-H or C-I bonds. Mechanistic studies suggest that in the case of eneynes a zirconacyclopropene-intermediate is formed first, in which the alkene is inserted in a second step. Scheme 3 depicts some representative zirconabicycles, that were generated by this method. The methods for the work-up and the corresponding yields are also given in this Scheme. In the cyclization of 1,6-dienes the two annulated rings usually turn out to be trunsconnected, whereas from 1,7-dienes cisannulated rings are formed preferentially (cf. (42) and (43)). With chiral substrates such reductive cyclizations proceed with high asymmetric induction. It should be noted that such cyclizations can be performed with catalytic amounts of “CpzZr” if one uses stochiometric amounts of the Grignard-reagent. [19] However, the method does have its limitations. Thus, cyclizations to small rings (fourmembered rings) and larger rings (sevenmembered rings) fail in most cases. The cyclization also does not work with substrates that contain allylic ethers. In this case cleavage of the allylic ether with the formation of an allylic zirconium species is observed. Nevertheless, this represents a new method for the cleavage of allylic protecting groups. [20] Moreover, it was shown by Taguchi et al. that for ally1 ethers in which the oxygen atom is part of a ring and simultaneously part of an acetal a zirconium-mediated ring contraction can be performed to yield carbocyclic compounds. [21] A case in point is the synthesis of an intermediate for carbocyclic oxetanocin. [22] Thus, treatment of (46) with Cp2Zr followed by BF3.Et20 provided the chiral cyclobutanone (48). Although the Negishi method for the generation of “CpzZr”, that is, CpzZrClz nBuLi, is operationally very sim-

+

105

1

I-

(47)

(48)

ple, the disadvantage is the lack of tolerance for functional groups. In a variant Buchwald et al. use instead the corresponding titanium reagent. (Cpz?iC12 2 EtMgBr), which is characterized by lower oxophilicity and therefore does not, for example, attack ester functions (cf. (41)). [23] In the presence of isonitriles even catalytic amounts of titanocene are sufficient for the cyclization. [24]

+

Reactions of Hetero Olefin Complexes The group four metallocenes not only complex molecules with CC-multiple bonds, but they are also able to bind hetero olefins. As an additional method for the synthesis of complexes of a zirconocene unit and a carbonyl

106

B. Organornetallic Reagents in Organic Synthesis

group, insertion of carbon monoxide in a Zr-C bond followed by migration of a second residue from the zirconium to the acyl-carbon can be used (cf. (49)+(51)). [25] As an aside, reaction of the above-mentioned zirconacycles with carbon monoxide and isonitriles also takes place according to this scheme. If carbonyl complexes with a a-H atoms are intermediates, enolates may be formed; a fact that restricts the use of carbonyl - and imine complexes for reductive coupling with unsaturated fragments. In addition, metallocene-heteroolefin complexes can also be prepared by direct synthesis from Cp,Zr- and Cp,Tiequivalents (e.g. Cp,Zr(CO),, Cpzl3(PMe3),) and hetero olefins. [26]If such complexes are not stabilized by a further ligand, they usually associate to give dimers. For the preparation SiMe, of heteroolefin complexes, the Buchwald procedure in particular has broad application. R’ R2 R3 yieM(%) This method relies on the elimination of H Ph Ph 75 methane in the presence of trimethyl phosphine. By this route a large number of zirco(56) nocene thioaldehydes could be generated. [27]Thus, if dimethyl zirconocene is treated with one equivalent of a thiol, (alky1thio)me- reoselectively to give amino alcohols. [29]The thylzirconocenecomplexes are formed. At a major products are always the threotemperature of around 80 “C the second mole- compounds (60) and (61) (threolerythro cule of methane is lost with the formation of 2:1-1O:l). The ratio of (60) to (61) is quite the desired complexes, which can be stabilized temperature dependent. At 0°C and at room with trimethyl phosphine. According to the temperature mostly (60) is formed, whereas at same principle, zirconocene-imine complexes higher temperature the ratio is reversed in can be generated. However, in this case one favor of (61). As this example shows, the starts from zirconocene methyl chloride, Negishi procedure for the generation of which is treated with N-silylated lithium am- “CpzZr” is applicable to the preparation of ides. Subsequent elimination of methane is imine complexes without undesired sidefacilitated enormously by the N-silyl group reactions, although the possible substrates are and succeeds even at -10 “C. Imine complexes limited to imine derivatives of aromatic aldesuch as (54) react with a large number of unsa- hydes. If, however, aldehydes with a-H atoms are turated molecules with concomitant insertion in the Zr-C bond. Thus, with alkynes ally1 converted to the corresponding hydrazones, amines are obtained after insertion and hydro- then it is possible to form complexes of them with zirconocene according to the Negishi lysis. [28] By reaction of ‘‘Cp2Zr” with the chiral method. As Livinghouse et al. reported, unimine (57), Taguchi et al. generated the metal- saturated hydrazones cyclize in high yield to lacycle (58), which reacts with aldehydes ste- give the metallacycles (63). [30]These in turn

Carbon-Carbon Bond Formation with Group Four Metallocenes pn

Me0

-,

A completely different concept of using transition metals for C-C bond formation is to use carbene complexes that react with unsaturated fragments (olefins, alkynes, dienes, etc.) in the sense of pericyclic reactions. Accordingly, with complexes of metal-heteroatom double bonds one should be able to form carbon-heteroatom bonds in an analogous manner. In this regard, intramolecular variants have proven particularly elegant and effective. Livinghouse et al. describe the application of intramolecular [2 21cycloadditions of metal-imido complexes with alkynes for the synthesis of nitrogen heterocycles. [31] If one treats alkynyl amines, for example (65) with CpTiC13the titanium-imido complex (66) is formed first, which then undergoes a [2+2]cycloaddition to give (67). Protonation cleaves the metallacycle to the enamine, which tautomerizes to the pyrroline (68). Because formation of the titanium-imido complex is accompanied by the generation of HCl, catalytic amounts of CpTiC13 (0.3 equiv.) are sufficient. If equimolar quantities of CpTi(CH,),Cl or CpZr(CH,),Cl are used whereby methane is eliminated - the metallacycles are not hydrolyzed and can be functionalized in various ways. It should be noted that CpzZr=NR complexes practically do not undergo cycloaddition.

+

Ph

R

Ph, Me

P

+

p

e.g. R = Ph:

temp. yiekl 6oB1 PC) 0 64

75

946

84

5:95

can be derivatized by hydrolysis and acetalization. If olefinic hydrazones are used, ciscycloalkylhydrazides are formed with high selectivity. It should also be mentioned that the cyclization of unsaturated ketones is possible under the action of the “Cp,Ti”-equivalent CpzTi(PMe&. [26]

CH3 CpTiCb Ph

NMe,

1. H+

2. acetylatiin

..

(CHqN‘Wl

(6848%) R = Ph. nBu. SiMe3

R

(64)

107

tp

-2HCI Ph

108

B. Organometallic Reagents in Organic Synthesis

Hydrozirconation Reactions Interesting developments are also seen for one of the most useful organometallic reactions: the hydrozirconation of olefins and alkynes. This reaction was discovered a couple of years ago by Schwartz et al., whereby CpzZr(H)C1 serves as the reagent. [32] Another reaction of similar significance is the carboalumination reaction of alkynes catalyzed by zirconocene dichloride. [4d] Recently, some improved procedures for the preparation of CpzZr(H)C1became known. In addition, new valuable transformations of vinyl- and alkylzirconocenes were found, for example the above-mentioned synthesis of alkyne complexes according to Buchwald, the preparation of butenolides from propargyl alcohols, [33] and the hydrocyanation of olefins. [34] Moreover, by the hydrozirconation of highly functionalized, in part even metallated, substrates, it became‘possible to open up new applications for this reaction. For the preparation of Cp2(H)Cl according to Buchwald, Cp,ZrC12 is reduced with LiAlK, which produces a mixture of CpZZr(H)C1and overreduced CpzZrHz. On treatment with dichloromethane the latter is then converted to Cp,Zr(H)Cl, thus enabling a very efficient and cheap synthesis. [35] In some cases it is possible to use Cp,Zr(H)Cl which has been generated in situ. This can be performed by reduction of Cp,ZrCl, with LiEt3BH, a procedure which works well for the hydrozirconation of many alkynes. [36] As serveral groups have shown, it is possible to activate vinyl- and alkylzirconocenes with other metals (transmetalation) thereby making it possible to adjust the reactivity to the other reaction partner and the reaction. Thus, one succeeds in the conjugate addition of vinylzirconocenes to enones under the catalytic influence of [Ni(acac),]. [37] If the chlorine atom in compounds of type (69) is exchanged for methyl, a subsequent facile conversion to organocuprates (71)is possible.

-

Et3W

OSiMes

(73);92%

These in turn may be added effectively in a 1,Cmode to enones. The synthesis of the prostaglandin derivative (73) by this strategy may serve as an example. [38] In a similar manner alkyl groups can be transferred to enones by hydrozirconation of alkenes and transmetalation with catalytic amounts of Cu(4 salts. [39] If acid chlorides are used instead of enones this represents a flexible synthesis of ketones. [40] Clean transmetalation of vinylzirconocenes to vinylboranes is possible by reaction with haloboranes. [41] The advantage as compared with the direct hydroboration lies in the higher regioselectivity. The chloride in alkenyl- and alkylzirconocene chlorides can be replaced not only by nucleophiles, but it may also be removed with appropriate Lewis-acids, whereby cationic zirconocene species are generated that themselves possess Lewis-acid character and are therefore able to increase the electrophilicity of carbonyl groups. This fact was exploited by

109

Carbon-Carbon Bond Formation with Group Four Metallocenes

r

R

i

L

(74)

R 2

CP, + Zr-X

cb

1

C104-

(75)

X = CI or

examples:

( + (76);90%

4

OH

3

tiie

(77); 94% (diastereomericmixlure 1:i)

Suzuki et al. for the transfer of organic substituents to aldehydes. Whereas compound (69) reacts only slowly with aldehydes without added Lewis-acid, the corresponding additions are complete within minutes in the presence of catalytic amounts of AgClO,. [42] It is assumed that with AgC10, zirconocene cations of type (75) are formed that are able to form a complex with the carbonyl group and thereby facilitate transfer of the alkenyl group from the zirconium to the aldehyde. Moreover, such cationic zirconium species are also important for glycosylation reactions. [43] Particular interesting reagents are formed by the hydrozirconation of functionalized alkenes and alkynes. Thus Knochel et al. found that by hydrozirconation of alkenylzinc halides in dichloromethane 1,l-bimetallic reagents of type (79) are formed regiospecifically. [44] Although these reagents are not all to stable, they can be trapped with carbonyl groups to give olefins (80) in good yields. Aldehydes react selectively to (E)-disubstituted olefins. In an analogous manner the hydrozirconation of alkynylzinc halides yields 1,l-bimetallic alkenes which react with aldehydes to give allenes. For the stereoselective preparation of synthetically useful (2)-vinyltin compounds, Lip-

R'

R2 F?

Hept H CH2Ph H (CH,),CN H -(CH2)4-

cHex Pent cHex cHex

R4 H H H H

yield (?/)

83

89 55

76

shutz et al. made use of the hydrozirconation of alkynyltin compounds. Initially, the 1,lbimetallic alkenes are formed, which then are converted to the desired compounds by protonolysis. [45] If the allylstannane (81) is treated with Cp2Zr(H)C1, the 1,l-bimetallic reagent is not formed but rather the 1,3-bimetallic reagent (82), which represents at the same time an allylzirconocene derivative. This reacts with carbonyl groups via the six-membered transition state (83) to give the intermediate (84). With Bronsted- or Lewis-acids spontaneous p elimination of the tin and oxygen-functions takes place and (E)-1,3-dienes (85) are formed with high selectivity. [46]

Wittig-Analogous Reactions The prototype example of a 1,l-bimetallic compound that contains a group four metallocene unit is the Tebbe reagent (86), which is

110

B. Organometallic Reagents in Organic Synthesis

X = OR H. AHcyl. AM

-F i 92% (VZ= 96:4)

g,f!

- 0 >N-i

75%

(vz= 9&2)

formed from Cp2TiC12and two equivalents of A1(CH3)3with the formation of methane and A1(CH3)2Cl.This complex is able to olefinate carbonyl groups in a Wittig-type reaction, whereby the advantage lies in the fact that even ester groups react with the formation of enol ethers. [47] Such olefination reactions are also possible with dialkyl titanocenes (87) although in this case a higher temperature is necessary. Despite that, this reaction represents an effective method for transferring methylene groups and for converting carbonyl compounds to styrene derivatives, vinyl silanes, or alkylidene cyclopropanes. [48] As reactive species are titanocene alkylidene complexes most probably intermediates. This

follows from the fact that compound (87) reacts with alkynes to form titanacyclobutenes. [48d] These in turn can react with ketones and aldehydes to form six-membered metallacycles, whereby insertion is observed in the Ti-alkyl as well as the Ti-vinyl bond. [@I

Outlook As this summary demonstrates, group four metallocenes are versatile reagents for performing C-C bond formation. [50] Particularly with a view to asymmetric and enantioselective reactions these metallocenes conceal an enormous potential. Finally, it should be noted that the chemistry of the group four metallocenes carries many other facets, such as the stabilization of planar tetracoordinate carbon centers [51] or the use as catalysts for polymerization reactions of olefins. [52] Due to space limitations, these and many other interesting topics could not be considered.

Carbon-Carbon Bond Formation with Group Four Metallocenes

111

zirconocene-complexes with 1,3-dienes, see : E.Neghishi, S. R. Miller, J. Org. Chem. 198!), 54, 6014-6016. [l] D.Seebach Angew. Chem. 1990, 102, 1363-1409; Angew. Chem. Int. Ed. Engl. 1990, [ll] a) D. R. Swanson, E.Neghishi, Organometallics 1991,10, 825-826; b) See also: PBinger, 29, 1320. F!Miiller, R. Benn, A. Rufinska, B. Gabor, [2] a) S.L. Blystone, Chem. Rev. 1989, 89, C.Kriiger, P.Betz, Chem. Ber. 1989, 122, 1663-1679; b) Chem. Rev. 1992,5, issue num1035- 1042. ber 5. [3] Chiral group four metallocenes are also avail- [12] E. Neghishi, T. Nguyen, J. P. Maye, D. Chouein, N.Suzuki, T.Takahashi, Chem. Lett. 1992, able from cyclopentadienyl ligands that are chi2367-2370. ral in the E2-space: a) A.Schafer, E.Kar1, M. Kageyama, V. Denisov, L. Zsolnai, G. Huttner, H.-H. Brintzinger, J. [13] T. Takahashi, R. Hara, E. Neghishi, Tetrahedron Lett. 1993, Organomet. Chem. l98'7,328,87; b) S . Collins, 34,687-690. B. A. Kuntz, Y. Hong, J. Org. Chem. 1989,54, 4154-4158; c) R.B. Grossman, R.A. Doyle, [14] T.Takahashi, T. Seki, Y.Nitto, M. Saburi, C. J. Rousset, E. Neghishi, J. Am. Chern. SOC.1991, S. L. Buchwald, Organometallics 1991, 10, 113,6266-6268. 1501-1505. [4] For reviews, see: a) G. Erker, Acc. Chem. Res. [15] a) A.H. Hoveyda, Z.Xu, J. Am. Chem. SOC. 1991, 113, 5079-5080; b) A. F. Houri, M. T. 1984,17, 103-109; b) H.Yasuda, K.Tatsumi, Didiuk, Z.Xu, N.R. Horan, A.H. Hoveyda, A.Nakamura, Acc. Chem. Res. 1985, 18, J. Am. Chem. SOC.1993,115,6614-6624. 120-126; c) G. Erker, Angew. Chem. 1989,101, 411-426; Angew. Chem. Int. Ed. Engl. 1989, [16] W. A. Nugent, D. L. Thorn, R. L. Harlow, J. Am. Chem. SOC. 1987,109,2788-2796. 29, 397 d) E. Negishi, T. Takahashi, Synthesis 1988,1-19; e) S.L. Buchwald, R.B. Nielsen, [17] a) T.V. RajanBabu, W. A. Nugent, D. F. Taber, P.J. Fagan, J. Am. Chem. SOC. 1988, 110, Chem. Rev. 1988,1047-1058; f ) E. I. Negishi in 7128-7135; b) P A . Wender, F.E. McDonald, Comprehensive Organic Synthesis (Eds.: B. M. Tetrahedron Lett. 1990,31,3691-3694; c) E. C. Trost, I. Fleming), Vol. 5, Pergamon, Oxford Lund, T.Livinghouse, J. Org. Chem. 1989, 54, 1991,1163-1184; g) R.D. Broene, S.L. Buch4487-4488. waldt, Science 1993,261, 1696-1701. [5] S.L. Buchwald, B.T. Watson, J. C. Huffman, [18] a) W.A. Nugent, D.F. Taber, J. Am. Chem. SOC.1989,111, 6435-6437; b) M.Mori, N.UeJ. Am. Chem. SOC. 1987,109,2544-2566. saka, M.Shibasaki, J. Org. Chem. 1992, 57, [6] a) S.L. Buchwald, S.M. King, J. A m . Chem. 3519-3521; c) D. F. Taber, J. P. Louey, J. A. SOC. 1991, 113, 258-265; b) see also: G.D. Lim, Tetrahedron Lett. 1993,34,2243-2246. Cuny, A. Gutierrez, S. L. Buchwald, Organo[19] K. S. Knight, R.M. Waymouth, J. Am. Chem. metallics 1991,10, 537-539. SOC. 1991,113,6268-6270. [7] G.Erker, K.Kropp, J. Am. Chem. SOC. 1979, [20] H. Ito, T.Taguchi, Y.Hanzawa, J. Org. Chem. 101,3659-3660. 1993,58,774-775. [8] a) E. Negishi, E E. Cederbaum, T. Takahashi, Tetrahedron Lett. 1986, 27, 2829-2832; b) [21] H. Ito, Y. Motoki, T. Taguchi, Y. Hanzawa, J. Am. Chem. SOC. 1993,115, 8835-8836. E. Neghishi, D.R. Swanson, T.Takahashi, J. Chem. SOC., Chem. Commun. 1990, [22] H. Ito, T. Taguchi, Y. Hanzawa, Tetrahedron Lett. 1993,34, 7639-7642. 1254-1255. [9] a) E. Neghishi, E E. Cederbaum, T. Takahashi, [23] R.B. Grossman, S.L. Buchwald, J. Org. Chem. 1992,57,5803-5805. Tetrahedron Lett. 1986, 27, 2829-2832; b) E.Neghishi, D.R. Swanson, T.Takahashi, J. [24] S. C. Berk, R.B. Grossman, S. L. Buchwald, J. Am. Chem. SOC. W3,115,4912-4913. Chem. SOC., Chem. Commun. 1990, [25] a) G. Erker, U. Dorf, P. Czisch, J. L. Peterson, 1254-1255. Organometallics 1986,5 , 668; b) R.M. Way[lo] a) T. Takahashi, N. Suzuki, M.Hasegawa, mouth, K.R. Clausen, R.H. Grubbs, J. Am. YNitto, K. Aoyagi, M. Saburi, Chem. Lett. Chem. SOC. 1986, 108, 6385; c) G.Erker, 1992, 331-334; b) for reactions of alkene-

References

112

B. Organometallic Reagents in Organic Synthesis

M. Mena, C. Kriiger, R. Noe, Organometallics 1991, 10, 1201-1204, and references cited therein. [26] D.F. Hewlett, R.J. Whitby, J. Chem. SOC., Chem. Commun. 1990,1684-1686, and references cited therein. [27] a) S.L. Buchwald, R.B. Nielsen, J. Am. Chem. SOC. 1988,110, 3171-3175; b) W.Ando, T.Ohtaki, T. Suzuki, Y.Kabe, J. Am. Chem. SOC. 1991,113,7782-7784. [28] a) S. L. Buchwald, B. T. Watson, M. W. Wannamaker, J.C. Dewan, J. Am. Chem. SOC.1989, 111, 4486-4494; b) J.M. Davis, R. J. Whitby, A. Jaxa-Chamiec, J. Chem. SOC., Chem. Commun. PNl, 1743-1745; c) N.Coles, R.J. Whitby, J.Blagg, Synlett 1992, 143-145; d) see also: A. S. Guram, R.F. Jordan, J. Org. Chem. 1992,57,5994-5999; e) enantioselective example: R.G. Grossman, W.M. Davis, S.L. Buchwald, J. Am. Chem. Sac. 1991,113,2321-2322. [29] H. Ito, T. Taguchi, Y. Hanzawa, Tetrahedron Lett. 1992,31, 4469-4472. [30] M. Jensen, T.Livinghouse, J. Am. Chem. Soc. l989,111,4495-4496. [31] a) P.L. McGrane, M. Jensen, T.Livinghouse, J. Am. Chem. SOC.1992,114,5459-5460; b) P.L. McGrane, T. Livinghouse, J. Org. Chem. 1992, 57, 1323-1324. [32] Review: a) J. Schwartz, J. A. Labinger, Angew. Chem. 1976, 88, 402; Angew. Chem. Int. Ed. Engl. 1976, 15, 333 b) see also ref. 4d); c) E. Negishi, T. Takahashi, Aldrichimica Acta 1985,18,31. [33] S.L. Buchwald, Q.Fang, S.M. King, Tetrahedron Lett. NiB, 29,3445-3448. [34] S. L. Buchwald, S. J. LaMaire, Tetrahedron Lett. M ,28, 295-298. [35] a) S.L. Buchwald, S.J. LaMaire, R.B. Nielsen, B.T. Watson, S.M. King, Tetrahedron Lett. 1987,34, 3895-3898; b) S.M. Buchwald, S.J. LaMaire, R.B. Nielsen, B.T. Watson, S.M. King, Org. Synth. 1992, 71,77-82. [36] B. H. Lipshutz, R. Keil, E. L. Ellsworth, Tetrahedron Lett. 1990,31,7257-7260. [37] R.C. Sun, M.Okabe, D.L. Coffen, J. Schwartz, Org. Synth. 1992, 71. 83-88. [38] a) B.H. Lipshutz, E.L. Ellsworth, J. Am. Chem. SOC. 1990,112, 7440-7441; b) K.A. Babiak, J. R. Behling, J.H. Dygos, K.T. McLaughlin, J.S. Ng, V. J. Kalish, S. W. Kra-

mer, R.L. Shone, J. Am. Chem. SOC.1990, 112,7441-7442. [39] P.Wipf, J.H. Smitrovich, J. Org. Chem. 1991, 56, 6494-6496. [40]P. Wipf, W.Xu, Synlett 1992,718-720. [41] T.E. Cole, R. Quintanilla, J. Org. Chem. 1992, 57,7366-7370. [42] H. Maeta, T. Hashimoto, T. Hasegawa, K. Suzuki, Tetrahedron Lett. 1992, 33, 5965-5968; see also: P. Wipf, W.Xu, J. Org. Chem. 1993, 58,825-826. [43] K. Suzuki, H. Maeta, T. Suzuki, T.Matsumoto, Tetrahedron Lett. 1989,30,6879-6882. [44]C.E. lbcker, P.Knoche1, J. Am. Chem. Soc. 1991,113,9888-9890; see also: R. D . Dennehy, R. J. Whitby, J. Chem. SOC., Chem. Commun. 1992,35-36. [451 B. H. Lipshutz, R. Keil, J. C. Barton, Etrahedron Lett. 1992,33,5861-5864. [46] M. Maeta, T. Hasegawa, K. Suzuki, Synlett 1993, 341-345. [47] a) E N . Tebbe, G. W. Parshall, G.S. Reddy, J. Am. Chem. SOC.1978,100,3611-3613; b) S.H. Pine, G.Kim, V.Lee, Org. Synth. 1990, 69, 72-79. [48] a) N.Petasis, E.I. Bzowej, J. Am. Chem. SOC. 1990,112, 6392-6394; b) N. Petasis, E. I. Bzowej, J. Org. Chem. 1992, 57, 1327-1330; c) N.Petasis, I. Akritopoulou, Synlett 1992, 665; d) N. Petasis, E.I. Bzowej, Tetrahedron Lett. 1993,34, 943-946, and references cited therein. [49] a) K. M. Doxsee, J. K. M. Mouser, Tetrahedron Lett. 1991, 32, 1687-1690; b) K.M. Doxsee, J.K.M. Mouser, J.B. Farahi, Synlett l992, 13-21, and references cited therein. [SO] Zirconium-catalyzed allylation reactions of allylic ethers: a) G.D. Cuny, S.L. Buchwald, Organometallics, 1991, 10, 363-365; b) N. Suzuki, D. Y. Kondakov, T.Takahashi, J . Am. Chem. SOC. 1993,115, 8485-8486; c) J.P. Morken, M.T. Didiuk, A.H. Hoveyda, J. Am. Chem. SOC. 1993, 115, 6997-6998; 3Oxacyclohexyne-zirconocene complex : M. C. J. Harris, R.J. Whitby, J.Blagg, Synlett 1993, 705-707. Insertion of alkynes and alkenes into a cationic iminoacyl-zirconocene-complex: A.S. Guram, R.F. Jordan, J. Org. Chem. 1993, 58, 5595-5597. Intermolecular pinacol cross-coupling of anionic zirconaoxiranes with

Carbon-Carbon Bond Formation with Group Four Metallocenes

aldehydes: F. R. Askham, K. M. Carroll, J. Org. Chem. 1993,58,7328-7329. [51] a) G. Erker, Nachr. Chem. Tech. Lab. l992,40, 1099-1104; b) G. Erker, M. Albrecht, C.Kriiger, S.Werner, J. Am. Chem. SOC. 1992, 114, 8531-8536; c) M. Albrecht, G. Erker, C. Kriiger, Synlett 1993,441-448. [52] a) W. Kaminsky, K. Kiilper, H. H. Brintzinger, F.W. R.P. Wild, Angew. Chem. 1985, 97, 507-508; Angew. Chem. Int. Ed. Engl. 1985, 24, 507. b) J.W. Roll, H.-H. Brintzinger, B.Rieger, R.Zalk, Angew. Chem. 1990, 102,

113

339; Angew. Chem. Int. Ed. Engl. 1990,29, 279. c) G.Erker, Pure Appl. Chem. l992,64, 393-401; d) R. E Jordan, P. K. Bradley, R. E. LaPointe, D. F. Taylor, New J. Chem. 1990,14, 505-511; e) R.F. Jordan, Adv. Organomet. Chem. 1991,32,325; f) S. Collins, D. G. Ward, J. Am. Chem. SOC. 1992,114, 5460-5462; g) G. Erker, M. Aulbach, M. Knickmeier, D. Wingbergmiihle, C. Kriiger, M. Nolte, S.Werner, J. Am. Chem. Soc. 1993, 115, 4590-4601, and references cited therein.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Aluminum Enolates Herbert Waldmann

For the directed and highly selective formation of C-C bonds metal enolates are efficient reagents. Their reactivity is determined decisively by the nature of the respective metal ions. Thus, enolates embodying counterions of the first and the second main group, tin or zirconium and the respective titanium [l]and boron [2] reagents have been applied in numerous cases in organic synthesis. In addition, aluminum enolates have recently been added to the tools of current synthetic methodology. Aluminum enolates can be generated by various techniques, for example, by nickelcatalyzed [3a, b] or photochemically initiated [3c, 91 conjugate addition of aluminum alkyls to a,gunsaturated carbonyl compounds, by conjugate addition of the group "X" embodied in Lewis acids R&X (X = SPh, [3d] SeMe, [3d] C=CR, [3e] H [3f, g, 5, 61)

or the alkyl moiety of R,AlCI [3c] to these electrophiles, and by direct deprotonation of a carbonyl compound and trapping of the enolate with an aluminum amide or phenolate. [3h, i] However, in the majority of cases a transmetalation of an analogous lithium enolate is carried out (see below). The aluminum alcoholates and the corresponding alkali metal derivatives often display distinctly different reactivities. Thus, cyclohexene oxide (I) reacts with lithium tert-butyl acetate to give (2) in only 8 YOyield, whereas the diethylaluminum intermediate makes this alcohol available in 68% yield. [4a] If enantiomeric-

Ph-JOM,

(3)

(4) (iBugAIH. MeCu. HMPTA, 50 "C

4 O U

OtBu

fsUo+

1

A U ,

w+

quant.

PhJ-OM.

94%

B. Organometallic Reagents in Organic Synthesis

116

(50) R'. (Sb)

R':

d.: =Q Ot Bu

d.: H

R' R2

=O

72

50

70

10 -0 10 Ot8u. H

0th. H

J-4 vitamin D,

(15)

04)

Scheme 1. Conjugate reduction and electrophilic substitution of the indane derivatives (5) and (11) via aluminum enolates.

Aluminum Enolates

ally homogenous (S)-propylene oxide is used the respective transformation proceeds with a stereoselectivity of 94:6. [4b] The selective conjugate reduction of a,punsaturated aldehydes, ketones and esters (e.g., (3) and (4)) can be carried out by protonation of the aluminum enolates that are formed by addition of diisobutylaluminum hydride (DIBAH) to the vinylogous carbonyl compounds. [3f, 5, 61 However, the desired selectivity and a sufficient reactivity are only achieved if a copper alkyl and HMPTA are added. Under these conditions the competing 1,Zaddition does not occur and additional carbonyl groups present also remain unaffected. If the enolates are quenched with alkyl halides instead of acids, the corresponding a-alkylated esters, ketones and aldehydes are formed in high yield. [3g, 61 These transformations have proven their efficiency, for instance, in the construction of steroids [3f, 5, 61 (Scheme 1). By this means the chemoselective reduction of the tetrahydroindanedione ( 5 4 , which is available in enantiomerically pure form by the Hajos-Eder-Sauer reaction, to give the trunsdiketone (7) with a trunslcis selectivity of 30:l can be carried out. [5b] In the course of the alternative catalytic reduction, on the other hand, the cis-configured product is predominantly generated. If the intermediate (6u) is trapped with aldehydes, ally1 bromides, acyl chlorides or bromine, the truns-hydrindanedions (8u) are obtained. [6a] After transmetallation with ZnC12, (66) was thioalkylated successfully with a-chloro-Zphenylthioalkanes. [6d] Compound (8u) (R = Br) can be converted in a few steps to the alcohol (9), a well known congener to vitamin D3 and its hydroxylated analogs. From the aldol adduct (8u) (R = rn-MeOPh-CH2-CH(OH)-) estrogens like 9-(ll)-dehydroestrone-3-methylether (IOU) can easily be generated. [6c] However, for this purpose the use of the thioalkylation product (ah) seems to be more advantageous. [6d] Finally, this synthetic strategy opens a route to compactin (15) (Sche-

117

me 1). [6e] The (-)-enantiomer of the ketone (5u) reacts with the protected yhydroxyaldehyde (12) to give the diastereomeric mixture (13) (isomer ratio 2:l). After chromotagraphic separation the main component of (13) was transformed into the alcohol (14), a known precursor of compactin. The application of aluminum enolates may also be beneficial in aldol reactions [3b, d, i, h, 71 and nucleophilic additions to Schiff’s bases. In a particularly impressive manner this is demonstrated by the reactions of aldehydes with the chiral iron complexes (16) (Scheme 2). [7] Whereas the lithium enolates of the acetyl complexes ruc-(16u) and the propionyl complex ruc-(166) (R = CH3) react with aldehydes with virtually no stereocontrol, the aluminum compounds ( 1 7 ~ )and (176), which were generated by transmetallation with Et2AlCl, deliver the /3-hydroxyacyl complexes ( H a ) and (18b) at -100°C with high isomer ratios. [7b, c, d] In these transformations ( 1 6 ~ )proves to be a highly diastereoselecting acetate aldol equivalent, whereas the propionyl derivative (16 6) after oxidative decomplexation, makes predominantly the anti-aldols (19b) available. With other established auxiliaries both classes of aldol adducts are accessible with high diastereomeric excess in only a few cases. If the corresponding enantiomerically pure iron complexes are introduced instead of ruc-(16), asymmetric syntheses can be carried out. The reaction of (S)-(16u) with Boc-prolinal (20) gives the aldol adduct (21) with a selectivity of 300:l (Scheme 2). [7e] After removal of the N-protecting group and oxidative decomplexation from (21) the pyrrolizidinone (22) is formed. Analogously, to assign the absolute configuration of some marine peroxides, (S)-(16b) was converted to the acyloxy iron complex (23) (unti:syn = 15:l). [7f] If ( 1 7 ~is) treated with imines (24) or nitrones aminoacyl iron complexes (25) are formed with high diastereoselectivity. [7b] On treatment with bromine in CS2 they cyclize to give

118

B. Organornetallic Reagents in Organic Synthesis

diastereomeric ratio 20 to 25 : 1

(26) 56 - 82 %

(25)

rac-(16a): R = H rac-(Gb): R = CHs R1 = Me, Et, Bzl, iPr, t Bu, Ph

(19b): R

Ho*R' 0

&-go%

diastereomeric ratio 20: 1 to > loo: 1 for (18a)

83 %

J

R

(19a): R = H

OH

CH3

R' = Me, Et, i Pr, t Bu; 86 - 90 % anti: syn > 10: 1

(1% b)

(22)

75 %

Scheme 2. Stereoselective aldol reactions employing aluminum enolates of the chiral iron complexes rac-(16a, b), (S)-(16a) and (S)-(16b).

Aluminum Enolates

the lactams (26). By analogy, the aluminum enolates of simple carboxylic acid esters and amino acid esters directly give p-lactams. [8] Aluminum enolates can also be advantageously employed in asymmetric syntheses with a,Punsaturated N-acyl urethanes, for example, the oxazolidinone (27). [3c] Thus, Et2AlCl reacts with this electrophile in an ionic reaction to form (28a), which, after work up, delivers the Pbranched amide (29u) in high yield and with a diastereomer ratio of 93:7. On the other hand, after photochemical initiation, the conjugate addition of MezAICl proceeds by a radical mechanism. Such a pathway is unexpected for the combination of a strong Lewis acid with the polar acceptor (27). Furthermore, the intermediates (28) can be oxidized stereoselectively with triplet oxygen (if Me,AlCl is used) or with sulfoxaziridine (30) (if EtzAICl is used) to give Pbranched ahydroxy acid derivatives like (31). Aluminum enolates play a particularly interesting role in the development of a new method for the photochemically induced fixation of C 0 2 (Scheme 3). [9] The transformations employed for this purpose are based on the observation that the nucleophilicity of

119

axial ligands in (tetrapheny1porphyrinato)aluminum complexes [(TPP)Al-XI, for example, (32), can be enhanced by irradiation with visible light. If, for instance, the enolates (32u) (obtained from (TPP)Al-NEt, and aromatic ketones) are irradiated in the presence of Nmethylimidazole and COz, they add to the dioxide and the Pketocarboxylate complexes (33) are formed, from which the Pketo acids (34) can be obtained in high yield. [9a] This reaction sequence can be regarded as an analogy to the biological assimilation of CO, during which pyruvate is carboxylated to oxaloacetate via phosphoenolpyruvate. Malonic acid derivatives are obtained if (TPP)aluminum alkyl complexes (32b) are irradiated in the presence of a,/hnsaturated esters like (35) and C 0 2 (Scheme 3). [9b] Under these conditions, first a conjugate addition of the aluminum alkyls to the vinylogous carbonyl system occurs, and the enolates (36) formed thereby then react with C 0 2 to give the malonate complexes (37). On addition of diethylzinc this process proceeds even catalytically. If C 0 2 is excluded in these experiments, (36) undergoes conjugate addition to surplus a,Punsaturated ester to generate (38), which

120

B. OrganometallicReagents in Organic Synthesis

R

-

CHS. EZ iPr. Eu

R = CH,: 83 X R = Et: 67% 7"s " O p - 9- C H 2 w s 0

-

-= Mil

COOtBu

EE

%-x

d

1.08-1,20

M"

x

-

7'

= o-c=w-# P p N x (a) b X Ue,.Et c: X = NEt2 Scheme 3. Photochemically initiated fixation of C 0 2 using (tetraphenylporphyrinat0)-aluminumenolates. a:

can then undergo the same transformation again. [Sc, d] Overall, the continuation of this reaction sequence allows for an anionic polymerization of the electron-deficient olefin in a process that has strong similarities to the well known group transfer polymerization. By this method living polymers with a narrow molecular weight distribution are built up, which can also be employed for the construction of block copolymers. In the light of the examples highlighted above it may be expected that the variation of the metal in enolate chemistry also in future research will provide surprising and unexpected results. In particular the aluminum

enolates that have not been studied intensively so far may offer new opportunities for the development of new synthetic methodologies.

References [l] K.H. Dotz, Nachr. Chern. Tech. Lab. 1990,38, 1244. [2] M.Braun, Nachr. Chern. Tech. Lab. 1990, 38, 1244. [3] a) E. A. Jeffrey, A.Meisters, T.Mole, J . Organomet. Chem. 1974, 74, 365; b) E.A. Jeffrey, A. Meisters, T. Mole, J . Organomet. Chem. 1974, 74, 373; c) K.Riick, H.Kunz, Angew.

Aluminum Enolates

121

Chem. 1991,103, 712; Angew. Chem. Int. Ed. [7] a) Review: S.G. Davies, Aldrichimica Acta FBO,23, 31, b) L.S. Liebeskind, M.E. Welker, Engl. 1991, 30, 694; d) A.Itoh, S.Ozawa, R. W. Fengl, J. Am. Chem. SOC. 1986,108,6328; K. Oshima, H. Nozaki, Tetrahedron Lett. 1980, c) S. G . Davies, I.M. Dordor-Hedgecock, 361; e) J. Schwartz, D. B. Can, R. T. Hansen, P.Warner, R. H. Jones, K. Prout, J. Organomet. EM. Dayrit, J. Org. Chem. 1980, 45, 3053; f ) Chem. 1985, 285, 213; d) S.G. Davies, I.M. T. Tsuda, T. Hayashi, H. Satomi, T. Kawamoto, Dordor-Hedgecock, J. C. Walker, P. Warner, TetT.Saegusa, J. Org. Chem. 1986, 51, 537; g) rahedron Lett. 1985,26, 2125; e) R.P. Beckett, T.Tsuda, H. Satomi, T.Hayashi, T. Saegusa, J. S.G. Davies, J. Chem. SOC., Chem. Cornmun. Org. Chem. 1987, 52, 439; h) H.Nozaki, 1988, 160; f) R. J. Capon, J.K. MacLeod, S. J. K.Oshima, K.Takai, S.Ozawa, Chem. Lett. Coote, S.G. Davies, G.L. Gravatt, I.M. 1979, 379; i) J.Tsuji, T.Yamada, M.Kaito, Dordor-Hedgecock, M. Whittaker, Tetrahedron T. Mandai, Tetrahedron Lett. EV9, 2257. 1988,44, 1637. [4] S. Danishefsky, T. Kitahara, M. Tsai, J. Dynak, J. Org. Chem. l976, 41, 1669; b) T.-J. Sturm, [8] F.H. van der Steen, G. P. M. van Mier, A. L. Spek, J.Kroon, G. van Koten, J. Am. Chem. A.E. Marolewski, D.S. Rezenka, S.K. Taylor, SOC. 1991,113, 5742-5750 and references given J. Org. Chem. 19119,54,2039. therein. [5] a) T. Tsuda, T. Kawamoto, Y. Kuwamoto, T. Saegusa, Synth. Commun. 1986, 639; b) A.R. [9] a) Y. Hirai, T. Aida, S. Inoue, J. Am. Chem. SOC. 1989, 111, 3062; b) M.Komatsu, T.Aida, Daniewski, J. Kiegiel, Synth. Cornmun. 1988, S.Inoue, J. Am. Chem. SOC. 1991,113, 8492; c) 115. M.Kuroki, T.Aida, S.Inoue, J. Am. Chem. [6] a) A. R. Daniewski, J. Kiegiel, E. Piotrowska, SOC. 1987, 109, 4737; d) M.Kuroki, T.WataT. Warchol, W. Wojciechowska, Liebigs Ann. nabe, T.Aida, S.Inoue, J. Am. Chem. SOC. Chem. 1988, 593; b) A.R. Daniewski, J.Kiegiel, J. Org. Chem. 1988, 53, 5534; c) A.R. 1991,113,5903-5904. Daniewski, J.Kiegie1, J. Org. Chem. 1988, 53, 5535; d) U. Groth, T. Kohler, T. Taapken, Tetrahedron 1991,36, 7583; e) A.R. Daniewski, M.R. Uskokovic, Tetrahedron Lett. 1990, 31, 5599.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

C. Silicon in Organic Synthesis Selective Transformations with Pentacoordinate Silicon Compounds Dieter Schinzer Selective reactions with acyclic systems are still a challenge in organic synthesis. [l] Besides selectivity the reagents used should be easily accessable, easy to handle, and the reactions should be simple to operate. Especially in organo metallic chemistry very useful reagents have been introduced during the last decade. [2-51 In particular silicon was of interest, because many transformations of vinyland ally1 silanes with acceptor groups have been reported. [6-91 In the following paragraph a permanent growing part in organosilicon chemistry is presented: reactions with pentacoordinate silicon compounds. Silicon atoms can be penta- and hexacoordinated besides the normal four bonds. Compact and electronegative ligands like fluorine are required to increase the degree of coordination. [lo] The driving force in such reactions is the relative high Lewis acidity of silicon (Scheme 1).[ll] R-F

+ Six,$

R-F-SIX,

R+

+ FSiX,-

Scheme I

This type of pentacoordinated compounds is a very mild Lewis acid, because the negative charge is stabilized by electronegative ligands. This combination of properties makes these reagents quite promising in reactions with acceptor groups. Commercially available hydrosilanes of type (2) reduce carbonyl groups in the pre-

sence of fluoride ions to the desired alcohols (Scheme 2). [ 121

The advantage of this new method is that no expensive metal catalyst is required because the intermediate formation of the pentacoordinated hydridosilicates activates the carbonyl group like a Lewis acid and transfers the hydride ion to yield the alcohol (Scheme 3).

d-7

[L4Si-H] 0

hydride source

A

I

weak Lewis acid

Scheme 3

The chemical yields in reductions of carbonyl groups are in general high. 2-Amino- and 2-hydroxyketonescannot be reduced at all or only with low diastereoselectivity using classical reagents. On the other hand hydridosilicates generated in situ reduce these compounds with excellent chemical and stereochemical yield (Scheme 4). [12] Besides the regio- and chemoselectivity perfect control of stereoselectivity is obtained, as shown in the reduction of 2-methylcyclo-

124

C. Silicon in Organic Synthesis

0

OH

bw’ 0 OH

Me

anti :syn

-

> 99

: 1

PhMezSiH

(12)

(13)

anti :syn = 76 : 24

Scheme 6

anti: syn = 96 : 4

The anti-selectivity observed in acyclic systems can be explained by the Felkin-Anh model for transition states, which is based on steric interactions. [13] It should be mentioned that in no case has racemization been observed. For example, (S)-Zacetoxy-1phenylpropanone (14) (88 % ee) was reduced to give (lS, 2S)-phenyl-1,2-propanediol,also in 88 % ee (Scheme 7).

(14) 88% ee

(15) 88% ee anti: syn

Scheme 7

au (10) Me

= 95 : 5

E)H

0%

The reduction described can also be run under acidic conditions but with the opposite ( 1 1 ) Me stereochemical result: with excellent stereoanti : syn = 86 : 14 chemical yields the syn-products are obtained. These results can be explained by the use of Scheme 4 the cyclic Cram model for transition states. hexanone (12) to give trans-Zmethyl- [14] Again, the operation is very simple: cyclohexanol (13) in 94 % stereoselectivity instead of fluoride ion, trifluoroacetic acid (TFA) is added (Scheme 8). (Scheme 5 ) . B

> (12)

U

Y 86%

+e

(13)

anti : syn

anti :syn

= 94 : 6

Scheme 5

The selectivity obtained can be directly correlated with the bulkiness of the ligand used at silicon: If a phenyl group is replaced by a methyl group the selectivity drops to 76 % , as shown in the reaction (12)+(13) (Scheme 6).

Ph&NHSO$’h (17) Me

= 7 : 93

:7m,

ph$,NHSO*Ph

0%

(18) Me

66x

anti: syn = 2 : 98

‘TFA = trifluoroacetic acid

Scheme 8

a''

Selective Transformations with Pentacoordinate Silicon Compounds

In order to demonstrate the usefulness of this stereoselective reduction in asymmetric synthesis two syntheses of simple, but pharmacologially active, compounds will be presented. [12] Compounds (19) and (22) are reduced diastereoselectively to (20) and (23) using the reducing system diphenyl methyl silane in the presence of WA. Compound (20) is reduced again with LAH to give Lephedrine (21) in 80% yield, and (23) is hydrolyzed with KOH to give L-methoxamine (24) in 84 % yield (Scheme 9).

a n t i : syn = WH, --+ THF

60O C

OH

&Me

Ph

~

80%

Me0 @NHCOOEt 0

1 ; 99

+ HSICI,

i h

4 THF

OLi

(25)

[aO\~/OO]

(26)

0

'0

Li 0

0 '

(27)

OCH' (27)

3

96%

(29)

(28)

8"o (32)

(21) NHMe L-ephedrine

<

2

125

(27)

,

D

O

H

85%

(33)

0

(34)

Scheme 10 Me0

(22)

The same group has isolated for the first time a compound of type (27). [161 C-C bond formation with allyl metal reagents is a very important reaction in organic synthesis. Reagents based on boron, [2] sili(23) con, [17] tin, [5] and titanium [18] have been anti : syn = < 1 : 99 studied extensively. Even more important in this context are transformations using crotyl metal compounds in 1,Zadditions to aldeMeo (24) hydes. This type of transformation creates L-rnethoxamine homo allyl alcohols containing two new asymScheme 9 metric centers. In addition, these compounds Sakurai et al. have reported another entry can be transformed into Fhydroxy carbonyl to these new reducing reagents starting from compounds by oxidative cleavage, so the overtrichlorosilane and dilithio catecholate. The all transformation is equivalent to the aldol silicate (27) obtained in situ, is stable in solu- reaction. [19] Mixtures of 2- and E-crotyltrimethylsilanes tion, reduces aldehydes and ketones, but does not reduce esters like (34) (Scheme 10). [15] react with aldehydes in a stereoconvergent

126

C. Silicon in Organic Synthesis

way to yield syn-homo allylic alcohols. The reaction is promoted by titanium tetrachloride (Scheme 11). [17] OH

Scheme 11

The stereochemical outcome can be explained by an acyclic open transition state. [2] It is therefore impossible to synthesize anti-homo allylic alcohols by the use of crotyl silanes. The problem can be solved by the use Scheme 13 of pentacoordinate silicates as shown by Sakurai et al. [20, 211 Reaction of allyltrichlorosi- -SiF3 lane in the presence of dilithio catecholate (39) generated (36), which adds diastereoselectiv0 ity to aldehydes without additional Lewis SiF, W acids (Scheme 12).

0

MF

+ CsF +WSIF,

Cs'

(40)

Cs'

+ RCHO +

(40)

(35)

(4 1)

R2YR1

R R R R

= Ph = n-CgH,, = CH3(CH2),CH(C2H,) = PhCH4H2

(42)

92%;onti: syn 96%; onti: syn 68%;anti: syn 77%; unti: syn

= 99 : 1 = 99 : 1 = 99 : 1 = 98 : 2

R2YR1 19

PhCHO

+

(37) OH

w

ph*

R2 R'

(38)

Scheme 12

R' = R2 = H R1 = R2 = Me R' = Me, R2 = H anti: syn = 88

90% 80% 82% : 12

R1 = H, R2 = Me 91% anti: syn = 22 : 78

(46)

R = Ph R = n-C8Hl7 R = CH3(CH2),CH(C,Hd R -i: PhCHSCH,

Scheme 14

-

96%;anti: syn = 1 :99 8 9 % anti: syn 2 :98 8 9 %onti: syn = 2 : 98 77%;anti: syn = 2 :98

Selective Transformations with Pentacoordinate Silicon Compounds

The high degree of diastereoselectivity is consistent with a six-membered cyclic transition state, [2] in which, because of the electrophilic properties of silicon, a hexacoordinate silicon species is involved (Scheme 13). Therefore both syn- and anti-homoallylic alcohols can be obtained with this new class of reagents, dependent whether 2- or Ecrotyltrichlorosilanes are used as starting materials. The simplest way to carry out this transformation is to use of crotyltrifluorosilanes in the presence of CsF in THF. [20] Stereochemically homogeneous synthesis of either (42) or (46) is obtained by using pure Zor E-trifluorocrotylsilanes, respectively (Scheme 14). The results presented in this chapter clearly show that reductions and C-C bond forming reactions with pentacoorinate silicates are powerful means to construct various types of alicyclic compounds diastereoselectively.

References P.A. Bartlett, Tetrahedron 1980,36, 3. R. W. Hoffmann, Angew. Chem. 1982,94,569. Angew. Chem. Int. Ed. Engl. 1982, 21,555. M.T. Reetz, Top. Curr. Chem. 1982,106, 1. B. Weidemann, D. Seebach, Angew. Chem. Angew. Chem. Int. Ed. Engl. 198), 22, 474.1983,95, 12.

127

[5] Y. Yamamoto, K. Maruyama, Heterocycles E%2,18,357. [6] T.A. Blumenkopf, L.E. Overman, Chem. Rev. l986,86, 857. [7] I. Fleming in (Eds. : D.H. R. Barton and W. D. Ollis) Comprehensive Organic Chemistry, vo1.3., Pergamon Press, Oxford, 1979,541. [8] H.Sakurai, Pure Appl. Chem. l982,54, 1. [9] D. Schinzer, Synthesis 1988,263. [lo] H.Biirger, Angew. Chem. 1973, 85, 519. Angew. Chem. Int. Ed. Engl. 1973,12,474. [ll] H.Sakurai in Selectivities in Lewis AcidPromoted Reactions, (Ed. : D . Schinzer), Reidel, Utrecht-Boston, 1988 [12] M. Fujita, T. Hiyama, J. Am. Chem. SOC.1984, 106,4629. [13] M. ChCrest, H.Felkin, N.Prudent, Tetrahedron Lett. 1968,2199. [14] D. J. Cram, D. R. Wilson, J. Am. Chem. SOC. l963,85, 1245. [15] M.Kira, K.Sato, H.Sakurai, J. Org. Chem. 1987,52,949. [16] M. Kira, K.Sato, H. Sakurai, Chem. Lett. 1987,2243. [17] T. Hayashi, K. Kabeta, I. Hamachi, M. Kumada, Tetrahedron Lett. 1983,2865. [18] M.T. Reetz, M. Sauenvald, J. Org. Chem. l984,49,2293. [19] C.H. Heathcock, Science EN,214, 395. [20] M. E r a , M. Kobayashi, H. Sakurai, Tetrahedron Lett, 1987,4081. [21] M.Kira, K.Sato, H.Sakurai, J . Am. Chem. SOC. 1988,110,4599.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Oxidative Cleavage of Silicon-Carbon Bonds Dieter Schinzer

The masking of functional groups as so-called “synthons” is a major strategy in modern organic synthesis for handling complex multifunctionality in long step sequences. [ll] The maneuver to provide the functionality needed from a synthon should be simple and efficient. In addition, the masked group should be stable during standard chemical operations so that it can be tolerated over several steps in a synthesis; given the complexity of modern stereoselective synthesis this is no easy goal. The technique of synthons should not replace the classical protecting group but should be added for planning a rational and convergent synthesis. The following chapter deals with the masking of hydroxyl groups, which are important functional groups in almost any target molecule, such as macrolides or the natural product class of taxanes. [2] The analysis of potential groups that might be used for this purpose will almost automatically come up with a silyl group, because of its unique features: the electronic and steric behavior can be changed easily and “tuned” for the requirements needed. The trimethylsilyl group is relatively stable towards most oxidizing reagents, but if one methyl group is replaced by a fluorine atom the silyl group can be transformed into a hydroxyl group under mild conditions (silaBaeyer-Villiger rearrangement) ; [3] the same process can be achieved with higher coordi-

nated silicon compounds. [4] The silyl group acts as the synthetic equivalent of a hydroxyl group (Scheme 1). A related reaction has already been observed with acylsilanes in which an acid is

‘.-

R R+-0

__3

Ph

Scheme 1

Scheme 2

R,Si

/ \

OR OCOPh

C. Silicon in Organic Synthesis

130

formed regioselectively and under mild conditions in the presence of a peracid. [5, 61 Acylsilanes of type (1) could be transformed stereoselectively after a short sequence (deprotonation with LDA, alkylation, followed by Peterson olefination) [7] into trisubstituted a,Punsaturated acids of type (7). Acylsilanes of type (8) can be transformed diastereoselectively into the syn-aldol products of type (9). Acylsilane (9) was transformed directly in a one-pot procedure into /% hydroxy acid (10) with three defined stereogenic centers (Scheme 3). [8]

PhSe

Ph

PhKSiMe3 0

Me3SiXSiMe3 ( 1 7)

(18) 46Z

Scheme 5

The reaction of vinylsilanes with nitrile oxides leads to trimethylsilyl oxazolines. A cycloreversion is used to synthesize silylenol ethers (21) with retention of the olefin configuration (Scheme 6). [ll]

'

R g i i M e 3 CH~CNO Me 1

R

(10)

Scheme 3

Rx7e3 R (21)

I

PhSC-SiMe3 I

R I

PhSC-SiMe3 II I OH

RCHO

R I 4 PhSC-SiMe3 RX

I

R A I --3 PhSC-OSiMe3

I

H

(13)

F72 A1

R' = R2 =

H; Me H; Me

R3 = H; Me

Scheme 6

In the same category the sila-Pummerer reaction can be discussed. An a-silylsulfide is deprotonated, alkylated, oxidized, rearranged into the silyl ether, and finally hydrolyzed into the aldehyde (15) (Scheme 4). [9] An analogous reaction with selenium has been reported by Reich et al. (Scheme 5). [lo] Li

MCPBA

In addition, the transformation of vinylsilanes to carbonyl compounds via a,@epoxysilanes is a useful operation in synthesis: the reaction is directed by the regioselective opening of the epoxide (peffect of the silyl group). Depending on the position of the silyl group, either aldehydes or ketones are obtained. Therefore, all reactions leading to vinylsilanes can, in principle, be used for the synthesis of carbonyl compounds (Scheme 7). [12, 131

H30@

4

(14)

(15)

R = H, Me, Et, Pr, Bu, s-Bu, PhCH,

-

overall yield = 68 85%

Scheme 4

A

(20)

(19)

6H 0

,"

R 3 zzS i M e 3 +

MCPBA = rn-chloroperbenzoic acid

Scheme 7

Oxidative Cleavage of Silicon-Carbon Bonds

Finally, the oxidation of allylsilanes to allylicalcohols via allylselenides should be mentioned. [14] The addition of phenylselenyl bromide depends only on steric interactions, as shown in the equation (34)+(35). In the presence of H202 compounds of this type undergo an oxidative 2,3-sigmatropic rearrangement to the desired allylic alcohols such as (36) (Scheme 8).

further variation of an anti-Markownikoff hydration, via hydrosilylation of olefins (an alternative to hydroboration or hydroalumination), will be possible (Scheme 9). [15] RCH=CH2

+ HSiCI,

RCH,CH,SiC13

catalyst 1. C U F ~

2. MCPBA

>

RCHZCH20H

Scheme 9

The stereochemical outcome of the silaBaeyer-Villiger rearrangement was first studied with the norbornyl systems (37) and (39). [16] Both, the exo- and endo-derivatives react stereospecifically with retention of configuration (Scheme 10).

1. Phsecl

I

131

(37) H ex0 100%

(30)

(29)

1. PhSeCl

(38) H

ex0 100%

2. cat. SnCI,

Me35

OH

PhSe

(33)

(32) Me$i

84%

1. PhSeCl

(34)

(39) SiF3 endo 95%

Scheme 10

Optically active alcohols can be obtained by an asymmetric hydrosilylation of norbornene (41) using a chiral catalyst and subsequent oxidation (Scheme 11). A very useful application of this rearrangement chemistry has been used by Fleming et al. [17, 181 The addition of silyl cuprates to Michael systems and subsequent alkylation of the in situ formed enolate with methyl iodide provides the anti-compound (46) diastereoselectively, probably via a chelated transition state (47) (Scheme 12). The phenyldimethylsilyl group used has the advantage of smooth protodesilylation [191 to form the fluoro compound, which can be transformed stereospecifically into the alcohol (48) (Scheme 13).

> ySePh OAc OH OAc H20z

(35)

(36) 68%

Scheme 8

The most important area using oxidative cleavage reactions of silyl groups is the treatment of “unactivated” alkyl- or aryl groups. Scope and limitations of this type of transformations will be presented in the following paragraph. Penta-coordinated silicates can be used as well as fluorosilanes. [4] In addition, a

I

(40) OH endo 953;

C. Silicon in Organic Synthesis

132

JKF Scheme 14

WOMe % R k PhMe2Si

PhMe i R

(R,S) - PPFA-Pd

Scheme 11

'

R1AR2 (45)

(44) 1. (PhMe,Si)CuLi

2.Mel

R 1 = Ph, Me, n-C6H13

(53)

H

uR2

R1

,,,C02Me

(54)

OH

OAc

-

Me (46)

R2 = H, Me, Ph, OMe, OEt

(4 7) Scheme 12

Scheme 13

Besides acyclic compounds, cyclic compounds like (49) or (51) can also be used. Again, synthetically useful intermediates (50) or (51) are obtained stereoselectively by simple operations (Scheme 14). Furthermore, psilyl enolate (53) yields aldol products diastereoselectively in reac-

Scheme 15

tions with aldehydes. Therefore, a third chiral center can be controlled and was transformed into the important 1,3-diols (55) by a silaBaeyer-Vdliger reaction (Scheme 15). [20] The phenyldimethylsilyl group is used for three purposes: 1) It stabilizes the silyl cuprate; 2) Smooth protodesilylation to form the fluoro compound; 3) Stereospecific rearrangement into the alcohol. Therefore, the properties of masked alcohols are completely different from those of alcohol protecting groups (silyl groups are more electropositive, have poor conjugatingproperties, and have no lone pairs available). Retro-Michael reactions are not possible with Esilyl-substituted ketones, in contrast to Ehydroxy ketones. Instead of a phenyl group a furan ring has been used very successfullyin a total synthesis of reserpine (56) reported by Stork et al. (21) A central problem in this synthesis is the construction of the highly functionalized E-ring (63) with its five asymmetric centers. Com-

Oxidative Cleavage of Silicon-Carbon Bonds

133

formed into the fluoride, and finally rearranged, both in sila-Baeyer-Villiger- and “classical” Baeyer-Villiger-fashion, to obtain (60). The lactone (61) is cleaved with DIBAL into the monocyclic structure (63),which contains five asymmetric centers. A master piece in strategy (Scheme 16)! In summary, the oxidative cleavage of silicon-carbon bonds is a very useful tool in organic synthesis. It is the perfect technique to mask hydroxyl groups. An application in the total synthesis of a complex natural product has also been given that demonstrates the importance of this reaction sequence.

References

OMe

Scheme 16

(63)

pound (57), a synthetic equivalent of (58), is first used in a Diels-Alder reaction, trans-

D.Seebach, Angew. Chem. 1979, 91, 259. Angew. Chem. Int. Ed. Engl. 1979,18,239. D. Schinzer, Nachr. Chem. Tech. Lab. 1989,37, 172. E.Bunce1, A.G. Davies, J. Chem. SOC. 1985, 1550. D.Schinzer, Nachr. Chem. Tech. Lab. 1989,37, 28. G. Zweifel, S. J. Backlund, J. Am. Chem. SOC. 19TI,99,3184. J.A. Miller, G.Zweife1, J. Am. Chem. SOC. l98l,103,6217. D.J. Peterson, J. Org. Chem. 1%8,33,780. D.Schinzer, Synthesis, 1989,179. D. J. Ager, R. C. Cookson, Tetrahedron Lett, 19&0,21,167. H.J. Reich, S.K. Shah, J. Org. Chem. 19R, 42, 1773. R.F. Cunico, J. Organomet. Chem. 1981,212, C 51. G.Stork, E.W. Colvin, J. Am. Chem. SOC. l97& 93,2080. B.-G. Grobel, D. Seebach, Angew. Chem. 1974, 86, 102. Angew. Chem. Int. Ed. Engl. 1974,13,83. H. Nishiyama, K. Itagaki, K. Sakuta und K.Itoh, Tetrahedron Lett., l98l,22, 5285. [15] J. L. Speier,Adv. Organomet. Chem., 1979,17, 407.

134

C. Silicon in Organic Synthesis

[16] T. Hayashi, K. Tamao, Y. Katsuro, L. Nakae, M. Kumada, Tetrahedron Lett. 1980,21, 1871. [17] W. Bernhard, I. Fleming, D. Waterson, J. Chern. SOC. Chem. Commun. 1984,28. [18] I.Fleming, R.Henning, H.Plaut, J. Chem. Soc. Chem. Commun. 1984,29.

[19] D. Habich, F. Effenberger, Synthesis 1979,841. [20] I.Fleming, J. D. Kilburn, J. Chem. SOC.Chem. Commun, BNi, 305. [21] G . Stork, “Merck-Schuchardt-Lectureship l!)88”,Universitat Hannover; Pure and Appl. Chem. 1989,61,439.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Temporary Silicon Connections Martin Maier

Many chemical reactions can in principle lead to the formation of isomers. Therefore the efficiency of a certain transformation is determined not just by the yield but to what extent the selectivity can be controlled. The problem of selectivity can embrace many forms: chemoselectivity (differentiation between different functional groups of a molecule, regioselecriviry (relative orientation of reacting components), diusrereoselecrivity (control of relative stereochemistry), and enantioseZectivity (control of the absolute stereochemistry). [l] Usually, selectivity is determined by both reaction partners. Depending on which of the components exerts the dominant effect one refers to either of reagent- or substrate control. With a view to enantioselective syntheses, the development and application of chiral reagents that exert selectivity through reagent control is very important. On the other hand, in the synthesis of complex natural products, substrate control has been and still is the prominent strategy to induce, for example, regio- and diastereoselectivity. In this area, a high level of sophistication has been reached. [2] Nevertheless, there is still room for further progress since not all problems in the area of substrate control have been solved. [3] For example, the diastereoselective functionalization of a prochiral center across several bonds (remote stereocontrol) is only possible in special cases with high selectivity. Reactions in which the inherent substrate control leads to

the wrong isomer are also problematic in this regard. An elegant possibility even to enforce regio- and diastereoselectivity involves using temporary connections, which through cyclic transition states or templates guarantee an unequivocal and predictable course of a reaction and which can be removed easily after the end of the reaction. Accordingly, carbonheteroatom- and heteroatom-heteroatom bonds are be taken into consideration. Each of these bonds can appear as part of different functional groups. In and of itself, this strategy has been known for a long time, although recently, particularly through the use of silicon, there have been some interesting developments, which shall be described in this account. The same regularities that make conventional intramolecular reactions so powerful also apply, of course, to the use of temporary connections, but in addition impose some restrictions. Because bifunctional substrates are used in ring formation, the formation of oligomers or polymers as byproducts is possible. By considering entropic effects and ring strain, some general rules for ring closure can be derived. [4] Cyclization reactions to give 57-membered rings proceed faster than the corresponding intermolecular reactions. Smaller rings (3- and 4-membered) form less readily because of ring strain in the transition state. The most difficult rings to close are medium-

136

C. Silicon in Organic Synthesis

sized (8-11-membered) rings, because in these cases torsional and transannular interactions destabilize the transition state. Although larger rings (12- and higher membered) are almost free of strain, the unfavorable entropy prevents the reaction rates from being adequately high. Therefore, in the planning of temporary connections, the dependence of the activation bamer on the ring size must be taken into consideration. Depending on the number of atoms that are part of the temporary connection, one can easily reach a zone that is unfavorable for cyclization. There are other factors than ring size that influence the tendency of ring formation. Of great significance are steric effects on the chain connecting the reaction centers, such as backbone effects, [5] the gem-dialkyl effect, [6] and the oxygen effect. [4a] Stereoelectroniceffects at the reaction centers that take part in the cyclization are primarily responsible for the selectivity, which makes temporary connections so attractive. Depending on the hybridization of the atom that is attacked in the course of the cyclization, we can distinguish between tetragonal, trigonal, and digonal processes. Reactions at such centers have ideal transition state geometries, which logically cannot be achieved for all ring sizes in a similiar way. Deviations from these ideal, strainfree geometries will considerably destabilize the corresponding transition state. Therefore, ring closing reactions that can give rise to isomers usually have a high preference in favor of one or other isomer. The ring closures rules, formulated by J.E.Baldwin, [7] are valid for nucleophilic, electrophilic, and radical reactions. Why is silicon now especially so interesting for use as a position of cleavage? On the one hand, bonds of elements to silicon are longer than the corresponding bonds to carbon (cf. C-0 = 143 pm; Si-0 = 164 pm). Therefore, in cyclization reactions leading to small or middle-sized rings strain effects are smaller and the cyclization proceeds faster. On the

other hand, silicon-containing connections can be installed very easily. Thus, dialkyldichlorosilanes are more reactive than the corresponding carbon compounds and are therefore quite appropriate for the preparation of silicon connections. In particular, siliconcarbon bonds, which can also be incorporated advantageously in temporary connections, may subsequently be used in several ways. For example, it is possible to cleave and functionalize such a bond by protodesilylation, halogenation, or by silicon-Baeyer-Villiger rearrangement. [8] Finally, reactions can be performed with silicon compounds that are not possible in the carbon series. An example is hydrosilylation, which can be used, particularly in the intramolecular variant, for the regio- and stereoselective functionalization of olefins and carbonyl groups. However, this does not mean that other types of connections, such as those that contain C-0 bonds, are less important. Given that various connections are predestined for certain applications, they complement each other. For example, one can use C-0 connections in Wittig and Wittig-Homer reactions, respectively, whereby the intramolecular execution of the reaction secures the configuration of the newly formed double bond. [9] In the area of cycloaddition reactions ester groups are frequently used to make the two components react in a regio- and stereocontrolled manner. [lo] At the same time these tethers allow the incorporation of functional groups. Further possibilities for the application of temporary C-O connections lie in the regio- and diastereoselective functionalization of chiral olefins, such as homoallyl alcohols.

P I

In addition, temporary C-O connections are a valuable tool for stereocontrol in the area of radical reactions. [12] In one instance the electrophilic addition of allylic alcohols (often cyclic) to ethyl vinyl ethers is used to prepare mixed acetals (1) with a halogen atom in the a-position. The corresponding radicals

Temporary Silicon Connections

(7) BugSnH, AlBN

137

1

Et (5)

(4)

___)

&x (6)

which add with complete regio- and stereospecificity to the double bond, can be generated from these halo acetals. [13] On the one hand, 5-exo-trig-cyclizationsare favored compared with 6-endo-trig-cyclizations;on the other hand, a strain-free transition state is possible only in the case of a cis-annulation. A substantial extension of this methodology for the functionalization of allylic alcohols rests on the use of bromomethyldimethylsilyl ethers instead of the halogen acetals as radical precursors. [141 The corresponding radical cyclization also leads primarily to the 5membered product (5). Because this temporary connection can be dismantled to hydroxymethyl- or methyl groups, it represents a versatile procedure. It is precisely here that one recognizes how silicon connections expand the synthetic methodology. Crimmins et al. used this method in the course of the synthesis of the spiroacetal talaromycin A (10). The allylic alcohol (7) was converted to the ether (8) with bromomethyldimethylsilyl chloride. Radical cyclization led

to (9), which furnished the hydroxymethyl group on oxidative cleavage of the carbonsilicon bond. [15] It is remarkable that the addition of the radical takes place to an enol ether, since carbon radicals exhibit rather nucleophilic character and react preferentially with electron-poor olefins. It speaks in favor of the addition that a radical stabilized with an oxygen atom is being formed. [16] If the double bond to which the a-silyl radical adds is part of a ring, 5-exo-cyclizations are generally favored. The situation is less clear in case of exocyclic ally1 alcohols, as shown by Koreeda. [17] With an a-silyl radical in an axial position and a @)-methyl group, 5exo-cyclization (cf. 11 412) is observed preferentially, except when this channel is obstructed on steric grounds. If the olefin has a (E)-configuration (cf. 13), the two regioisomers (12) and (14) are formed in a 1:l ratio, each of them stereoselectively. The resulting 5- and 6-membered siloxanes can be cleaved oxidatively to the corresponding diols. In the case of an equatorial a-silyl radical, the cy-

138

C. Silicon in Organic Synthesk

OH

clization is less selective and proceeds in lower yield. By adding a radical to a double bond, a new radical is formed, which for its part can add inter- or intramolecularly to another olefin. Such reaction cascades [18] can also be initiated from the appropriate bromomethyldimethylsilyl ethers and can be employed for the synthesis of polycyclic products. [191 Another functionalized silicon reagent, 1bromovinyldimethylsilyl chloride (16) can be used, after etherification with allylic alcohols, for the intramolecular addition of an asilylvinyl radical to the double bond. Heating compound (17) with tributyltin hydride in the presence of catalytic amounts of azoisobutyronitrile (AIBN) furnishes mainly the 5membered ring product (18) in addition to small amounts of the 6-membered ring and the reduced compound. The silicon connection may be removed or cleaved in various ways. Oxidation with hydrogen peroxide provides the acetyl derivative (19), while treatment with base leads to the olefin (20). Alternatively, conversions to the bromovinyl com-

Br

(3091

121)

pound (21) or the I-trimethylsilyl compound (22) are possible. [20] In order to control regio- and stereochemistry in the addition of an a-hydroxy radical to an ally1 alcohol, Myers et al. made use of a connection via a dimethylsilyl acetal. Suitable cyclization substrates are available from aldehydes, for example (23), phenylselenol, dimethyldichlorosilane and an allylic alcohol, for example (24). Although, according to the Baldwin rules, 6-exo- and 7-endo-trig-c~clizations are stereoelectronically allowed, only formation of the 7-membered ring (26) is observed. Cleavage of the silyl acetal liberates the 1,6diol structure. In connection with the synthesis of the antibiotic tunicaminyl uracil, this reaction served as a key reaction. The allylic alcohol (27) and the aldehyde (28) were first connected to compound (29). After radical cyclization of (29) which, like in the model, gives the 7-membered ring, and subse-

Temporary Silicon Connections

139

acetonitrile with a ratio of 4: 1.Removal of the protecting groups provided the natural product. [21] In the above examples in which silicon ethers are used, the radical precursor is situated on the silicon side, that is a to the silicon atom. Conversely, silicon tethers can also be used to attach radical acceptors (olefins, acetylenes) to alcohols, which contain radical precursors. This strategy, pioneered by Stork, found use in the synthesis of prostaglandins and in the stereospecific synthesis of C-glycosides. [22] The appropriate substrates were prepared from phenylselenoglycosides, which bear a free hydroxyl group, and (phenylethinyl) dimethylsilyl chloride. The stereochemistry of the C-glycoside follows automatically from the stereochemistry (a or /3) of the original OH group. Thus, radical cyclization of (31) followed by subsequent desilylation

0

::* 1. BugSnH, AIBN,

BZlO

(31) I OMe

benzene

SePh

ph 2.&4NF,THF

(8396)

O - s , H df

i

\

-++ b

H

OH

quent hydrolytic removal of the temporary connection, the two diastereomers ( 3 0 ~and ) (30b) were isolated. While the wrong diastereomer is formed primarily if toluene is used as a solvent, the desired isomer is preferred in

::% (34)

OMe

Ph

H

vz = 20:l

140

C. Silicon in Organic Synthesis

with tetrabutylammonium fluoride gave the aC-glycoside (32). If the radical donor is in the @position, the PC-glycoside (34) is formed exclusively, although the substrate has to pass through a conformational change. The intramolecular C-glycoside formation proceeds satisfactorily even if in the course of the cyclization 6- or 7-membered rings must be formed. The additional expenditure for the preparation of the tethered substrates seems quite reasonable in the light of the good yield and the selectivity. It should be noted, however, that radicals at the anomeric center of

(35)

carbohydrates generally also react intermolecularly with oiefins in a stereoselective manner. [23] Temporary silicon connections may also be used advantageously in cycloaddition reactions. For acyclic dienes and dienopiles, respectively, which bear a stereocenter at the allylic position, the connection via a silicon acetal induces highly diastereoselective cycloaddition.Thermolysis of the substrate (35) leads primarily to the formation of the cycloadduct with cis-annulation of the two newly formed rings. To rationalize the observed selectivity, transition state (38) is suggested in which the methyl group points away from the reacting area, thereby evading destabilizing steric interactions. [24] If the stereocenter is in the dienophile part, the cis-product (40) can even be formed exclusively. In this work, it appeared, however, that the preparation of the silicon acetals from dialkyldichloro silanes was not without problems. In part the first connection step is not very selective, so that symmetrical acetals are formed to a significant extent as byproducts. Moreover, these acetals are not too stable towards silica gel chromatography. An essential improvement was proposed by Fortin et al. with the use of di-tertbutylsilylacetals. To guarantee a sequential attachment of alcohols to the silicon atom, ditert-butylsilylchlorosilane monotriflate (41) was used as a reagent. Because of the graduated reactivity of the two leaving groups, selective functionalizations are possible. This was illustrated with the substrates ( 4 4 4 and (44b). First, the triflate was substituted with the alcohol (42) and, in a second step, the intermediate was treated with a dienolate to give the silicon acetal. The cycloaddition of ( 4 4 4 and (44b) proceeds regiospecificaiiy, although for electronic reasons the regioisomer would be favored. The observed stereoselectivity is explained in the endo-transition state (47). [25] In the em-transition state the residue R and one of the tert-butyl groups cross each others path.

Temporary Silicon Connections

(49) 70

xylem

tBu

3f

tBu’ ‘ o e C 0 2 E t

IR

141

(50) 30

160-180%

(>m)

45/46 R’

R2

H

H H

Me

(47)

Because both silicon-oxygen and silicon carbon bonds can be cleaved relatively easily, it is possible, if necessary, to vary the length of the connections. Thus, despite the fact that in the substrate (48) diene and dienophile are connected, one observes not only the melaregioisomer (49) but also the para-isomer (50) which would be favored based on the polarization of the reactants. The complete pericyclic repolarization was successful only if the connection was shortened by one atom, such as in substrates of type (51). Cyclohexanone deriv-

H H Me CN

Me Ph Me Pr

atives were obtained by oxidative cleavage of the vinyl silanes. [26] In another variant of the temporary connection, the dienophile is connected via a carbonsilicon bond with the rest of the substrate. The corresponding substrates are easily accessible by etherification of dialkylvinylchlorosilanes with dienyl alcohols. Cycloaddition of (54) proceeds under mild conditions and delivers exclusively the endo-product (55). The silicon connection in (55) can be removed by protodesilylation or oxidative cleavage as occasion

142

C. Silicon in Organic Synthesis

demands. These intramolecular cycloadditions are even possible without an activating group at the dienophile, although in these cases a somewhat higher temperature is necessary. Even so, it is possible to bring synthetic equivalents to a reaction that would normally not take place. Thus, by functionalization of the cycloadduct (59), formal cycloaddition of ethylene or acetaldehyde-en01 could be realized. [27] The glycosylation of carbohydrates is also an area in which, due to the inherent selectivity of some glycosyl donors, not all glycosidic bonds are accessible with the same ease.

c;

CO2Et

cis-l,2 I trans-1.2= 7030

These limitations hold true despite some very powerful leaving groups for the anomeric center of carbohydrates. [28] One of the problematic cases is the stereocontrolled construction of the /l?-D-mannopyranoside linkage. This represents a 1,2-cis-arrangernentof the substituents that, for steric reasons and because of the anomeric effect, is disfavored compared with the 1,2-truns-stereochemistry. Accordingly, by intermolecular methods, this 1,Zcis-arrangementcan only be reached with some expenditure. One possibility consists of forming a 1,Ztrans-glycosideinitially and subsequently inverting the configuration at C-2. [29] In a conceptually new procedure several groups now use temporary connections to transfer an aglycon intramolecularly to the anomeric center. [30] Because of the intramolecular reaction, the formation of 1,Zcisglycosides is enforced. An example by Stork et al. might serve to illustrate the underlying principle : First, the 6-OH free compound (62) is converted with dichlorodimethylsilane to the chlorodimethylsilyl ether (63). Subsequent reaction with the 2-OH free thioglycoside (64) yields the silicon acetal (65). The essential glycosidation takes place via the sulfoxide (66). Treatment with trifluorosulfonic acid anhydride in the presence of 2,6-ditert-butylpyridine produce the pmmannopyranoside (68) exclusively. Presumably, the reaction proceeds through the intermediate (67), which, after aqueous hydrolysis, leads directly to the glycoside (68). An important reaction from silicon chemistry is the transition-metal catalyzed hydrosilylation of olefins. [31] In combination with an oxidative cleavage of the silicon-carbon bond this procedure allows - similiar to the hydroboration - hydration of olefins. Particularly with regard to stereoselectivity,the intramolecular reaction is superior to the intermolecular variant. In this way higher substituted olefins can also react under mild conditions. On the other hand, this offers the opportunity to control the regioselectivity and additionally,

Temporary Silicon Connections

B BzlO z l

r

N

nBuLi, CleSiMep

THF

Bz'oOM e

b-

BzlO B z l O a o+

Jam

BzlO

tBu

(73%)

143

BzlO

BzlO BzlO

BzIOoMe

(67)

by using chiral olefins, to control diastereoselectivity. As Tamao et al. could show in systematic studies, the intramolecular hydrosilylation of allyl- and homoallyl alcohols proceeds regioselectively, whereby 5- or 6membered rings are formed preferentially. [32] In the case of chiral homoallylic alcohols that contain a Z-double bond or a trisubstituted double bond, one can achieve high stereoselectivity. [33] A typical substrate is the alcohol (69), which is first converted to the silyl ether (70). In the presence of a platinum catalyst, the 5-ring product (71) is formed, from which the diol (72) is obtained by subsequent oxidation. Mechanistically, the reaction proceeds through a hydrometalation, that is, first coordination of the olefin to the metal takes place, followed by insertion into the Si-H bond to give (73). Then the olefin inserts

(68)

into the metal-H bond with concomitant formation of the metallacycle (74), from which the catalyst is regenerated by reductive elimination. The stereochemical result is explained by assuming the transition state (73), in which the methyl group adopts a pseudoequatorial position. Reasonably good selectivity can also be obtained in the hydrosilylation of allyl alcohols of type (75). In these cases the synisomers are formed preferentially. The method is therefore complementary to the intermolecular hydroboration, which furnishes the anti-isomers from such allylic alcohols. For the interpretation of the stereochemical result, the transition state (78) is invoked. If chiral a-hydroxy enol ethers are used, this method opens the way to polyhydtoxylated compounds. [34] For example, hydrosilylation

144

&okl

C. Silicon in Organic Synthesis

2.3-anti > 1O:l 3,4-syn = 711

of (79) yields, after oxidative work-up, the trio1 derivative (81) stereoselectively. For these acid-labile enol ethers the use of a neutral platinum vinylsiloxane catalyst proved to be important. The stereochemistry can be rationalized by a transition state of type (78). The starting materials (cf. 79) are obtained by addition of metallated vinyl ethers to aldehydes. However, by this route they are not easily available in optically active form. In particular, the addition of metallated vinyl

ethers to chiral a-alkoxy aldehydes is unselective. Accordingly, this method has found almost no use in the synthesis of complex natural products. However, an alternative method for the preparation of a-hydroxy enol ethers, which is based on the Tebbeolefination of chiral a-alkoxy esters, should offer advantages in this regard. Holmes et al. used this route in the synthesis of the enol ether (82) with an exocyclic double bond. Using a rhodium-catalyst, intramolecular hydrosilylation of (82) provided the stereoisomer (84)almost exclusively. Interestingly, the diastereoselectivity could be inverted by changing the catalyst and the reaction conditions. [35] Instead of a hydroxyl group one can also use an amino group for the attachment of the silicon functionality. In contrast to the hydro-

HO

i61%; d.r. > 95:5

HO

(84)

Temporary Silicon Connections

silylation of allylic alcohols, l-aza-2silacyclobutanes are obtained from allylamines. These heterocycles are converted to 1,Zamino alcohols on oxidation with hydrogen peroxide. [36] The 173-arrangementof hydroxy groups is a common structural element, particularly in macrolides. Therefore, methods are in demand that allow the selective generation of either syn- or anti-diols. [37] The reduction of phydroxy-ketones (85) to anti-diols can be performed, among several methods, by intramolecular hydrosilylation. First an organosilane is attached to the hydroxy group and subsequently reduction of the carbonyl group is induced by Lewis-acid catalysis. The 1,3-diols (88) can be liberated from the transsiladioxanes (87), which are formed with high selectivity. For the interpretation of the intramolecular hydride transfer, the authors suggest a chair-like transition state. [38] As this summary demonstrates, temporary silicon connections can be used in manifold ways for the solution of regio- and stereo-

R’

R2

anti/syn yield (88)

iPr Bu iPr

iPr Bu Me

120:l 40:l 50:l

67% 44% 61%

145

chemical problems. Certainly, this strategy is not restricted to the types of reactions and substrates presented herein, but may be broadened widely in its application. [39]

References [l] B.M. Trost, Science 1991,254, 1471-1477 and references therein. [2] N. Anand, J. S. Bindra, S.Ranganathan, Art in Organic Synthesis, 2nd ed., Wiley, New York, 1988; b) Synthesis of erythronolide B: J. Mulzer, H. M. Kirstein, J. Buschmann, C. Lehmann, P.Luger, J. Am. Chem. SOC. 1991,113, 910-913. [3] For a review on substrate-directable chemical reactions, see: A. H. Hoveyda, D. A. Evans, G.C. Fu, Chem. Rev. 1993, 93, 1307-1370. [4] a) G. Illuminati, L. Mandolini, Acc. Chem. Res. 1981,14,95-102; b) M.A. Winnik, Chem. Rev. 1981, 81, 491-524; c) B.Capon, S.P. McManus, Neighboring Group Participation, Vol. 1, Plenum, New York, 1976. [5] D.F. DeTar, J . Am. Chem. SOC. 1974, 96, 1255-1256. [6] a) M.E. Jung, J.Gervay, J. Am. Chem. SOC. 1991, 113, 224-232; b) see also: M.E. Jung, I. D. Trifunovich, N. Lensen, Tetrahedron Lett. 1992,33, 6719-6722. [7] J.E. Baldwin, J. Chem. SOC., Chem. Commun. 1976,734-736. [8] Review: D. Schinzer, Nachr. Chem. Tech. Lab. W ,37,263-266. [9] D.A. Evans, E.M. Carreira, Tetrahedron Lett. l990,31,4703-4706. [lo] [4+2]-Cycloadditions: D. Craig, Chem. SOC. Rev. W , 1 6 , 187-238; [3+2]-Cycloadditions: B.M. Trost, T.A. Grese, J. Am. Chem. SOC. 1991, 113, 7363-7372; 1,3-Dipolar Cycloadditions: a) S. Takano, Y. Iwabuchi, K. Ogasawara, J. Am. Chem. SOC.1987,109,5523-5524; b) M.Ihara, M.Takahashi, K.Fukumoto, T.Kametani, J. Chem. SOC.,Chem. Commun. 1988, 9-10; c) J.M. Sisko, S.M. Weinreb, J. Org. Chem. l99l,56, 3210-3211. [ll] J. J.-W. Duan, P. A. Sprengler,A. B. Smith, 111, Tetrahedron Lett. 1992,33,6439-6442 and references cited therein.

146

C. Silicon in Organic Synthesis

[12] a) M. Regitz, B. Giese, Methoden Org. Chem. (Houben-Weyl) 1986,Band E 19a and references cited therein; b) C.P. Japserse, D.P. Curran, T.L. Fevig, Chem. Rev. 1991, 91, 1237-1286; c) D.P. Curran in Comprehensive Organic Synthesis (Eds.: B.M. Trost, 1.Fleming), Vo1.4 (Ed.: M.F. Semmelhack), Pergamon, Oxford, 1991,779-831. [13] G.Stork, Bull. Chem. SOC. Japan 1988, 61, 149-154. [14] a) H. Nishiyama, T. Kitajima, M. Matsumoto, K.Itoh, J. Org. Chem. 1984,49,2298-2300; b) G.Stork, M.J. Sofia, J. Am. Chem. SOC.1986, 108,6826-6828. [15] M. T. Crimmins, R. O’Mahoney, J. Org. Chem. 1989,54, 1157-1161. [16] J. C. Lopez, B. Fraser-Reid, J. Am. Chem. SOC. 1989, 111, 3450-3452 and references cited therein. [17] M. Koreeda, D. C. Visger, Tetrahedron Lett. 1992,33, 6603-6607; see also: K.Matsumoto, K. Miura, K. Oshima, K. Utimoto, Tetrahedron Lett. 1992,33,7031-7034. [181 For a review on sequential reactions in organic synthesis, see: L. F. ‘Iietze, U.Beifuss, Angew. Chem. 1993,105, 137-170; Angew. Chem. Znt. Ed. Engl. 1993,32, 131-163. [19] M. Jounet, W. Smadja, M. Malacria, Synlett 1990,320-321. [20] K.Tamao, K.Maeda, T.Yamaguchi, Y.Ito, J. Am. Chem. SOC. l9S, 111,4984-4985. [21] A.G. Myers, D.Y. Gin, K.L. Widdowson, J. Am. Chem. SOC. 1991,113,9661-9663. [22] G.Stork, H.Suh Suh, G.Kim, J. Am. Chem. SOC. 1991,113,7054-7056. [23] B.Giese, Pure Appl. Chem. 1988, 60, 1655-1658. [24] a) D.Craig, J.C. Reader, Tetrahedron Lett. 1992,33,4073-4076; b) D. Craig, J. C. Reader, Tetrahedron Lett. 1992,33,6165-6168. [25] J. W. Gillard, R. Fortin, E. L. Grimm, M. Maillard, M. Tjepkema, M. A. Bernstein, R. Glaser, Tetrahedron Lett. l99l,32, 1145-1148. [26] K. J. Shea, A. J. Staab, K.S. Zandi, Tetrahedron Lett. 1991,32,2715-2718. [27] a) G. Stork, T. Y. Chan, G. A. Breault, J. Am. Chem. Sac. 1992,114,7578-7579; b) S. M. Sieburth, L.Fensterbank, J . Org. Chem. 1992,57, 5279-5281.

[28] a) R.R. Schmidt in Comprehensive Organic Synthesis (Eds.: B.M.Trost, I.Fleming),Vol.6 (Ed.: E. Winterfeldt), Pergamon, Oxford, 1991, 33-64; b) H.Waldmann, Nachr. Chem. Tech. Lab. 1991,39,67.5-682. [29] H. B. Boren, G. Ekborg, K. Eklind, P. J. Garegg, A. Pilotti, C.-G. Swahn, Acta Chem. Scand. 1973, 27, 2639; see also: H.Paulsen, O.Lockhoff, Chem. Ber. 1981,114, 3102. [30] a) G.Stork, G.Kim, J . Am. Chem. SOC. 1992, 114, 1087-1088; b) M.Bols, J . Chem. SOC., Chem. Commun. 1992, 913-914; c) EBarresi, O.Hindsgau1, Synlett 1992, 759-760; d) Y.C. Xin, J.-M.Mallet, P.Sinay, J. Chem. SOC., Chem. Commun. 1993,864-865. [31] T. Hiyama, T. Kusumoto in Comprehensive Organic Synthesis (Eds. : B. M. Trost, I. Fleming), Vo1.8 (Ed.: I. Fleming), Pergamon, Oxford, 1991,763-792. [32] K. Tamao, T. Tanaka, T. Nakajima, R. Sumiya, H.Arai, Y.Yto, Tetrahedron Lett. 1986,27, 3377-3380. [33] K. Tamao, T. Nakajima, R. Sumiya, H. Arai, N.Higuchi, J.Ito, J . Am. Chem. SOC. W86, 108, 6090-6093; see also: M.R. Hale, A.H. Hoveyda, J. Org. Chem. 1992,57,1643-1645. [34] K. Tamao, Y. Nakagawa, H. Arai, N. Higuchi, Y.Yto, J . Am. Chem. SOC. 1988, 110, 3712-3714. [35] N. R. Curtis, A.B. Holmes, Tetrahedron Lett. 1992,33,675-678. [36] K. Tamao, Y. Nakagawa, Y. Ito, J. Org. Chem. l990,55,3438-3439. [37] D.A. Evans, J. Gauchet-Prunet, E.M. Carreira, A.B. Charette, J. Org. Chem. 1991,56, 741-750. [38] S.Anwar, A.P. Davis, J . Chem. SOC., Chem. Commun. 1986,831-832. [39] a) Intramolecular Dotz reaction: B. L. Balzer, M.Cazanoue, G.Finn, J . Am. Chem. SOC. 1992, 114, 8735; b) Intramolecular amidoalkylation: H. Hioki, M. Okuda, W. Miyagi, S. Ito, Tetrahedron Lett. 1993,34, 6131-6134.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

D. Enzymes in Organic Synthesis Enzymatic Carbon-Carbon Bond Formation Herbert Waldrnann Methods for the stereoselective formation of the ketophosphate, but it accepts aldehydes C-C bonds lie at the heart of organic synthe- with broadly varying structure, so that, oversis. For this purpose powerful chiral auxili- all, more than 75 of these carbonyl comaries and, recently, chiral catalysts have been pounds could be identified as substrates. developed during the last decades. Moreover, These studies revealed that sterically unhinthese methods are being complemented by dered aliphatic and a-heterosubstituted aldebiocatalyzed C-C bond forming reactions [l] hydes are rapidly converted to the aldol employing either isolated enzymes or whole adducts, whereas tertiary, a,punsaturated and, in particular, aromatic compounds are cells (e.g. yeast) as biocatalysts. not accepted or are only poor substrates. In all aldol reactions carried out on a preparative scale so far, the enzyme showed virtually complete stereospecificity and always formed a DAldolases threo-diol. Recently, however, this has been Practically every organism has developed questioned (see below). FDP aldolase has aldolases for the execution of stereoselective been used in manifold ways for the construcaldol reactions. More than twenty C-C bond tion of monosaccharides embodying four to forming enzymes belonging to this class have nine carbon atoms in the chain. [ l a , b, 2a, 41 been characterized in detail, and some of Thus, the D-threo-hexulose phosphate (3) them have already been used for synthetic could be built up on a 1 molar scale from purposes. The catalytic protein that has been DHAP (1) and propionaldehyde (2) studied most thoroughly and that has been (Scheme 1). [2a] The subsequent removal of applied most often on a preparative scale is the phosphate by means of acid phosphatase fructose-1,6-diphosphate aldolase from rabbit delivered the deoxygenated monosaccharide muscle (FDP aldolase, RAMA). It catalyzes (4). A further interesting example consists of synthesis of 3-deoxy-~-arabinothe stereoselective addition of dihydroxyacet- the one phosphate (I) (DHAP) to various aldehy- heptulusonic acid-7-phosphate (7), [2b] a des (Scheme 1). [ l a , b, 2, 41 In addition, central intermediate in the biosynthesis of enzymes displaying similar substrate specific- aromatic amino acids via the shikimic acid ity and stereoselectivity, but showing a higher pathway. In the course of this chemoenzylong-term stability were isolated from E. coli matic route the racemic aldehyde (5) derived [3a] and from Staphylococcus curnosus. [3b] from aspartic acid was converted by the The enzyme from rabbits is fairly specific for enzyme to the desired aldol adduct (6), which

148

D . Enzymes in Organic Synthesis

FDP-

(1) t

37 % aldolase

AcHN Meo&+opol-

OH 0 OH

(6)

OH 0 N3+OPO~B~ HO OH

i

HO HO

OH 0 +oP038a

3

=

GO OH

1) Dowex (W) 2) acid phosphalase

(1 0)

3) Dowex (KO,-) 4) yIP1-C

OH

HO HO

(1 1)

(12)

Scheme 1. Enzymatic aldol reactions employing FDP aldolase as biocatalyst.

was then transformed to the heptose (7). A particularly valuable feature offered by the aldolase is that it allows rapid syntheses of polyfunctional carbohydrate analogues to be carried out, for example, deoxy-, [4a] fluoro-, [4b] alkoxy-, [4b] C-alkyl-, [4c, h] and azasubstituted [4a-g] saccharides. In particular,

the analogues mentioned last are of current interest, since the piperidines and pyrrolidines accessible from these compounds, for example, 1-deoxynojirimicin (11) and l-deoxymannojirimicin (12) (Scheme l ) , are potent glycosidase inhibitors that may be used in numerous different pharmacological studies.

Enzymatic Carbon-Carbon Bond Formation

ICJI, 0

0

0 HO&OPO~~

+

OH 0

O *H

1) FDP-

149

2) acid

phosphalase

(1)

(13)

1

(14) OH I

1 1) acetone 2) MaBy, ElOH all, 13) Nao,

transkelolase

(1 7)

0

OH (18)

M2'

TPP 45 %

'

0

OH (19)

Scheme 2. Chemoenzymatic syntheses of (+)-exo-brevicorninemploying RAMA or transketolase as biocatalysts.

To build up (11) and (12) [4d, el the racemic aldehyde (8) and DHAP were condensed under the influence of the aldolase to give the diastereomeric 6-azidohexose phosphates (9) and (10) quantitatively and in a stereochemically defined way. These carbohydrate analogs were then separated chromatographically and the phosphoric acid esters hydrolyzed by means of acid phosphatase. In the course of the subsequent hydrogenolysis over platinum the azides were transformed into amines, which formed cyclic imines with the carbonyl group of the furanose, only to be hydrogenated further to the piperidines (11) and (12). The fact that aldolase can also be used advantageously for the construction of natural products that are structurally unrelated to carbohydrates was demonstrated by a chemoenzymatic synthesis of the bark beetle phero-

mone (+)-em-brevicomin (16). [5a] As the key step the enzyme-catalyzed conversion of 5-oxohexanal (13) was employed, which gave only the desired stereoisomer (Scheme 2). After removal of the phosphate and treatment with acid, the ketotriol (14) formed the bicyclic brevicomin precursor (15). Subsequent reduction of the keto group and deoxygenation of the vicinal diol formed thereby delivered the enantiomerically pure pheromone. In a further application, also the naturally occurring spiroketal sphydrofuran [5b] and the CI1-CMfragment of pentamycin [5c] were constructed in chemoenzymatic approaches employing FDP aldolase . Brevicomin (16) can also be constructed chemoenzymatically by means of the C-C bond forming enzyme transketolase. [6b] In the presence of thiamine pyrophosphate (TPP) and Mg2+-ions

150

D. Enzymes in Organic Synthesis

this biocatalyst decarboxylates a-hydroxypyruvate (17) and transfers its ahydroxyketone unit to the D-enantiomer of 2hydroxyaldehydes to form D-threo-diols. [6] Taking advantage of this property the racemic 2-hydroxybutyraldehyde (18) was converted with simultaneous resolution of the racemate to the trio1 (19) in 45 YO yield and with > 95 YO diastereoselectivity. The geminal diol present in (19) was then protected and the ahydroxyketone degraded to the aldehyde. After chain-extension via a Wittig reaction, reduction of the resulting olefin (20) and removal of the acetal protecting groups by treatment with acid, enantiomerically pure (+)-exo-brevicomin (16) was also obtained by this route. Whereas the fructosediphosphate aldolase generates the D-threo stereochemistry (3S, 4R), the three remaining stereoisomers can be formed by employing the enzymes rhamnulose-1-phosphate aldolase (RhuA : Lthreo; 3R, 4S), [7b, d] fuculose-1-phosphate aldolase (FucA: D-erythro; 3R, 4R) [7a, b, d] and tagatose-1-phosphate aldolase (TagA: L-

erythro; 3S, 4s) [7c] (Scheme 3). These biocatalysts are not commercially available, but must be isolated from microorganisms. In addition, for RhuA and FucA genetically engineered overexpression systems have been developed, [7a, b] so that these aldolases are available in larger amounts if desired. The aldol additions of DHAP to various aldehydes mediated by these enzymes proceed with complete stereoselectivity with respect to the stereogenic center at C,; however, depending on the structure of the electrophile, varying amounts of the undesired stereoisomers may be induced (RhuA and FucA: up to 30%, TagA: 10-90%; Scheme 3). A closer inspection of the stereodifferentiation in the FDPaldolase mediated transformations (see above) revealed that depending on the aldehyde used in these aldol-reactions - in contrast to earlier reports - up to 30% of the “wrong” configuration at C, of the aldol adduct is formed. [7e] Although classical chemical aldol technology also often meets with varying success concerning its general applicability, these results clearly reduce the

OH

2 + -.

aH

syn:anti = 97 : 3

7 J 4 -P O 3 2 -

-

&I

anti: syn

70 : 30

Scheme 3. Enzymatic aldol reactions mediated by FucA-, RhuA- and TagA aldolases.

Enzymatic Carbon-Carbon Bond Formation

willingness of synthetic organic chemists to establish enzymatic C-C bond formation as a standard methodology in organic synthesis, in particular if the biocatalyst must be isolated or cloned in a laborious enterprise. In addition to the aldolases that use DHAP as nucleophile in aldol reactions, some enzymes that employ different CH-acidic compounds have also been applied for preparative purposes. Thus, 3-hexulosephosphate synthetase (HPS aldolase), [Sa] 3-deoxy-~-arabinoheptulusonic acid phosphate synthetase (DAHP synthetase), [Sb] 3-deoxy-~-manno2-octulusonic acid-8-phosphate synthetase (KDO synthetase), [Sc] and N-acetylneuraminic acid aldolase (NeuAc aldolase, NANA aldolase) [Sd] have been used for the construction of complex carbohydrates (Scheme 4). Furthermore, enzyme-catalysed aldol reactions have been carried out with a cloned 2-deoxyribose-5-phosphate aldolase. 18hl High expectations have been raised in particular concerning the application of NeuAc aldolase. This biocatalyst accelerates the reaction between pyruvate and N-acetylOH 0 e03p0*H

0po;-

ACO;

+

mannosamine (ManNAc) (22) and accepts a variety of analogs of this monosaccharide as substrate. [Sd] The product of the occurring aldol reaction is N-acetylneuraminicacid (23), a complex carbohydrate that plays a decisive role in biological recognition phenomena. The availability of neuraminic acids with modified structure is of great interest for biological and immunological studies, and the preparation of these compounds by classical chemical techniques is very cumbersome. Continuous NeuAc aldolase catalyzed aldol reactions could be realized advantageously in an enzyme-membrane reactor, including the in situ generation of the expensive ManNAc from the inexpensive N-acetylglucosamine (21) by an epimerase in a coupled enzyme system. [Sg] By means of this technology the enzymatic generation of N-acetylneuraminic acid on a large scale may become feasible.

(R)- and (S)-Oxynitrilase (R)-Oxynitrilase from bitter almonds catalyzes the highly enantioselective addition of

DW-

OH OH 0

-,,-:-

dH

OH DAHP rop0:-


epimerase

.

>-

HOH oH -

HO

.OH AcHN

+OH

0 F.CH2,!kcH,

Hq

deoxyribose-

+

151

5-phosmat~ aldolase

40 X

Scheme 4. Synthesis of complex carbohydrates by means of various aldolases.

OH

35 %

D. Enzymes in Organic Synthesis

152

~4~ HCN t

(P)-on/nitrilase from biller alrmnds

/

R

il"

\

(SJ-mqnitrilase

H

from sorghum bicolor

CN

(24)

(R)oxynitrilase: R = alkyl,aryl, 75 - 99 %, 14 - 99 % ee (S)oxynitrilase: R = aryl, 61 -97%, 54-99% ee

HCN to aromatic and aliphatic aldehydes to give the (R)-cyanohydrins (24). [9a, b] Unfortunately, due to the competing nonenzymatic reaction the optical yield of the reaction often is low if aqueous reaction media are used. This drawback was successfully overcome by adsorbing the enzyme onto cellulose and using it in this immobilized form as biocatalyst in ethyl acetate, a solvent in which the nonenzymatic cyanohydrin formation proceeds only slowly. [9b] However, in the cases of sterically demanding carbonyl compounds (e.g. pivalaldehyde) and aldehydes carrying a basic atom (e.g., nicotinaldehyde) the nonbiocatalyzed reaction cannot be suppressed completely even in organic solution, so that the enantiomeric excess remains unsatisfactory if such electrophiles are used. By employing an oxynitrilase from Sorghum bicolor [9c, d] or from Heveu brusiliensis [9f] the enantiomeric (S)-cyanohydrins (25) are also accessible with moderate to high ee values. The biocatalyst from Sorghum bicolor accepts only aromatic aldehydes as substrates. Once more ethyl acetate as solvent is recommended to achieve a high enantiomeric excess. [9c] However, in these cases the use of an aqueous solvent, the pH of which is lowered to 3 4 , is more advantageous. [9d] (R)-Oxynitrilase is also capable of synthesizing ketone cyanohydrins with high stercoselectivity. [9e] For the enantioselective enzymatic synthesis of ali-

phatic (S)-cyanohydrins the enzyme from Heveu brusiliensis is currently the best biocatalyst available. [9f]

Baker's Yeast The fermentation of suitable substrates with baker's yeast opens a route to various C-C bond formations. [ l c , d] The yeast-mediated acyloin condensation of aromatic and aliphatic aldehydes with an acetaldehyde equivalent (Scheme 5) has been the subject of intensive studies. [lo] The enzyme responsible for this transformation is pyruvate decarboxylase. Similar to transketolase (see above) in the presence of M$+ ions and TPP this biocatalyst transfers a G-unit, which formally resembles acetaldehyde, to the aldehyde substrate. Thereby, initially a-hydroxyketones like (26) are formed, which may either be isolated under suitable conditions or which may be further reduced by the yeast (Scheme 5). Although the yields are low, in this easily executable reaction the diols (27) are formed as virtually pure anti-isomers with excellent ee values. Using benzaldehyde as carbonyl component, this process was applied for the commercial manufacture of D-(-)-ephedrine (28). This route belongs to the first industrial processes in which microbial and classicalchemical steps were combined advantageously. [111 The enzymatic acyloin condensation is not restricted to aromatic aldehydes and acetaldehyde : aromatic and particularly a,/hnsaturated carbonyl compounds can also be used. Instead of acetaldehyde from the corresponding keto acids with simultaneous decarboxylation a fragment can be transferred that is equivalent to propionaldehyde or butyraldehyde. [12] Diols like (27) have found numerous applications as chiral building blocks in natural product syntheses. [ lc , d] For instance, by means of this technique from cinnamic aldehyde several L-carbohydrates and pheromones were constructed, and a-

Enzymatic Carbon-Carbon Bond Formation

153

22-32%

9 7 - 9 9 % ee

(30)

R = CHs,: 26%, 93% ee R = Et: 41 %, 91 % ee

(31) L

C

N

yeast, glucose

rwm tenp.

48 h, 88 46

(33)

54

(32)

47 %, 79 % ee HE,

& +N

(3)

t

Et

(35)

syn : anti

ee> 99%

HQ &CN Et

(36)

34 : 66

Scheme 5. Enzymatic C-C bond formation employing baker’s yeast as biocatalyst.

methyl-/3-2-furylacrolein could be converted to enantiomerically pure vitamin E. Moreover, processes that resemble a Michael addition or the alkylation of a CH-acidic compound can be carried out by yeast [13] (Scheme 5). If a,@unsaturated esters and ketones like (29) and (31) are fermented in the presence of trifluoroethanol, the trifluoromethylcarbinols (30) and (32) are formed in yields of 26-47% and with ee values of 79-93%. [13a] Yeast also transforms acyanoacetone (33) to a mixture of the nitriles (35) and (36). [13b] The ketone (34) is formed as an intermediate that is reduced with high

stereoselectivity.The enzymes responsible for these conversions are not known, but it is prudent to speculate that in the first case pyruvate decarboxylaseinitiates a transformation in the sense of a Stetter reaction followed by a reduction step. In the second case a yeastmediated reduction of a C=C bond formed by aldol condensation between (33) and acetaldehyde may be assumed. Furthermore, baker’s yeast contains a sterolcyclase activity which can be advantageously employed to effect the cyclization of the squaleneoxides (37). [14] After ultrasound treatment the steroid frameworks (38) are

154

D. Enzymes in Organic Synthesis

pH 7.4 ultrasound

(38)

constructed in the enzyme-catalyzed reactions with simultaneous resolution of the racemates. Finally, the steric steering of DielsAlder reactions by using baker’s yeast was reported. [15] Maleic acid (39) and cyclopentadiene in organic and aqueous media usually react to give predominantly the endocycloadduct (40) whereas in the presence of the microorganism the exo-isomer (41) is formed exclusively. However, it remains uncertain whether this effect is indeed caused

c)+r OOH

organic medium:

endo : ex0 = 80 : 20

aqueous medium without ylast:

endo: e m = 93 : 7

aqueous medium with ylast:

endo:exo=O:loo

yield 74%

by the influence of a specific biocatalyst or whether unspecific hydrophobic proteins are responsible (such observations have, for instance, been made for bovine serum albumine [16]). In conclusion, the examples highlighted demonstrate that by means of appropriate biocatalysts a variety of synthetically important C-C bond formations can be carried out stereoselectively in a convincing way. However, for most of the reaction types discussed powerful classical chemical alternatives are also available. Both methodologies represent important tools available from the arsenal of organic synthesis. The choice as to which is to be preferred must be directed by the demands posed by the problems at hand and must be critically evaluated in each individual case.

References [l] Reviews: a) E.J. Toone, E.S. Simon, M.D. Bednarski, G. M. Whitesides, Tetrahedron 1989, 45, 5365; b) D. G. Drueckhammer, W. J. Hennen, R.L. Pederson, C.E Barbas 111, C.M. Gautheron, T. Krach, C.-H. Wong, Synthesis 1991,499; c) S.SeM, Synthesis 1990, 1; d) R. Csuk, B. I. Glanzer, Chem. Rev. 1991,91, 49. [2] a) A comprehensive discussion of the properties of FDP-aldolase relevant to organic synthesis is given in: M.D. Bednarski, E.S. Simon, N. Bischofberger, W.-D. Fessner, M.J. Kim, W. Lees, T. Saito, H. Waldmann, G. M. Whitesides, J. Am. Chem. SOC.1989,111, 627 and references given therein; b) N. J. Turner, G.M. Whitesides, J . Am. Chem. SOC. 1989, 111, 624; c) W.J. Lees, G.M. Whitesides, J. Org. Chem. 1993,58,1887 and references therein. [3] a) C. H. von der Osten, A. J. Sinskey, C. F. Barbas 111, R. L. Pederson, Y.-E Wang, C.H.Wong, J. Am. Chem. SOC. 1989,111, 3924 and references therein; b) H. P. Brockamp, M.R. Kula, Tetrahedron Lett. 1990,49,7123. [4] a) C.-H. Wong, E I? Mazenod, G. M. Whitesides, J. Org. Chem. 1983, 48, 3493; b) J. R.

Enzymatic Carbon-Carbon Bond Formation

Dunwachter, D. G. Drueckhammer, K. Nozaki, H.M. Sweers, C.-H.Wong, J. Am. Chem. SOC. 1988,108,7812; c) J. R. Dunwachter, C.-H. Wong, J. Org. Chem. 1988,53,5175; d) A. Straub, F. Effenberger, P. Fischer, J. Org. Chem. 1990,55, 3926; e) R. L. Pederson, M.J. Kim, C.-H. Wong, Tetrahedron Lett. 1988, 37, 4645; f ) T.Kajimoto, K.K.-C. Liu, R.L. Pederson, Z.Zhong, Y.Ichikawa, J.A. Porko, Jr, C.-H. Wong, J. Am. Chem. SOC. 1991,113, 6187; g) R.H. Hung, J.A. Straub, G.M. Whitesides, J. Am. Chem. SOC. 1991, 56,3849; h) W.-D. Fessner, C.Walter, Angew. Chem. WZZ, 104, 643; Angew. Chem. Int. Ed. Engl. WZZ,31, 614. [5] a) M. Schultz, H. Waldmann, H. Kunz, W.Vogt, Liebigs Ann. Chem. 1990, 1010; b) B. P. Maliakel, W. Schmid, Tetrahedron Lett. 1992, 33, 3297; c) M.Shimagaki, H.Muneshima, M.Kubota, T.Oishi, Chem. Pharm. Bull. 1993, 41, 282. [6] a) J.Bolte, C.Demuynck, H.Samaki, Tetrahedron Lett. 1987, 28, 5525; b) D.C. Miles, P.J. Andrulis 111, G.M. Whitesides, Tetrahedron Lett. 1991, 32, 4835; c) Y.Kobori, D. C. Myles, G.M. Whitesides, J. Org. Chem. WZZ, 57, 5899; d) F. Effenberger, V.Null, T. Ziegler, Tetrahedron Lett. 1992,33, 5157. [7] a) A. Ozaki, E. J. Toone, C. H. von der Osten, A. J. Sinskey, G.M. Whitesides, .I Am. . Chem. SOC. 1990,112,4970; b) W.-D. Fessner, G. Sinerius, A. Schneider, M. Dreyer, G. E. Schulz, J.Badia, J. Aguilar, Angew. Chem. 1991, 103, Angew. Chem. Int. Ed. Engl. 1991, 30, 555; 596; Angew. Chem. Int. Ed. Engl. 1991,30, 555; c) W.-D. Fessner, O.Eyrisch, Angew. Chem. 1992, 103, 76; Angew. Chem. Int. Ed. Engl. 1992,31, 56; d) W.-D. Fessner, J. Badia, 0.Eyrisch, A. Schneider, G. Sinerius, Tetrahedron Lett. 1992,33, 5231; e) W.-D. Fessner, Fourth Chemical Congress of North America, New York, 1991, Abstracts of Papers BIOL 9; W.-D . Fessner, personal communication. [8] a) R. Beisswenger, G. Snatzke, J.Thiem, M.R. Kula, Tetrahedron Lett. 1991, 32, 3159; b) L.M. Reimer, D.L. Conley, D.L. Pompliano, D.L. Frost, J. Am. Chem. SOC. 1986, 108, 8010; c) M.D. Bednarski, D. C. Crans, R.DiCosimo, E. S. Simon, P. D. Stein, G. M. White-

155

sides, Tetrahedron Lett. 1988, 29, 427; d) C.AugC, %David, C.Gautheron, A.Malleron, B. CavayC, New. J. Chem. 1988,12,733; e) M.J. Kim, W.J. Hennen, H.M. Sweers, C.-H. Wong, J. Am. Chem. SOC. 1988, 110, 6481; f) A. Schrell, G. M. Whitesides, Liebigs Ann. Chem. 1990, 1111; g) U.Krag1, D.Gygax, 0.Ghisalba, C. Wandrey, Angew. Chem. EWl, Angew. Chem. Int. Ed. Engl. 1991, 30, 827; 103, 854; h) C.F. Barbas, Y.-F. Wang, C.H. Wong, J. Am. Chem. SOC. 1990,112,2013; i) C.-H. Lin, T. Sugai, R. L. Halcomb, Y. Ichikawa, C.-H. Wong, J. Am. Chem. SOC. 1992, 114, 10138. [9] a) W.Becker, E.Freud, E.Pfei1, Angew. Chem. 1965, 77, 1139; Angew. Chem. Int. Ed. Engl. 1965, 4, 1079; b) EEffenberger, T.Ziegler, S.Forster, Angew. Chem. 1987, 99, 491; Angew. Chem. Int. Ed. Engl. 19t7,26,458; c) F. Effenberger, B. Horsch, S. Forster, T. Ziegler, Tetrahedron Lett. 1990, 31, 1249; d) U. Niedermeyer, M.-R. Kula, Angew. Chem. 1990, Angew. Chem. Int. Ed. Engl. 1987, 26, 458; 102, 423; e) EEffenberger, B. Horsch, E Weingart, T. Ziegler, S. Kuhner, Tetrahedron Lett. 1991, 32, 2605; f ) N. Klempier, H. Griengl, M. Hayn, Tetrahedron Sctt. 1993, 34, 4769. [lo] a) C.Fuganti, P. Grasselli, F. Spreafico, C. J. Zirotti, J. Org. Chem. 1984,49, 543; b) C. Fuganti, P.Grasselli, Chem. Ind. B77, 983; c) H. Ohta, K. Ozaki, J. Konishi, G. Tsuchiashi, Agric. Biol. Chem. 1986,1261. [ll] A. H. Rose Industrial Microbiology, Butterworths, Washington DC, 1961, p. 264. [12] C.Fuganti, P. Grasselli, G.Poli, S. Servi, A.Zorzella, J. Chem. SOC., Chem. Commun. 1988,1619. [13] a) T. Kitazume, N. Ishikawa, Chem. Lett. 1984, 1815; b) T. Itoh, Y. Takagi, T. Fujisawa, Tetrahedron Lett. 1989,30, 3811. [14] a) J. Bujons, R.Guajardo, K. S. Kyler, J. Am. Chem. SOC. 1988, 110, 604; b) A. Krief, P.Pasau, L.Quere, Bioorg. Med. Chem. Lett. 1991, I , 365 and references therein. [15] K.Rama Rao, T.N. Srinivasan, N.Bhanumathi, Tetrahedron Lett. 1990,31, 5959. [16] S. Colonna, A. Manfredi, R. Annunziata, Tetrahedron Lett. 1988,29, 3347.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Enzymatic Synthesis of 0-Glycosides Herbert Waldrnann

Carbohydrates are involved in a multitude of important biological processes and, consequently, the chemistry of these multifunctional natural products has been intensively studied and is subject to a pronounced interest also from the view point of medicinal chemistry. To solve the central goal of carbohydrate chemistry, that is, the regio- and stereoselective formation of glycosidic bonds, a variety of efficient classical chemical methods is available. [l]Nevertheless, syntheses of oligosaccharides generally are laborious and timeconsuming multistep sequences. According to a recent estimation [2] for the attachment of each saccharide unit seven weeks’ work is required. However, the classical chemical techniques are increasingly being complemented by promising enzymatic methods. [3] In principle, two classes of enzymes can be used for biocgtalyzed glycosylations: glycosidases and glycosyl transferases.

Glycosidases Glycosidases usually cleave glycosidic bonds (1)+(3). They display a high specificity for the terminal non-reducing carbohydrate and the type of the glycosidic bond, but the structure of the aglycon may vary within a wide range. By shifting the equilibrium of the cleavage reaction the hydrolysis can be reversed and

+ R’ -OH

thereby the synthesis of saccharides can be achieved. Furthermore, glycosides (4) may be built up by trapping the activated intermediates (2) with nucleophiles. The process mentioned first, the so-called reverse hydrolysis, is thermodynamically controlled and is influenced by suitable measures, for example, increasing the concentration of the educts or removing the products from the equilibrium. In the second case, the so-called transglycosylation, the formation of the product is kinetically controlled. Activated substrates such as p-nitrophenyl glycosides, disaccharides and glycosyl fluorides are employed as glycosyl donors and the extent of glycoside formation (1)+(4) depends on the velocity of the competing hydrolysis (1)+(3) of the donor sub-

D. Enzymes in Organic Synthesis

158

strate. In general, the transglycosylation proceeds with higher yield than the reverse hydrolysis and, therefore, is usually preferred. By means of this technique for instance Thiem et al. synthesized fucosyl- [4a] and N acetylneuraminyl glycosides [4b] (Scheme 1). Thus, in the presence of the p-nitrophenyl a-L-fucoside (6) the Pmethyl galactoside (5), which was used in 2.5 fold excess, was regiose-

lectively glycosylated by a-fucosidase at the 2OH group (to give (7)) and the 6-OH group (to give (8)) in a combined yield of 16.5%. Similarly, (5) was coupled with the pnitrophenyl glycoside (9) of N-acetylneuraminic acid in the presence of sialidase to give the a-(2-3)glycoside (10) (5 YO yield) and a-(2-6) glycoside (11) (15 YO yield). Glycosyl moieties can also be transferred to non-

H O u O C H 3 OH

(5)

O O N O 2

-

a-L-fumsidase

imb.

sia'idy ,, AcHN

5 days

HO

OH

(6)

Hoe OCH3 t

HO

HO

OH (7)

OCH3

(10)

5 Yo t

(8)

6.5 %

HO

10 %

COOH

AcHN

P 1)

OH

OCH3

15 %

p-galactosidase from E. coli

(15)

OH

(1 6)

Scheme 1. Glycosidase mediated transglycosylations according toThiem et al. [4a, b] and Gais et al. [4c].

Enzymatic Synthesis of 0-Glycosides

carbohydrates. For instance, Gais et al. exploited the Egalactosidase from E. coli to transfer the galactose unit present in lactose (12) to meso substrates, for example, (13) and (14) (Scheme 1). In these processes the desired glycosides (15) and (16) were formed in 20 % and 24 % yield, respectively, and the transglycosylations proceeded with acceptable to high stereoselectivity. These and numerous further examples (for an extensive tabular survey see ref. 3a) demonstrate that glycosidases allow for regioselective one-step glycosylations to be carried out. However, they clearly show the limitations of the method, that is, the yields are generally low and mixtures of regioisomers are formed that have to be separated. Both disadvantages can be overcome by employing glycosyltransferases for the formation of the glycosidic bonds.

Glycosyltransferases The overwhelming majority of the more than 100 glycosyltransferases characterized so far transfers a monosaccharide from a nucleosidediphospho carbohydrate (17) to a glycosylacceptor (18) to form the desired glycoside (19) and a nucleoside diphosphate (20). An exception is given by N-acetylneuraminic acid, which is activated as a nucleoside monophosphate [CMP-NeuAc (17h)l. To build up

159

the bewildering variety of the required oligosaccharides, the biosynthetic machinery of mammals needs eight activated building blocks: uridine-5‘-diphospho glucose (17a) (UDP-Glc), -glucuronic acid (17b) (UDPGlcUA), - N-acetylglucosamine (17c) (UDPGlcNAc), -galactose (17d) (UDP-Gal), -Nacetylgalactosamine (17e) (UDP-GalNAc), guanosine-5’-diphospho mannose (17f) (GDP-Man) and -fucose (17g) (GDP-Fuc) as well as cytidine-5’-monophospho N-acetylneuraminic acid (17h) (CMP-NeuAc). Each glycosyl donor is transferred by different enzymes to various glycosyl acceptors. In general, these enzymes are specific for the activated carbohydrates, the type of the glycosidic bond, the glycosyl acceptor and a specific hydroxy group in the glycosyl acceptor. From these findings the notion was deduced that in each case one specific enzyme is responsible for the formation of a particular glycosidic bond (one enzyme - one linkage concept [5]). However, systematic evaluations of the substrate specificity of some glycosyltransferases indicate that this may not be the case (see below). In order to employ glycosyltransferases on a preparative scale, the glycosyl donors (17) must be available in sufficient amounts. For this purpose, classical-chemical, enzymatic and chemoenzymatic processes were developed so that (17a-17h) now can be prepared in amounts of 1 g up to more than

@

H

-

galactmamine mannose

@

-&

GDP-Yan(f7f)

160

D. Enzymes in Organic Synthesis

100 g. [6] However, the large-scale synthesis and use of these frequently also very sensitive substances itself is laborious, time-consuming and expensive, and, in addition, many glycosyltransferases are inhibited by the liberated nucleoside diphosphates (20) resulting in low yields of the glycosides. Therefore, it is highly desirable to employ the cofactors not in equimolar amounts, but rather to regenerate them in situ by suitable enzymatic transformations from the products (20). Both methodologies

have been realized successfully with different glycosyltransferases.

Galactosyltransferase The enzyme most frequently used for glycoside syntheses on a preparative scale is a galactosyltransferase isolated from milk. This biocatalyst transfers a Pgalactose from UDPGal (17d) to the 4-OH group of N -

UDPGP:

UDP-GlGpyW phosphorylase UFDPGE UDP-Glc-4’-

TI

PGM:

epirnerase phosphogluc&

PPase:

rnutase pyrophosphatase

p-Gal. a-Fuc. ~ - N e u k ( C 0 ~ C H d (27)

OH 0

Ho

x2 -

OH H

R‘ HO

OH, oligosaccharide, polymer, peptide

UAcyl

Scheme 2. Enzymatic 0-glycoside synthesis by means of ~(1-4)-galactosyltransferase.

Enzymatic Synthesk of 0-Glycosides

acetylglucosamine residues. [7, 8a-q 8 e-fl If these enzymatic transformations are camed out with stoichiometric amounts of the nucleotide cofactor often only unsatisfying yields are recorded. Higher yields are obtained if a regeneration system for UDP-Gal is employed, which was developed by Whitesides et al. [7a] In this reaction cascade the galactose incorporated in UDP-Gal (17d) is transferred to the glycosyl acceptor (21) to give the saccharide (22) and UDP (23) (Scheme 2). Subsequently, UDP is converted to UTP (25) by pyruvate kinase (PK) which employs phosphoenol pyruvate (24) as phosphorylating reagent. UTP then is further coupled enzymatically with glucose-1-phosphate (26) to give UDP-glucose (17a). To shift the equilibrium in the last mentioned step to the desired side, the pyrophosphate formed is also cleaved by means of pyrophosphatase. Finally, an epimerase converts the activated glucose derivative (17a) to the analogous galactosyl compound ( 1 7 4 to complete the cycle. This pioneering method by which, for instance, Nacetyllactosamine was built up on a 10 g scale, has proven its efficiency in a variety of applications. Thus, it allowed for the construction of galactosylated glycopeptides, for example, (27) [7d] and, by simultaneous galactosylation of two GlcNAc residues, the hexasaccharide (28) [7c] could be constructed (for a detailed review of the glycosylations carried out with glycosyl transferases see ref. 3a). In particular, this methodology opens up a route to modify or repair unwanted glycan chains of glycoproteins that may be isolated from natural sources or that may have been produced by genetic engineering. To this end, GlcNAc residues are unmasked on the surface of the macromolecules by enzymatic removal of undesired carbohydrates, and subsequently galactose is attached enzymatically. [7k] Since the galactosyltransferase displays a relatively broad substrate tolerance as far as the glycosyl acceptor is concerned, it may be widely applied for various purposes. For instance, it

161

tolerates the presence of different substituents at the OH-groups in position 1, 2, 3 and 6 of the acceptor and the ring oxygen may also be replaced by other heteroatoms (NH,S) or a CH, group [7d-i] (Scheme 2). Furthermore, in the presence of a-lactalbumine the enzyme is capable of glycosylating the 4-OH group of glucose. [7d]

Sialyltransferases The non-enzymatic synthesis of sialylated oligosaccharides often proceeds only with low yield and unsatis’fying stereoselectivity. Therefore, the use of biocatalysts for this purpose might serve to circumvent a real bottle-neck in carbohydrate chemistry. Sialyltransferase mediated glycosylations were developed independently and almost simultaneously by the groups of Paulson, [Sa-c] Thiem [8d] as well as David and Augt. [7b, 8e-f] By means of this method in the presence of equimolar amounts of the activated glycosyl donor CMPNeuAc (17h) various enzymes were applied to transfer sialic acid to the 3-OH group or the 6OH group of terminal, non-reducing galactose units in order to build up the trisaccharides (29), [7b, 8a, 8d] (30) [gal and (31) [gel in satisfying yields (Scheme 3). Particularly impressive are the chemoenzymatic syntheses of the complex oligosaccharides (32) and (33) as well as (34) and (35) by Paulson et al. [8c] and Jennings et al., [9a, b] respectively. In the construction of (32) and (33) in both cases a trisaccharide, which was built up using classical methodology, was first galactosylated twice and then sialylated twice enzymatically. In the case of the decasaccharide (35) an octasaccharide was synthesized non-enzymatically and the a-(2-3) linked N-acetylneuraminyl residues were then attached simultaneously by means of a sialyltransferase. If stoichiometric amounts of CMP-NeuAc are used in the enzyme catalyzed glycosylations the CMP formed inhibits the glycosyl-

Y 0

HO'

0

-

OH

+--0 OH OH

R AcHN

HO,

OH

OH

R = (CH2),COOCH3

(35)

OH

IH

AC

,-. .

HOCHz

AcHN

OzH

HO

HO.

no

F \ o & N H C O C H

wo

= H. OCHj

(30) R = (CH2)sCOOCHg

(29) NHAc

HO

CO2H

S'

2

Q 3

h a

P

Enzymatic Synthesis of O-Glycosides

H

O-UDP

Ho

transferase. galactosyl-

OH

H

W

pH 7.4

phosphatase

+ uridine + 2 P,

c

R * :J-7 & o H

AcHt.4

no

HO

+ CyDdln

OH

+ PI

(36); R = Aloc-Phe-AsnSer-Thr-Ile-OH 82.4% overall yield

(37): R = H-Gly-Gly-A~n-Gly4Iy-OH 86 % overall yield

OH

163

tioned step the equilibrium is shifted to the product side by enzymatic cleavage of the liberated pyrophosphate. By application of this multi enzyme system 2 g of the trisaccharide (29) was synthesized in 97% yield. In addition, it was recently used in the chemicalenzymatic synthesis of the sialyl Lewis* tetrasaccharide and derivatives thereof. [lob] However, the enzymatic regeneration of cofactors offers further opportunities. Thus, Wong et al. [lOc] developed an even more elaborate one-pot procedure in which the disaccharide (22),which is the glycosyl acceptor in the sialyl transfer reaction, is built up in situ via enzymatic galactosylation (C in Scheme 4), as described above (see Scheme 2). In addition, N-acetylneuraminic acid (41) is generated in situ by an aldolasecatalyzed C-C bond formation from N acetylmannosamine (42) (B in Scheme 4). In this complex system nine enzymes cooperate to give the trisaccharide (29) in 22% overall yield starting from three monosaccharides.

transferase so that only low yields of the desired glycoside are obtained. This can be overcome by destroying CMP in situ by means Glucuronic Acid Tkansferase and of an alkaline phosphatase. Thus, Paulson N-Acetylglucosaminyltransferases et al. [8b] constructed the saccharide part of the N-glycopeptides (36) and (37)in a one-pot Gygax et al. [ll] developed the enzymatic reaction via successive attachment of galac- transfer of glucuronic acid to alcohol acceptose and neuraminic acid. The efficiency of tors (Scheme 5). UDP-GlcUA (17b) required the enzymatic sialyl transfer is further for this purpose is generated in situ from enhanced if a cofactor regeneration system UDP-Glc (174 by a dehydrogenase, and the developed by Wong et al. [loa] is employed UDP liberated during the glycosylation is (A in Scheme 4). The CMP (38) liberated in recycled to UDP-Glc by means of the enzythe enzymatic glycosylation is converted to matic process highlighted above. This method the diphosphate CDP (39) by means of the provides an easy access to phenolic glycosides enzyme nucleoside monophosphate kinase and steroid glycosides like (43) and (44) since (NMK) or myokinase (MK). CDP is then all the enzymes required are present in a raw phosphorylated by pyruvate kinase to give extract from pig or rabbit liver and therefore CTP (40). The activated monosaccharide no isolation of the biocatalysts is necessary. Hindsgaul et al. [2, 121 described the synCMP-NeuAc (17h), which is required for a further acyl transfer step, is then formed by thesis of the complex oligosaccharides (46) CMP-NeuAc synthetase, which was obtained and (47) by enzymatic transfer of two Nby overexpression in E. coli. In this last men- acetylglucosamine units to the trisaccharide

164

D. Enzymes in Organic Synthesis

I

0

I I I I I l I

OPO$

>coo-

&coo-

I

I I I

I

i NeuAca-2,6-Galp-l,rl-GlcAc HO I I

OPO,~

MK

&coo-

(29)

I I I

I I I

; I I

lramsferase

I I

I

I

I

HO

NHAc

OH

I

H O l i ~ C O o AcHN

"V"

HO

I I

I I

I I

UDP-Glc

mn-

I I

H O T

I

HO

NMK: nucleosidemonophosphatekinase MK: myokinase PK: pyruvate kinase

Scheme 4. Enzymatic synthesis of sialylglycosides with in situ regeneration of CMP-NeuAc according to Wong et al. [lo].

(45), which was built up non-enzymatically (Scheme 5 ) . First (45) serves as substrate for N-acetylglucosamine transferase I, which selectively attaches a glucosamine to one of the two mannoses present. The tetrasaccha-

ride (46) formed thereby is then a good substrate for the second transferase, which generates the pentasaccharide (47). In addition to UDP-GlcNAc, the enzyme mentioned first also accepts the respective activated 3'-, 4'- or

165

Enzymatic Synthesis of 0-Glycosides 2 NADH

2 NAD

UDP-Glc-pyrw phospharyiase

WP-GlcVAlransferase

OH

pyruvale

phosphoenol pynnrate

a-D-Manp(1- 6), a-D-Manp(1- 3)’ I

pD-ManpO(CH2).&OOMe

3H

H

(43)

HO

HO

(6)

WP-Glcp NAC, GlcNAC-transferaseI

a-D-Manp(1- 6), P-D-GlcpNAc-(l-2)-a-D-Manp(l-3f I

P-D-GlcpNAc-(l-2)-a-D-Manp(l-6),

~D-GlcpNAc-(l-2)-a-D-Manp(l-3f

P-D-ManpO(CH2)&OOMe (46) WP-Glcp NAC, GlcU4c-lransferaseII

P-D-ManpO(CH2)&OOMe (47)

Scheme 5. Enzymatic synthesis of glucuronyl glycosides and N-acetylglucosaminyl glycosides according to Gygax et al. [ll]and Hindsgaul et al. [12].

6’-deoxy hexosamine and thereby allows for rides may be generated. They then serve as the synthesis of selectively deoxygenated oli- substrates in enzymatic glycosylations during which glycosidic bonds are formed that are gosaccharides. In conclusion, enzymatic glycosylation difficult to construct by the conventional methods provide interesting alternatives to methodology. At present, the wide application classical chemical techniques. For the con- of this method is hindered by the limited availstruction of complex oligosaccharides a com- ability of the glycosyl transferases required. bination of both techniques appears to be par- However, by taking advantage of modern ticularly advantageous. By means of non- gene technology this problem should soon be enzymatic glycosylations first smaller saccha- overcome. [131

166

D. Enzymes in Organic Synthesis

Dumas, G.C. Look, J. Am. Chem. SOC. 1991, 113, 8137; k) R. Schneider, M.Hamme1, E.C. Berger, 0.Ghisalba, J. Nuesch, D. Gygax, [l] Review: K.Toshima, K.Tatsuta, Chem. Rev. Glycoconjugate J. 1990,7, 589. 1993,93, 1503. [8] a) S.Sabesan, J.Paulson, J. Am. Chem. SOC. [2] G. Srivastava, G. Alton, 0.Hindsgaul, Carbo1986, 108, 2068; b) C. Unverzagt, K. Kunz, hydr. Res. 1990,207,259. J.C. Paulson, J. Am. Chem. SOC. 1990, 112, [3] Reviews: a) E.J. Toone, E.S. Simon, M.D. 9308; c) S. Sabesan, J.Duus, EDomaille, Bednarski, G. M. Whitesides, Tetrahedron S.Kelm, J.C. Paulson, J. Am. Chem. SOC. 1989, 45,5365; b) D. G. Drueckhammer, W. J. 1991,113,5865; d) J. Thiem, W. Treder, Angew. Hennen, R.L. Pederson, C.E Barbas 111, Chem. 1986, 98, 1100;Angew. Chem. Int. Ed. C.M. Gautheron, T.Krach, C.-H. Wong, SynEngl. l986,25, 1096; e) C. AugB, C. Gauthethesis 1991,499; c) U. Korf, J. Thiem, Kontakte ron, H.Pora, Carbohydr. Res. 1989,193, 288; (Merck) 1992, (l), 3; d) K.G.I. Nilsson, TIBf ) C. AugC, R. Fernandez-Fernandez, C. GauTECH 1988,256. theron, Carbohydr. Res. 1990,200, 257; g) see [4] a) S.C.T. Svensson, J.Thiem, Carbohydr. Res. also: H.H. de Heij, M.Kloosterman, EL. 1990, 200, 391; b) J.Thiem, B.Sauerbrei, Koppen, J. H. van Boom, D. H. van den EijnAngew. Chem. 1991,103, 1521; Angew. Chem. den, J. Carbohydr. Chem. 1988, 7, 209 and Int. Ed. Engl. 1991,30, 1503; c) H.-J. Gais, M.M. Palcic, A.P. Venot, R.M. Ratcliffe, P.Maidonis, Tetrahedron Lett. 1988,29, 5743. 0.Hindsgaul, Carbohydr. Res. 1989,190, 1. [5] A.Hagopian, E.H. Eylar, Arch. Biochem. [9] a) V. Pozsgay, J.-R. Brisson, H. J. Jennings, J. Biophys. 1%8,128,422. Org. Chem. 1991, 56, 3377; b) V.Pozsgay, [6] Review: J.E. Heidlas, K.W. Williams, G.M. J. Gaudino, J. C. Paulson, H. J. Jennings, Whitesides, Acc. Chem. Res. 1992,25, 307. Bioorg. Med. Chem. Lett. 1991,1, 391. [7] a) C.-H. Wong, S.L. Haynie, G.M. White[lo] a) Y.Ichikawa, G.-J.Chen, C.-H.Wong, J. sides, J. Org. Chem. l982,47, 5416; b) S.DaAm. Chem. SOC. 1991, I13, 4698; b) Y.Ichivid, C. AugC, Pure Appl. Chem. WtV,59,1501; kawa, Y.-C. Lin, D. P. Dumas, G.-J. Shen, c) C. AugC, C. Mathieu, C. Mkrienne, CarboE. Garcia-Junceda, M. A. Williams, R. Bayer, hydr. Res. 1986,151, 147; d) J.Thiem, T. WieC. Ketcham, L. E. Walker, J. C. Paulson, C.mann, Synthesis EW2, 141; e) J. Thiem, T. WieH. Wong, J. Am. Chem. SOC. 1992, 114, 9283; mann, Angew. Chem. 1991, 103, 1184; Angew. c) Y.Ichikawa, J.L. Chu, G.Shen, C.Chem. Int. Ed. Engl. 1991, 30, 1163; f ) H. Wong, J. Am. Chem. SOC.1991,113,6300. M. Palcic, O.P. Srivastava, O.Hindsgau1, Carbohydr. Res. 1987, 159, 315; g) C.-H.Wong, [ll] D. Gygax, P. Spies, T. Winkler, U. Pfaar, Tetrahedron 1991, 47,5119. T. Krach, C. Gautheron-Le Narvor, Y. Ichi[12] K. J. Kaur, G. Alton, 0.Hindsgaul, Carbokawa, G.C. Look, F.Gaeta, D.Thompson, K.C. Nicolaou, Tetrahedron Lett. 37, hydr. Res. 1991,210, 145. 4867; h) C. Gautheron-k N ~ c.-~ 1131~See for ~ instance: , a) J. C. Paulson, K. C. Colley, H.Wong, J. Chem. SOC., Chem. Commun. J. Biol. Chem. 1989,264,17615; b) L. K. Ernst, 1991, 1130; i) C.-H.Wong, Y.Ichikawa, VP. Rajan, R.D. Larsen, M.M. Ruff, J.B. T. Krach, C. Gautheron-Le Narvor, D. P. Lowe, J. Bwl. Chem. 1989,264, 3436.

References

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

E. Cyclization Reactions Electrophilic Cyclizations to Heterocycles: Iminium Systems Dieter Schinzer The stereoselective synthesis of heterocyclic ring systems - especially the constructions of medium-sized rings - is one of the major targets in synthesis. With this series of articles a systematic overview in the expanding area of cyclizations with iminium-, oxonium-, and sulfonium-ions will be presented. Parallels and significant differences in this family of reactions will be extracted. In this initial account mostly stereoselective transformations of Mannich systems, i.e. iminium ions, will be discussed, with the major emphasis being placed on intramolecular processes. In these reactions regio- and stereoselectivity in particular can be controlled quite easily. In principle, two partners are involved in these reactions: the iminium system as acceptor and the nucleophilic n-system as donor. Two of these reactions, the Pictet-Spengler and the Bischler-Napieralski reactions, proceed by a simple route in which the aromatic system terminates the reaction by proton elimination and rearomatization. [l,21 On the other hand, the reaction path of olefins, like vinyl silanes is not so easy because the cation intermediate can be stabilized in various ways. We shall first focus on a cyclization of Meyers et al. in connection with an asymmetric total synthesis of yohimbone. [3] Key reaction is the transformation (8) + (19), with optically active materials synthesized with optically active formamidines. The synthesis is

based - except for the key step - on the previously published racemic synthesis of yohimbone from Winterfeldt et al. [4] If one starts with optically active (8), which induces asymmetry to the new chiral center in (lo), an analysis can be made on the mechanistic path of this key reaction step (Scheme 1). In this particular cyclization the question arises whether (10) is produced via a 3,3sigmatropic rearrangement [5] with equilibration of the iminium ion, which would give rise racemic (lo), or whether (8) cyclizes by a direct electrophilic reaction of the iminium ion yielding optically active (10) (Scheme 2). Indeed, the reaction proceeds via equilibrium of the iminium ion, generating racemic (10). This particular equilibrium has been interrupted in Meyers’ synthesis by reduction of the ketone (7) to the alcohol ( I ] ) , which was obtained as a mixture of diastereomers. Assisted by the external nucleophile methanol the “donor power” to the iminium ion was increased, which resulted in a direct electrophilic cyclization to optically active (lo), which was transformed in a short sequence to the natural product yohimbone (14) (Scheme 3). A second, in this context, interesting study has been published by Overman et al. [6] Cyclizations terminated by vinyl silanes are a powerful way in which to construct a large variety of systems. [7-111 The starting materials can be synthesized easily, by either carbo-

168

E . Cyclization Reactions

N f l (2)

t-BuO (7)

(3)

-

CH,O

t-BuO’ 1 . 2 M HCI

y

2. N,H,, HOAc

MeO

(4)

OtBu

OMe

(Racemate) Na; NH,

Scheme 1

the desired 1,2,5,6-tetrahydropyridine(20). In general, only products built by the “endo(5) OMe modus” [14] will be obtained, governed by the so called peffect of silyl group, stabilizing the cation formed /3 to the silicon atom metallation [12], or hydroalumination [13] of (Scheme 5). triple bonds (Scheme 4). The stereochemistry of the vinyl silane is The cyclization of (2)-4-trimethylsily1-3not important in this type of reaction, as butenylamine (18) with excess paraformaldeshown in the transformation of the (E)-isomer hyde in the presence of camphor sulfonic acid (21) to compound (22) (Scheme 6). proceeded regio- and stereoselectively to give At the nitrogen atom unsubstituted tetrahydropyridine (25) can be obtained directly by proton catalyses via the protonated imine (24) (Scheme 7). H These cyclizations also have an interesting aspect. Again, two alternatives can be disH cussed: The simplest possibility would be the 0 S(-)-(lO) 0 (8) direct cyclization of the iminium ion (27) to the j3-silyl cation (29) followed by desilylation Scheme 2

(q$-+y

Electrophilic Cyclizations to Heterocycles: Iminium Systems NaCNBH,

R+

R4 1

=I$(7))

";c

I

0

R'

i

(18)

R1

(19)

R4 CH*o'

I

R'

OH

53.95% yield

(20)

R' = Alkyl, Aryl R2= H, Alkyl RS= H, Alkyl, SiMe, R' = H, Alkyl, Aryl

Scheme 5

Scheme 6

pS NH2 iMe3

RcHo, ( qNS i Mi eR3

()H1,

R

Scheme 7

Me$

%e: (18)

NHR~

11

Scheme 4

to (30). Alternatively, compound (28) could cyclize via an aza-Cope rearrangement to (30) (Scheme 8).

Scheme 8

.1

R

R

(28)

(30)

169

E. Cyclization Reactions

170

Two experiments demonstrate elegantly that the isomerization of the allyl silane is faster than the direct cylization. The smooth cyclization (21) + (22),which proceeds under the same conditions as the cyclization of the Z-isomer, can only be explained by isomerization to the allylic silane (28) prior to cylization. The best argument for the allyl silane route is the following experiment (Scheme 9). The unsaturated amino alcohol (32) is available by aminolysis of epoxide (31) as a 3 : 1 mixture with compound (33).The mixture was directly treated under acidic conditions with an excess of paraformaldehyde. The only product isolated was compound (36) (86 %), which was converted into the more stable

alcohol (37). No trace of (38) could be detected. The experiment precludes direct cyclization of the vinyl silane because (36) was obtained from (35) via an intramolecular Mannich reaction. In addition, allyl silanes are more nucleophilic than vinyl silanes and therefore more reactive toward iminium ions. Another new aspect of these cyclizations is the assistance of external nucleophiles. Pioneering work in this area has been done by Winterfeldt et al., who published the first example in their carboline work. [15] Overman et al. have systematically investigated the reaction of simple alkynes, which are less reactive towards iminium ions in comparison with alkenes. [16] These results demonstrate that these reactions only work in the presence of external nucleophiles. Under these conditions alkynes are even more reactive than alkenes. If hexynylamine (39) is treated with camphor sulfonic acid in the presence of paraformaldehyde no reaction occurs. On the other hand, if tetrabutylammonium bromide is added the exocyclic bromide (40) is obtained in 90 % yield (Scheme 10).

(40)

6r

Scheme 9

(371

Scheme 10

In most cases the exo-products will be generated preferentially. [14] Sometimes the endo-compounds (43) are produced, which can be explained by the peffect of the silyl group (Scheme 11). The potential of this new cyclizationtechnique is clearly demonstrated by the competitive cyclization of (44) (Scheme 12). In the presence of water only (45) is produced, whereas in the presence of sodium

Electrophilic Cyclizations to Heterocycles: Iminium Systems

(42)

(43)

X = I; Br; N,

Scheme ZZ

t ‘ NH

Based on the high degree of stereospecificity these reactions appear to be more concerted than electrophilic cyclizations. [191 These reaction have already been applied toward syntheses of chinolizidine alkaloids, for example, the enantioselective synthesis of (-)-8a-epipulmiliotoxin C (58) (Scheme 15). Starting material is the known chiral alcohol (53), which was transformed in a number of steps to the aldehyde (54). Under Mannich conditions the cycloadducts (56) and

11

U

1. CH20. He

\%

(45)

2.

Scheme 12 (53)

(54)

1 J

iodide only (46) is generated. The halogen compounds obtained by this process can be transformed in a very flexible way as shown in the Scheme 13. Finally, a new area in this context will be presented : the Diels-Alder reaction of iminium ions with dienes under Mannich conditions. Grieco et al. recently published two papers demonstrating the power of this method (Scheme 14). [17, 181

171

172

E. Cyclization Reactions

were obtained (2.2: 1).The stereoselectivityin this cyclization was only moderate and can be explained by a “chair-like’’ transition state (59). The alternative (60) is sterically disfavored (Scheme 16). Amino acids can also be used as chiral building clocks (via in situ formation of iminium ions). Waldmann et al. obtained several heterocycles in quite high diastereoselectivity (Scheme 17). [20] The reactions presented in this article using iminium ions should be understood as additions to known cyclization reactions. Reactions with “hard electrophiles” like acyl imi-

(59)

(56)

-NH2

H H H

0

(57)

(60)

Scheme 16 @

CI@

CHzO

H3N\_/C02CH3

(63) R = i-BU

Scheme 17

:

3

References [l] W. M. Whaley, T. R. Govindachari, Org. React. 1951,6 , 74, 151. [2] A. Katritsky, C. W. Rees; Comprehensive Heterocyclic Chemistry, Vols. 1-6, Pergamon Press, Oxford, 1984. [3] A.I. Meyers. D.B. Miller, F.H. White, J . A m Chem. SOC. 1988,110,4778. [4] W.Benson, E. Winterfeldt, Chem. Ber., 1979, 112,1913. [5] L.E. Overman, M. Kakimoto, M. Okazaki, G.P. Meier, J. Am. Chem. SOC. 1983, 105, 6629. [6] C.Flann, T. C. Malone, L. E. Overman, J. Am. Chem. SOC. 1987,109,6097. [7] T.A. Blumenkopf, L.E. Overman, Chem. Rev. l986,86, 857. [8] L.E. Overman, Lec. Heterocycl. Chem. 1985, 8, 59. [9] L.E. Overman, T.C. Malone, G.P. Meier, J. Am. Chem. SOC. 1983,105, 6993. [lo] L.E. Overman, R.M. Burk, Tetrahedron Lett. 1984,25, 5739. [ll] L. E. Overman, N. H. Lin, J. Org. Chem. 1985, 50.

_3

97

nium ions were not covered in this chapter and only reactions with “soft electrophiles” like iminium ions were presented. Their potential in synthesis can be extended by the use of external nucleophiles.

(64)

R

[12] J.E. Baldwin, J. Chem SOC. Chem. Commun. 1976, 734. [13] J. F. Normant, A. Alexakis, Synthesis l98l,841. [14] G. Zweifel, J. A. Miller, Org. React. 1984,32, 375. [15] E. Winterfeldt, K. H. Feuerherd, V. U. Ahmad, Chem. Ber. 19R,110,3624. [16] L.E. Overman, M.J. Sharp. J. Am. Chem. SOC. 1988,110,612. [17] P. A. Grieco, D.T. Parker, J. Org. Chem. NB, 53,3325. [18] P. A. Grieco, D. T. Parker, J. Org. Chem. 1988, 53, 3658. [19] S . D. Larson, P. A. Grieco, J. Am. Chem. SOC. 1985,107, 1768. [20] H.Waldmann, Angew. Chem. 1988,100, 307. Angew. Chem. Int. Ed. Engl. 1988,27, 274.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Electrophilic Cyclizations to Heterocyles : Oxonium Systems Dieter Schinzer

Oxacyclic natural products are isolated from a variety of sources in nature. Many different types of structures are known, combined with various types of rings, exo- and endo-cyclic functionality. The unusual halogen substituents, mostly located in natural products of marine origin are a challenge for synthesis. [l] The synthesis of medium-sized rings is particularly highlighted in this chapter. Mostly new results will be presented in order to understand the different strategies used to sythesize this interesting class of natural products. Besides oxacycles, carbocycles can also be obtained, depending on the “planned frontier point” of the initiator. This chapter will only focus on cyclizations in which oxonium ions are involved. The major reaction to generate oxonium ions from acetals is treatment with acids or Lewis acids. The oxonium ion formed is trapped in an intramolecular process by the double bond (Scheme 1).[2] The regiochemistry of the double bond in such a carbocyclization cannot be controlled and leads to a mixture of products. This problem can be solved by the use of allylsilanes of type (4) (Scheme 2). [3] Fleming et al. showed that only (6) was obtained, in which the regiochemistry of the double bond was controlled by the /%effect of the silyl group. An interesting reaction leading to aromatic compounds has been described by Tius et al. [4]Starting with ketone (7) an ally1

lithium reagent was added first, and the resulting alcohol (8) was directly cyclized by the use of titanium tretrachloride into the aromatic compound (10).In this particular cyclization the reaction was terminated by a vinyl silane, which has already been used extensively with iminium ion chemistry (see the preceeding article iminium systems (Scheme 3).) A useful way to synthesize cyclic ethers has been reported by Itoh et al. Compound (14) can be obtained by the use of SnCh, promoting a regioselective cleavage of mono thioace-

174

Me

E. Cyclization Reactions

(8)

A/

Me

I1

(9) @OMe

/

Ph-CH2-CH2-0-CH2-S-Me /tr\

'dl

+ CH2=CHASiMe3

*

Me

(7 1)

Scheme 3

(17)

Scheme 4

ae'

CH&H

N S M e (78)

tals. [5] The selective cleavage of the C-S bond can be explained by the high affinity of n - C 6 H 1 3 F S i M e 3 tin for sulfur. In contrast, the C-0 bond can OMEM n-C6H13 be cleaved smoothly with EC&.These effects (19) (20) 96% have been demonstrated by the transformation of (15) with SnC&to give (17), and with Ph Tic&to yield (18) (Scheme 4). 85% The non-symmetrical MEM-ethers can also (2 7) (22) be cleaved regioselectively. Again, Tic& has been used successfully by Itoh et al. Ally1 si- MEM (2-Methoxyethoxy)methyl lanes have been used as electron-rich olefins scheme (Scheme 5). [6] The regioselective cleavage of the MEMether can be explained by the chelate (23). The oxonium ion formed is trapped in situ by the ally1 silane (Scheme 6). Silyl enol ethers as terminators in intramo(23) lecular aldol reactions with acetals have been used successfullyby Kocienski et al. [7, 81 In a short sequence (27) could be obtained in op1 tically active form. The following Mukaiyama+ (24) type aldol reaction in the presence of TiC14 yields (29),which can be used as an intermediate for the cytotoxic natural product pederin ($cH2)2 (Scheme 7). (25) Scheme 6 I

-

Electrophilic Cyclizations to Heterocycles: Oxonium Systems PhMepH,

0

OMe

175

A

-(Ph3P)3RhCI

F

(27) OSiMelPh

& >& Zn; HCO,H

OCH2C13

Again, under regioselective cleavage the same group has synthesized seven- and eightmembered rings. The reaction proceeds only with Tic& as the Lewis acid catalyst. The smooth formation of the medium-sized rings without high dilution can be explained by a template effect, because titanium can complex both the acetal oxygen and the oxygen of the silyl enol ether (Scheme 8):

OH

(35)

(36)

Scheme 9

Fleming et al. were the first to study the influence of the stereochemistry of the vinyl silane in reactions with oxonium ions. [lo] It has been demonstrated that E-vinyl silanes react much more slowly than the corresponding Z-vinyl silanes. This is a further result to

Scheme 8

The cleavage of tetrahydropyran ethers (obtained from homo ally1 alcohols) under acid catalysis has been reported by Kay et al. [9] Products of type (34) are formed under stereoselective conditions. In a short sequence (34) could be transformed into the pheromone (36) of the olive gly ducus oleue (Scheme 9).

ZnBr2. 24h, 10% 55%

Me0

OMe

(38) Scheme 10

OMe

(39)

176

E. Cyclization Reactions

show that vinyl silanes react in the presence of electrophiles with retention of configuration (Scheme 10). [ l l ] The first example in which an alkyne has been transformed in to a cyclic ether was reported by Bunnelle et al. [12] Similar to the reactions with iminium ions assistance of an external nucleophile - in this example the chloride ion of the Lewis acid - is required. The reaction proceeds again via a cation-ncyclization, which was initiated by acetal cleavage (Scheme 11).

The most important contributions along these lines have been reported by Overman. [13] Besides development of synthetic methods many complex total syntheses have been reported from his laboratories. As terminating systems mostly vinyl silanes have been used, which were synthesized in a straightforward short sequence (Scheme 12).

chains that contain the initiator; Control of the regiochemistry during cyclization; and, finally, control of the configuration of the double bond in the cyclization product. Both exoand endo-products are possible. [14] With this strategy in hand 5 , 6-, and 7-membered rings have been synthesized. To initiate the reactions the tried and trusted MEM-ethers were cleaved under Lewis acid conditions. The Lewis acid of choice in these cyclizations is SnCI, and the selectivity observed is always > 98% (Scheme 13).

Scheme 13

E-Vinylsilane (51a) is transformed smoothly to the alkylidene tetrahydrofuran (52),but Zvinylsilane (51b) produced only tetrahydropyran (54). This is the first example in which the stereochemistry of the double bond controls the ring size. The product is obtained via the (43) (44) six-centered transition state (53), in which the butyl group is oriented equatorially. The destabilization of the a-cation is compensated by the attack of the chloride ion of the Lewis acid (Scheme 14). Endo-cyclizations can be used to form eight-membered rings if suitable substitution (45) (46) patterns are present in the side chain and the Scheme 12 initiator. [15] The mechanism of this particular The silylgroup has to perform three tasks: cyclization is similar to that of the ene reacStabilization of the carbanion in the a- tion, but the conditions are much milder position of the silyl group to hook on the side (-20°C). [16] The most important result in this

Electrophilic Cyclizations to Heterocycles: Oxonium Systems

177

R’

R’ MEhlo+R2

(5 7 0)

-20%

-5%

SiMe,

(52) 8 1X

Me

(55)

Me

R’ = n-Bu; R2 = H

Me

(56)

cis : trans = 30 : 1

(53)

study is the control over both configuration in (56).The result can be explained by the transtion state (%), in which both substituents are pseudo-equatorial orientated, and the Eoxonium ion is attacked from the a-face (Scheme 15). These results have opened the gate for the first and enantioselective total synthesis of the unusual marine natural product laurenyne (73). [17] In addition to the unusual eightmembered ether ring, the two sensitive unsaturated side chains and the chlorine substituent are noteworthy. Various problems could be solved by Overman, except the low selectivity in the epoxide opening (64)+(65). The choice of the correct initiator initially caused some problems. Overman demonstrated that only (68) cyclized to the desired ring (69). All attempts to functionalize the acetal “in a better way” before

Scheme 15

cyclization failed. In addition, the total synthesis of laurenyne led to a correction of the absolute configuration. The synthesis starts with the bromide (60),which was transformed in straightforward manner into (67). The acetal (68) cyclized in 37 % yield to (69). The final steps of the synthsis are the elaboration and functionalization of the side chains (Scheme 16). The total synthesis presented demonstrates the potential of this new cyclization technique and allows an entry into a class of complex natural products with sensitive functionality. The cyclization can be mediated by a Lewis acid. The selection of the initiator was crucial for the success in the total synthesis.

178

-

E. Cyclization Reactions Me3SiQ

1. PCC

It

2. (CF,CH,O),P-CH,CO,Me:

CI /,/OTs

HO

Me3siY-3 C02Me

r‘‘

2. PCC 3.Me SiiT1;

(69)

PdbAc),

“

(62)

KN(SiMe,),

-2‘

o*

H

“Sharplessepoxidatlon”

l.’k{fi$idine

1 . DIEAH

dz,/OTs

,

2. MsCl 3. NaBH,. HMPT

(70) 1. NaCN. DMSO

, \ “ ’

/

(73)

Scheme 16

References [l] D. J. Faulkner, Nut. prod. Rep. l986,1. [2] A.van der Gen, K. Wiedhaupt, J. J. Swoboda, H.C. Dunathan, W. S. Johnson, J. Am. Chem. SOC. 1973, 95, 2656.

[3] I.Fleming, A.Pearce, R.L. Snowden, J. Chem. SOC. Chem. Cornmun. 1976,182. [4] M. A. Tius, Tetrahedron Lett. M, 22, 3335. [5] H. Nishiyama, S. Marimatsu, K. Sakuta, K.Itoh, J. Chem. SOC. Chem. Commun. 1982, 459. [6] H. Nishiyama, K.Itoh, J. Org. Chem. EXB, 47, 2496. [7] K. Isaac, P.Kociensky, J. Chem. SOC. Chem. Commun., 1982,460. [8] G . S . Cockerill, RKocienski, J . Chem. SOC. Chem. Commun. 1983,705. [9] I.T. Kay, E.G. Williams, Tetrahedron Lett. 1983,24, 5915. [lo] H.-F. Chow, I.Fleming, J. Chem. SOC. Chem. Commun. 1984, 1815.

Electrophilic Cyclizations to Heterocycles: Oxonium Systems

[ll] T.H. Chan, P. W. K. Lau, W. Mychajlowskij, Tetrahedron Lett. 19R,17, 3317. [12] W.H. Bunnelle, D . W. Simon, D . L . Mohler, T.F. Ball, D.W. Thompson, Tetrahedron Lett. 1984,25,.2653. [13] L.E. Overman, A.Castaiieda, T.A. Blumenkopf, J. Am. Chem. Soc. 1986,108,1303. (141 J. E. Baldwin, J . Chem. SOC. Chem. Commun. 1976, 734.

179

[15] L. E. Overman, T. .A. Blumenkopf, A. Castaiieda, A.S. Thompson, J . Am. Chem. SOC. 1986,108,3516. [16] H.M. R.Hoffmann, Angew. Chem. 1969, 81, 597. Angew. Chem. Int. Ed. Engl. l969,8,556. [17] L.E. Overman, A.S. Thompson, J . Am. Chem. SOC. 1988,110, 2248.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Electrophilic Cyclizations to Heterocycles: Sulfonium Systems Dieter Schinzer

Thioacetals (I) are mostly known as protecting groups or in connection with umpolung of carbonyl groups. [l]These compounds can be deprotonated by a large number of bases, like butyl lithium, which makes them useful intermediates for a variety of transformations. Simple alkylation of ( I ) leads to starting materials for potential cyclization (2) in which both the initiator and the terminator are present (Scheme 1). [2]

Me-S

(3)

--+

-

DuTsF Me-S\a\OT0 MS

Me-Su\OTMS

(4)

Me-S (44

Scheme 2

under mild conditions as an alternative to mercury-promoted hydrolysis (Scheme 3). [3] (1)

z.B.: R = Alkyl:

Scheme 1

R’ = Alkenyl

(2)

The reagent of choice to cleave thioacetals, in order to initate cyclization, is dimethyl (methy1thio)sulfonium tetrafluoroborate (DMTSF). [3] The resulting sulfonium ion (4) can be trapped in intramolecularly by a variety of terminators (vinyl silanes, silylenol ethers, ally1 stannanes) to form cyclic compounds (Scheme 2). Sulfonium ions of type (4) have a long history and were reported first by Meerwein et al., [4] but it took almost 15 years to discover their potential in synthesis. Initially, sulfonium ions have been used to cleave thioacetals

R1

\ /

S-Me

C

R2/ ‘S-Me

,,

DkmF

R1,

+ 2. H20

R2/

c=o

Scheme 3

The research group of Trost first used intramolecular reactions with sulfonium ions. [2] The reactive intermediates can be trapped with nucleophilic olefins, e.g. vinyl silanes, (7)+(9). The primary cyclization product (8) was not isolated, because it rearranged in situ to product (9) (Scheme 4). [2] Compound (10)can be transformed chemoselectively in the presence of the vinyl silane to ketone ( I I ) , which can be cleaved to the enone (12) with HgClz and DBU. The overall process represents a selective aldol reaction (Scheme 5).

E. Cyclization Reactions

182

Me-S Me-S

MxlsF

Me-S

(15)

SiMe,

(7)

87%

(16) 90%

Scheme 6 1. BUU

v

(9)

AEXX-siMe3

67%

Scheme 4

DUTSF

Scheme 7

Scheme 5

An intramolecular aldol reaction of (13) yielded exclusively 1-acetyl-2-methylcyclopentene (14). [5] On the other hand, (I5), on addition of DMTSF, yielded only the sevenmembered ring (16) (Scheme 6)! Surprisingly, (17) cyclized to the spirosystem (28) in the presence of two terminators: a vinyl silane and the ketone. The pnmary cyclization occurred with the vinyl silane, because (18) cannot be obtained from (11) or (22) (Scheme 7).

Another report of Trost’s group provided an approach to the phenatrene skeleton. [4] In a short sequence starting from (I) (20) would be obtained, which was transformed with DMTSF into (21). The latter could be transformed in three steps to (24) (Scheme 8). Even in intermolecular reactions chemoselective transformations can be obtained with sulfonium ions. In addition to olefins, acetylenes, ester groups, and keto groups are tolerated. Very reactive terminators, like ally1 stannanes, attack exclusively sulfonium ions (Scheme 9). [7]

Electrophilic Cyclizationsto Heterocycles: Sulfonium Systems

Jq1.m

Me0 W0

2. CISiMe,

S

M

e

56%

(19)

SMe

- 78% 0-TMS

(20)

OMe (21)

74%

HgC12. O W

(22)

73%

OMe

%”Q& (23)

80% OMe

(24)

As a result of this outstanding chemoselectivity, sulfonium ions of type (4) can be regarded as “super-carbonyl-equivalents”. The synthesis of medium-sized rings is complicated and the synthesis of large rings is even more difficult. In particular, macrocyclizations that lead to macrolides are quite important. The transformation of (3I)+(32) shows the potential of sulfonium ion initiated cyclizations. Compound (32) was obtained chemoselectively in 48 % yield (Scheme 10). [7] The alternative reactivity of thioacetals is noteworthy: First, the thio group is used to stabilize a carbanion in the alkylation sequence. Second, a Lewis acid forms the sulfonium ion, which initiates a chemoselective reaction with nucleophiles. Cationic intermediates are also known in the Pummerer reaction. [8] Compounds of type (36) react smoothly in intramolecular fashion with aromatic systems. Especially with anion stabilizing groups, like the cyano group, 1. Buti 2. B~CHz)$r

70% OMe

Scheme 8

(26)

0

0

62%

(27)

(28)

Scheme 9

53%

183

(32) Scheme 10

h e

E. Cyclization Reactions

184

Pel (33)

(CF3CO&0

CN

C0,Et

'CN]

(37)

t-BuO* K"

Wz3)

--+ (36)

(39)

(38)

92%

Scheme 12

Scheme 11

these reactions are quite powerful. The trifluoroacetate first attacks the sulfoxide (33) to form (36), which spontaneously cyclizes to (37) (Scheme 11). [9] The basic studies of Vedejs et al. have enormously extended the potential of this new cyclization technique. [lo, 111They have studied ring-expanding reactions of sulfur ylids to form medium and large rings. Even if these reactions can be regarded more as 2,3sigmatropic rearrangements, they can be discussed here. The eight-membered ring (43) could be synthesized in 80% yield, from simple precursors (Scheme 12). An almost quantitative yield is obtained in the formation of a nine-membered ring (Scheme 13)! Finally, a complex seven-membered ring annulation in connection with an approach of the lathrane diterpenes from Fuchs will be discussed. [12, 131 Key reaction of the synthesis is a tetra cyclic intermediate, which is formed by a sulfonium ion-induced cyclization (51)+(52).

(44)

Scheme 13

aox

2r .Q

96%

(45) Co2Et

A model study was not necessary because the authors could make use of known results from Trost's group. [6] Starting from optically active (46), cyclization precursor (51)could be obtained in a sequence of steps. The masked acetyl group is elegantly introduced as a lithiated vinyl ether, (49)+(50). The enolate can be formed with potassium diisopropylamide, which was trapped with TMSCl to give the desired silyl enolether (51). The latter was cyclized under standard conditions (DMTSF) to give (52) in 65 '70 yield (Scheme 14). This final sequence demonstrates that molecules with different functionality can also be selectively transformed into complex ring systems. This series of three chapters clearly shows the potential of cation-initiated cyclizations. The main emphasis in these articles was to point out the general principles and the slight differences in these cyclization tech-

Electrophilic Cyclizatiom to Heterocycles: Sulfonium Systems

Swern-

Oxidation

(47)

DBU

185

niques. Iminium ions are mostly used to form five- and six-membered N-heterocycles, whereas oxonium ions can be used to form seven- or eight-membered ethers, as elegantly demonstrated by the total synthesis of laurenyne. Of course, five- and six-membered ethers can also be obtained! The situation with sulfonium ions is quite different. Carbocyclizations are mainly obtained in which the thio group occurs as a substituent that can be cleaved in a later stage of the synthesis. Large rings in particular were synthesised using this technique. In conclusion, each type of cyclization has its own application in synthesis, but all reactions make use of the same terminators, like silylenol ethers, vinyl silanes, allyl silanes, and allyl stannanes.

References

CH,S SCH,

-

(49)

1. KDA

2. CISiMe,

CH3S SCH3 (50)

Scheme 14

E.J. Corey, D.Seebach, R.Freedman, J . Am. Chem. SOC. l967,89,434. B.M. Trost, E.Murayama, J . Am. Chem. SOC. 1981,103, 6529. J.K. Kim, J.K. Paw, M.C. Caseno, J . Org. Chem. 1979,44,1544. H.Meerwein, K.F. Zenner, R.Gipp, Liebigs Ann. Chem. 1965,688,67. T.R. Marshall, W.H. Perkin, J . Chem. SOC. 18!)0,57, 241. B.M. Trost, E.Murayama, Tetrahedron Lett. 1982,23,1047. B.M. Trost, T. Sato, J . Am. Chem. SOC. M, 107, 719. P.Welze1, Nachr. Chem. Tech. Lab. 1983,31, 892. M. Hori, T. Kataoka, H. Shimitzu, M. Kataoka, A.Tomoto, M. Kishida, Tetrahedron Lett. 1983, 24, 3733. E. Vedejs, Acc. Chem. Res. 1984,17, 358. E.Vedejs, D.Powel1, J . Am. Chem. SOC.1982, 104.2046. [12] T. F. Braish, J. C. Saddler, P. L. Fuchs, J. Org. Chem. 1988,53,3647. [13] D.Uemura, K. Nobuhara, Y.Nakayama, Y.Shizuri, Y. Hirata, Tetrahedron Lett. 1986, 27, 4593.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Polycyclization as a Strategy in the Synthesis of Complex Alkaloids Dieter Schinzer

In no other class of natural products are so dium itself is the most common member many different types of structures found as in (Scheme 1). Lycopodium has been synthesized already the field of alkaloids. Even hexa- or heptacyclic compounds with complex functionality several times. [2-41 The basic structure conare quite common. Since most of the biologi- tains a tetracyclic framework combined with cally active compounds are alkaloids, many five asymmetric centers. The synthesis pubinvestigations concerning their synthesis have been performed. Many elegant syntheses are oriented on biosynthesis (so-called biomimetic synthesis), because quite simple types of reactions can be used combined with a high degree of “refinement” in the final products. A great expert in biomimetic syntheses is R Clayton Heathcock, who has used this technique in many total syntheses of complex structures. With a minimum of transformations (mostly so-called “low-tech’’ reactions are used) a maximum of success is reached in 0 these strategies. 4. W H 4 The first class of compounds that will be n presented in this article are the lycopodium alkaloids. [l] This alkaloid family consists of about 100 compounds, of which lycopo-

(4?“

p“

(1) Lycopodin

Scheme 1

(2)

Lycodolin

(3)

Lycodin

yMe

188

E. Cyclization Reactions

lished by Heathcock is the most efficient; only 8 steps are required to obtain the natural product in 13% overall yield. [5-81 A functionalized enone (4), which is easily accessable from commercial material, was used as starting material. Compound (4) can be treated alternatively with a cuprate reagent or an allylsilane, whereas the Sakurai reaction provides the better chemical and stereochemical yield. [9] The sequence ozonolysis, ketalization and reduction of the nitrile to the amine (6) produces the key intermediate of the synthesis (Scheme 2). After benzoylation of the amine and reduction of the benzamide the crucial step of the synthesis is performed: under thermodynamic conditions (MeOH, HCI) a Mannich reaction is used to stereoselectively produce the tri-

cyclic ketone (7). The configuration of the methyl group was already established with the Sakurai reaction. Everything else is controlled by thermodynamics! The configuration of the side chain is of no interest, because only the axial epimer will cyclize into the iminium ion. The more stable equatorial epimer cannot reach the iminium ion for geometrical reasons. Since (11) and (12) are in equilibrium via (9) and (lo), only the “correct compound” (11)cyclizes to the tricyclic (7) (Scheme 3).

n

FMe

Me 1. CICOOEI. E13N

H2N(CH&OCH2Ph

2. 3. LIAIH4

6

JI Me H EtOH *’Pt’

Scheme 3

Scheme 4

cQ0

Polycyclization as a Strategy in the Synthesis of ComplexAlkaloids

The natural product can be synthesized by a modification of the amine side chain. But these details are important during the total synthesis, as shown in the transformation (16)+(17). This particular transformation proceeded under more drastic conditions and took 14 d reaction time to yield (17) (64% !). After hydrogenolysis of the benzyl ether, Oppenauer oxidation (benzophenone as oxidizing agent), [101 intramolecular aldol condensation to (19), a final hydrogenation yielded the natural product ( I ) (Scheme 4). Analysis of the synthesis shows that only simple C-C bond forming reactions have been used (only textbook reactions) to construct a complex molecule. The great accomplishment of this work is the strategy of the synthesis. The next example will focus on the synthesis of 2,3,3-trialkylindoline alkaloids, which also belong to a complex family of compounds. [ll]One has to remember the unique synthesis of strychnine by R. B. Woodward. [12] Again, Heathcock has synthesized vallesamidine (20) in a very efficient way (Scheme 5). [13]

189

Et (27)

Scheme 6

Scheme 5

Starting with the simple ketone (21) compound (22) can be obtained in a Michael addition. Key reaction is then a Michael addition of the tautomeric enamine (241, which is lactamized to (25). At the end of the sequence the indoline part is obtained by an intramolecular alkylation (26)+(27). (Scheme 6). Neither the Woodward nor the Stork strategy allows the synthesis of this type of alkaloids. [14] In only seven steps and 19 % overall yield this synthesis is also very efficient.

Even more complex are the class of daphniphyllume alkaloids which got isolated from unusual Japanese trees. [15] The first total syntheses of these compounds were also reported by Heathcock et al. [16-181 The strategy is again based on very simple C-C bond forming reactions that proceed in onepot operations in high chemical yield. The daphniphyllium alkaloids are pentaand hexa-cyclic compounds with several asymmetric centers in which the construction of the frame-work looks quite hopeless (Scheme 7). The problem could be solved elegantly by Heathcock in two total syntheses (Scheme 8). [16-18]

190

E. Cyclization Reactions

followed by in situ alkylation with homogeranyl iodide - yielded (34). DIBAL reduction and cleavage of the amide generated lactone (35), which was reduced to the diol (36) with lithium aluminumhydride. The following Swern oxidation yields an unstable dialdehyde (37), that is treated in situ first with ammonia

6h

Scheme 7

The starting material of a 10 step synthesis of methylhomoseco daphniphllate (40) with an overall yield of 42% is the amide (33). A tandem reaction - Michael addition of the enolate of (33) with a cyclic unsaturated ester,

H,-Pd/C. HCI

(39)

[85% 2. 1. lones MeOH. based H,SO, on @@I

Scheme 8

>q& (a

Polycyclization as a Strategy in the Synthesis of Complex Alkaloids (37)

Scheme 9 OEt

(58)

191

and then with acetic acid to give the stereochemically pure pentacyclic compound (38). This compound can be transformed into the natural product (40) by simple operations (Scheme 8). In the sequence (37)+(38) four rings are constructed in a one-pot procedure. In the presence of ammonia intermediate (42) is generated, which is trapped by an intramolecular aza-Diels-Alder reaction to form (42) (Scheme 9). The iminium ion (42) closes the final ring by way of a n-cyclization to give (38). The fascinating part in this synthesis is the interplay of electrophilic and nucleophilic properties of the reactive template, which generates a very complex skeleton in a one-pot procedure. The hexacyclic daphnilactone A (32) is available by simple modifications of this strategy. The synthesis starts with ester (43), which is deprotonated with potasium disilazide and alkylated with homogeranyl iodide. Reduc-

192

E. Cyclization Reactions

tion of the ester group, and reaction with acetylbromide yields the highly functionalized ester (44). The subsequent intramolecular Reformatsky reaction (44)-+(45) generates the tricyclic lactone (45). The diol (46) is transformed into the hexacyclic compound (47) by the procedure described already for (40). The aminoalcohol (48) is obtained by an interesting fragmentation induced by DIBAL (47)+(48), followed by Jones oxidation, and treatment with formaldeyhde under biometic conditions, which gave the natural product (32) (Scheme 10). The presentation of the last two syntheses has demonstrated how powerful biomimetic strategies can be applied in synthesis mostly using so-called “low-tech reactions” with simple and cheap reagents. By this technique very complex molecules could be synthesized in a very short and efficient way.

References [l] K. Wiesner, Fortschr. Chem. Org. Naturst. 1962,20, 271. [2] G. Stork, R. A. Kretschmer, R. H. Schlesinger, J. Am. Chem. SOC.1968,90,1647. [3] W.A. Ayer, W.R. Bowman, T.C. Joseph, €?Smith, J. Am. Chem. SOC.B68,90, 1648.

[4] D. Schumann, H.-J.Miiller, A. Naumann, Liebigs Ann. Chem. 1982, 1700. [5] C.H. Heathcock, E.F. Kleinman, E.S. Binkley, J. Am. Chem. SOC. 1978,100, 8036. [6] E.E Kleinman, C. H. Heathcock, Tetrahedron Lett. 1979, 4125. [7] C.H. Heathcock, E.F. Kleinman, J. Am. Chem. SOC. 1981,103,222. [8] C.H. Heathcock, E.F. Kleinman, E.S. Binkley, J . Am. Chem. SOC. 1982,104,1054. [9] T.A. Blumenkopf, C.H. Heathcock, J. Am. Chem. SOC. 1983,105,2354. [lo] R. B. Woodward, H. L. Wendler, F. J. Brutschy, J. Am. Chem. SOC. 1945,67, 1425. [ll] G.A. Cordell, J.E. Saxton, Alkaloids (N.Y.) 1981,20, 1. [12] R. B. Woodward, M. P. Cava, W. D. O h , A.Hunger, H.V. Daniker, K.J. Schenker, f. Am. Chem. SOC.1954, 76,4749. [13] D.A. Dieckman, C.H. Heathcock, J. Am. Chem. SOC.1989,111, 1528. [14] G.Stork, J.E. Dolfini, J. Am. Chem. SOC. 1963,85,2872. [15] S. Yamamura, The Alkaloids (Ed. : A. Brossi) l986,26, 265. [16] C. H. Heathcock, S. K. Davidson, S. Mills, M.A. Sanner, J . Am. Chem. SOC. 1986, 108, 5650. [17] R.B. Ruggeri, M.M. Hansen, C.H. Heathcock, J. Am. Chem. SOC. 1988,110, 8734. [18] R. B. Ruggeri, K.F. McClure und C.H. Heathcock, J. Am. Chem. SOC. 1989,111, 1530.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

F. General Methods and Reagents for Organic Synthesis Domino Reactions Herbert Waldmann For the total synthesis of complex organic thetic endeavors aimed at the construction ot’ compounds nowadays a rich arsenal of power- natural products appear to be uneffective and ful synthetic methods is available. However, circumstantial. In nature, biocatalysts often in comparison with the biosyntheses taking carry out sequential transformations, that is, a place in biological systems many total syn- series of bond formations or scissions without the accumulation of intermediates. Although ci+# the multienzyme systems involved in these 20% 4h biosyntheses can advantageously be employed for preparative purposes, [l]the development of analogous nonenzymatic synthetic sequen(1) (2) ces opens up new and promising opportunities for organic chemistry. In particular, the socalled “domino reactions” (frequently also

-

(4) 81 x cis: trans = > 9 9 : 1

(3)

EDDA: HSN+-CH2-CH,-+NH,

(OAC-)~

ZnBrJ

20 “C

n

(5)

W2Me

(8) 54-86 X tmne: du = 953 :4.2 99.7 :0.3

-

ZnBtg

room temp.

IH

COzMe (6)

-

73-88x

tmns: cis

> 99

:1

194

E General Methods and Reagents for Organic Synthesis

g=s o

II

L

X

a

m

ci

0

+

+

II

z

Domino Reactions

described as “tandem reactions” or “cascade reactions”) prove to be very elegant and effective processes. The term “domino reactions” describes two or more subsequently occurring bond forming or bond breaking transformations, during which subsequent reactions occur at the functionalities generated in the respective preceeding step. [2] Tletze et al. have developed three very flexible domino reactions. In the first case, in a tandem Knoevenagel-hetero-Diels-Alder sequence, an aldehyde, for example, (I), undergoes condensation with a 173-dicarbonyl compound, for example, (21, to give a l-oxa173-butadiene(3), which undergoes cycloaddition with a dienophile to give (4). [2a, b, e, 31 The dienophile may be accessible intramolecularly, as in ( I ) , or it may be added as a third component to the reaction mixture. If a 1,3-dicarbonyl compound that cannot react further in a hetero Diels-Alder reaction, for example, dimethyl malonate (5), is introduced into the initiating Knoevenagel condensation, an ene reaction terminates the sequence [e.g., (5)+(6)]. [4] If, in addition, aldehydes are used that embody an allyl silane moiety, for example, (7), the cascade is terminated by an allyl silane cyclization [e.g., (7)+(8)]. [5] A broad variety of aldehydes and CH-acidic compounds can be employed in the tandem Knoevenagel-hetero-Diels-Alder reactions, including such nucleophiles in which the dicarbony1 structure is hidden in a heterocycle, for example, (9) and (10). The simple diastereoselectivity is generally high and by using enantiomerically pure aldehydes, [6a, 7-91 1,3dicarbonyl compounds [6b] or chiral Lewis acids [6c] asymmetric syntheses proceeding with excellent stereoselectivity can be carried out. Furthermore, this domino sequence has proven its efficiency in the construction of various natural products and pharmacologically active compounds (Scheme 1). For instance, the psychotropic (-)-hexahydrocannabinol (14) was obtained in a few steps in enantiomerically pure form by following this

195

method. [7] To this end, (R)-citronella1 (11) was converted to (12) and after subsequent cycloaddition the Diels-Alder adduct (13) was formed, which could be transformed to the desired (14). On the other hand, the aldehyde (15) and Meldrums’s acid (16) deliver the tricyclic intermediate (17), from which deoxyloganine (18) was obtained in six steps. [S] This iridoid glycoside plays a central role in the biosynthesis of numerous alkaloids. Takano et al. used this method to construct the cycloadduct (20) from the protected glycerol aldehyde (19). [9] Compound (20) served as congener to the indole alkaloids (-)-ajmalicine (21a) and (-)-tetrahydroalstonine (21b). Domino reactions offer a wealth of new opportunities for alkaloid chemistry. For instance, Winterfeldt et al. [lo] took advantage of the subsequently occurring diastereoselective conjugate addition of the enantiomerically pure enaminone (22) to the a$unsaturated aldehyde (23) and a following Pictet-Spengler reaction to generate the tetra-

(22)

9

diastereomericratio 88 : 12

Me02

(24)

R* =

(25)

HA

196

E General Methods and Reagents for Organic Synthesis

3 TOSOH, 10 MI 5 (CYO)"

y o / acetone 10 : 1

100°C

L

(32)

J

2) MOH-

B)Li/NH,

(34): R = X = H

Scheme 2. Domino sequences which are initiated by an iminium salt formation according to Grieco et al. [ll]and Overman et al. [12].

cyclic compound (24), which is a central intermediate in the construction of the corynanthe alkaloids, for example, geissoschizine (25). Grieco et al. [ll] and Overman et al. [12] employed the Mannich reaction in very elegant ways to initiate cyclizations (Scheme 2). Thus, on treatment with formaldehyde in aqueous solution the secondary amine (26) forms an iminium intermediate (27) to undergo a polyene cyclization that is finally terminated by an allylsilane cyclization. [111

The tertiary amine (28) formed thereby can be transformed to yohimbone (29). A nucleophile-assisted iminium ion-alkine cyclization served as the key step in the synthesis of the alkaloid allopumiliotoxine 339A (34). [12a] In the course of this. sequence the oxazine (31), which was built up from the proline derivative (30), was converted to the iminium salt (32) by treatment with aqueous formaldehyde, Assisted by iodide as nucleophile the correctly placed acetylene in (32) then attacks

Domino Reactions

’

197

(35)

OMe

1

OMe (37)

*

2) ClCOoMe

Me0

Me0

H

COOMe

(39)

70-90%

Scheme 2. continued

the heteroanalogous carbonyl compound and with simultaneous loss of the acetonide protecting group the intermediate collapses to give the heterocycle (33). In the course of the construction of the pentacyclic aspidosperma alkaloid 16-methoxytabersonine (40), [12b] Overman et al. combined the initiating iminium ion formation (35)+(36) even with an aza Cope rearrangement (36)+(37), a Mannich reaction (37)+(38) and the formation of a Schiff base (38) +(39). In addition, the authors recently used this impressive multistep reaction cascade as the key step in the first enantioselective total synthesis of strychnine. [12c] A hetero Cope rearrangement also forms the core of the elegant and efficient domino syntheses developed by Blechert et al. (Scheme 3) [13] The sequence starts with in

situ generation of nitrons, which then react with acceptor-substituted allenes in 1,3dipolar cycloadditions to give the adducts (41).These intermediates embody a l-aza-loxa Cope system and by a spontaneous [3,3]sigmatropic rearrangement followed by a retro Michael reaction and elimination of water they are converted to the 2-vinylindoles (42), which are viable congeners for the construction of complex alkaloids. If the moiety “R” in (42) incorporates an appropriately placed double bond, the reaction cascade can further be extended by an intramolecular Diels-Alder reaction and the perhydroellipticine derivative (43) is formed in a one-pot-reaction in 40% overall yield. [13a] Furthermore, Blechert et al. developed new routes to iboga-, [13d] uleine- [13a] and tetrahydrocarbazole alkaloids. [ 13el

198

E General Methods and Reagents for Organic Synthesis

ecN L

--+G

C H

N

0

NH2

R

H (42) 50-77%

R

Me

H

(43)

overall yield 40 %

Scheme 3. Construction of complex frameworks of alkaloids by using domino reactions according to Blechert et al. [13].

(46) 45%

Schinzer et al. described the combination of a Beckmann rearrangement with an allylsilane cyclization. [14] On treatment of the oxime mesylate (44) with diisobutylaluminum hydride (DIBAH) at low temperature the Lewis acid first initiates a rearrangement leading to the intermediate (45). The latter is then trapped by the allylsilane terminator to give an imine, which is directly reduced to the amine by DIBAH. Compounds such as (46) may prove to be interesting intermediates in the construction of azepine alkaloids. Particularly interesting opportunities for the development of powerful domino reactions are opened up by the use of transition metal mediated transformations. An impres-

Domino Reactions

sive example is provided by the cobaltcatalyzed directed cyclotrimerization of alkynes developed by Vollhardt et al. (Scheme 4). [15] For instance, bis(trimethy1sia)

1

SiMe3

>

+

CpcO(W)2

A

SiMe3

199

1yl)acetylene (47) (BTMSA), which is unable to undergo self-trimerization, reacts with the 1,5-diacetylene (48) in the presence of the catalyst C ~ C O ( C O ) ~ (=C cyclopentadienyl) ~

TMs TMS

\

(56)

(57)

Scheme 4. Construction of a) estrone and b) the indole (53) by domino reactions according to Vollhardt et al. [15]and c) construction of estrone according to Quinkert et al. [16].

200

E General Methods and Reagents for Organic Synthesis

to give the isolable benzocyclobutane (49). This strained compound is subject to a ringopening reaction leading to the orthoquinodimethane (50), which under the reaction condition serves as diene in an intramolecular Diels-Alder reaction leading to (51). The tetracyclic (51) was converted to rucestrone (52) via regioselective protodesilylation at C-2 and oxidative cleavage of the C-3Si bond. [15b] In the course of applying this methodology to the construction of various targets, the authors, for instance, built up the indole derivative (53), which embodies the basic framework of the polycyclic indole alka-

C02Me COpMe

loid strychnine (Scheme 4 b) . [15c] According to Quinkert et al. reactive ortho-quinodimethane intermediates can also be generated photochemically from alkyl-substituted benzophenones. [16] By irridation of (54) the tautomer (55) is formed, which is converted immediately to (56) by a stereoselective intramolecular Diels-Alder reaction. After dehydration (57) is formed, from which enantiomerically pure estrone can be synthesized (Scheme 4c). By applying palladium-mediated transformations surprising polycyclization can be realized (Scheme 5). Thus, Oppolzer et al.

0.1 eq. . W W 2 0.4 eq. trifurylphosophine CH&gcoOtr 1t 0%. 2 h

OAc

MeO&,

.C02Me

(59)

J

+ EtO&

p

OMe

COpEt

(65) 75% (63) (64) Scheme 5. Domino Heck reactions according to Oppolzer et al. [17], Negishi et al. [18] and de Meijere et al. ~91.

Domino Reactions

201

[3] L.F. Tietze und U.Beifuss in Comprehensive described that the trans-1,Ccycloheptene (58) Organic Synthesis, Vo1.2 (ed.: B.M. Trost), is converted in one step to the complex tetraPergamon, 1991,p. 341. cyclic compound (60) by treatment with a 141 a) L.F. IIietze, U.Beifuss, M. Ruther, J . Org. palladium(0)-catalyst. [17] In the course of this Chem. 1989,54, 3120; b) L.F. Tietze, U.Beireaction cascade a palladium ene reaction fuss, M. Ruther, A. Riihlmann, J. Antel, G. M. gives (59), followed by two intramolecular Sheldrick, Angew. Chem. 1988, 100, 1200; Heck reactions. Finally, the sequence is terAngew. Chem. Int. Ed. Engl. 1988,27,1186;c) minated by reductive elimination of the pallaL.F. Tietze, U.Beifuss, Angew. Chem. 1985, dium. Similarly spectacular are the domino 97, 1067; Angew. Chem. Int. Ed. Engl. 1985, 24, 1042; d) L.E Tietze, U.Beifuss, Liebigs Heck cyclizations of (61) to (62) and of (63) to Ann. Chem. 1988,321. (65), developed by Negishi et al. [18] and de [5] L.F. Tietze, M.Ruther, Chem. Ber. 1990,123, Meijere et al. [19] In both cases most probably 1387. first a vinylpalladium intermediate like (64) is a) L. F. Tietze, S. Brand, T. Brumby, J. Fennen, [6] formed, which then cyclizes with the neighAngew. Chem., 1990,102, 675; Angew. Chem. bouring alkyne to form a new alkenyl metal Int. Ed. Engl. 1990,29, 665; b) L.E Tietze, species. In both cases the 0-hydride eliminaS. Brand, T. Pfeiffer, J. Antel, K. Harms, G. M. tion of palladium ends the tandem reaction. Sheldrick,J. Am. Chem. SOC.1987,109,921;c ) The highlighted syntheses provide only a L. F. Tietze and P. Saling, Synlett l992,281. few selected examples out of a wealth of [7] L. E Tietze, G. v. Kiedrowski, B. Berger, Angew. Chem., 1982, 94, 222; Angew. Chem. applications of domino reactions (for extenInt. Ed. Engl. 1982,21, 221. sive reviews see in particular refs. [2a, g]). [8] L. F. Tietze, H. Denzer, X. Holdgriin, M. NeuThey demonstrate, however, that sequential mann, Angew. Chem., 1987,99, 1309; Angew. transformations in many cases open up short, Chem. Int. Ed. Engl. 1987,26, 1295. efficient, and at the same time, elegant routes [9] a) S. Takano, Pure Appl. Chem. 1987,59,353; to complex molecules. It is to be expected that b) S.Takano, S.Satoh und K.Ogasaware, J. this new synthetic strategy will establish itself Chem. SOC. Chem. Commun. 1988,59. as a powerful tool of organic synthesis. [lo] C. Bohlmann, R.Bohlmann, E. G. Rivera,

C. Vogel, M. D. Manandhar, E. Winterfeldt, LiebigsAnn. Chem. 1985, 1752. References [ll] P.A. Grieco, W.E Fobare, J. Chem. SOC. Chem. Commun 1987,185. See, for instance. : a) G. M. Whitesides, C.-H. [12] a) L. A. Overman, L. A. Robinson, J. ZabWong, Angew. Chem. 1985, 97, 617; Angew. locki, J . Am. Chem. SOC. 1992, 114, 368; b) Chem. Int. Ed. Engl. 1985,24,617; b) H. WaldL.E. Overman, M.Sworin, R.M. Burk, J . mann, Nachr. Chem. Techn. Lab. 1992, 40, Org. Chem. 1983, 48, 2685; c) S.D. Knight, 828. L.E. Overman, G.Pairaudeau, J . Am. Chem. a) Reviews: L.F. Tietze, U.Beifuss, Angew. SOC. 1993,115,9293. Chem. 1993, 105, 137;Angew. Chem. Znt. Ed. [13] a) S.Blechert, Synthesh 1989, 71; b) J.WilEngl. 1993, 32, 131-163; b) L.F. Tietze, J. kens, A. Kiihling, S. Blechert, Tetrahedron, Heterocycl. Chem. 1990,27, 47; c) EZiegler, 1987, 43, 3237; c) S.Blechert, Liebigs Ann. Chem. Rev. 1988, 88, 1423; d) G.H. Posner, Chem. 1985, 673; d) S.Blechert, Helv. Chim. Chem. Rev. 1986, 86, 831; e) L.F. Tietze in Acta 1985, 68, 1835; e) S.Blechert in 40 Jahre Selectivity - A Goal for Synthetic Efficiency Fonds der Chemischen Industrie 1950-1990, (eds.: W. Bartmann, B. M. Trost), VCH, WeinFrankfurt, 1990,p.41. heim, W, p.299; f ) H.M.R. Hoffmann, [14] D.Schinzer and Y.Bo, Angew. Chem. 1991, Angew. Chem. 1992,104, 1361; Angew. Chem. 103, 727; Angew. Chem. Int. Ed. Engl. 1991, Int. Ed. Engl. 1992,31, 1332; g) T.-L. Ho, Tan30, 687. dem Organic Reactions, Wiley, New York, 1992.

202

E General Methods and Reagents for Organic Synthesis

[U]a) K.P.C. Vollhardt, Angew. Chem. 1984, 96, 525; Angew. Chem. Int. Ed. Engl. 1984, 23,

539; b) R.L. Funk, K.P.C. Vollhardt, J. Am. Chem. SOC.19&0,102,5253; c) D.B. Grotjahn, K.P.C. Vollhardt, J. Am. Chem. SOC. 1986, 108,2091 and 1990,112, 5653. [16] a) G.Quinkert and H.Stark, Angew. Chem. 1983, 95, 651; Angew. Chem. Znt. Ed. Engl. 1983, 22, 637; b) G. Quinkert, U. Schwartz,

H. Stark, W.-D. Weber, F. Adam, H. Baier, G. Frank, G . Dumer, Liebigs Ann. Chem. 1982, 1999. [17] W. Oppolzer, R.J. de Vita, J. Org. Chem. 1991, 56, 6256. [18] Y. Zhang, G. Wu, G.Agne1, E.Negishi, J . Am. Chem. SOC. M, 112,8590. [19] F. E. Meyer, A. de Meijere, Synlett 1991,777.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Group Selective Reactions Martin Maier

There is no doubt that in the last decade asymmetric synthesis has reached such a high level that the stereocontrolled formation of any given arrangement of stereocenters in a molecule no longer poses an insurmountable challenge. [l]Thus, it is possible to functionalize prochiral centers in chiral starting materials by taking advantage of substrate control. In this area a large body of knowledge has been accumulated over the years. [2] Equally, for the transformation of achiral compounds into chiral, nonracemic products, one has a large array of chiral auxiliaries at one's command. Recently, these methods have become complemented by very efficient chiral catalysts. [31 In most cases, the transformations that convert a prochiral center into a stereocenter take place at sp*-hybridized atoms (e.g. olefins, dienes, carbonyl groups) or sp2-hybridized intermediates (e.g. enolates). If one of the two faces of the molecule is attacked preferentially, one speaks of facial selectivity. In stereochemical terminology this means that in the course of such reactions, depending on the starting material, enantiotopic or diastereotopic faces are differentiated. However, stereocenters can also be generated by the discrimination of enantiotopic or diastereotopic groups, respectively. For example, the stereocenter in (3) may be generated either from the olefin (I) through a facially selective hydroboration or, alternatively, by selective reduc-

tion of one of the hydroxymethyl groups of the diol (2) (Scheme 1). In fact, such group selective reactions are common in nature. Some esterases are able to hydrolyze selectively one of two enantiotopic ester functions. Accordingly, enzymatic methods have found widespread use in the area of enantioselective synthesis. [4] It is the purpose of the following account to show that chemical methods are also very powerful for the differentiation of groups. In particular, these methods offer advantages that cannot be achieved with faceselective reactions.

h

R

R

differentiation of enantitotopic faces (cf.hydrobration)

\r

differentiation of enantiotopic amps (ct. selective

(3) Scheme 1. Facial and group differentiating reactions for the generation of a stereo center. If R is chiral these are stereodifferentiating reactions.

204

E General Methods and Reagents for Organic Synthesis

The internal arrangement (topology) of constitutionally identical ligands (atoms and atomic groups) within a molecule may be classified according to symmetry criteria (Scheme 2). [5] If groups can be transformed into each other by internal C,-symmetry operations, they are called homotopic. If a molecule possesses apart from a C,-axis ( n is usually 2, sometimes 3), no further symmetry elements, it is called dissymmetric, that is chiral [cf. compound (4)]. Logically, constitutionally equal groups that do not fulfill the criteria for homotopy are termed heterotopic. Heterotopic ligands may be further subdivided into enantiotopic and diastereotopic groups. If a molecule belongs to the point group C,, that means the only symmetry element is a mirror homotopk

x

x

AA

%-axis

Simultaneous Synthesis in two Directions

heterotoplc enantlotopic

diastereotopic x x

C,-symmetry

odd

/

chiitopic center

mesa

\r,

center of pseudo-asymmetry

Scheme 2. Topology of groups.

plane, the groups to the left and right side of this plane are enantiotopic. [cf. molecules (5), (7), (S)].Tetrahedral atoms that lie on the mirror plane are prochiral. However, the presence of a mirror plane in the molecule does not exclude elements of chirality in the molecule itself. Molecules that consist of equal numbers of chiral elements with opposite chirality, are called meso-compounds. These in turn can be classified into odd and even mesocompounds. In odd meso-compounds a central C-atom is termed a center of pseudoasymmetry. On the other hand, if constitutionally identical ligands are not superimposable on each other by symmetry operations, they are diastereotopic. It should be noted that diastereotopic groups can also exist in achiral molecules. Besides the above mentioned symmetry criteria for the classification of groups one can also verify the topology by mutually exchanging the ligands with test groups. [6]

even

Particularly in the case of chain-like molecules the constitutionally symmetrical substrates for group selective reactions may be prepared very efficiently by applying a two-directional chain synthetic strategy (Scheme 3). [7] The major advantage of the simultaneous modification of a molecule in two directions is that the number of synthetic transformations is reduced compared with that of a onedimensional synthetic strategy. Essentially, this means that more material can be processed. The application of a two-dimensional synthesis is recommended, according to Schreiber, [7] for three classes of symmetrical molecules: 1) For molecules with Cs-symmetry; 2) for molecules with C2-symmetry; and 3) for molecules possessing pseudo-C2symmetry. In doing so one tries to keep the symmetry for as long as possible and to diffe-

Group Selective Reactions

(9)

construction of the stereo centers by substrate control (10) breaking of the C,-symmetry requires reagent control; differentitin can deliver either enantimer with high ee

x

(13) Met'

(12)

t

4

I

x

x

x

x 1

Y

(15)

205

x

differentiation requires only monofunctionalization (I4) construction of stereo centers usually by substrate control double addition of a chiral reagent to the homotopic groups of an achiral starting material gives a C,-molecule

x

x

1

Z

1

Y

differentiation of the groups by a diastereotopic group selective reaction through substrate control (16) in case of an achiral starting material (C,-molecule) a doubk addition of a chiral reagent to the enantiitopic groups is necessary

Z

Scheme 3. Two-dimensional synthesis.

rentiate the two ends at the latest stage possible in the synthetic sequence. The relative stereochemistry in the course of the construction of new stereocenters can be controlled as usual by internal asymmetric induction. For

the preparation of an optically pure compound from a Cs-symmetricmolecule a subsequent differentiation of the ends is necessary, whereby external chiral reagents (reagent control) must be used. Under certain circumstan-

206

B General Methods and Reagents for Organic Synthesis

ces, that is if both enantiotopic groups of the Cs-molecule may react principally with the chiral reagent, extremely high enantiomeric excesses are possible. If a two-dimensional synthesis of a Cz-symmetric molecule starts from an achiral starting material, an initial addition of a chiral reagent to both sides of the homotopic groups of the achiral substrate is necessary [cf. (11)+(13)]. The definite generation of new stereocenters in the twodimensional elongation is also possible by substrate control. When the occasion arises, external chiral reagents must be used. In order to differentiate the homotopic ends of a Czsymmetric molecule, monofunctionalization is sufficient. Finally, a two-dimensional synthesis can also be advantageous with pseudo-Czsymmetric molecules. This description refers to a molecule that has a central C-atom that carries two different ligands as well as two identical chiral ligands. For example, reduction of a Cz-symmetricalketone would lead to a pseudo-C2-symmetrical molecule. Despite the fact that such molecules are chiral, the central atom is not an asymmetric center! That is, reduction can only lead to a single alcohol. Because this central atom is in a chiral environment, it is called chirotopic, according to Mislow. [S] Pseudo-C2-symmetric molecules, such as (15), can also be obtained from the chiral pool. Alternatively, they are available from odd meso-compounds by double addition of a chiral, non-racemic reagent to the ends of the molecule. Because the groups in a pseudo-Cz-symmetrical molecule are diastereotopic, internal differentiation of the two ends is possible. In the course of the differentiation process, the central atom becomes an asymmetric center.

Dmerentiation of Homotopic Groups The groups in a Cz-symmetricalmolecule are chemically identical, therefore differentiation

only requires monofunctionalization. Because of the statistical effect one can usually reach a differentiation with one equivalent of reagent. A selective monofunctionalization will also be successful if, for example, the first product is less reactive than the second. The best method, however, is to convert the difunctional compound into a derivative that can only react once. A classical example is the reductive ring opening of the acetal (17), which is available from tartaric acid. [9] The product obtained after isopropylidenation can be functionalized in various ways. Strictly speaking, the groups (OH and ester) of compound (17)are not homotopic but rather diastereotopic because of the benzylidene protecting group. This does not, however, influence the course of the reaction. Finally, monofunctionalization is guaranteed if the intermediate from the first reaction step reacts subsequently with the other functional group. Thus, the Ni (0)-catalyzed cyclization of (19) in the presence of H-SIR, furnishes the cyclohexane derivative (20) in which the two olefins are differentiated. [lo] The same principle is realized in the formation of the cyclopentane derivative (22) from the Cz-symmetrical a,punsaturated diester (21) by a double Michael-addition. [ll] It is suggested that the reactive conformation is (23) in which the largest substituents, the OTBS groups occupy an antiperiplanar orientation. [12] In the depicted conformation the “outsides” of the olefinic faces are homotopic, so that it does not matter which of the olefins is attacked first. A similar conformation also explains the diastereoselective course in the hydroxylation of one of the double bonds of (21) [13] and in the cycloaddition with 1,3-dienes, [14] such as cyclopentadiene. It is obvious that compounds of type (19) and (21) are very easily accessible by a two-dimensional synthesis from the appropriate tartaric acid or from D-mannitol [15] [cf. ent- (21)]. [16] Using this concept of a two-dimensional synthesis of a Cz-molecule, an elegant synthesis of the antibiotic hikizimy-

207

Group Selective Reactions

cin was developed (Scheme 5 ) . [17] In this compound the nucleobase is connected Nglycosidic with an undecose. Hikiziymycin is attributed with significant antibiotic and anthelmintic properties. Starting with L-( +)diisopropyl tartrate, in the first step, the hydroxyl groups are protected. Subsequently, the molecule is elongated in a one-pot reaction (reduction and Wittig-Homer reaction). A double hydroxylation, which is controlled by internal induction, furnishes (25) with eight carbon atoms and six stereocenters (Scheme 5). Treatment with DIBAH leads via a selective mono-reduction and thus a desymmetrization to (26). The choice of the bulky TBS-protecting group is apparently responsible for the high selectivity. Through sequential elongation in two directions (26) is then transformed into (27). First, the alcohol is oxidized to the aldehyde, which subsequently is converted with the Tebbe reagent into the vinyl group. The a, Punsaturated ester functionality at the other end of the chain is manipulated by reduction, oxidation and a subsequent Wittig-Homer reaction. The elegance of the synthesis somehow suffers because the asymmetric induction in the dihydroxylation of (27) to (28) is unsatisfactory. In order to improve the diastereoselectivity in favor of the undecose (28), the authors take advantage of an asymmetric dihydroxylation according to Sharpless. From (28) another 14 steps provide the target molecule (29). It should be mentioned that optically active C2-symmetriccompounds generally are well suited, without differentiation of the groups for the preparation of interesting building blocks, if after a twodimensional synthesis the molecule is cleaved in the middle. [18] For example, the preparation of the 2,3-isopropylidene aldehyde from D-mannitol falls into this category. [19]

'

E

s

o

~RMgEr/Cul(l:l) ~ ~

~

Et20, -20 OC

TBSO"

(21)

R

R

(22)

CHpCH-

Me El

Ph

yield(%) %de

W

92

7

40

7

a >w

-

.w

TBSO

R

Scheme 4. Differentiation of homotopic groups.

208

E General Methods and Reagents for Organic Synthesis OBzl

'

E0C t,-

\ C4Et

TBSO

1. Os04 I NMO (71%) b

2. TBSOTf, 2,6-lutiiine (100%)

6BZl TBSO

OBZl

oms COzEt

EtOzC TBSO

b z l OTBS

1. Swem Oxidat. (97%)

O B Z l OTBS

2. Cp2TiCH2CIAIMe2 (82%) *OH

3. DlBAH (95%) 4. Swem Oxidat. (100%) 5. Wig-Homer (97%)

I OTBS

b

HO TBSO

OBZl OTBS

EtO&

TBSO

OBzl OTBS

(89Yo)

BzloHOl

(27)

(28)

OH

Ho

OH

14 steps __)-

HO

(29) (-)-HikWmycin Scheme 5. Synthesis of (-)-hikizimycin with incorporation of a two-dimensional synthetic strategy.

Differentiation of Enantiotopic Groups

trative example is the enantioselective lactonization of 4-hydroxypimelic acid (Scheme 6). [20] This reaction succeeds with high enantioselectivity by neutralization of the correIn molecules with a mirror plane as the only sponding disodium salt (30) with 1-(S)-( +)symmetry element, corresponding groups to camphorsulfonic acid (CSA). The authors both sides of this plane are enantiotopic. For could show that the reaction probably takes the differentiation of such groups one has to place through an initial enantioselective prorefer to chiral auxiliary reagents or catalysts, tonation followed by lactonization and prowhich by formation of diastereomeric inter- tonation. An opposite reaction is described by mediates or transition states selectively render Heathcock et al., who open a cyclic comone of the enantiomers accessible. An illus- pound, the Cs-symmetrical anhydride (32),

Group Selective Reactions

w

209

HMG-CoA-reductase inhibitors. Interestingly, the optically active alcohol (33) was prepared by an enzyme catalyzed transesterifica(30) tion reaction from the racemate. These processes however, represent rather isolated examples. The differentiation of enantiotopic carboxyl or hydroxyl groups is clearly a domain of biochemical methods. It should be C02H noted that there were earlier more or less successful attempts for the enantioselective acyla(31) 84Y'ee tion of glycerol derivatives. [22] Only recently, however, Ley et al. reported the enantioselective desymmetrization of glycerol using a C2-symmetric disubstituted bis-dihydropyran (bis-enol ether). [23] In molecules with point group C, with CH acidic groups, one can achieve a desymmetrization with chiral bases. Because these methods have been summarized recently, [24] only some representative examples are listed here. For example, the enantioselective deprotonation of enantiotopic methylene groups is possible in 4COZH alkylcyclohexanones and in several mesoketones of various ring sizes with prepara1. carbonyldiirnidazole tively interesting selectivity. The lithium b 2. MeONHMe amide (37) turned out to be a useful base. 3. LiCH2PO(OMe)2 With this base, enolization of ketone (36) proceeds with an enantioselectivity of 85 %. Usu(34) ally the intermediate enolates are trapped as d.r. = 40-50:l the corresponding silyl enol ethers, which can be functionalized in various ways. If one assumes that the chiral amine can be recycled, this procedure also appears to be interesting on a preparative scale. [25] Moreover, chiral lithium amides can be used for the enantioselective opening of meso-epoxides to give Scheme 6. Differentiation of enantiotopic carbo- allylic alcohols. In the case of cyclic epoxides, the best results with up to 92% ee are xylic groups. obtained with the amide (40)derived from Lproline (see Scheme 7). [26] The selectivity with the chiral alcohol (33). [21] Thereby the drops, however, with acyclic substrates. Posmonoester (34) is obtained with high selectiv- sibly, this method may be improved by the use ity (40 to 50:l). By manipulation of the car- of other counter ions, for example aluminium, boxylic group, (34) is converted to the keto- that from better complexes with the oxirane phosphonate (35), which was used, for exam- oxygen. Besides the base-induced opening of ple, for the synthesis of the lactone part of epoxides, there are practical methods at availNa0&

OH

C02Na

O'cri-

(+)-CSA, MOH, -78 OC

210

E General Methods and Reagentsfor Organic Synthesis

(38)

Thus, Shibasaki described the palladiumcatalyzed cyclization of the triflate (43) [available from the triketone (42)] to give the cisannulated bicycle (44) (Scheme 8). In this case the Noyori ligand (S)-BINAP, which induces an enantioselectivity of 80 % ,functions as the source of the optical information. [29] Similiar to this is the cyclization of the biscarbamate (45) to the oxazolidinone (47). Trost et al. found with optically active diphosphines such as (46) easily obtainable ligands, which, with palladium as the central metal, provide for an effective discrimination during the cyclization of (45). [30] The highly functionalized cyclo-

85%ee

n (42)

(39)

(43)

(41) 90% ee

Scheme 7 . Differentiation of enantiotopic methylene groups.

(44)

80%-

able that allow enantioselective opening of TosHN NHTos epoxides with nucleophiles. [27] (45) It is remarkable that enantiotopic protons of alcohols, the OH-function of which has been protected as the carbamate, can be deprotonated with high selectivity. As a base, the complex between sec-butyllithiumand the chiral diamine (-)-sparteine finds application. Because the corresponding akylation products generally are formed with very high selectivity, this method has enormous practical significance. [28] I (94%) Tos If in the course of an enantiotopic group (47) selective reaction ring closure has taken place 88% ee with the addition to an sp2-center, then one usually observes not only the enantioselectiv- Scheme 8. Differentiation of enantiotopic groups ity but also a complete diastereoselectivity. with concomitant diastereotopicfacial selectivity.

Group Selective Reactions

pentene (47) obtained by this strategy served as a chiral starting material for the preparation of the mannosidase inhibitor mannostatine A. [31J Very high enantio- and diastereoselectivity are also observed in the intramolecular hydrosilation of di(2-propeny1)methanol in the presence of a Rh(1)-complex, which contains, for example, (R,R)-diOpas a ligand. [32] Although these examples are already quite impressive, the full power of the group differentiating reaction is only reached in a certain type of compound. These substrates are characterized by the fact that they can in principle kl

L-(+)-DIPT,

211

react twice with the chiral, nonracemic reagent. Of course, this double reaction is not desired, although it can serve to increase the enantioselectivity with progressing reaction time. The textbook example is the asymmetric epoxidation of symmetrical divinyl carbinol. In the starting material there are four olefinic faces available for epoxidation (two pairs of enantiotopic faces; the two sides of an olefin are diastereotopic). If we assume, for the sake of simplicity, a highly diastereoselective epoxidation to the erythro-compound (49) (Scheme 9), then in the first step the formaOH

140 h, -25 OC > 97% 88, > 99.7 de

OH

Ti(OiPr)4,

(48)

tBuOOH

I

OH OH

d.r. = 90%

(51)

(49)

8.r. = 94:6

Scheme 9. Epoxidation of divinyl carbinols with enantiotopic group- and diastereotopic face selectivity.

212

E General Methods and Reagents for Organic Synthesis

tion of two enantiomeric epoxides is possible, of which one should be favored (k, >> k2).In the wrong isomer ent-(49) however, the double bond, which actually should have reacted, is available for a further fast epoxidation. Indeed, the wrong isomer is destroyed with increasing reaction time (kl’> k2’),resulting in the product (49) with very high enantiomeric excess. The first step converts the achiral substrate into a chiral, nonracemic product (e.g. 9O:lO ratio), whereas the second reaction increases the enantiomeric excess in a kinetic resolution. This reaction of Cs-divinyl glycols was probably independently discovered by two groups. [33] A mathematical model that describes the kinetics of such coupled reaction is due to Schreiber. [34] Since both isomers of tartaric acid are available, entry to both enantiomeric series is possible. In addition to the choice of the tartrate for the asymmetric epoxidation there exists a further possibility of controlling the conversion of the epoxides to further products, as shown by Jager et al. [35] Hydrolysis of (49) under acidic conditions yields the triol (51). Alternatively, (49) can first be rearranged under basic conditions to the internal epoxide (52) with inversion at C-2. Subsequent acid hydrolysis leads via inversion at C-3 to the triol ent- (51), the enantiomer of (51). Jager distinctively speaks of a dual system of stereocontrol. Epoxides of type (49) indeed represent almost universal building blocks for natural product syntheses. Under carefully controlled conditions it is possible to protect the OHgroup of (49) without observing a Payne rearrangement. Subsequently, the epoxide function ca be opened with various kinds of nucleophiles. For example, starting from (49) an enantioselective synthesis of the cyclohexyl part of FK506 was developed using this route. [36] Although these examples clearly appear very elegant, some practical problems during the isolation of (49) should not be kept secret: The compound is very water-soluble, very vol-

atile, and can only be obtained pure with considerable effort. This is also expressed in the various rotations that are given in the literature for (49) [Schreiber: [34] [ a ] ” ~ 48.8” (c = 0.73, CHC1,); Jager: [35] [ a ] ” ~ 61.1” (c = 2.31, CHCb). These problems obviously can be avoided if the substrate 1,5bis-trimethylsilyl-1,4-pentadien-3-olis used for the epoxidation instead of (48). [37] The principle of enrichment of the desired isomer by coupled asymmetric reactions is of course applicable to other substrates and reactions. Thus, achiral 5-alkyl-cyclopentadienes (53) can be converted with high optical purity via hydroboration to trans-alkyl-cyclopentenols (55). [38] Compounds of this type represent important intermediates for the syntheses of terpenes, carbohydrates, and particularly prostaglandins. In the ene-reaction of the diene (56) with methyl glyoxylate in presence of the optically active Lewis-acid (57) the product (58) is supplied in very high optical purity. [39] This result might also be traced back to the destruction (double ene-reaction) of the isomer of (58) (Scheme 10). A further logical development of this concept is the application of a two-dimensional synthesis for the preparation of larger molecules with Cssymmetry (mostly mesocompounds), which are subsequently desymmetrized with appropriate reagents. This combined strategy was used by Schreiber for the synthesis of several polyol systems. [40] The advantage in this case is that the desymmetrization will generate a large number of stereo centers in a single step! How fast one gets to bigger symmetrical molecules with the twodimensional synthesis is demonstrated in an elegant piece of work by Wang et al. [41] (Scheme 11). From the C,-building block epibromohydrin (59) the alcohol (60) was prepared by sequential epoxide opening. The alcohol (60) already contains all C-atoms of the meso-dialdehyde (63). Partial cishydrogenation of the triple bonds with nickel boride and stereocontrolled epoxidation pro-

+ +

Group Selective Rections

213

tivities on each side multiply in the form of a polynomial, thereby delivering the major product with extremely high selectivity. [42] Of course with (65) an optically active compound (dr > 15:1, ee > 98%) is on hand, yet it is still constitutionally symmetrical. That is, the chemical differentiation still remains to be done. An elegant solution comes from the odd number of hydroxyl groups. Cleavage of the silyl protecting groups liberates the corresponding heptaol, which is treated with acetone and a trace amount of camphorsulfonic acid. Inevitably, one of the hydroxyl groups must remain unprotected. Which one will result from the stability of the possible 1,3acetonides. It is clear that the syn-hydroxy groups are protected preferentially, because syn-1,3-acetonides are thermodynamically more stable than anti-1,3-acetonides. The authors speak of a diastereotopic group selective acetonide formation. Compound (66) is formed with excellent selectivity (15 :1). Subsequently, the two olefins can be differentiated very easily by a hydroxyl-directed epoxidation. Beforehand, however, the configuration of the free OH-group is inverted by a MitScheme 10. Differentiation of enantiotopic olefins sunobu reaction. Through a cuprate addition to the epoxide, followed by manipulation at by hydroboration and ene reaction. the hydroxyl groups, the octamethoxy-lalkene (67) is obtained, which represents the vided the bis-epoxide (61). In the subsequent active principle of a toxin-producing algae. Birch-reduction not only the aromatic rings are reduced but also the two epoxides are opened regiospecifically (benzylic opening). Ozonolysis liberated the pketoester groups. Differentiation of Diastereotopic In a chelation-controlled reduction the diester Groups with syn-arrangement of the hydroxyl groups was prepared from (62). The Cs-symmetry is In principle, the differentiation of diastereobroken up at the stage of the aldehyde (63) by topic groups is a simple task, because their using one of the Brown reagents (+)- or (-)- chemical environment is different. Consediisopinylcampheyl ally1 borane, which is quently, one should expect different activation added to both aldehyde groups. The choice of energies or different energies of the products the reagent determines the configuration in in any functionalization reaction and therefore the addition reaction. Simultaneously, the selectivity. Since, however, these differences configuration of all the other stereocenters is usually do not allow unequivocal differentiaestablished. In this double addition the selec- tion in practice, except perhaps by NMR-

214

W 0

R General Methods and Reagents for Organic Synthesis

B

r

1.3-M@OPhUU, BF3.Et20

* -.

1.H2, N F , EtOH ______.)

2. KOH, 3.sameas 1.

(59)

OH

1. CH3CN. HF

2. VO(OIPr)3, tBuooH

//

Q?

OTBS OTBS OTIPS OTES OTBS OH

(65) 1. Mitsunobu-inversion

OH 5

OxO

O x O

2. VO(ioPr)g, tBuooH 3. (nBu)gCuLi

OxO

/ 5. KH, Me1

(66) OMe

OMe

OMe

OMe

OMS

OMe

OMS

OMe

(67) Scheme 11. 'ILvo-dimensionalsynthesis of an odd meso-polyol and diastereofacial and diastereotopic groupselective reactions.

spectroscopy, some structural presuppositions have to be present in the substrates. It is quite favorable if the molecule bears a further functional group in the middle that can react with one of the diastereotopic groups with concomitant ring formation. Thereby steric interac-

tions in the transition state or in the products are important. If there is no central group, one has to try to convert the groups into a derivative that only can react once in a subsequent reaction. Among the functional groups that can be differentiated quite easily are

Group Selective Reactions

hydroxyl-, ester-, carboxylic-, and olefinic groups. The differentiation of diastereotopic groups can follow two purposes. On the one hand, it can proceed with a constitutional differentiation. On the other hand, one can use this method to ultimately differentiate enantiotopic groups. An example with enormous practical significance is the differentiation of the two diastereotopic OH-groups in D-(-)-quinic acid (68) (Scheme 22). In the reaction with carbonyl compounds exclusively the cis-acetal is formed with participation of the central OHgroup. [43] Starting from compound (69) a large number of interesting cyclohexane derivatives are accessible. Danishefsky et al. preby reducpared the cyclohexenone (70) [a], tion of. the carboxylic function to the alcohol, subsequent periodate cleavage, mesylation and elimination. This optically pure compound is interesting as a dienophile for cycloaddition reactions and also as a Michael acceptor. From (70) the cyclohexenone (72) with the double bond on the other side can be obtained. Similarly, as in the case of the differentiation of diastereotopic OH-groups, in bis-

acids two carboxyl groups can be played off against each other if a central OH-group is present, because in a lactonization one of the carboxylic groups should react preferentially. [4S] For applications in the area of natural product syntheses, the requisite bis-acids must, of course, be available in optically active form. We recall that pseudo-C2symmetrical molecules can be prepared efficiently by a two-dimensional synthesis. Schreiber et al. have demonstrated this in the context of the bis-ester (78) [36] (Scheme 13). The chiral (pseudo-C2-symmetrical) L-(-)arabitol(72) served as a starting material. This is converted with the Moffatt reagent (73) through the intermediate (74) to the epoxide (75), which represents an ideal substrate for the two-dimensionalelongation. By treatment of (75) with the lithium anion of ethoxyacetylene in the presence of boron trifluoro etherate and subsequent lactonization, the bislactone (76) was obtained. Double methylation of (76) proceeds with good selectivity (dr = 10: 1) and leads to @um-stereochemistryin both lactones. By using standard reactions the bis-methyl ester (78) was generated from (77). The differentiation of the two ester groups succeeds by an acid-catalyzed lactonization, whereby the lactone (80) was formed selectively. The preferential formation of this diastereomer may be rationalized by invoking a reactive conformation (79) with the smallest destabilizinginteractions. In a chemoselective reaction, the lactone was reduced to the lactol, which was opened with dithiane. Simultaneously the lactone (81) was formed. Four more steps from (81) made the building block (82) available, which was used in the synthesis of FKS06. The procedures for the differentiation of hydroxyl groups rely exceptionally on the use of acetal templates. Thus, the hydrazone (83) was cyclized under acid catalysis to the spiro acetal (84) (Scheme 14). [46]Because there is also a hydroxyl group in the “right” part of the molecule, only one of the “left” hydroxyme-

H02cxoH H02cxoH

y L =ms*Ana

u+

(68)

/

0

2. DBU

3.RX

(70)

OR (71)

Scheme 22. Differentiation of diastereotopic OHgroups.

215

216

R General Methods and Reagents for Organic Synthesis

-

p e OMe Me

Me

4 steps

M

e

0

(78)

2

C

PPTS

d

6H

Scheme 13. no-dimensional synthesis of a pseudo-C2-symmetrica1molecule and diastereotopic group differentiating reaction.

thy1 groups can participate in acetalformation. The original stereocenter in the “right” part of (83) not only controls the differentiation of the hydroxymethyl groups, but also leads via enol ether intermediates to equilibration of

the stereocenters in the a-position to the spiro acetal. Compound (84) is the most stable of all possible spiro acetals that can be formed from (83). In (84) there are two anomeric effects operating. In addition, the substituents of the

Group Selective Reactions

0 - X O

-

(83) Me

1. TmCI, NEt3 2. LiBEt3H

H

l+o

(84

Me

(86)

Scheme 14. Differentiation of diastereotopic hydroxymethylene groups by acetal formation.

rings occupy equatorial positions. Transformation of the free hydroxymethyl group into a methyl group and opening of the acetal with ethanedithiol/BF,-,O furnished (86). In another version the hydroxyl groups to be differentiated are first incorporated in an acetal and subsequently one of the diastereotopic C-0 bonds is opened selectively. [47] Oku dexterously used the concept of the differentiationof diastereotopic C-0 bonds in an acetal for the conversion of Cs-symmetrical diols into enantiomerically pure compounds (Scheme 15). The principle of this method consists of the acetalization of diols containing enantiotopic OH-groups with an optically active ketone. [48] (-)-Menthone (87) served as an appropriate ketone. Steric effects guar-

217

antee that the spiro scaffold [cf. (SS)] exists in an unequivocal conformation. The chair conformation of the cyclohexane ring is fixed by the two alkyl groups. Hence, the chair conformation of the 1,3-dioxolane ring follows from this, in which the part of the menthone occupies the equatorial position that leads to the isopropyl group. The acetals of the various Cs-diols will form in such a way that allows their residues in the dioxolane ring to occupy equatorial positions. In some instances mixtures are formed, which must be separated, ) used. for example, if diols of type ( 8 8 ~are The differentiations are based on the observation that of the two C-O bonds of the spiro acetal, the equatorial bond is cleaved in Lewis-acid-induced reactions with high selectivity throughout. A particularly intriguing example is the application of this method to . the mixture of the 1,3-diolsof type ( 8 8 ~ )Of , only the meso- and d, I-diols ( S ~ C )selectively meso-diol is acetalized, so that in this manner a simultaneous separation of meso- and d,ldiols can be achieved. Because of the two substituents of the meso-diol, only the diastereomer with residues in the equatorial position is formed. Ring opening in (89) takes place by reaction with the acetophenone trimethylsilyl ether in the presence of titanium tetrachloride. Subsequently, the free OH-group is protected and the chiral auxiliary is removed by pelimination. Alternatively, the acetal cleavage is possible with the reagent combination allyltrimethylsilane/titaniumtetrachloride whereby in this case the optically active products are set free under acidic conditions. This method even offers the possibility to acetalize meso-polyols enantioselectively,although the ratios are not too favorable. On the contrary, optically active diols can be used to differentiate enantiotopic groups in C,-symmetrical ketones. For example, such acetals may be converted in a group selective reaction to chiral enol ethers [49] by using appropriate Lewis acids.

218

R General Methods and Reagents for Organic Synthesis

K

OH

OH

HO

R

R l R 2

OH

OH

OH

OH

OH

OH

OH

R

1. TMSCI

(884

d,l-mixture

CHpC(Ph)(OTMS),

nci4

I

(90)

P = MOM, M P

(92)

Scheme 15. Differentiation of diastereotopic hydroxy groups by acetalization with a chiral ketone.

Recently, examples have also become known of diastereoselective deprotonation. In this case chiral alcohols, the OH-function of which is protected as the carbarnate, are deprotonated to the corresponding aoxycarbanions. These in turn can be treated with various electrophiles. [50]

But what about the differentiation of diastereotopic olefins? In this case, group- and facedifferentiating reactions can be combined (see Scheme 16). Let us consider as an example the pseudo-C2-symmetrica1heptadienoic acid (93). Here, not only the two olefins are diastereotopic, but also the olefinic faces. That is, in

Group Selective Reactions

219

If carboxylic acids that contain enantiotopic olefins are converted with chiral amines to the L corresponding amides, the two olefins and their faces also become diastereotopic. In the Me Me iodolactonization, there are four possible (93) transition states and hence four possible products. However, since the chiral auxiliary is not present in the product two of the products are O / p enantiomeric in nature. This means that with Me Me -+I Me Me this method such carboxylic acids can be lactonized enantioselectively. [52] (94) 142 Another class of bis-olefins can be generated very easily from aromatic precursors. Wipf et al. describe the oxidation of the tyrosine derivative (99) with a hypervalent iodine reagent to the dienone (100)in which the two olefins are diastereotopic (Scheme 17). [53] Methanolysis of the spiro lactone (100)under (96) 4.7 . basic conditions provides out of four possible diastereomers exclusively the bicycle (101). In summary, it can be noted that group selective reactions represent a valuable tool for asymmetric syntheses and that they ideally H supplement enzymatic methods. Particularly in combination with a two-dimensional syn(97) thetic strategy high efficiency can be achieved, Scheme Z6. Differentiation of diastereotopic olefins both with regard to material throughput and by simultaneous facial selectivity by halolactonizaoptical purity. It is therefore advisable, even tion. 12,4. NaHCO3

ep-1

OH

0

the lactonization of (93), formation of four products is, in principle, possible (neglecting regioisomers). The result of the lactonization of (93) is convincing. [51] The two olefins are differentiated with a group selectivity of 147:1 H NHR R=Cbz,Boc [(94) (96):(9.511. Simultaneously, a high RHN facial selectivity in the lactonization step [ (94):(96) = 30 :11 is observed. The preferential reaction of the “left” olefin is explained by conformational effects. In the favored conNaHCg formation around the C,-C, bond, the carMeOH boxy group and the olefin are situated in close (75%) proximity, whereas in the energetically lowest rotamer around the C&2, bond the corre(101) sponding groups are anti-periplanar and there- Scheme 17. Differentiation of diastereotopic olefins in dienones. fore unfavorable for the cyclization.

+

220

F General Methods and Reagents for Organic Synthesis

with bigger synthetic targets, to look for [ll] S. Saito, Y. Hirohara, O.Narahara, T.Moriwake, J. Am. Chem. SOC. l!W, 111, domains of constitutional symmetry. Some4533-4535. times, it can even be rewarding to invert, add, or remove stereocenters temporarily, to reach [12] S. Saito, 0.Narahara, T. Ishikawa, M. Asahara, T. Moriwake, J. Gawronski, F. Kazmierca certain symmetry that will allow the applicazak, J. Org. Chem. 1993,58, 6292-6302. tion of a group selective reaction. [54] [13] S. Saito, Y. Morikawa, T. Moriwake, Synlett

1990,523-524. [14] S. Saito, H. Hama, Y. Matsuura, K. Okada, T.Moriwake, Synlett 1991,819-20. [15] S. Takano, A. Kurotaki, K. Ogasawara, SyntheReferences sis 1987,1075-1078. [16] For a further example, see: H. Kotsuki, H. Nishikawa, Y.Mori, M.Ochi, J. Org. Chem. [l] See, for example: (+)-Calyculin A: D.A. Evans, J.R. Gage, J.L. Leighton, J. Am. 199t,57,5036-5040. Chem. SOC. W,114,9434-9453. [17] a) N.Ikemoto, S.L. Schreiber, J. Am. Chem. [2] See, for example: a) Stereocontrol by exploitaSOC. 199t, 114, 2524-2536; b) For another tion of 1,3-aUylic strain: R.W. Hoffmann, example of a two-dimensional synthesis of a C2-symmetricchain molecule, see: C. S. Poss, Chem. Rev. l!W,89, 1841-1860; b) SubstrateS.D. Rychnovsky, S.L. Schreiber, J. Am. directed chemical reactions: A. H. Hoveyda, Chem. SOC. 1993,115, 3360-3361. D.A. Evans, G.C. Fu, Chem. Rev. 1993, 93, [18] a) S.Saito, S.-I. Hamano, H.Moriyama, 1307-1370. K. Okada, T. Moriwake, Tetrahedron Lett. [3] See, for example: Chem. Rev. 1992, 92, num1988, 29, 1157-1160; b) T. Takahashi, T. Shiber 5; this issue is completely devoted to the topic of enantioselective synthesis. mayama, M.Miyazawa, M.Nakazawa, [4] a) H.-J. Gais, H.Hemmerle, Chem. Unserer H. Yamada, K. Takatori, M. Kajiwara, TetraZeit, WO, 24, 239-248; b) J.Mulzer, H.-J. hedron Lett. 1992,33,5973-5976; c) M. Jayaraman, A.R.A.S. Deshmukh, B.M. Bhawal, J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig, Organic Synthesis Highlights, VCH, New Am. Chem. 19w,59, 932-934; d) K.H. Ahn, D. J. Yoo, J. S. Kim, Tetrahedron Lett. 1992,33, York, 1991;c) C. R. Johnson, A. Golebiowski, 6661-6664. D.H. Steensma, J. Am. Chem. SOC.1992,114, [19] a) C.R. Schmid, J.D. Bryant, M.Dowlatze9414-9418 and references cited therein. dah, J. L. Phillips, D. E. Prather, R. D. [5] Y. Izumi, A. Tai, Stereo-Diflerentiating Reactions, Kodansha, Tokyo/Academic Press, New Schantz, N.L. Sear, C.S. Vianco, J. Org. Chem. 1991, 56, 4056-4058; b) C.R. Schmid, York-San Franscisco-London, l977. J.D. Bryant, Org. Synth. 1993, 72, 6-12 and [6] E.Elie1, J. Chem. Educ. 19Q0,57, 52-57. references therein. [7] a) S.L. Schreiber, Chemica S c r i p 1987,27, 563-566; b) C. S. Poss, S. L. Schreiber, Acc. [20] a) K.Fuji, M.Node, S.Terada, M.Murata, H.Nagasawa, T.Taga, K.Machida, J. Am. Chem. Res. 1994,27, 9-17. Chem. SOC.1985, 107, 6404-6406; see also: [8] K.Mislow, J.Siege1, J. Am. Chem. SOC.1984, Y. Yamamoto, A. Sakamoto, T. Nishioka, 106,3319-3328. J. Oda, YFukazawa, J. Org. Chem. 1991,56, [9] a) R.M. Wenger, Helv. Chim. Acta B83,66, 1112- 1119. 2308-2321; b) D. Seebach, E. Hungerbiihler in Modern Synthetic Methods (Ed. : R. Schef- [21] a) P.D. Theisen, C.H. Heathcock, J. Org. Chem. 1988, 53, 2374-2378; b) for a similiar fold), Salle und Sauerlbder, Berlin, l980,152; example, see: YYamada, Synlett 1992, c) S. Valverde, B. Herradon, M. Martin151-152. Lomas, Tetrahedron Lett. 1985,26,3731-3734; d) see also: RSomfai, R.Olsson, Tetrahedron [22] a) T. Mukaiyama, Y. Tanabe, M. Shimizu, Chem. Lett. FBI, 401-404; b) J.Ichikawa, l993,49,6645-6650. M.Asami, T.Mukaiyama, Chem. Lett. l984, [lo] K.Tamao, K.Kobayashi, Y.Ito, J. Am. Chem. 949-952. SOC.1989,111, 6478-6480.

Group Selective Reactions [23] G. J. Boons, D. A. Entwistle, S.V. Ley, M. Woods, Tetrahedron Lett. 1993, 34, 5649-5652. [24] H.Waldmann, Nachr. Chem. Tech. Lab. 1991, 39, 413-418. [25] P.J. Cox, N.S. Simpkins, Synlett 1991, 321-323; see also: M.Majewski, G.-Z. Zheng, Synlett 1991,173-175. [26] M.Asami, Tetrahedron Lett. 1985, 26, 5803-5806. [27] I.Paterson, D. J. Berrisford, Angew. Chem. 1992,104, 1204-1205; Angew. Chem. Int. Edn. Engl. 1992,31, 1179. [28] a) M.Peatow, H.Ahrens, D.Hoppe, Tetrahedron Lett. 1992,33, 5323-5326 and references therein; for a summary, see: PKnochel, Angew. Chem. 1992, 104, 1486-1488; Angew. Chem. Int. Ed. Engl. 1992,31, 1459. [29] a) K.Kagechika, M.Shibasaki, J. Org. Chem. 1991,56, 4093-4094; b) see also: K.Kondo, M. Sodeoka, M. Mori, M. Shibasaki, Tetrahedron Lett. 1993,34,4219-4222; c) for an early, classical example, see: Z. G. Hajos, D. R. Parrish, Org. Synth. 1985,63, 26-36; d) K. Okrai, K. Kondo, M. Sodeoku, M. Shibasaki, J. Am. Chem. SOC. l994,116, 11737-11748. [30] B.M. Trost, D.L. van Vranken, C.Binge1, J. Am. Chem. SOC. 1992,114,9327-9343. [31] B. M. Trost, D.L. van Vranken, J. Am. Chem. SOC. 1991,113,6317-6318. [32] K.Tamao, T.Tohma, N.Inui, O.Nakayama, Y. Ito, Tetrahedron Lett. 1990,31, 7333-7336. [33] a) S.Hatakeyama, K. Sakurai, S.Takano, J. Chem. SOC., Chem. Commun. 1985, 1759-1761; b) B. Hafele, D. Schroter, V. Jager, Angew. Chem. 1986, 98, 89-90; Angew. Chem., Inf. Ed. EngL. 1986,25, 87-88; c) see also: S.Takano, Y.Iwabuchi, K. Ogasawara, J. Am. Chem. SOC. 1991,113,2786-2787. [34] a) S.L. Schreiber, T. S. Schreiber, D. B. Smith, J. Am. Chem. SOC. 1987, 109, 1525-1529; b) D. B. Smith, Z. Wang, S. L. Schreiber, Tetrahedron 1990,46, 4793-4808. [35] V. Jager, D. Schroter, B. Koppenhofer, Tetruhedron 1991,47,2195-2210. [36] M. Nakatsuka, J. A. Ragan, T. Sammakia, D.B. Smith, D.E. Uehling, S.L. Schreiber, J. Am. Chem. SOC. 1990,112,5583-5601. [37] E Sato, Y. Kobayashi, Synlett 1992, 849-857 and references therein.

221

[38] J.J. Partridge, N.K. Chadha, M.R. Uskokovic, Org. Synth. 1985,63, 44-56. [39] a) K.Mikami, S.Narsaw, M.Shimizu, M.Terada, J. Am. Chem. SOC. W2,114,6566-6568; 9242.see also: b) J.K. Whitesell, D.E. Allen, J. Org. Chem. 1985,50,3025-3026. [40] a) S. L. Schreiber, M.T. Goulet, G. Schulte, J. Am. Chem. SOC. l.!XV,109,4718-4720; b) S.L. Schreiber, M.T. Goulet, J. Am. Chem. SOC. 1987,109,8120-8122. [41] Z.Wang, D.Deschenes, J. Am. Chem. SOC. 1992, 114, 1090-1091. See also: S.D. Burke, J. L. Buchanan, J. D. Rovin, Tetrahedron Lett. 1991,32,3961-3964. (421 T. R. Hoye, J. C. Suhadolnik, Tetrahedron 1986,42,2855-2862. 1431 a) S. Hanessian, Y.Sakito, D.Dhanoa, L.Baptistella, Tetrahedron 191(9, 45, 6623-6630; b) A. V. Rama Rao, T. K. Chakraborty, D. Sankaranayanan, A. V. Purandare, Tetrahedron Lett. 1991,32,547-550. I441 a) J.E. Audia, L.Boisvert, A.D. Patten, A.Villalobos, S. J. Danishefsky, J. Org. Chem. 1989,54, 3738-3740; b) L. 0. Jeroncic, M.-C. Cabal, S.J. Danishefsky, G.M. Schulte, J. Org. Chem. 1991,56,387-395. [45] T.R. Hoye, D.R. Peck, T.A. Swanson, J. Am. Chem. SOC. 1984,106,2738-2739. [46] S.L. Schreiber, Z.Wang, J. Am. Chem. SOC. 1985,107,5303-5305. [47] a) S. L. Schreiber, B.Hulin, Tetrahedron Lett. 1986, 27, 4561-4564; b) S.L. Schreiber, Z. Wang, G. Schulte, Tetrahedron Lett. 1988, 29, 4085-4088; c) C. Iwata, N. Maezaki, M. Murakami, M. Soejima,T. Tanaka, T. Imanishi, J. Chem. SOC., Chem. Commun. 1992, 516-518. [48] a) T.Harada, T.Hayashiya, I. Wada, N.Iwaake, A.Oku, J. Am. Chem. SOC. 1987, 109, 527-532; b) T. Harada, I. Wada, A. Oku, Tetrahedron Lett. 1987,28,4181-4184; c) T. Harada, K. Sakamoto, Y. Ikemura, A. Oku, Tetrahedron Lett. 1988, 29, 3097-3100; d) T.Harada, I.Wada, A.Oku, J. Org. Chem. 1989, 54, 2599-2605; e) T. Harada, Y. Ikemura, H. Nakajima, T.Ohnishi, A.Oku, Chem. Lett. 1990, 1441-1444; f) T.Harada, I.Wada, J.-I. Uchimura, A.Inoue, S.Tanaka, A.Oku, Tetrahedron Lett. 1991, 32, 1219-1222; g) T.Harada, H. Kurokawa, Y. Kagamihara, S. Tanaka,

222

l? General Methods and Reagents for Organic Synthesis

A.Inoue, A.Oku, J. Org. Chem. 1992, 57, 1412-1421; h) T.Harada, A. Inoue, I. Wada, J.Uchimura, S.Tanaka, A. Oku, J. Am. Chem. SOC. 1993,115, 7665-7674; i) review: T.Harada, A. Oku, Synlett 1994,95-104. [49] M. Kaino, Y. Naruse, K. Ishihara, H. Yamamoto, J. Org. Chem. 1990,55,5814-5815. [50]J. Schwerdtfeger, D. Hoppe, Angew. Chem. 1992, 104, 1547-1549; Angew. Chem. Znt. Ed. Engl. 1992,31, 1505. [51] M.J. Kurth, E. G. Brown, J . Am. Chem. SOC.

l987,109,6844-6845.

[52] a) K.Fuji, M. Node, Y. Naniwa, T.Kawabata, Tetrahedron Lett. 1990,31,3175-3178; b) For a similiar example: T. Yokomatsu, H. Iwasawa, S.Shibuya, J. Chem. SOC., Chem. Commun. 1992,728-729. [53] P.Wipf, Y.Kim, Tetrahedron Lett. 1992, 33, 5477-5480. [54] For further examples of group selective reactions, see: desymmetrization of a mesoanhydride by a chiral Grignard reagent: S.D.

Real, D. R. Kronenthal, H.Y. Wu, Tetrahedron Lett. 1993, 34, 8063-8066; Differentiation of enantiotopic carbonyl groups by the HomerWadsworth-Emmons reaction: K. Tanaka, Y. Ohta, K. Fuji, T. Taga, Tetrahedron Lett. 1993, 34, 4071-4074; N. Kann, T. Rein, J. Org. Chem. 1993,58,3802-3804: Diastereoselective and enantioselectivecyclization of symmetrical 3,4-disubstituted 4-pentanal using chiral rhodium(l) complexes: X.-M. Wu, K. Funakoshi, K.Sakai, Tetrahedron Lett. 1993, 34, 5927-5930; Oxazaborolidine catalyzed enantioselective reductions of cyclic meso-imides: R.Romagnoli, E.C. Roos, H.Hiemstra, M. J. Moolenaar, W.N. Speckamp, B. Kaptein, H. E. Shoemaker, Tetrahedron Lett. WM, 35, 1087-1090; group selective ring expansion of prochiral ketones to the corresponding ringexpanded lactams: J. Aube, Y. Wang, M. Hammond, M.Tano1, ETakusagawa, D. V.Velde, J. Am. Chem. SOC. 1990,112,4879-4891.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Hypervalent Iodine Reagents Herbert Waldmann

In the course of multistep organic synthesis Periodic Table, the valence state of which frequently difficult transformations can only exceeds the respective lowest stable valence of be carried out by making use of heavy metal 3, 2, 1 and 0, respectively. [2] This definition derivatives like Pd(o)-, Pd(n)-, T~(III)-, was chosen to stress that the atoms involved Hg(II)-, Mn(rv)- and Cr(w) reagents. How- use more binding electron pairs in the hyperever, the efficiency of these synthetic tools is valent compounds than are required for their unfavorably contrasted by their high toxicity stabilization according to the Lewis-Langmuir and the fact that they are often not readily theory (formation of stable octets). In the majority of cases the mechanisms by available. Therefore, alternative heavy metalfree reagents that display similar reactivity, or which the reactions of the hypervalent iodine that allow equivalent transformations to be reagents proceed can be explained by an carried out, are of considerable interest to initial attack of a nucleophile at the iodonium organic synthesis. A class of compounds that center, resulting in displacement of a substituat least partly fulfills these demands is formed ent (e.g., A + B). Similarly, iodonium salts by the so called “hypervalent iodine re- form tricoordinated iodine intermediates such agents”, for example, (1)-(9). [l]The term as, D. In a subsequent step either iodoben“hypervalent” is attributed to molecules or zene is eliminated accompanied by a simultaions of the 5th to the 8th main groups of the neous radical or converted coupling of two

R k D i ! P h OToa

A

$Ctt:!yph Ph

% ,>

0

II

-1aOn

B

R-N-C-0

+

C

R’kHi(,

[

Ph

, I

0

li

Ph-CH2-C-R

E

Ph*

J

+*CHA]

224

l? General Methods and Reagents for Organic Synthesis

ligands (D E),or iodobenzene is released from the molecule in a process that may be regarded as an intramolecular nucleophilic substitution proceeding with retention of configuration (e.g., B + C).Various nucleophiles with widely varying structure can be used successfully in these reactions, for example, alcohols, amines, alkyl-, aryl-, alkenyl- and alkinyl anions, and enolates, silylenol ethers, and ally1 silanes.

Oxidation The phenyliodonium acetates (2) and (3) can be used advantageously to substitute lead tetraacetate in the oxidation of glycols to carbo-

Me

R = alkenyl, alkinyl, aryl, perfluoroalkyl

nyl compounds. [3] The oxidation of simple alcohols to aldehydes and ketones can also be carried out with these reagents. For this purpose the use of the Dess-Martin periodinane (5) in particular is recommended. [4] The

Hypervalent Iodine Reagents

respective reaction conditions are so mild that, for instance, in the synthesis of the polyketide natural products denticulatin A and B [5a] the Phydroxyketone present in (10) could be converted to the 1,3-diketone (11) without racemisation of the 1,3-dicarbonylcompound formed. Furthermore, this reagent proved to be superior to the oxidants MnOz and pyridinium dichromate in transformations of sensitive enyne alcohols. [5b] Particularly interesting is the use of the bistrifluoroacetate (3) in the conversion of the 4-alkyl substituted phenol reticuline (12) to salutaridine (14), [6a] a central intermediate in the biosynthesis of the morphine alkaloids. In the course of this transformation the phenol most probably attacks the iodonium center and the intermediate (13) formed thereby then cyclizes via formation of a C-C bond to give the spirodienone (14). In this transformation the iodonium reagent clearly is superior to the oxidants thallium(III)-tris(trifluoroacetate) and lead tetraacetate. By analogy, spirodienones can be constructed that are congeners to the discorhabdin alkaloids. [6b] Furthermore, oxidation of phosphites to phosphates under non-aqueous conditions in oligonucleotide synthesis [7a] and the opportunity to convert pyrazolones to alkinyl- and alkenylcarboxylic acid esters is of preparative interest. [7b]

To&,

225

,OTos

"'q; Me

(17)

44%

the stereospecificity is lost and competing rearrangements occur. To explain this unusual cis addition, which is formally equivalent to the cis-hydroxylation of an olefin with OsO,, it is assumed that a non-ionic iodine(v) species (16) is formed as an intermediate, which transfers a tosyloxy group intramolecularly. After exchange of the remaining hydroxy ligand for a further tosyloxy group, the second functional group is also introduced with retention of configuration. If enols or, better, silylenol ethers or silylketene acetals are employed as nucleophiles, the transfer of sulfonyloxy groups to the a-position of esters, [9a] ketones [9b-d] and 1,3-dicarbonyl compounds [9b-d] also becomes feasible (Scheme 1). Whereas for simple unsymmetric ketones in these transformations the regioselectivity is low, the corresponding silyloxy compounds (e.g., (18)) react with complete selectivity and give higher yields. Furthermore, the use of silylenol ethers allows for the functionalization of acid-labile compounds, for example, the furane derivative (19), withOxygenation out the side reactions that would otherwise In addition to oxidation reactions, hyperva- occur. If the olefins or carbonyl compounds to lent iodine reagents can also be applied to be functionalized contain additional nucleocarry out hydroxylations and to introduce philes, cyclizations can be carried out via acyloxy- and tosyloxy groups. Thus, simple intramolecular attack on the iodonium interalkenes like cis-Zpentene (Is) react with the mediates, for example, (20)-+(21) [lo] and tosyloxyiodonium compound (4) to give vici- (22)+(23). [1d] a-Hydroxylations of esters and ketones can nal ditosyloxyalkanes, [8] for example, the erythro compound (17). The corresponding be achieved by employing iodosobenzene (7) trans pentene delivers exclusively the threo or the iodonium-bis-acetate (2) in alkaline isomer. If phenyl-substituted olefins are used methanol. Under these conditions the bis-

226

B General Methods and Reagents for Organic Synthesis

Phl(0HPTos

ZR , , ! ,

R'

,

CH*% or CH,CN

+ PhI + H20

R'

OTos 40-94 R',

x

= Me, H; Et. Me; Ph, H; Ph, Ph;

a-thienyl, H; -(CHJ4-

6Tos 60% to quant.

OTos

R ' . R ~ = Ph,

Me; Ph,

60-81 7;

Et: Et, Me

do

Me0

(21)

1

HY

OMS

56%

6

HO

(79)

88-90

x

Ph T

d

xydimethylacetal (26). This transformation has proved itself in natural product chemistry 1,3-dicarbonyl compounds by means of hypervalent [ll] and has been, for instance, used to advaniodine reagents. tage for the conversion of pregnenes to glucocorticoids via transformation of the exocyclic methoxy derivative PhI(OCH,), is formed. acetyl groups to the dihydroxy acetone side The latter is attacked at the iodine atom by the chain of these steroids (27)+(28). In the enol of the carbonyl compound and then course of this reaction double bonds and furtransfers a methoxide to the carbonyl group. ther secondary alcohols are not attacked. The tetrahedral intermediate (24) generated [llb] The reaction conditions are so mild that thereby eliminates iodobenzene to form a even oxidation-sensitive chromium carbonyl methoxy-substituted epoxide (25), which is complexes like. (29) remain unaffected. [llc] opened by methanol to give a a-hydro- The steric course of the hydroxylation of (29), Scheme 1. a-Oxygenation of esters, ketones and

Hypervalent Iodine Reagents

4

227

+

that is the OH group and the chromiumtricarbony1 fragment are on the same side, proves the mechanism proposed for this transformation. Accordingly, the iodonium compound first adds trans to the chromium and the epoxide corresponding to (25) subsequently must that is, the nucleophile initially attacks the be formed by attack of the tetrahedral inter- iodonium center and then the C-C bond is mediate (24) from below. formed via reductive elimination of iodobenzene. Similarly, alkinyliodoniumsalts (31) and alkenyl copper reagents can be transformed Carbon-Carbon Bond Formation into enynes (32). [13] These reactions are formally equivalent to the Pd-mediated coupling The use of alkenyl-, alkinyl- and aryliodonium of vinyl halides and organometallic reagents. salts opens up interesting routes to the forma- Anions of 1,3-dicarbonyl compounds, on the tion of C-C bonds. Vinyliodonium salts like other hand, add to the triple bond of alkinyl(30) can be coupled with C-nucleophiles like iodonium reagents to generate unstable iodoorganocuprates and anions of 1,3-dicarbonyl nium ylides like (33). These intermediates compounds to give substituted alkenes. [12] eliminate iodobenzene and thereby form These transformations most probably follow highly reactive alkylidene carbenes, for examthe mechanistic scheme highlighted above, ple, (34), which give cyclopentenes by intra-

228

E General Methods and Reagents for Organic Synthesis PhJeXe

Ph?OEt

0

05 R-CH2NO2

93 x:

molecular C-H-insertion. [141 This tandem conjugate addition-carbene insertion sequence could also be used to synthesize highly substituted furans. The transfer of aryl groups to a variety of Cnucleophiles can be realized by employing diaryliodonium salts. [lb] Thus, products become accessible that can hardly be synthesized with other methods. Moreover, the transfer of aryl groups to 0-,N-, S- and Pnucleophiles, like alkoxides, phenolates, carboxylates, amines, sulfides and phosphines can be carried out under mildest conditions by using these reagents (Scheme 2). [lb] These C-C bond forming reactions proceed in the sense of the formation of D and its conversion to E,which in many cases involves the formation of free radicals as intermediates. The anions of arylacetic acid esters, ketones, nitroalkenes, 173-dicarbonylcompounds, and enamines can be introduced as nucleophiles. Some representative examples are given in Scheme 2. If aryl Grignard and aryl lithium reagents are employed, triaryliodonium intermediates (35) are generated that react further via coupling to biaryls. [14] Particularly interesting is the use of the 3-indolyliodoniumsalt (36),which reacts with various nucleophiles to give 3-substituted indoles (37). Thereby an “umpolung” of the reactivity at the 3-position of the indole nucleus is achieved. [14c]

8 P

O

E

Ph@X 68%

d

P h p x8

w x e 67 X

t

Phq O E t

0

54-68 X

EtqCooEt COOEt

(34)

57 X

Ph@X

R-

Ph

FPhH-NOZ

;;x::::: P

O

E

t

6OX

1)

&J%e

2) HzO 8-18%

0 4

ONo

R-ON0

PhpX 4OX

&$%8 67-00 X

w;ph R-0-Ar

R = alkyl, aryl Ph-NH2

Phpx

Ph-NH-Ph

SOX

Ph@X

e

75 X

0 Ar-SH

PhpXe

48-87 X

Ph

@

Ar-S’

p

P ‘h

Scheme 2. Arylation of C-, 0-,N- and S-nucleophiles by means of diaryliodonium salts.

Hofmann Rearrangement By means of the bis-trifluoroacetate (3) [15] and the tosyloxyiodonium salt (4) [16] a transformation analogous to the Hofmann rearrangement can be initiated. In this process ali-

Hypervalent Iodine Reagents

229

(35) RLi

- 78 “C R = Me, Bu. Ph. allyl, OMe 60-7 1 %

OH NH2

(38)

+

Ph-1

I

-w

I

OTos

(39)

Ph (45)

93%

mildly acidic conditions (pH 1-3), which also prevent attack of the amine formed (41) on the isocyanate. This transformation is of particular interest as a tool for the generation of amines at bridgeheads, for example, in the case of the cubylammonium salt (42) and the adamantylammonium salt (43). [16c] Goodman et al. [15c, d] used this reaction, which was first described by Loudon et al. [15a, b] for the construction of “retro-inverso” peptides. These compounds are isosteric peptide analogues in which a peptide bond is inverted [ - HN - CR(R) - C(0) - NH - CH(R) C(O)+-HN-CH(R) -NH-C(0) -CH(R) - C(0)-1, and in which the absolute configuration of the former amino acid moieties is phatic carboxamides (38) are converted to reversed. To build up retro-inverso peptides, amines (41) via the intermediate formation of amides like (44) are converted with complete N-phenyliodonium amides (39), which rear- retention of configuration at the migrating Crange to isocyanates (40). A noteworthy fea- atom to the respective geminal aminoalkylature of the reaction is that it proceeds under mides (45) by treatment with the bis-

230

E General Methods and Reagents for Organic Synthesis

trifluoroacetate (3). These acylated aminals can be cleaved by hydrolysis, but their stability is sufficient to allow for acylation with a further amino acid unit.

[9] a) R.M. Moriarty, R.Penmasta, A.K. Awasthi, W. R. Epa, I. Prakash, J. Org. Chem. 1989, 54, 1101; b) G.E Koser, A. G. Relenyi, A.N. Kalos, L.Rebrovic, R.H. Wettach, J. Org. Chem. W ,47, 2487; c) N.S. Zefirov, V.V. Zhdankin, Y.V. Dan’kov, A. S. Koz’min, 0.S. Chizhov, Zh. Org. Khim. 1985, 21, 2461; d) J. S. Lodaya, G.F. Koser, J. Org. Chem. 1988, References 53,210. [lo] R.M. Moriarty, R.K. Vaid, T.E. Hopkins, B. K. Vaid, O.Prakash, Tetrahedron Lett, 1990, [l] Reviews: a) A.Varvoglis, Chem. SOC. Rev. 31, 201. 1981, 10, 377; b) A.Varvoglis, Synthesis 1984, 709; c) R.M. Moriarty, O.Prakash, Acc. [ll] a) S.N. Suryawanshi, P.L. Fuchs, Tetrahedron Lett., 1981,22, 4201; b) R. M. Moriarty, L. S. Chem. Res. 1986,19, 244; d) R.M. Moriarty, John, P.C.Du, J. Chem. SOC.,Chem. ComR. K. Vaid, Synthesis 1990,431; e) R. M. Morimun. 1981,641;c) R.M. Moriarty, S.G. Engearty, R. K. Vaid, G. E Koser, Synlett 1990,365; rer, O.Prakash, I.Prakash, U.S. Gill, W.A. d) P. J. Stang, Angew. Chem. 1992, 104, 281; Freeman, J. Chem. SOC., Chem. Commun. Angew. Chem. lnt. Ed. Engl1992, 31, 274; e) 1985,1715. A.Varvoglis, The Organic Chemistry of Polycoordinated Zodine, VCH, Weinheim, 1992. [12] a) M. Ochiai, K.Sumi, YNagao, E.Fujita, Tetrahedron Lett. 1985, 26, 2351; b) M.Ochiai, Int. Ed. Engl. 1969,8, 54. K. Sumi, Y.Takaoka, M. Kunishima, Y.Nagao, [2] J.I. Musher, Angew. Chem. 1969, 81, 68. Int. M.Shiro und E.Fujita, Tetrahedron 1988, 44, Ed. Engl. 1969,8,54. 4095. [3] a) D.E Banks, Chem. Rev. l966, 66, 243; b) R. Crieg6e Oxidation in Organic Chemistry, [13] P. J. Stang und T.J. Kitamura, J. Am. Chem. SOC. Iwn,109,7561. Academic Press, New York, 1965, p.365; c) S.J. Angyal, R.J. Young, J. Am. Chem. SOC. [14] a) F. M. Beringer, A. Brierley, M. Drexler, E.M. Gindler, C.C. Lumpkin, J. Am. Chem. 1959,81, 5251. SOC. 1953, 75, 2708; b) EM. Beringer, J.W. [4] D.B. Dess, J. C. Martin, J. Org. Chem. 1983, Dehn, M.J. Winicov, J. Am. Chem. SOC.1%0, 48, 4155. 82, 2948; c) R.M. Moriarty, Y.Y. Ju, M.Sul[5] a) M. W. Andersen, B.Hildebrandt, R. W. Hoftana, A.lhncay, Tetrahedron Lett. Iwn, 28, mann, Angew. Chem. 1991, 103, 90;Int. Ed. 3071. Engl. 1991, 30, 97; b) W.H. Okamura, M.L. [15] a) G.M. Loudon, M.E. Parham, Tetrahedron Curtin, Synlett 1990,l. Lett. 1978,5,437;b) G.M. Loudon, A. S. Rad[6] a) C. Szsntay, G.Blask6, M.B&czai-Beke, harkrishna, M.R. Almond, J.K. Blodgett, P. Pkchy, G. Dornyei, Tetrahedron Lett. 1980, R. H. Boutin, J. Org. Chem. 1984,49,4272; c) 21, 3509; b) Y.Kita, T.Yakura, H.Thoma, P.Pallai, M.Goodman, J. Chern. SOC., Chem. K. Kikuchi, Y. Tamura, Tetrahedron Lett. 1989, Commun. W82, 280; d) P.V. Pallai, S.Rich30, 1119. man, R.S. Struthers, M.Goodman, Znt. J. [7] a) J.-L. Fourrey, J. Varenne, Tetrahedron Lett. Pept. Prot. Res. m , 2 1 , 84. 1985,26, 1217; b) R. M. Moriarty, R. K.Vaid, V.T. Ravikumar, T. E. Hopkins, P. Farid, Tetra- [16] a) I.M. Lazbin, G.E Koser, J. Org. Chem. 1986,51,2669; b) A. Vasudevan, G. E Koser, J. hedron 1989,45, 1605. Org. Chem. 1988,53, 5158; c) R.M. Moriarty, [8] a) G.F. Koser, L. Rebrovic, R.H. Wettach, J. J. S. Khosrowshahi, A. K. Awasthi und R. PenOrg. Chem. 1981, 46, 4324; b) L.Rebrovic, masta, Synth. Commun. l988,18, 1179. G.E Koser, J. Org. Chem. 1984,49,2462.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Furan as a Building Block in Synthesis Martin Maier

Expressions such as synthetic building blocks, synthetic design, architecturally interesting molecules, and so on, emphasize that the synthesis of natural products bears similarities to the construction of complex buildings. Yet, the synthesis of molecules is probably more complicated, because the starting point, that is the starting material, is not immediately evident and in the path to the target many possible variants and many obstacles exist. Of utmost importance for the success and the efficiency of a synthesis is not only an appropriate global synthetic strategy [l] (e.g. transform-based strategy) but also the proper choice of synthetic building blocks. Optimal building blocks are characterized by the fact that they lead in the course of a reaction directly to the structural prerequisites for another central synthetic operation so that laborious touch-ups, such as protecting group manipulations, the changing of oxidation states of functional groups or changes on the molecular backbone, are superfluous. These requirements are fulfilled, for example, in the so-called tandem reactions and cascade cyclizations. [2] Synthetic building blocks may be classified according to their number of carbon atoms (e.g. G-building blocks) and the number and nature of functional groups (e.g. 1,4-bis-electrophiles). In combination with heteroatoms and the principle of Umpolung, [3] it is possible to choose suitable building blocks for almost any situation. The impor-

tance of a certain building block depends to some extent on how it can function as a starting point for several fundamentally different synthetic transformations. One of these central building blocks is furan (I).This molecule contains four C-atoms, a 1,4-difunctionalized diene, and an enol ether substructure. Thus, furan can undergo cycloaddition either as C4-(diene) or G-component (dienophile, dipolarophile). [4] In addition, reactions are possible that are typical of enol ethers, such as the addition of electrophiles, carbenes, or metalation. [4] Although one might describe the use of furan as classical, [4] its synthetic potential is not by any means exhausted, as underscored by recent application that are the subject of this summary.

Cycloaddition Reactions Furans can react with reactive dienophiles (2) by [4+2]cycloaddition to give 7-oxabicyclo[2.2.l]hept-5-ene (3), whereby the furan takes the role of a 1,Cdisubstituted electronrich diene. The cyclic arrangement fixes the diene in the reactive conformation, thereby favoring the cycloaddition for entropic reasons. This reaction is, however, rather slow at room temperature due to the aromatic character and ring strain in the cycloadduct. Although a higher temperature favors the reverse reaction, it is possible to increase the

232

R General Methods and Reagents for Organic Synthesis

Scheme I. Examples of dienophiles that undergo cycloaddition with furan.

reaction rate by applying high pressure [5] or by the use of Lewis acid catalysis. [6] Some dienophiles that have reacted successfully with furan are depicted in Scheme 1 (4)-(11). [7-141 With regard to the preparation of optically active compounds, symmetrical dienophiles such as (6) or (7) proved to be particularly versatile, because they form mesocycloadducts. From these in turn, the whole material can in principle be converted to optically active derivatives by group selective reactions. Of the unsymmetrical dienophiles, the a-acetoxyacrylonitrile (lo), R = Ac) [13] is of particular importance because it allows one to perform a formal ketene cycloaddition

that facilitates subsequent transformations. This reaction principle was further developed by Vogel et al., who developed two procedures for the synthesis of enantiomerically pure furan cycloadducts. One possibility is to initially hydrolyze the racemic endolexomixture of the 5-acetoxy-5-cyano-7-oxabicyclo[2.2.l]hept-2-ene to the corresponding cyanohydrins. From these cyanohydrins one stereoisomer can be obtained by fractional crystallization with brucine. [15] In the other method, the chiral 1-cyanovinylcamphanate (10, R = (S)-camphanate) is used, whereby a diastereomericmixture of four cycloadductsis obtained, from which the adduct (12) can be obtained in pure form by crystallization in 29 % yield. [16] An advantage of this method is that from the other three isomers the chiral dienophile can be recovered by thermolysis (retro-Diels-Alder reaction). Quite recently, Corey reported an enantioselective cycloaddition between furan and a-bromo-acrolein under the action of a chiral Lewis-acid, which represents an efficient route to numerous chiral7-oxabicyclo[2.2.l]heptenederivatives. [171 Because all these cycloadducts contain a dihydrofuran-subunit, they are predestined for conversion to carbohydrates and related natural products. Usually, the double bond is functionalized first, whereby the bicyclic ring system guarantees stereoselective attack of the reagent. Subsequent cleavage of the bicyclic ring system leads to highly functionalized tetrahydrofuran derivatives. This concept was exploited by Vogel et al. in connection with the synthesis of a large number of natural products. [18] A representative example is the preparation of D-allose (18) (Scheme 2). [19] The compound obtained from the cycloadduct (12) by dihydroxylation and isopropylidenation was hydrolyzed to the ketone (13) and subsequently converted to the silyl enol ether. By oxidation with a peracid, a stereospecific hydroxylation to (15) takes place, whereby the initially formed epoxide is opened by mchloro perbenzoic acid, followed by migration

Furan as a Building Block in Synthesis

233

Hosm HO

(17)

(18)

Scheme 2. Synthesis of D-allose from the cycloadduct (12).

of the acyl group. Cleavage of the bicyclic ring was performed by a regiospecific BaeyerVilliger oxidation, subsequent lactone hydrolysis, and acetalization to give compound (17). Two further steps made D-allose (18) available. Oxabicycles of type (12) not only can be opened to monocycles by cleavage of a C-C bond but also alternatively by cleavage of one of the C-0 bonds. This opening is particularly facile if the original furan possesses a hetero substituent in the 2-position. Suzuki et al. used this strategy in an elegant synthesis of the antitumor compound gilvocarcin M (Scheme 3). [20] One of the key steps is the regiospecific cycloaddition of 2-methoxyfuran (20) to the arine, which was generated in situ by reductive elimination from the C-glycoside (19). By opening the cycloadduct (21), the naphtyl derivative (22) is formed in which the two hydroxyl groups are already differenti-

ated. After esterification to give (23),the aryl residue is introduced by an intramolecular coupling. Cleavage of the benzyl protecting groups by catalytic hydrogenation provided the natural product (24). A conceptually different method for the cleavage of a C-0 bond is to treat the oxabicycle with a nucleophile. This strategy recently was applied by Lautens et al. to oxabicyclo[2.2.1]-systems as well as the homologous oxa-bicyclo[3.2.1]-systems.[21] The latter are available very easily via a [4+3]cycloaddition between a furan and a cationic 2-oxoallyl species. [22] Organo cuprates, organolithio compounds, and diisobutylaluminium hydride can be used for the opening of the bicyclic compounds. Thus, one obtains the cyclohexenes (26) in a regio- and stereospecific manner from (25) and alkyllithium compounds. [23] This method found application in a synthesis of the C,,-G-subunit of the anti-

234

E General Methods and Reagents for Organic Synthesis

r

OBzl I

Me

OTf

ezlo$BzlOBzlO

OBzl

We

1

+

(19) OBzl

W e

-

OBzl OMe

esterifiiin

Me OH BzlO

BzlO

0

Me

(22) OH

1. Pd-catalyzedintra-

molecular coupling

OMe

Me

2. Hp, Raney-Ni I OH

0

(+)-GilvocarcinM (24)

Scheme 3. Synthesis of (+)-gilvocarcin M through a furan-aryne cycloaddition.

biotic ionomycin. [24] Reductive opening of the oxabicyclo compound (27) furnished the cycloheptenol (281, which contains four stereocenters with defined configuration. After inversion of the stereochemistry at the G,-center and protection of the OH-function, the ring was cleaved by ozonolysis. The corresponding open-chain compound could then be converted to the target molecule (29). Use of p-methoxybenzyl protecting group allowed differentiation of the primary OH-groups through an oxidative acetal formation. A disadvantage of this route is that optically active compounds are not available (yet) without a major effort.

Furans also proved quite versatile in intramolecular cycloaddition reactions [25] - particularly with a view to the synthesis of polycyclic target molecules. Because furans may be functionalized very easily, the syntheses of the substrates for the cycloaddition reactions are in general straightforward. This is expressed very well in a synthesis of bilobalide, which incorporates an intramolecular [2+2]photocycloaddition as a key step (Scheme 4). [26] Starting with 3-furanaldehyde, the aldehyde (31) was constructed in four steps. This in turn was treated with the enolate (30) to give (32).From this addition product, the substrate (33) for the intramolecular cycloaddi-

Furan as a Building Block in Synthesis

&,)--R

RLi , Et20,O "C

Me

OTIPS -b OTlPS (96100 "/o)

(25)

OBZl DlBAH

Me

OMe

I. Swern-Oxidat.

2. DIBAH

3.NaH, PMBBr

4.

cg,MeOH; NaBH4

5. D W

tion could be obtained in two steps. Irradiation of (33) furnished compound (34) as the major product. Addition to the less substituted double bond was observed as a side reaction. Further key steps on the route to the target molecule are the oxidative cleavage of the cyclopentanone ring and a Baeyer-Villiger reaction at the four-membered ring. Altogether, this synthesis embraces only 17 steps, which is relatively few in light of such a highly complicated molecule. Bilobalide was isolated from gingko-trees, extracts of which have found use as a medicament. Among the reactions of furans with heterodienes it is particularly the reaction with singlet-oxygen that is of great preparative significance. [27] For example, the preparation of 5-hydroxybutenolide (39) from 2furancarboxylic acid or furfural is possible with this reaction. This oxidation proceeds via a [4+2]-cycloaddition with the formation of a bicyclic endoperoxide (37), followed by fragmentation. A very elegant application of compound (39) is described by Feringa et al., who generated optically active butenolides by treatment of (39) with 1-menthol. Although both diastereomers (40) and (41)are formed in the course of the acetalization, the amount

-

TBSO

TBSO

1.KF

THF, -78 OC

0 HO tBu

(85%)

235

HO HO t h

3. TMscl

(33) (34) (3.5) Scheme 4. Synthesis of bilobalide by an intramolecular [2+2]-cycloaddition as key step.

236

B General Methods and Reagents for Organic Synthesis

0

MeOH

oms

(45) one diastereomer

I

accessible 2-(trimethylsilyloxy) furan (44) [29] can be used as a nucleophilic C,-building block for the chain elongation of aldehydes and imines. These reactions proceed with high selectivity, whereby the two newly formed chiral centers possess syn(threo)-stereochemistry. [30] In the addition to a-alkoxy-aldehydes, one observes preferential Cram addition that of isomer (40) can be increased by crystalliza- is, the 4,5-syn, 5,6-anti-product is formed tion. Compound (40) was used for asymmetric selectively.This result can be rationalized with Diels-Alder reactions and Michael-additions. a transition state such as (46), which corresponds to that of a Diels-Alder reaction of the P I furan and therefore is energetically favored. The so-formed butenolides may be further functionalized in various ways, for example by Reactions of Functionalized cis-hydroxylation. [31] Using this route, CasiFurans raghi et al. prepared octopyranose derivatives by addition of (44) to the aldehyde (43). With functional groups at the periphery of the Furans with a hydroxyalkyl group in the 2furan ring, more interesting synthetic building position (furfuryl alcohols) (47) are also very blocks are available that also open up addi- interesting synthetic building blocks. If furfutional reaction paths. For example, the easily ryl alcohols are oxidized, whereby a large

Furan IIS a Building Block in Synthesis

I

(48)

(47)

number of reagents such as MCPBA, Br,, VO(acac)2/tBuOOH, etc. can be used, rearrangement to ulose derivatives (hydroxy pyranones) (50) takes place. It is obvious that these pyranones are predestined for the synthesis of carbohydrates. [32] In addition, by application of this strategy, a large number of polyoxygenated natural products have been prepared. [33] In order to obtain furfuryl alco-

237

hols of type (47) in optically active form, several methods are available. One is to add metallated furans to chiral aldehydes. However, the selectivity depends very much on the substrate and on the reaction conditions. Another important entry is addition of chiral C-nucleophiles to furfuryl aldehydes. Since there are now very powerful chiral reagents available, such as the aldol reagents of Evans (34) or ally1 boranes, [35] the furfuryl alcohols can be obtained using this approach without any problem. Finally, it should be noted that optically active furfuryl alcohols can be obtained by resolution of racemates. [36] Two examples from the recent literature might serve to illustrate the application of furfuryl alcohols for the synthesis of natural products. In case of the synthesis of the Clo-C, fragment of the immunosuppressive FK506 (Scheme 5), initially by adding a metalated furan (prepared from (52) by halogedmetal exchange) to the aldehyde (51), the furfuryl alcohol (53)was prepared. Addition of zinc(I1) bromide to the lithiated furan induces exclusive formation of the desired syn-isomer (53) by chelation control. Subsequent hydroxyldirected epoxidation causes the rearrangement to the hydroxypyranone, the anomeric Me

1. cat. v0(acac)2,

tBuOOH (73vo)

T

Me nO M e O

D

2. HC(OMe)3,BF3-Et20 (51 %)

OH

\yM (53)

Me OMeOMe

3

5 steps

I

(54)

OMe

Me

(55)

10 We

Scheme 5. Synthesis of the C-10-C-20 fragment of the immunosuppressiveFK506 via a hydroxyalkyl furan intermediate.

238

E General Methods and Reagents for Organic Synthesis

center of which was protected as the methyl glycoside (54). The conformationally fixed pyran scaffold ensured a stereocontrolled introduction of the remaining two stereocenters. These were generated by reduction of the carbonyl group (NaBH,,) and hydrogenation of the double bond (H2, Pd/A1203),whereby attack of the reagents took place from the aface. This synthesis is the shortest known for such a building block. [37] The other route, namely an asymmetric aldol reaction between the Evans reagent (56) and furfural(36) was followed by Martin et al. in the synthesis of the furfuryl alcohol (57) (Scheme 6). Oxidative rearrangement and protection of the anomeric hydroxy function with tert-butyldimethylsilyl triflate (TBSOTf) yielded the a-anomer (58) (a:P= 3: 1) as the major product. The axial methyl group was introduced stereoselectively by conjugate addition of dimethyl cuprate to the enone (58). The stereochemical course of the addi-

tion explains itself from the reactive conformation (61) with an axial OTBS and equatorial substituent R. For stereoelectronic reasons (chair-like transition state) the addition takes place anti to the OTBS-group. Subsequent reduction of the ketone (59) to the equatorial alcohol proved to be problematic. The reduction always favored the axial isomer, so that (59) was converted via a modified Mitsunobu reaction to the desired alcohol (60). The latter served as an important intermediate in the synthesis of the ansamycin antibiotic (+)-macbecin I. [38] As these examples demonstrate, it is worthwhile to examine furfury1 alcohol based concepts if molecules must be synthesized that contain a diol structure (cf. centers 13 and 14 in (55)) within a complex stereochemical setting. These hydroxy pyranones not only represent easily available templates for asymmetric synthesis, but they are furthermore precursors for carbonyl ylides. On this basis, Wender et

- do" 1. Br2,

MeCN, H20

2. TBSOTf

(67%)

l o

5steps

i

OTBS

(60)

(61) H

Scheme 6. Synthesis of an important intermediate for the antibiotic macbecin I through a furan route.

Furan as a Building Block in Synthesis

al. developed a synthesis of the tumor promoter phorbol (Scheme 7). [39] Beginning with furfuryl alcohol and proceeding via (62), (63) was prepared as a mixture of diastereomers. Compound (63) was then oxidatively rearranged to the hydroxypyranone. On treatment of (64) with DBU, an oxidopyrilium intermediate is formed, which, as a carbonyl ylide, undergoes intramolecular cycloaddition to the double bond. Transition state (65) in which the side-chain assumes a chairlike conformation, explains the observed stereochemistry. In the further course of the synthesis, the cycloadduct is converted to the methylene ketone (67). This, in turn, is subsequently

2. AcCI, Py

2 . A qO

oms

Q

0

DBU, CH2Cl2, RT

OTBS

(92%)

OAC

(64)

-

-

transformed to (68) via an intramolecular nitrile-oxide cycloaddition. From (68) another six steps made compound (69) available, which served as an entry to the synthesis of phorbol. Furthermore, alkoxypyranones can also be rearranged to truns-4-alkoxy-5-hydroxy-cyclopentenones (e.g. (70)-(73)). This rearrangement is possible, for example, with the buffer system benzoic acidpotassium acetate although the yield is generally not too high. [40]This appears to be an attractive procedure for the preparation of functionalized cyclopentenones because of the ease of access to the corresponding educts. These cyclopente-

1. MCPBA

OTBS

239

OAc

3. Ph3PCH2

OTBS

(65)

(66)

-

5. Mn% OTBS

(67)

1. vinyl-cuprate 2. TMSCN, Znl2

3. DIBAH 4. NH20H, NaOCl

oms (68)

oms (69)

Scheme 7. Synthesis of a phorbol precursor with incorporation of an intramolecular oxidopyrilium-alkene cycloaddition.

240

R General Methods and Reagents for Organic Synthesis OH

...--.

(74)

4

i

1. ZnClq,

I

R

-A

H20,lOOOC

i

(75)

i

2. Mel, K2CO3 acetone

R

I

OeSiMe,

(71)

(72)

nones, in turn, are interesting as building blocks in the context of prostaglandin syntheses. Mechanistically, this rearrangement probably proceeds through tautomerization to (71), subsequent electrocyclic ring opening (72), and, finally, an intramolecular vinylogous aldol reaction. Interestingly, the rearrangement to cyclopentenones also succeeds directly with furfuryl alcohols, as shown by Dygos et al. [41] Thus, the reaction of (74) with zinc(@ chloride in water produces - probably via the intermediates (75) and (76) - the cyclopentenone (77).This was used for the synthesis of a prostaglandin derivative. Of course, it would be better if one could perform these rearrangements enantioselectively. Another class of functionalized furans are those that contain silicon residues as substituents, whereby the silyl group can serve, for example, as a protecting group. [42] In order to convert furans into butenolides, Pelter et al. used boron-substituted furans. First, the furans are metallated and the resulting anion is treated with chlorodimethoxyboraneto give (79). The furyldimethoxyboranes were then oxidized to 2-(3H)-butenolides by m-chloroperbenzoic acid. [43]

h r A'

0

.-

C0,Me

(77)

(78)

(79)

MCPBA, Na2CQ

(67-90%)

R

As this summary shows, furans are indeed versatile building blocks because they come into question as a platform for many different applications. From these furans, short syntheses result that are clearly not without elegance. The list of possible uses could be continued almost at will. [44]For example, furans can be used as C1-build&gblocks [45] or ter-

Furan as a Building Block in Synthesis

241

minators in cyclization reactions. [46]This [18] Review: P.Voge1, Synlett 1990,173-185. review also shows that progress in synthesis [19] Y.Auberson, P.Voge1, Helv. Chim. Acta 1989, 72,278-286. can result from the refinement and a further [20] a) T. Matsumoto, T. Hosoya, K. Suzuki, J. Am. development of known reactions and strateChem. SOC.1992,114, 3568-3570; b) see also: gies. T. Hosoya, E. Takashiro, T. Matsumoto, K. Suzuki, J. Am. Chem. SOC. 1994,116,1004-1015. [21] M. Lautens, Synlett 1993,177-185. References [22] a) R.Noyori,Acc. Chem. Res. 1979,12,61-66; b) H.M.R. Hoffmann, Angew. Chem. 1984, 96,29;Angew. Chem. Znt. Ed. Engl. 1984,23, [l] E. J. Corey, X.-M.Ming, The Logic of Chemi1. c) A. Hosomi, Y. Tominaga in Comprehencal Synthesis, Wiley, New York, 1989. sive Organic Synthesis (Eds.: B.M. Trost, [2] L.F. Tietze, U.Beifuss, Angew. Chem. 1993, I.Fleming), Vo1.5, Pergamon, Oxford l99l, 105, 137-170; Angew. Chem. Int. Ed. Engl. 593. 1993,32, 131-163. [3] D.Seebach, Angew. Chem. 1979,91, 259-278; [23] M.Lautens, P. Chiu, Tetrahedron Lett. 1993, 34,773-776. Angew. Chem. Int. Ed. Engl. 1979,18,239. [4] For a review, see: B.Lipshutz, Chem. Rev. [24] M. Lautens, P.Chiu, J. T. Colucci, Angew. Chem. 1993,105,267-269; Angew. Chem. Int. l986,86,795-819. Ed. Engl. 1993,32, 281. [5] W.G. Dauben, H.O. Krabbenhoft, J. Am. [25] [4+2]-Cycloadditions: a) L.L. Klein, M. S. Chem. SOC. 1976, 98, 1992. Shanklin, J. Org. Chem. 1988,53,5202-5209; [6] H.Takeyama, A. Iyobe, T.Koizumi, J. Chem. b) E.Bovenschulte, P.Metz, G. Henkel, SOC. Chem. Commun. 1986,771 and references Angew. Chem. 1989, 101, 204-206; Angew. cited therein. Chem. Int. Ed. Engl. 1989, 28, 202; c) [7] G.Just, M.I. Lim, Can. J. Chem. W I , 55, H.Finch, L.M. Harwood, G.Robertson, 2993. R.Sewell, Tetrahedron Lett. 1989, 30, [8] A. P. Kozikowski, A. Ames, J. Am. Chem. SOC. 2585-2588; d) B.L. Feringa, O.J. Gelling, 1981,103, 3923. L.Meesters, Tetrahedron Lett. 1990, 31, [9] R. R. Schmidt, A.Lieberknecht, Angew. 7201-7204; e) L. M. Harwood, T. Ishikawa, Chem. 1978, 90,821-822; Angew. Chem. Int. H.Phillips, D.Watkin, J. Chem. SOC. Chem. Ed. Engl. 1978,17, 769. Commun. 1991,527-530; f ) D.P. Dolata, L. M. [lo] M. Ohno, Y.Ito, M. Arita, T. Shobata, K. AdaHarwood, J. Am. Chem. SOC. 1992, 114, chi, H. Sawai, Tetrahedron 1984,40, 141-152. 10738-10746; [4+2]-Cycloadditionsof vinylfuJ. Gustafsson, 0.Sterner, 1. Org. Chem. 1994, rans: a) J. A. Cooper, P. Cornwall, C. P. Dell, 59, 3994-3997. D.W. Knight, Tetrahedron Lett. 1988, 29, T. Takahashi, A. Iyobe, Y. Arai, T. Koizumi, 2107-2110; b) K. Hayakawa, F. Nagatsugi, Synthesis 1989,189-191. K.Kanematsu, J. Org. Chem. 1988, 53, a) R. R. Schmidt, C. Beitzke, A. K. Forrest, J. 860-863; [4+3]-Cycloadditions: a) M. HarChem. SOC. Chem. Commun. 198t, 909-910; mata, S. Elahmad, Tetrahedron Lett. 1993,34, b) E. Vieira, P.Voge1, Helv. Chim. Acta 198t, 789-792, and referenced cited therein. 65, 1700-1706. V. K. Aggarwal, M. Lightowler, S. D. Lindell, [26] M. T. Crimmins, D. K. Jung, J. L. Gray, J. Am. Chem. SOC. 1992,114,5445-5447. Synlett 1992,730-732. K.A. Black, P.Voge1, Helv. Chim. Acta 1984, [27] a) Review: B.L. Feringa, Red. Trav. Chim. 67, 1612-1615. Bas. W , 106, 469-488; b) M.R. Kernan, D.J. Faulkner, J. Org. Chem. 1988, 53, E. Vieira, P.Voge1, Helv. Chim. Acta 1983,66, 2773-2776; c) G. C. M. Lee, E. T. Syage, D. A. 1865-1871. Harcourt, J.M. Holmes, M. E. Garst, J . Org. E. J. Corey, T.-P.Loh, Tetrahedron Lett. 1993, 34, 3979-3982. Chem. l99l,56,7007-7014.

242

B General Methods and Reagents for Organic Synthesis

[28] a) B.L. Feringa, J.C. de Jong, J. Org. Chem. 1988, 53, 1125-1127; b) B.L. Feringa, B. de Lange, J.C. de Jong, J. Org. Chem. 1989,54, 2471-2475. [29] M. A. Brimble, M.T. Brimble, J. J. Gibson, J. Chem. SOC., Perkin Trans.I, 1989,179. [30] a) D. W. Brown, M. M. Campbell, A. P. Taylor, X.Zhang, Tetrahedron Lett. M,28,985-988; b) C. W. Jefford, D. Jaggi, J.Boukouvalas, Tetrahedron Lett. 1987,28, 4037-4040. [31] a) G. Casiraghi, L.Colombo, G. Rassu, P. Spanu, G. Gasparri Fava, M.Ferrari Belicci, Tetrahedron 1990,46,5807-5824; b) G. Casiraghi, L.Colombo, G.Rassu, P.Spanu, J. Org. Chem. 1991, 56, 2135-2139; c) G.Rassu, P. Spanu, G. Casiraghi, L. Pinna, Tetrahedron 1991,47,8025-8030. (321 a) A. Zamojski, G. Grynkiewin in Total Synthesis of Natural Products (Ed.: J. ApSimon), Wiley, New York, 1984,141-235; b) P.G. Sammes, D.Thetford, J. Chem. SOC., Perkin Trans.1, 1988, 111-123 and references cited therein. [33] a) K.Mori, H.Kisida, Tetrahedron 1986, 42, 5281-5290; b) S.Piku1, J. Raczko, K. Akner, J.Jurczak, J. Am. Chem. SOC. 1987, 109, 3981-3987; c) S.F. Martin, D.E. Guinn, J. Org. Chem. 1987, 52, 5588-5593; d) P.DeShong, R.E. Waltermire, H.L. Ammon, J. Am. Chem. SOC. 1988,110,1901-1910; e) S.E Martin, C. Gluchowski, C.L. Campbell, R.C. Chapman, Tetrahedron l988,44,3171-3180; f ) S.F. Martin, G. J. Pacofsky, R.P. Gist, W.C.Lee, J. Am. Chem. Sac. 1989, 111, 7634-7636; g) K.Mori, H. Kikuchi, Liebigs Ann. Chem. 1989,963-967; h) M.F. Semmelhack, N.Jeong, Tetrahedron Lett. 1990, 31, 605-608; i) J. Raczko, A. Golebiowski, J. Krajewski, P. Gluzinski, J. Jurczak, Tetrahedron Lett. 1990, 31, 3797-3800; j) T.Honda, Y.Kobayashi, M. Tsubuki, Tetrahedron Lett. 1990, 34, 4891-4894; k) LPaterson, M.A. Lister, G.R, Ryan, Tetrahedron Lett. 1991, 32, 1749-1752; I) S.E Martin, P. W. Zinke, J. Org. Chem. 1991, 56, 6600-6606; m) S.J. Shimshock, R.E. Waltermire, P.DeShong, J. Am. Chem. SOC. 1991,113,8791-8796; n) S . F.Martin, N.Chen, c.-P.Yang, J. Org. Chem. 1993, 58, 2867-2873; 0) T. Honda, K.Tomitsuka,

M.Tsubuki, J . Org. Chem. 1993, 58, 4274-4279. [34] J.R. Gage, D. A. Evans, Org. Synth. 1989,68, 83-91, and references cited therein. [35] U.S. Racherla, Y.Lao, H. C. Brown, J. Org. Chem. 1992, 57, 6614-6617, and references cited therein. [36] a) Y.Kobayashi, M. Kusakabe, Y. Kitano, ESato, J. Org. Chem. 1988,53,1587-1590; b) H. Waldmann, Tetrahedron Lett. 1989, 30, 3057-3058; C) W.-S.Zhou, Z.-H.Lu, Z . M.Wang, Tetrahedron Lett. l99l, 32, 1467-1470. [37] M.E. Maier, B.Schoffling, Tetrahedron Lett. 1991,32, 53-56. [38] S.E Martin, J.A. Dodge, L.E. Burgess, M.Hartmann, J. Org. Chem. 1992, 57, 1070-1072. [39] a) P.A.Wender, H. Y. Lee, R. S. Wilhelm, P. D. Williams, J. Am. Chem. SOC. 1989, 111, 8954-8957; b) P.A. Wender, H.Kogen, H.Y. Lee, J.D. Munger, Jr., R.S. Wilhelm, P.D. Williams, J. Am. Chem. SOC. El@, I l l , 8957-8958. [40] H.C. Kolb, H. M.R. Hoffmann, Tetrahedron 1990, 56, 5127-5144, and references cited therein. [41] J.H. Dygos, J.P. Adamek, K.A. Babiak, J.R. Behling, J.R. Medich, J.S. Ng, J.J. Wieczorek, J. Org. Chem. 1991,56,2549-2552. [42] a) E. J. Corey, Y. B. Xiang, Tetruhedron Lett. 1987,28, 5403-5406; b) G.Beese, B.A. Keay, Synlett 1991,33-34. [43] A. Pelter, M. Rowlands, Tetrahedron Lett. 1987,28, 1203-1206. [44] Synthesis of furan-3,4-diyl oligomers: Z. Z. Song, H. N. C. Wong, J. Org. Chern. 1994,59, 33-41. Intramolecular Michael addition of an electron-rich furan to a cyclohexenone followed by an aldol condensation: M.E. Jung, C.S. Sieden, J. Am. Chem. SOC. 1993, 115, 3822-3823. [45] S.J. Danishefsky, M.P. DeNinno, S. Chen, J. Am. Chem. SOC.EXB,110,3929-3940. [46] a) S.P. Tanis, M.C. McMills, T.A. Scahill, D.A. Kloosterman, Tetrahedron Lett. 1990,31, 1977-1980; b) S.R. Angle, M. S. Louie, Tetrahedron Lett. 1989,30,5741-5744.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Fluorine in Organic Synthesis Rolf Bohlrnann

Fluorine is the most reactive of all the elements. It has a higher natural abundance in the mantle of the earth than the other halogens and has pronounced properties in both elemental form and in its compounds. The extreme electronegativity, the high energy of the C-F bond, the low nucleophilicity of fluoride ions in protic solvents and the steric similarity with hydrogen are noteworthy. [l] The emphasis of this highlight is on the preparative aspects of monofluorinated compounds of biological importance. Despite the wide range of polyfluoro products and their often large scale of world-wide production they are not discussed here due to brevity. The number of known naturally occurring fluorinated products, such as the fluoro acetic from the South African “Gifblaar”, is very small. Selective fluorination of biologically interesting compounds is of great interest in drug discovery, because of the close similarity of the van der Walls radii of fluorine and hydrogen (135 versus 120 pm). [2] This is the reason why fluoroanalogs of biomolecules are used as tools for the study of electronic effects in the absence of strong steric changes. The preparation of fluorinated drugs requires safe methods for the directed monofluorination of the fluorine-free precursors. The search for safe, selective fluorine transferring reagents is a pursuit currently in progress. [3] In protic solvents the fluoride anion forms the stable FHF anion, which is highly solvated

and only mildly acidic and nucleophilic. The Olah reagent (70 % HF in pyridine) has been used for the introduction of fluoride into many acid stable compounds. [4] The solubility of inorganic fluorides in aprotic solvents is limited. Therefore, phase transfer catalysis or tetrabutyl ammonium fluoride (TBAF) is in common use for this purpose. TBAF is not stable, however, without water. [5] In contrast to the above mentioned FHF the strongly basic “naked” fluoride anion triggers elimination at the tetrabutylammonium cation with formation of amine ( I ) and butene. Tetramethylammoniumfluoride cannot undergo Hofmann elimination. Therefore it is possible to remove water from this reagent completely and it acts as a strongly basic nucleophile in acetonitrile [6] or dichloromethane. [7] 2 (nC4H9)4NfF-+ (nC4H,),NfFHF + (nC4H9)3N CZHTCH=CHZ nCaH,OH+DAST-+ nCsHlTF (90 %) - 50 “C The transformation of hydroxyl groups into fluorides by diethylaminosulfur trifluoride (DAST) has been widely used for several years now. [S] Besides the reagents for the introduction of nucleophilic fluorine there is an urgent demand for reagents in which fluorine acts as an electrophile. Elemental fluorine itself is the simplest reagent of this type. Safe handling and selectivity of this element are much less simple, however. [9, 101An explanation of the low selectivity often observed is the participa-

+

244

E General Methods and Reagents for Organic Synthesis

tion of radical reactions. Therefore stable and safe reagents, which act as sources of elemental fluorine, are of great value. Acommon feature of such reagents is an F-X bond. The X group in those reagents should be more electronegative than the carbon in the target molecule. Well known examples of this type are CF30F, FC103 or CF3COOF.These gases are not without problems: CF30Fis as dangerous and unselective as elemental fluorine, FC103forms explosive reaction mixtures, and

CF3COOFis unstable, toxic, and reacts with low chemoselectivity. Better selectivity has been observed by Rozen with acetyl hypofluorite (3). [ll, 121 Many mild reactions of alkenes ( 2 ) , (6), (7) and (14), aromatics (9) and (10) and ketones (12) with acetyl hypofluorite (3) are reported (Scheme 1). Not only electron-rich double bonds as in (14), but also normal alkenes as (2) and (6), and electron-deficient olefines like (7) undergo rapid addition of the hypo-

(4) 50%

(5) 7%

C6HRcsH5 ------+ (3)

H

+

(4) 1%

(5) 51%

H

(6)

F

(8) 64%

(7)

No@

& k c H 3

(12)

(3),

G O C H s

( f 3 ) 60%

x;n,,II (14)

-% :x&o

=4

62

0 (15) 83%

Scheme 1. Fluorination of different types of substrates with acetyl hypofluorite (3).

Fluorine in Organic Synthesis

fluorite (3). The reaction is regioselective, fluorination of the more nucleophilic center being preferred. Acetoxylation occurs accordingly at the site with higher stabilization for cations. The stereochemistry of the reaction is syn, as exemplified in the formation of threo(5) and erythro-fluoroacetate(4) from the cis(6) and trans-olefin (2) in the given ratios. Apart from addition to olefins other useful examples are the fluorination of (12) and (10) to fluoro compounds (13) and (11) by (3). Direct fluorination of the aromatic ring (9) is also possible. - Despite all these interesting results it must be mentioned that two authors report unpredictable explosions with acetyl hypofluorite (3). [13, 141 The limited storage stability of (3) requires the reagent to be proF

I PhS02N- t Bu

duced from elemental fluorine immediately before its use or in situ. Safety hazards are a common problem with all known hypofluorites. The N-fluoro reagents (17), (19), (21) and (24) come much closer to the ideal profile. The Nfluorosulfonamides first described by Barton [15] and introduced as fluorinating agents by Barnette [16, 171 are now commercially available. Handling of these reagents is easy. It is even possible to purify them by chromatography on silica gel without decomposition. They are used without special precautions in organic solvents like THF, diethyl ether or toluene for the fluorination of reactive anions like (16), (18), (20), (22) and (23). Examples of the fluorination with N-fluorosulfonamides

( I 7)

- 12ooc (16)

75%

12%

F

I

T o s N - ~ B u (19)

A RT

60%

(18) F

-

TosN exo-2norbonyl (2 1 )

- 50°C

CI Ph

-0 52% F

C6H5MgBr

(19) RT

C,H,F

Et02C 0 CO2Et

CH3

I

Tos-N-CH2-f

No@

50% (23) Scheme 2. Examples for fluorinations with N-fluorosulfonamides. (22)

245

Bu (24)

RT

(25) 53%

246

E General Methods and Reagents for Organic Synthesis

(17), (19), (21) and (24) are shown in Scheme 2. The solubility of phenylsulfonamide (17) is better than that of the similar tosylamide (19). For reactions at -120°C this difference is very important. Anions with low reactivity and neutral enols, however, do not react with these mild reagents. Reagents with higher reactivity are the Nfluorosulfonimides (26) first described by DesMarteau. [181This reagent is activated by two strong acceptors at the central nitrogen atom and therefore shows increased electrophilicity of the attached fluorine. The anion EtOZC

CO2Et o N ,, CH3

6 '

(23)

TEt (CF,sO2l2NF

(26)

- 10%

H3C F 'OZEt (25) 96%

6 ,& g 50%

(26)

+

\

12 h in CDCI,

60%

F

40%

Scheme 3. Reactions with the highly reactive Nfluorosulfonamide (26).

(23) reacts with sulfonimide (26) at lower temperature with higher yield to the fluoromethylmalonate (25) than with N-fluorosulfonamide (24), as illustrated in Scheme 3. Aromatic compounds are oxidatively fluorinated to fluoroaromatic compounds. The high reactivity of this reagent requires a careful choice of the solvent, which should not be fluorinated itself. The reagent is not commercially available. It is made by reaction with elemental fluorine. The first reagent for the chiral electrophile fluorination of anions was reported by Lang and Differding. [19] The highest observed enantiomeric excess in the fluorinated product is 70%. This is an important start, which leaves room for improvement (Scheme 4). The preparation of this reagent also involves the use of elemental fluorine. The commercial availability of the Nfluoropyridinium salts, which were first described by Meinert [20] and introduced as fluorinating agents in organic synthesis by Umemoto, [21, 221 allows simple application of these reagents without access to elemental fluorine. The triflates (30), (32) and (34) are more reactive than tetrafluoroborates, hexafluoroantimonates, or perchlorates also investigated. Donor substituents at the pyridine result in reduced reactivity, whereas acceptor substituents give increased reactivity. Therefore it is possible to find a reagent matching the reactivity of the substrate of interest. The scope of the reaction is wide despite the low

(27) Scheme 4. The camphor sultame (27) as chiral fluorinating agent.

(29) 63% (70%ee)

Fluorine in Organic Synthesis

A U

M F . 0 OC. 10 min

(28)

247

trophilic fluorinating agents are not only fluorinating but also strong oxidants. A single reagent cannot satisfy all requirements. It is exciting to see what new selective and safe fluorinating reagents and methods will offer in the future.

U 78%

(yOEt

References

837.

6 56%

OAc

CH2Cl2. 10 h, A

@

0

F 71% ( a : @= 1 : 2 )

Scheme 5. Examples for fluorinations with several N-fluoropyridinium salts.

solubility of the pyridinium salts in organic solvents. Some examples for fluorinations with Nfluoropyridinium salts (30),and (34) are given in Scheme 5. The reagents react not only with anions (28), but also with enols (31) and (33). Even benzene is oxidatively fluorinated to fluorobenzene by reagent (32). Amines and other oxidizable substrates are therefore not suitable for direct fluorination under these electrophilic conditions. The “naked” fluorideion is not only nucleophilic but also a very strong base. Strong elec-

[l] H. Meinert Fluorchemie, Akademie Verlag, Berlin, 1979. [2] J.T. Welch, Tetrahedron 1987,43, 3123. [3] A.Haas, M.Lieb, Chimia l985,39, 134. [4] G. A. Olah, J. T. Welch, Y.D. Vankar, M. Nojima, I.Kerekes, J.A. Olah, J. Org. Chem. 1979, 44, 3872. [5] R.K. Sharama, J. L. Fry, J. Org. Chem. 1983, 48, 2112. [6] T. J. Tewson, J. Org. Chem. 1983,48, 3507. [7] K. 0. Christe, W. W. Wilson, J. Fluorine Chem. 1989,45,4. [S] W. J. Middleton, J . Org. Chem. 1975, 40, 574. [9] H. Vyplel, Chimia l985,39, 305. [lo] S.T. Pumngton, B.S. Kagen, T.B. Patrick, Chem. Rev. 1986,86,997. [ll] S.Rozen, O.Lerman, M.Kol, J. Chem. SOC., Chem. Commun. 1981,443. [12] S.Rozen, Acc. Chem. Res. 1988,21,307. [13] M. J. Adam, Chem. Eng. News l985,63,2. [14] E.H. Appelman, M.H. Mendelsohn, H.Kim, J. Am. Chem. SOC. 1985,107,6515. [15] D . H.R. Barton, R.H. Hesse, M.M. Pechet, H. T. Toh, J. Chem. SOC., Perkin Trans. I, 1974, 732. [16] W.E. Barnette, J. Am. Chem. SOC. 1984,106, 452. [17] S.H. Lee, J.Schwartz, J. Am. Chem. Soc. 1986,108,2445. [18] S. Singh, D.D. DesMarteau, S. S. Zuberi, M.Witz, H.N. Huang, J. A m . Chem. Soc. 1987,109, 7194. [19] E.Differding, R. W. Lang, Tetrahedron Lett. 1988,29,6087. [20] H.Meinert, Z. Chem. l965,5,64. [21] T. Umemoto, K.Tomita, Tetrahedron Lett. l986,27, 3271. [22] T. Umemoto, K. Kawada, K. Tomita, Tetruhedron Lett., 1986,27, 4465.

Part 11. Applications in Total Synthesis

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

A. Synthetic Routes to Different Classes of Natural Products and Analogs Thereof Synthesis of Hydroxyethylene Isosteric Dipeptides Rolf Henning Renin is a highly specific aspartic proteinase, cleaving the circulating serum glycoprotein angiotensinogen between the amino acids leucine-10 and valine-11. Subsequent removal of a C-terminal dipeptide by angiotensin converting enzyme (ACE) produces the octapeptide angiotensin 11, which causes an elevation of blood pressure by, amongst others, direct vasoconstriction and stimulation of aldosterone release. Thus, inhibition of the enzyme renin represents a novel therapeutic approach for the treatment of hypertension. The search for renin inhibitors has greatly intensified during the past ten years. [l]The most promising chemical approach is based on the concept of analogy to the tetrahedral transition state intermediate involved in the enzymecatalyzed hydrolysis of a peptide bond. [2] Structures that correspond to this concept are, among others, statine (2) and statine analogues, which already have been described here, [3] and the so-called hydroxyethylene isosteric diptptides (3). These compounds both represent non-cleavable mimics of the Leu-Val dipeptide (I) (Scheme 1). The fact that the virus-coded proteinase of the human immuno-deficiency virus (HIV)is

Rbnin (1)

f3)

Scheme 1

also a member of the aspartic proteinases [4] has further boosted the pursuit of this transition state concept and of the corresponding non-peptidic structures; [5] inhibitors of the HIV proteinase could provide a therapeutic opportunity for the treatment of retrovirusassociated diseases such as AIDS. The vast majority of synthetic approaches to (3) starts from chiral a-amino acid derivatives as N-terminal components, thus ensuring the stereochemical integrity and the type of

252

A . Synthetic Routes to Different Classes of Natural Products

the side chain at C-5. For the further assembly of the dipeptide framework, three strategies can be distinguished: Amino acid + C1-electrophile+ C2-nucleophile (enolate) Amino acid Cl-nucleophile G-electrophile Amino acid + C3-nucleophile (homoenolate)

+

+

In many cases, however, complete control of the configuration at C-4 (using aldol-type reactions or reduction) and at C-2 (by alkylation) could not be achieved, thus necessitating a double separation of diastereomers during synthesis. Pioneering work on a whole series of dipeptide isosters was performed by Szelke and coworkers. The starting point of their synthesis of the hydroxyethylene isoster (9), following the Cl-synthon/enolate strategy, [6, 71 is the diazo ketone (4), itself easily obtainable from L-leucine. Reduction of the ketone (5) using sodium cyanoborohydride produces a 3 :1mixture (2R/2S) of the diastereomeric alcohols (6). The isovaleryl unit (as substitute for valine) at C-1 is added in a multi-step sequence via a malonate alkylation to give (8). Cleavage of the auxiliary ester function finally furnishes a mixture of the (2S/2R)-epimers (9) (Scheme 2). Two shorter routes, while following the same strategy of enolate alkylation, employ different alkylation agents. Evans and coworkers use the aminoalkyl epoxide ( I I ) , [8] which is available by the - nondiastereoselective - reaction of BOC-Lphenylalaninal (10) with dimethylsulfonium methylide [9] (1:l epimeric mixture). Malonate alkylation using this epoxide smoothly yields the lactone-ester (12) after spontaneous cyclization; unfortunately, acetate enolates do not react with (11). Incorporation of the second side chain in a separate alkylation step provides the key lactone (13) as a mixture of the C-2 diastereomers (Scheme 3).

("

/

NaBH3CN

I

I

PhW

PhtN OH

-

60n

1. NaCH(CO+u)Z 2. i-Prl, NaH

PhtN

00-t-Bu

1. PhCHzBr, NaOEt

2. NaOH 3. A

Scheme 3

BwHN&Ph

-0

(13)

In a synthesis developed by a Ciba-Geigy group, [lo] a different side chain and a modified ylide help to improve the diastereoselectivity of the Corey-Chaykovskyreaction [9] to 5: 1in favor of the desired isomer (15). In con-

Synthesis of Hydroxyethylene Isosteric Dipeptides

trast to the method described above, (15) is not used directly as alkylation agent, but first transformed into the apparently more reactive iodide (16). Reaction with the isovalerate enolate (17) in THFHMPA then affords the dipeptide isoster (IS) as a 1:l mixture of the C-2 epimers (Scheme 4). A significant improvement and simplification of the enolate method was recently achieved by chemists from Merck, Sharp & Dohme. [ l l ] The direct coupling of the chiral amide enolate derived from (20) with epoxide (11) provides the product (21) with the desired (2R)-configuration.The reaction proceeds with both excellent chemical yield and diastereoselectivity (> 99:1), if the electrophilicity of epoxide (11) is enhanced by pre-lithiation of the carbamate moiety (using a second equivalent of butyllithium in a one-pot procedure). Epoxide (11) is alternatively accessible via peracid oxidation of the corresponding olefin (19), [ l l , 121 again with improved diastereoselectivity (86: 14) compared with the CoreyChaykovsky reaction [9] (Scheme 5). Key step of a synthetic route [13] related to the enolate method is the Wittig-Horner reac-

Scheme 5

(zol

tion of aldehyde (24) with phosphonate (25). Aldehyde (24) is available by ozonolysis of the vinyl adduct (23) and can be equilibrated (7: 1) in favor of the desired anti isomer. However, catalytic hydrogenation of the double bond in (26) proceeds without significant diastereoselectivity with respect to C-2 (Scheme 6). An alternative route [14] to aldehydes of type (24) involves the chelation-controlled, diastereoselective (> 10: 1) addition of 2furyllithium (28) to aldehyde (27) in the presence of zinc bromide. The desired compound (31) is then obtained by oxidative cleavage of the furan ring (Scheme 7). In an original variation of the enolate strategy, [15] (31) is first converted into the dihy-

Z-HN' 1. CH2=CHYgBr

--

BoGHN

o3

__* 1. 2. k C 0 ,

1. M%CHCH(Li)C02Me ( l v

2. KW-Bu, H 2 0

Scheme 4

(18)

253

h"o -7

254

A. Synthetic Routes to Different Classes of Natural Products

Scheme 7

droxyethylene isoster (32) [16] by a highly diastereoselective aldol reaction ; Bartondeoxygenation [17] of the extra hydroxyl group then provides the hydroxyethylene isoster (34) with unambiguously defined configuration at C-2 (Scheme 8). The “Umpolung” variation of the enolate method [18] makes use of the Pketo phosphonate (36) which is readily available from amino acid ester (35) by a Claisen condensation. Wittig-Horner reaction of (36) with a-keto ester (37) smoothly yields the enone (38). Subsequent reduction of the keto group, cyclization and hydrogenation lead to the key lactone (39), albeit with unfavorable diastereoselectivity at C-2 and C-4 (Scheme 9). The use of homoenolate equivalents [19] enables a shortening of the reaction sequence. This strategy has increasingly gained attention during the last years. The first synthesis of this type was developed by Rich. [20] Addition of

the chiral Grignard reagent derived from (40), which is available in four steps applying the acyl oxazolidinone method of Evans, [21] and which is already endowed with the stereocenter C-2, to aldehyde (22) affords a 4: 1 mixture (4S/4R) of the secondary alcohol (41). Oxidation of the primary hydroxyl group then leads to (42) (Scheme 10). Homoenolate equivalents related to (40) include propyl bromide (43) [22] and butenyl bromide (44). [23] In these compounds, the phenyI substituent and terminal double bond, respectively, function as a masked carboxyl group on oxidative degradation (Scheme 11). Kleinman [24] uses propiolate as a homoenolate synthon. Hydrogenation of the adduct (45) followed by cyclization furnishes lactone (46) as a 4.5: 1 mixture in favor of the desired 4 s isomer. [25] Reaction of the dianion of (46) with methallyl bromide produces the target

-

+ BocHNG

Scheme 10

C

O

O

OAc EH3 (42)

H

Synthesis of Hydroxyethylene Isosteric Dipeptides B r w P h

-B r

255

\

Scheme I1 ,Ph

compound (47) as the preferred (15: 1) trans alkylation product (Scheme 12). Kempf [26] employs the dianion (48) of Nmethyl methacrylamide as homoenolate equivalent. Titanium(1v)-mediated addition to (10) gives a 1.6:l mixture of hydroxy amide (49). Incorporation of the second side chain can be accomplished by conjugate addition of alkyl cuprates to methylene lactone (50), but diastereoselectivities are rather low (Scheme 13). Allyltrimethylsilane (52) represents an additional homoenolate synthon. [27] Chelation-controlled reaction with aldehyde (22) in the presence of tin(1v) chloride preferably (20:l) yields the threo isomer (53). Subsequent hydroboration and oxidation then reveal the masked carboxyl function (Scheme 14).

(22)

BocHN OH (45)

1. H,, PdlBaSO,

2. b 3. separation

0

Scheme 12

1. separation

2. A

BocHN (491

(5 11

Scheme 13

Explicit homoenolates, finally, provide a straightforward access to the central lactone intermediates. [28] An example [28a] is the chelation-controlled addition of titanium homoenolate (55) to aldehyde (lo),leading to the key compound (56) with a (4Sl4R) diastereoselectivity of 16: 1 (Scheme 15). In this type of reaction, extent and direction of diastereoselectivity are strongly influenced by the nature of both amino protecting group and titanium ligands. [28, 291 In order to unambiguously control the configuration at C-4 and C-5, three synthetic approaches use chiral precursors other than simple a-amino acid derivatives. In the first route, [30] statine (2) (obtained by hydrolysis of pepstatin) is “degraded” to aldehyde (24) [13] in an eight-step sequence. The second route [31] starts from commercially available

256

A. Synthetic Routes to Different Classes of Natural Products

0

12 steps _ _ * - -

(57)

l . separation

_____, 2. HCI, MeOH

n

%

f- BuMe,SiO\'"

-"-ai-

The third route [32] employs D-mannose (60) as chiral starting material. After a threefold "deoxygenation" via an eight-step sequence, compound (61) is obtained. A reScheme 16 ('9) giospecific epoxide opening using phenyl magD-glucal (57), which is transformed in twelve nesium bromide in the presence of copper(1) steps to the valerolactone (58) and subse- iodide then provides the hydroxy lactol(62) as quently to the butyrolactone (59) the precursor to lactones of type (13) (Scheme 17). (Scheme 16). HO

Synthesis of Hydroxyethylene Isosteric Dipeptides

PhMgBr/Cul

257

-

H&'

Scheme 17

(62)

The chiral center in (64) now induces the configuration of the two centers that are not An asymmetric synthesis of dipeptide iso- yet functionalized (C-4, C-5). The critical step sters (3)that does not start from amino acid or is the diastereo- and regioselective (20: 1 and carbohydrate derivatives, that controls the 10:1, respectively) bromo lactonisation of stereochemistry of all three chiral centers and dimethylamide (67), leading to the thermodythat allows for a broad variation of the side namically more stable trans product (68). SN2 chains, has been developed [33] by chemists substitution at C-5 then gives the dipeptide from Ciba-Geigy. The key intermediate is the isoster (69) with correct configuration at all y,&unsaturated acid (64),readily available by a titanium(1v)-catalyzed Carroll rearrangement of the mixed malonate (63). A classical, O v d N M % two-step resolution procedure provides the (67) A desired (S)-enantiomer with 90% ee. An alternative route is given by the diastereosen lective (99: 1) alkylation of acyl oxazolidinone (66) with ally1 bromide (65), following the 1. NaN3 work of Evans [21] (Scheme 18). 3. H2, PdC 1. Ti(OEt),, 190 "C COzEt

__5

2. KOH

3. resolution

(64)

n

A

OH

Scheme 18

Scheme 19

258

A . Synthetic Routes to Different Classes of Natural Products

three stereocenters. A related approach, using the prolinol derivative (70), which also originates from Evans, [34] has been described in the patent literature [35] (Scheme 19). The interest in selective enzyme inhibitors as potential new therapeutics [36] has steadily increased over the last few years as a consequence of a deeper understanding of biochemical and physiological correlations. This is resulting in new challenges to stereoselective synthesis that can be met with confidence on the grounds of the progressing refinement on synthetic repertoire, as this overview was to illustrate exemplarily.

References [l] a) J. M. Wood, J. L. Stanton, K. G. Hofbauer, J. Enzyme Inhibition 1987, 1, 169; b) T.Kokubu, K.Hiwada, Drugs of Today 1987, 23, 101; c) J. Boger, Trends Pharmacol. Sci. 1987, 8, 370; d) W. J. Greenlee, Pharm. Res. 1987,4, 364; e) W.J. Greenlee, Med. Res. Rev. 1990, 10, 173. [2] a) R.Wolfenden, Nature 1%9, 223, 704; b) R. Wolfenden, Acc. Chem. Res. 1972, 5, 10. [3] H.-J. Altenbach, Nachr. Chem. Tech. Lab. l988,36,756. [4] L. H. Pearl, W. R. Taylor, Nature 1987,329,351. [5] G. B. Dreyer, B. W. Metcalf, T. A. Tomaszek, T. J. Carr, A. C. Chandler, L. Hyland, S. A. Fakhoury, V.W.Magaard, M.L.Moore, J.E. Strickler, C. Debouck, T.D. Meek, Proc. Natl. Acad. Sci. USA 1989,86,9752. [6] a) M. Szelke, D. M. Jones, B. Atrash, A. Hallet, B. Leckie, Proc. 8th Am. Pept. Symp. 1983, 579; b) M.Szelke, D.M.Jones, A.Hallet, B.Atrash, EP 118.223,19&1. [7] S.L.Harbeson, D.H.Rich, J. Med. Chem. 1989,32, 1378. [8] B. E. Evans, K. E. Rittle, C. E Homnick, J.P. Springer, J. Hirshfield, D. F. Veber, J. Org. Chem. 1985,50,4615. [9] E. J.Corey, M. Chaykovsky, J. Am. Chem. SOC. 1965,87, 1353. [lo] P. Buhlmayer, A. Caselli, W. Fuhrer, R. Goschke, V. Rasetti, H. Riieger, J. L. Stanton, L. Criscione, J. M. Wood, J. Med. Chem. 1988, 31, 1839.

[ll] D. Askin, M. A. Wallace, J. P. Vacca, R. A. Reamer, R. P. Volante, I. Shinkai, J. Org. Chem. 1992,57, 2771. [12] J. R. Luly, J. F. Dellaria, J. J. Plattner, J. L. Soderquist, N.W, J. Org. Chem. 1987,52, 1487. [13] P. G.M. Wuts, S.R.Putt, A.R. Ritter, J. Org. Chem. l988,53,4503. [14] M. A.Poss, J. A. Reid, Tetrahedron Lett. 1992, 33, 1411. [15] S.A.Boyd, R.A. Mantei, C. Hsiao, W.R. Baker, J. Org. Chem. 1991,56,438. [161 S. Thaisrivongs, D. T. Pals, L. T. Kroll, S. R. Turner, F.Han, J. Med. Chem. 1987,30,976. [I71 D. H. R.Barton, S. W. McCombie, J. Chem. SOC., Perkin Trans. 11975, 1574. [18] P. K. Chakravarty, S. E. de Laszlo, C. S. Sarnella, J. P. Springer, P. F. Schuda, Tetrahedron Lett. 1989,30, 415. [19] a) N.H.Werstiuk, Tetrahedon 1983,39, 205; b) D.Hoppe, Angew. Chem. 1984, 96, 930; Angew. Chem. Int. Ed. Engl. 19&1,23, 932. [20] a) M. W. Holladay, D. H. Rich, Tetrahedron Lett. 1983, 24, 4401; b) M.W.Holladay, F.G. Salituro, D.H.Rich, J. Med. Chem. 1987, 30, 374. [21] D. A. Evans, M. D. Ennis, D. J.Mathre, J. Am. Chem. SOC. l982,104,1737. [22] D.M.Jones, B.Nilsson, M.Szelke, J. Org. Chem. 1993,58, 2286. [23] G.B. Dreyer, D.M.Lambert, T.D.Meek, T. J. Can; T. A.Tomaszek, A. V. Fernandez, H. Bartus, E. Cacciavillani, A.M. Hassell. M. Minnich, S. R. Petteway, B. W. Metcalf, M. Lewis, Biochemistry 1992,31, 6646. [24] A.H.Fray, R.L.Kaye, E.F.Kleinman, J . Org. Chem. 1986,51, 4828. [25] T.Nishi, M. Kataoka, Y. Morisawa, Chem. Lett. 191E9, 1993. [26] D. J.Kempf, J. Org. Chem. 1986,51,3921. [27] J. V. N. Vara Prasad, D. H. Rich, Tetrahedron Lett. 1990,31, 1803. 1281 a) A. E. Decamp, A.T. Kawaguchi, R. P. Volante, I. Shinkai, Tetrahedron Lett. 1991, 32, 1867; b) S. Kano, T. Yokomatsu, S. Shibuya, ibid. Wl,32,233. [29] a) M. T. Reetz, M. W. Drewes, A. Schmitz, Angew. Chem. 1987,99, 1186; Angew. Chem. Int. Ed. Engl. 1987,26, 1141; b) M.T.Reetz, M. W. Drewes, K. Lennick, A. Schmitz, Tetruhedron Asymmetry 1990,1,375.

Synthesis of Hydroxyethylene Isosteric Dipeptides

[30] a) M.Nakano, S. Atsuumi, Y.Koike, S.Tanaka, H. Funabashi, J. Hashimoto, M. Ohkubo, H.Morishima, Bull. Chem. SOC.Jpn. WIO, 63, 2224; b) S.Atsuumi, M. Nakano, Y. Koike, S.Tanaka, K. Matsuyama, M. Nakano, H. Morishima, Chem. Pharm. Bull. 1992,40,364. [31] a) M. Shiozaki, T. Hata, Y. Furukawa, Tetrahedron Lett. 1989, 30, 3669; b) M.Shiozaki, Y. Kobayashi, T. Hata, E Furukawa, Z'etrahedron 1991,47,2785. [32] A. K. Ghosh, S. P.McKnee, W. J. Thompson, J. Org. Chem. 1991,56,6500.

259

[33] P. Herold, R. Duthaler, G. Rihs, C. Angst, J. Org. Chem. 1989,54, 1178. [34] D. A.Evans, J. M. Takacs, Tetrahedron Lett. 1980,21,4233. [35] J. B. Hester, D. T. Pals, H. H . Saneii, T. K. Sawyer, H. J. Schostarez, R. E. Tenbrink, S. Thaisrivongs, EP 173.481, 1986. [36] M. Sandler, H. J. Smith (Eds.), Design of Enzyme Inhibitors as Drugs, Oxford University Press, New York, 1989.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Synthesis of Natural Products for Plant Protection Hans- Peter Fischer

Introduction

A target-directed placement of products by new, innovative, user-friendly formulation, To provide acceptable solutions for crop propackaging and application technology. duction and to be successful as a supplier of Active ingredients must be effective when pest management solutions, it is necessary to used at forecast and with threshold levels. meet the steadily enhanced requirements that 0 A synergy with biological control methods, are requested by users of pesticides and contraditional breeding and gene technology sumers of agricultural goods. Besides the cri[4] and with a fit into antiresistance manteria for activities as herbicides, fungicides, agement and appropriate agricultural techinsecticides and parasiticides, and for the niques. [5] exposure and risk assessments based on toxi- 0 In addition, supporters of “soft” technolocological studies, much emphasis must be gies suggest basing future pesticide producgiven to ecological considerations in research tion on renewable resources and safe processes with minimum liberation of persisstrategies directed to future agricultural protent wastes. [6] ducts. [l] These challenges must be carefully balanced New technologies and product profiles in with economic criteria for the farmers, the displant protection markets aim at integrated tributors, the producers and the consumers. pest management strategies (IPM). This Many of the desirable properties would implies the following: Low dose rates to reduce environmental clearly point to a renaissance of natural product chemistry and efficient fermentation proimpact. [2] Minimized degradation time to reduce cesses, which are based on natural feedstocks. accumulation in the ecosystem, including Indeed, many natural products catabolize and prevention of leaching into the ground bioreintegrate into metabolic cycles rapidly, and accumulation of toxic residues can be water. [3] avoided. A number of examples demonstrate 0 Optimal physico-chemical properties of applied chemicals with special considera- that high pesticidal activities can be detected with microbial and plant metabolites. [7] tion of soil migration and evaporation. A selective mode of action targeted solely Commercial products of the most important at the pest organism and simultaneously class of agrochemicals derived from natural exhibiting a high safety margin and toler- products, the pyrethroid esters, are easily ance in the environment for beneficial degraded and mineralized. [8] However, the toxicity of natural constituents may not be organisms, users and consumers. 0

262

A . Synthetic Routes to Different Classes of Natural Products

more favorable when compared with that of synthetic chemicals. A sophisticated statistical evaluation of these two groups with different origins was published recently. [9] Thus, similar criteria for the responsible selection of appropriate development candidates must be applied for natural and synthetic products. Nevertheless, environmental considerations might be the main driving force to increase efforts in metabolite research. Many reviews give evidence of enormous efforts to change agricultural application practices to nature-based methods. [lo] In order to arrive at these ambitious objectives, a stage plan must be developed and a critical mass for R & D must be reached. [ll]Challenges of a natural product discovery programme include the following: To find new natural, active ingredients by systematic screening of broths and extracts of microbial cultures and of plant extracts. 1111 To discover leads and templates, whose properties can be improved by chemical modifications. [ll]

0

0

0

To find new plant protection principles by studying chemical and ecological interactions between organisms and by understanding the underlying modes and mechanisms of action of signal compounds, natural regulators and metabolites that enhance resistance, induce defense and assist in the survival of the species. [12] To develop economic (enantioselective) processes with minimum waste precipitation using recycling or bioremediation and fermentatiodbiotransformationtechnology using biomass as media. To increase the market penetration with profitable products of natural origin from a level of = $ 1.9 billion (= 8 Yo of the chemical plant protection market) to 2 12% in the year 2000. Estimated market figures of natural products per se and compounds that are based on natural templates are given in Table 1.

Table 1. Estimated sales of natural products and mimics for agriculture Use

Natural Products and Mimics

Estimated Sales 1991 $ .lo"

Herbicides

Phosphinothricin (1) Bialaphos') (2)

90

Fungicides I Bactericides

Diverse Antibiotics')[l3]

50

InsecticidesI Acaricides

Abamectin') (45) Pyrethrins (Hygiene) Bac. thuringiensis preparations') Pyrethroids Juvenoids

160

Animal Parasites

~~

I

Fermentation dependent products.

100 1500 100

Avermectins') Milbemycins')

850

Total market of natural product') (incl. mimics)

850

Synthesis of Natural Products for Plant Protection

263

Production

Phosphinothricin

Biotechnical processes, fermentations, and biotransformations compete with (enantioselective) synthesis for the production of natural products. In specific situations they may complement each other. Decisive factors for the selection of an industrial process are primarily based on economic considerations in production, available technical expertise of a producer, and patent coverage. In the future chiral products might be developed more frequently. [141 Continuous progress in finding new economically feasible enantioselective synthetic methods has been observed. [15] In academia, the intellectual challenge to make a complex molecule with sophisticated sequences is still attractive. Examples are outlined in the following chapters and approaches of several investigators are compared. In the industrial environment, however, the use of cheap starting materials and reagents, a small number of steps and acceptable levels of investment are decisive. Because knowledge about biotransformations and how to recover metabolites is steadily increasing, there might be a shift toward better economic pre-conditions for fermentation processes in the agrochemical industry. [16] This trend is also likely because process safety, bioremediation and other appropriate ecologically acceptable waste disposal methods will absorb additional investment for new manufacturing plants based on chemical steps. [17] As a result of the cost limitations of agricultural products, it is a difficult mission for industry to manufacture biologically active natural products competitively. Unit costs of only $ 10-20/acre/treatment are usual in the marketplace. These figures can be reached only, if natural products are found that can be applied at low dose rates of below 100 g/acre and production costs can be reduced, e.g. to less than $ 200/kg. [ll]

Phosphinothricin (1) is the hydrolysis product of the dipeptide bialaphos (2) and of phosalacine (3). These metabolites were isolated from culture broths of Streptomyces viridochromogenes and S. hygroscopicus as well as of Kitasatosporia phosalacinea sp. nov. KA-338. [18] The racemic ammonium salt of (I) was introduced by Hoechst under the names glufosinate, HOE 39’866, Basta@,and the single isomer (2) under the names bialaphos, MW 801, MW 831, SF-1293 Na, Meiji Herbiace@,all as contact herbicides with a broad spectrum of weed control. [19] Several syntheses of the racemate (I) were published before synthetic methods for the active (S)-isomer were investigated. [20] An efficient enantioselective synthesis by Zeiss [21] is based on Schollkopf’s amino acid synthesis via metallated bis-lactimethers. The lithium salt of the (3R)-bis-lactimether (4) is alkylated with isobutyl-2-chloroethyl-methylphosphinate (5) at -78°C in TKF with high enantioselectivity. After hydrolysis of (6) the natural (S)-( +)-phosphinothricin (I) is isolated with an optical purity of 93% ee and a total yield of 50 % .The alternative strategy of Minova [22] is based on the asymmetric Michael addition of the potassium enolate (lo), made by metallation of the Schiff base (9), to 0-methyl-methyl-vinylphosphinate (11). Compound (9) is easily obtained by reaction of glycine with the chiral auxiliary (S)-2hydroxypinanone (8). The amino acid (I) is obtained, after hydrolysis of (12) in 79 YOoptical purity. Recently (I) was also conveniently synthetized in six consecutive steps from Laspartic acid with 94 % ee and 35 % overall yield. [23] (S)-Phosphinothricin (1) was also prepared in 70 % yield by biotransformation from racemic 4-(ethoxymethylphosphinyl)-2acetamido-butanamide (13) by consecutive treatment with the commercial enzymes phosphodiesterase I, acylase I and glutaminase in 70 Yo yield. [24] In another bioconversion (1)

264

A . Synthetic Routes to Different Classes of Natural Products

was obtained by stereospecific transamination of 2-oxo-4-(hydroxy (methyl) phosphinyl) butyric acid with a phosphinothricin specific aminotransferase from E.coli K-12 and a number of amino-group donors. [25] Further progress in improving fermentation yields of bialaphos (2) can be expected based on the brilliant biosynthetic studies of Set0 et al. [26] Since the reaction conditions and the details of the scale-up trials are trade secrets, it is difficult to give a judgement on the prefered industrial solutions (Scheme 1).

Pyrrolnitrin Analogs The effectiveness of microbial antagonists as biocontrol organisms is based on a combination of several modes of interaction between a pathogen and the host. [5] In some well investigated examples it could be shown that the formation of certain antibiotics could be responsible for the dominance of a disease controlling biological over the pathogenic invader. [ll]Antagonistic strains of Pseudomonas fluorexem with activity against Rhi-

0

Scheme 1. Enantioselective syntheses of (S)-( +)-phosphinothricin ( I ) by Zeiss [21], Minowa [22], Natchev [a] and Schulz [25].

Synthesis of Natural Products for Plant Protection

zoctonia soluni are producing a number of antibiotics, among them pyrrolnitrin (15). [27] By applying pyrrolnitrin (15) the control of a number of pathogens in the rhizosphere of cotton and an increase of the survival rate of seedlings is achieved. The first synthesis of (15) involved six steps and gave an insufficient yield for making the antibiotic economically. [28] Later Nippon Soda described a two step synthesis to prepare the analog (16). [29] In field trials, however, 3chloro-4-phenyl-pyrrolslike (16) proved to be too photolabile. [ll,301 A new synthetic approach by Van Leusen et al. opened an easy preparation method for photostable mimics of (Is),3-cyano-4-phenyl-pyoles, like (18).[31] By using TosMIC (17)as a reagent preparation of analogeous a,d-unsubstituted pyrrols and an optimization of the fungicidal activities became possible (Table 2). The [2+3]-

265

cycloaddition opened a way to optimize the fungicidal activity of this class. Van Leusen's innovative synthetic step (17)+ (18)led finally to a cereal seed dressing agent Beret@ (18)[32] and Saphire@,a fungicide for soil and leaf-borne diseases. [ll,301

Strobilurins Strobilurin A (194 was first isolated by Musilek et al. under the name of mucidin from the fungus Oudemansiella mucida. [33] Independently, Steglich and Anke purified strobilurin A (19a) and B (19b) from Strobilurus tenacellus. The antibiotic family was complemented by the isolation of related Pmethoxyacrylates from other basidiomycetes and of the related oudemansins (20) (Table 3). [34] The strong fungicidal activities attracted a number of

Table 2. Comparison of syntheses of 3,4-disubstituted fungicidal pyrroles according to Gosteli [28], Ueda et al. [29] and Van Leusen [31]. ~~

Starting Materials; Critical Step

Steps (Yield)

Product

~

Light Stability (r-Suntest lamp)

X

I

O@K (3 /

+

COOC2HS

X-CH2-C=CH2 X

5

CI,

6 (20%)

Br

a) CICH,CH=CCICHO

2

0.5 h

CI

C2t3l-cyclooddition

H

266

A . Synthetic Routes to Different Classes of Natural Products

Table 3. Structure of natural fungicidal fl-methoxyacrylates [34]. Strobilurins

Oudemansins

Synthetic Mimic

OCH3

(19)

R

R’

(20)

A B C

H Me0 PrenylO H

H c1 H Me0

A B

X

groups to carry out total syntheses and the synthesis of mimics. The strategy of Sutter [35]for building the polyolefinic side chains of strobilurin B (196) was based on the application of consecutive Wittig reactions (Scheme 2). Since both geometrical isomers of the C=C bonds are normally formed, the yield of the final product (196) was very low, and the separation of the isomers by chromatography was laborious. However, all isomers were wanted for struc-

methoxymrbonylmthylentriphenylphmphoran. rellux, toluene (80 Yo)

X

ture-activity considerations. The natural (E,Z,E)-isomer (196) was most active in vivo against phytopathogens. Through the systematic modifications by Steglich it also became evident that the (E)-methoxyacrylate substructure was essential for high activity. Due to the photolability of the natural products only a short residual activity was found in field trials. Thus, mimics of the natural template like (21) were synthesized using Wittig technology (Scheme 3). A rich patent literature

-H,

k Y r.t.

>

30n

CCI H f l ~ c O o C H 3 CI-

(Ctso),Sq. &a3. W. r.1. (19b) 25 % Scheme 2. Synthesis of strobilurin B (196) [35].

(21)

(29) 27%

CHO ’C

Synthesis of Natural Products for Plant Protection

267

(+)-Hydantocidin is the only one of 16 possible diastereoisomers with the four contiguous stereogenic centers that showed strong herbicidal activity. [39] In the retrosynthetic strategy of Mirza tribenzyl-oxyribose (36) was used as chiral starting material. [40] The first step was based on the Bucherer reaction (36) -+ (37) + (38). The natural isomer (35) was made in six steps, as shown in Scheme 4. It was interesting to note that Sankyo's several synthetic strategies were distinct from Mirza's approach with exception of the final cisdihydroyylation step (42) -+ (35) lyxoisomer (44). A completely different approach to the spironucleoside (35) by Chemla is based on the readily available 1,2:3,4-di-O-isopropylidene-D-psicofuranose as a chiral starter unit using a new oxygen-bridged intramolecular Vorbriiggen coupling. [41] The production of ribantoin (35) by fermentation was inferior to the total synthesis due to very low fermentation yields and difficulties in separating ribantoin from other metabolites, such as desoxy-xylitol, 4hydroxyphenyl-glyoxylic acid and homomycin. [ ll]

+

(21)

Scheme 3. Synthesis of strobilurin-mimic (21) by Steglich [34].

from ICI, BASF, Maag and Ciba documents the high interest of pesticide manufacterers in this new class of fungicides. Two photostable development candidates (33) and (34) were recently presented at the British Crop Protection Conference in Brighton. [36]

AvermectindEmamectin - MK 244 and MK 243LMilbemycins A great deal of attention was drawn by papers of Merck, Sharp and Dohme, in which 4 deoxy - 4 - epi - methylamino - avermectin B1 hydrochloride, MK 244, emamectin (48) and MK 243 (49) were described. The semisyntheHydantocidin and Ribantoin tic derivative MK 244 (48) shows up to a 1600Additional synthetic work in the area of herbi- fold improvement in potency against lepidopcides is exemplified with a metabolite called teran larvae. [41] With MK 243 (49) it was (+)-hydantocidin (35) which was isolated observed that 0,02 ppm led to 100 % mortality from Streptomyces hygroscopicus, SANK of Spodoptera eridiana. [42] The successful synthesis of (48) and (49) 63'584 by Sankyo. [37]The same structure was independently characterized from S. hygrosco- started from avermectin B, (45) by the oxidapicus, m-2474, by Ciba and named (+)- tion of the 4"-hydroxy group of the a-Loleandrosyl -a - L - oleandrosyl - disaccharideribantoin. [38] BAS 490 F (33)

ICI A 5504 (34)

268

A . Synthetic Routes to Different Classes of Natural Products

D-Ribose

I

H

I

H

\

Ho

O I

I

(35) Rlbamoin

H

(44) Lyxo. 32 %

Hydantocldin

Scheme 4. Synthesis of ribantoin (35) by the Bucherer route [MI.

component by Swem-oxidation, after the more reactive 5-hydroxy group was protected as the 0-tert-butyl-dimethylsilylether (46). Reductive amination of (47) with CH3NH2 and NaCNBH3and cleavage of the protecting group in the 5-position gave a mixture of the 4”-methylaminogroup, and MK 244, with the equatorial 4”-methylamino group, were isolated (Scheme 5). The endoparasiticidal, acaricidal and insecticidal metabolites of the avermectin family are industrially produced by fermentation of optimized cultures of Streptomyces avermitilis,

for example, MA 4848 (ATCC 31’271). The mixture of avermectin B1, and Blb, abamectin, MK 936, which is less active in insedmite control than the semisynthetic compounds (48) and (49) is formed in an 80:20 ratio. Ivermectin (50) is isolated by hydrogenation of the double bond in position 22-23 of (45). This important product is a systemic endoparasiticide in animal health and can be used against tropical infections of humans with filaria, such as Onchocerca volvulus. [43] The total synthesis of avermectins (45) or their aglycons (51) and of the related milbe-

Synthesis of Natural Products for Plant Protection

R = H: Avermectin B,,, R = Si(CH,)&(CH,&:

lvermectin

269

(45) (46)

H3

(50)

Emamectin, MK 244 (48) [+MK243 (491

OH

Scheme 5. Modifications of avermectin B1, (45) to MK 244 (48) [41].

mycins, 13-deoxyavermectin-aglycons like (52), belong to the highlights of organic synthesis. New reactions were used and discovered in the course of these objectives. [44, 451 In this paper only the retrosynthetic strategy for the total synthesis of avermectin B1,-aglycon by Hannesian’s group is exemplified (Scheme 6). The stereochemical analysis of possible templates as chiral synthons was conceptually combined with enationioselective synthetic steps. The synthesis was indeed started on the basis of the decoded chiral starter units, suggested by a computer program, and finalized successfully in several steps. [44,461 In the course of these investigations a user-friedly computer program called “CHIRON” was developed, which assists che-

mists in the identification of useful chiral synthons for the synthesis of complex natural products. This software could be successfully applied to investigate alternative synthetic strategies for different industrial scale up processes of chiral pesticides. Whereas the synthesis of milbemycins by degradation of the corresponding ivermectinaglycons (56) + (57) and (52) is rather trivial, [46] it is more laborious to find methods for the reverse conversion, the regioselective oxidation of milbemycins (52) in the 13-position. [47] The direct diastereoselective microbial hydroxylation of milbemycin & (52), for example with Streptomyces violascens (ATCC 31,560), to 13-#3-hydroxymilbemycin (53), was successfully achieved in 92 % yield. [48] Com-

270

A . Synthetic Routes to Different Classes of Natural Products

HOr,

Me-"

HO CHO

H3

OH Template A,

Glucose

Template A,

bH

f

Template A

/

(-)-Chinaacid TemplateC

(StMalic acid

R

R

R

= Template A,

Scheme 6. Synthesic planning of avermectin B1,-aglycon (51)from simple chiral building blocks by retrosynthetic analysis [MI.

pound (53) can easily be transformed via (55) to (56) (Scheme 7). The pepimer (53) can also be used to investigate biological activities of recently discovered 13-phydroxymilbemycin derivatives. [49] The biotransformation process (52)+ (53) also opened the

possibility to make avermectin analogs from milbemycin & producing microorganisms. The avermectin and milbemycin [50] families find application as excellent parasiticides and insecticides in animal health, plant protection (Table 1) and, because of their activity

Synthesis of Natural Products for Plant Protection

J

(80%)

271

Swernoxidation

Bu,SnH toluene

,443

medium C ,

(53)

(92%)

(54)

Scheme 7. Microbial oxidation of milbemycins (52) [47, 481.

against filaria, they contribute to the wellbe- tribute important ideas to synthetic strategies ing of people with filarioses infections ("river and methodologies. They are focussed on synthesis, mimics and derivatives of antibiotics blindness") in the Third World. such as soraphen A (G. Hofle [51]), restricticidin (S. Jendrzejewski [52]), validamycins Additional Contributions (S. Ogawa [53]), P,y-unsaturated amino acids (R.Duthaler et al. [54]), on plant growth to Plant Protection regulators and herbicidal compounds like gibChemical synthesis and biotechnical processes berellic acid GA3 (Y. Yamada, L. N. Mander offer a broad variety of alternatives for the [55]), strigol (U. Berlage and 0.D. Dailey production of useful secondary metabolites. [56]), herbimycin A (M. Nakata [57]), anisoThis paper concentrates on a selection of mycin (I. Felner, R. Ballini [58]), on insectiimportant results within areas of potential cides and antifeedants like lepicidine A commercial application to plant protection. (D. A. Evans [59]), azadirachtin (S. V.Ley Other recent synthesis results relating to pest [ a ] ) , pyrrolomycin mimics (American Cyan[61]), nikkomycins (H. Zahner, control and regulators are impressive and con- amid

272

A . Synthetic Routes to Different Classes of Natural Products

W.A.Konig, A.G.M. Barret [62]), haedoxan (E. Taniguchi [63]), moncerin (K. Mori, M. Dillon [a]), philanthotoxins and andrimid (K. Nakanishi, A. V. R. Rao [65]), jasplakinolide (K. S. Chu [66]),allosamidin (A. Vasella, S. J. Danishefsky, S. Takahashi [67]), rocaglamid (R. J. K. Taylor, G. A. Kraus, B. M. Trost [68]) and the syntheses of numerous signal compounds, for example glycinoeclepin A (K. Mori 1691) and others. [70] A large number of effective metabolites must be isolated before synthetic work for production processes, biological development, toxicity and ecology studies with a selected active substance can be justified in industry, where the aim to reach a optimal cost/benefit/ecology ratio is given priority. In addition, studies of the mechanism of action of new natural products and regulators are important. Investigations with new inhibitors of plant, fungi and insecdparasite metabolisms give biochemistry enormous impulses. They may advance the knowledge in metabolic processes that are specific to pest organisms. Results could possibly be used for the biorational design of new pesticides. [71] Primarily, generous support of isolation work of natural products for agriculture in industry and academia and studies of their role in ecology are of the utmost importance for the advancement of pest related biosciences, of synthetic methodology, and to ultimately achieve greater market penetration with new nature-based plant protection methods that are safer, far less damaging to the environment than many chemicals currently in use, and that are well accepted by society.

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A . Synthetic Routes to Different Classes of Natural Products

chitra, Phytochemistry 1993,32, 67; EIshibashi, C.Satasook, M.B.Isman, G.H.N. Towers, Phytochemistry 1993, 32, 307; A.E. Davey, M. J.Schaeffer, R. J. K.Taylor, J. Chem. SOC. Perkin Trans.1 1992, 2657; B. M. Trost, P. D. Greespan, B. V. Yang, M.J.Saulnier, J. A m . Chem. SOC. 1990, 112, 9022; G.A.Kraus, J.O.Sy, . I . Org. Chem. 1989,54, 77.

[69] H.Watanabe, K.Mori, J. Chem. SOC. Perkin Trans.I 1991,2919. [70] K. Mori, Total Synthesis Natural Products, Vo1.9 (Ed. : J. ApSimon), Wiley, New York, m, pp. 1-521. [71] J. R. Finney in Pesticide Chemistry (Ed. : H. Frehse), VCH, Weinheim, 1990, pp. 555-576.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Penems: A New Generation of /?-LactamAntibiotics Gottfried Sedelmeier

Since the important class of plactam antibiotics was discovered by Fleming in 1929 (penicillin (I)),a large number of other very potent p lactam antibiotics have been found in nature, for example, cephalosporin (2) (1945), olivanic acids (3) [Id] (1976), and thienamycin (4) (1976). Other plactam antibiotics, such as monobactams, clavulanic acid, or nocardicins will not be discussed in this paper. For information on these substances the reader is referred to two articles [la] that have appeared in “Focus on Synthesis”, to the reviews cited in these articles, and to more recent studies. [ 1b-g] Imipenem (4a), a derivative of thienamycin (4), which was isolated from a microorganism by a group from MSD [2] is the only carbapenem currently available on the market. No thiapenem of type (5) has yet reached the market. Penems, which unlike carbapenems have a sulphur atom in their fivemembered ring, making them a “superimposition” of penicillin (1) and cephalosporin (2) to (6) [3], are synthetic products that have not yet been found to occur naturally. The 6a-[1(R)-hydroxyethyl] side chain has been shown to be crucially important in achieving maximum potency and a broad spectrum of activity, in the case of both carbapenems and thiapenems. Since it is not economical to produce thienamycin (4) - as opposed to (1) and (2) by biotechnology because its fermentation titer is too low, there has been a great challenge for many teams in industry and scientific

institutes to find economically and ecologically acceptable methods of synthesis for the very similar structures (4, (5),and (9).

Enantiomerically-PureCompound (EPC) Synthesis of a Common Intermediate Product Each approach is more or less aimed at the synthesis of a key intermediate of type (7), from which it should be possible to obtain (4), the synthetically produced pmethylcarbapenem (9) via (8), and type (5) penems. For industrial production, asymmetric synthesis of (7) (R = H, SiR’3; X = S0 2 R , 0-CO-R’) as an enantiomerically pure intermediate (EPC) [4] for a pharmaceutically active substance now requires synthetic techniques that take into account not just cost, but also environmental impact, in terms of process-integrated environmental protection, as well as by-products and degradation products (false diastereomers and enantiomers). The main problem with total synthesis of (4), (5), and (9), and so most importantly with (7), is controlling the relative and absolute stereochemistry of the three consecutive chiral centers and choosing a suitable and, if necessary, chiral starting material, at the most favorable cost possible.

278

A . Synthetic Routes to Different Classes of Natural Products

(4): R1 = H

7 y+k+

(9): R' = CH3

C,H,OCH,CONH

1 ('

0M

H

(7)

COOH

e

thienamycin (carbapenem) (4)

u-hydroxyethylpenem (5)

a olivanic acids (epi-thienamycine (3)

imipenem MK-787 (4a)

Scheme I , Several very potent @lactam antibiotics found in nature.

Of the three synthetic methods that might be used for this purpose (racemate separation, enantioselective conversion (stoichiometric or catalytic), and the "chiron approach") the latter [5] has been by far the most popular method with research groups (cf. Scheme 3).

Scheme2. Strategic bond formations that are (in principle) feasible in the synthesis of the chiral building block.

This article therefore only discusses those syntheses that used the chiral pool, although remarkable results were also achieved with other methods, for example chemoenzymatic synthesis with pig liver esterase (PLE) [6a] and baker's yeast. [6b] In planning the synthesis of the chiral penem building block (7), the various possible strategic bond formations shown in Scheme 2 were used: 0 plactam formation from a pamino acid derivative (formation of bond a); 0 cyclisation from nucleophile epoxide ring opening (bond b),

Penems: A New Generation of /%Lactam Antibiotics

279

Eaminopenicillanicacid (EAPA)

(F7)phydroxybutyric acid

-

L-threonine

\

o-glucose

butyric acid

o-glucosamine

L- aspartic acid

L-lactic acid

Scheme 3. Starting compounds for “chiron approach” syntheses of the chiral penem building block (7).

cyclisation of a Psubstituted amide (bond required absolute configuration at C-3 and C-1’, whereas the third stereocenter (C-4) is c) ; [2 + 21-cycloaddition of an isocyanate to an directed to the trans-position on the plactam ring. However, it must be pointed out that the alkene (c and d); necessary protecting-group technique, the use 0 [2+2]-cycloaddition of a ketene to an of mercaptans, and the relatively expensive imine (a and b); aldol addition of acetaldehyde or ethyl silyl reagents dicyclohexylcarbodiimide (DCC), Bu4NF, m-chlorperoxybenzoic acid (MCP ketone (e); functionalisation of a CH2-group to the BA), and cerium (1v)-ammonium nitrate, C m - g r o u p or transformation of a C-C tend to make these syntheses less economical and less ecologically acceptable. In addition, bond to a C-X bond (f). Some of the most important “chiron L-threonine is not one of the cheaper amino approach” syntheses shown in Scheme 3 are acids. [8] Variants of the “threonine sulphone routes” discussed below, selected on the basis of their are the “benzoate routes” of S. Hanessian [9] particular importance for the commercial synthesis of (7) or (8). The yields from individual and Ciba-Geigy [loa] are shown in Schemes 5 steps or total yields for each route were not a and 6. The same is true in respect of economy and criterion for selection because these cannot always be accurately ascertained (patents) and environmental impact for the threonine varialso depend on the stage of development of ants shown in Schemes 5 and 6 as for the sulfone routes. However, the benzoate route the method. (Scheme 5 ) uses the very cheap base K2C03in DMF for closing the plactam ring, whereas lithium-bis(trimethy1silyl)amide is employed Threonine Routes with the dibenzoate route. Whereas amide Starting with enantiomerically pure (2S,3R)- formation costs about the same (using either threonine there are several variations. [7, 9, mixed anhydride or acid chloride) for both 101 The threonine routes of Ciba-Geigy methods, removal of the nitrogen protecting (Scheme 4) [7b] and Sankyo [7a] have the group in the case of the dibenzoate route takes advantage that both threonine stereocenters place via selective enzymatic ester cleavage are converted without racemization to the followed by an “environmentally problemat-

280

A . Synthetic Routes to Different Classes of Natural Products

"

O/J-NH moperphthalic acid GYOAe, 18h

Scheme 5. Benzoate route of S. Hanessian [9].

ical" Jones oxidation. An interesting variation FEC 22101, FCE 22891, SCH 29482, and the of the Baeyer-Villiger oxidation has been SCH 34343 (see also Schemes 8 and 16). The reported more recently that avoids the use of advantage of the 6-APA route is that the /3organic peracids and does not require protec- lactam ring does not have to be constructed tion of the a-(R)-hydroxyethyl side chain. first. But the attraction of this route is slightly With this variant, =SO5 is employed under offset by the fact that the hydroxyethyl side chain, which in the case of penems has to be conditions of phase-transfer catalysis. [lob] added at C-6, is in a trans position to sulfur, which means that a series of often complex 6Aminopenicillanic Acid Routes transformations with relatively expensive reagents (e.g., AgCY1,8-diazobicyclo[5.4.0] Another educt for a chiron approach to the undec-7-ene (DBU) or ozone in CH2C12, synthesis of (7) is 6-aminopenicillanicacid (6- -75°C) are necessary to reconstruct and APA). These routes have been used in partic- extend the 6-APA skeleton. However, in the synthesis of FCE 22891, ular by Schering-Plough and Farmitalia to produce large quantities of various penem test [lc] a group from Farmitalia showed that it is preparations [lb, c] (Scheme 7), for example, not absolutely essential when using 6-APA as

Penems: A New Generation of PLactam Antibiotics

281

Jones oxidation

Scheme 6. Dibenzoate route of Ciba-Geigy [loa]. @r Y

1. HNO,, Br, 2. Me

C02H

so,,

0

K2h3

1. EtMgBr, THF

COzMe

2. MeCHO 3. crystallisation

6-APA

C02Me

-

1. fn. pH 6 2. TceCI. py

TceCl= C I , C G H , ~ O C I py = pyridine

4 2. KMnO, aq.

lC%OAC

Scheme 7. 6-APA routes of FarmitalidSchering-Plough[ll].

a starting material to proceed via an intermediate product of type (7), but that it is even possible to use primary structural components of the 6-APA five-membered ring to build the penem five-membered ring (Scheme 8). A group from Pfizer recently succeeded in improving the breakdown of the thiazoline ring and transformation to an intermediate of type (7) to make the procedure less expensive. [llc]

3-(R)-Hydroxybutyric Acid Routes Both enantiomers of 3-hydroxybutyric acid are suitable for the synthesis of (7). In order to produce the correct, absolute configuration by the enolate-imine approach [12] (Scheme 9) at C-3 of azetidinone, the (S)enantiomer [13] must be used, which means

282

A . Synthetic Routes to Different Classes of Natural Products

-.

1. MeMgBr, THF - 75 "C, then MeCHO

2. ZnlOHAc,

'

6-APA

CO2H

1. ZCI, imidazole

MeOH

C02CH20Ac

CO~CH~OAC

1. O,, CH,CI,

v O C O N H 2>-

- 75 "C,NaHSO,

2. P(OEI),,

MeCN. then H,NCO,CH,COCI

toluene 120 "C

COZCH~OAC

CO~CH~OAC

Scheme 8. FCE synthesis of FEC 22891 from 6-APA [1 C].

that the configuration at the stereocenter of the hydroxy ethyl side chain must be inverted by the Mitsunobu reaction in a later step of the synthesis. [14]

To circumvent this drawback it was necessary to look for syntheses using 3-(R)hydroxybutyric acid, which is also very inexpensive. The low-cost biopolymer PHB from ICI [15] is produced by the microorganism Alcaligenes eutrophus as an energy-storage material, glucose or molasses serving as nutrients. The price of PHB therefore depends on the world market price of glucose. The production costs of PHB should be around S 1000-1500 per ton for bulk production. [16] Methylester or ethylester obtained by depolymerisation and simultaneous esterification was used for the synthesis of (7). [17]

t-BuMe2Si

1. HC0,H. PPh,

C6H5 NC6H4-p-0CH3

(EmzCN='h 2.MeOH H+ 3. R,SiCI: imidazole

> 1. NaIO,

0.0,

Scheme 9. Enolate-imine approach of D. I. Hart, G. I. Georg et a].

Penems: A New Generation of PLactam Antibiotics

283

PHB biopol. from ICI

b(t?)hydroxybutyric acid ester

3) <, Pd/C

Synthesis of P-Lactam (7) via the Lactone Approach This method of synthesis (Scheme 10) is characterised by the use of simple transformations - with the exception of the first step (oxalic acid ester condensation at -60°C) and the last step (electrochemistry) - and the fact that no protecting groups are needed apart from persilylation (hexamethyldisilazane/trimethylchlorosilane) before Breckpot-Grignard cyclization to the plactam. [18] The correct absolute configuration at C-3/C-4 of the /3lactam is achieved by DBU-epimerization of the y-lactone to the thermodynamically most stable all-trans-diastereoisomer. The last step is a novel electrochemical decarboxylatiodacetoxylation reaction; [19a, b] this replaces the standard reaction used to date, the Pb(OAc),-reaction, which was environmentally critical. [20] Very good yields are obtained with this new electrochemical reaction. [21] (See Ref. [19b] for electrochemistry and polarography of (7) and of penems).

Enol Ether (Enol Ester)Chlorosulphonylisocyanate Cycloadditions Another method of synthesis, using optically pure (R)- or (S)-phydroxybutyric acid, is provided by the so-called enol ether and enol

(9:1)

LDA = lithium diisopropylamide DBU, cf. scheme 8

Scheme 10. Lactone approach of Ciba-Geigy [19]

ester/isocyanate cycloaddition (Scheme 11). The appropriate ester is reduced to aldehyde with DIBAL (at -70°C) after silylation at C-3. This is then transferred to silyl enol ether with trimethylchlorosilane by the Kanekafuchi route; [22] the Ciba-Geigy route [23] via silylated enol ester and cycloaddition of chlorosulfonylisocyanate (CSI) followed by reduction gives plactam. Whereas CSI-cycloaddition to silyl enol ether at -70°C gives a yield of 70 % , cycloaddition to enol ester gives a maximum yield of 17 % , which is unsatisfactory. The two low-temperature reactions (-70°C) with DIBAL and CSI and the relatively expensive reagents, tert-butyldimethylsilylchloride, DIBAL, and CSI in the case of the Kaneka route, are a disadvantage from the production point of view. Roche described a third route via thioenol ethedisocyanate cycloaddition. [24] Other enol ether/ isocyanate routes can be found in ref. [25]

284

A. Synthetic Routes to Different Classes of Natural Products

OH sH C O, , - ! ,

HyocoR' OR'

1) Csi I EbO - 20°C

HG OR' R' = SiRB

2) D I M

>

Ciba-Geigy route

DIBAL = diisobutyl aluminium hydride CSI chlomsulphonyl isocyanate

Scheme IZ. Enol ether (enol ester)-chlorosulphonylisocyanatecycloadditions (Kanegafuchi [22] and CibaGeigy [23]).

Kanekafuchi and Takasago are the only companies so far to offer the /%lactam building block (7) (R = rBuMe2Si, X = OAc) in bulk, but it is still very expensive. Sagami Ltd. has a new, very promising, enol ether/CSI-cycloaddition route that uses double chiral induction of (R)-hydroxybutyric acid and protected (S)-lactic acid aldehyde via a &-substituted 1,3-dioxene derivative with OH ACOOCH3

1) DlBALt Et

1) NaOH. then HCI

-

2 ) (S)-MeCH CHO/ PPTS

I

m

in CyCI,

HCOO

Scheme 22. Sagami route [26].

high diastereoselectivity (98:2). [26] Unfortunately, this method of synthesis also requires the two low-temperature reactions mentioned above for the Kaneka route, as well as some relatively expensive reagents. Furthermore, the chiral auxiliary (S)-benzyloxypropanal is destroyed by oxidation (RuC13,HI04), which means that it cannot be restored to the cycle (Scheme 12).

9

, 18°C

2 ) SOCl, I EI,N In

0

CyC&

PPTS pyridinium4-tduenesulphonate CSI = chlomsulphonylisocyanate MCPBA = mchloropebnzoic acid

CSI in toluene

Penems: A New Generation of PLactarn Antibiotics

The L-Aspartic Acid Route The cheap amino acid L-aspartic acid [8] was used by a group from Merck to synthesize (S)azetidinone carbonic acid. [30a, b] This approach (Scheme 13) allows the aconfigurated hydroxyethyl side chain to be introduced at C-3 with adequate diastereoselectivity. The two-step one-pot reaction (70-90% yield) of Bouffard and Salzmann, which uses a sterically hindered silyl ketone as an acetaldehyde equivalent, gives the desired trans-1'-(I?) -hydroxyethylazetidinonic acid (77 % isolated yield) [31] from (S)-azetidinone carboxylic acid, which can then be converted to (7) using the oxidative methods mentioned for the lactone approach (Scheme 10).

Routes via Other Molecules from the Chiral Pool Types of sugar, for example, D-glucose, [27] Dglucosamine, [28] and mannitol in the form of isopropylidene glycerol aldehyde, [29] have so

285

far been used, above all for synthesizing type (8) carbapenem building blocks. However, no industrial applications have been found for these approaches, presumably because they are lengthy and inefficient.

Synthesis and Biological Activity of Penems Various strategies have been developed synthesizing the five-membered ring system of penem and carbapenem active substances via the intermediate products (7) and (8), but these cannot be described in full here. In this context, therefore, only the frequently used Woodward route [3, 321 (intramolecular Wittig reaction with triphenylphosphine), substitution of acyloxy- or sulfonazetidinons of H XiH f!

NaSCOCH,NHCO,CH,-CH = CH, MeCN/H,O

0

>

X = 0-COR OH

),, ,

I

SCOCH~NHCOO-

J-NH

0

1. CICOC0,-CH,-CH = CH, 2. P(OEt&, toluene 110 "C

OR' 5COOH

si+

1) 2 LDA

2) MeCOSR3 then K-FBUOI 1-hOH

>

R' = C O C O O M

I

%'"Ai+ 0

HO _ . Pb(OAc),, EMF

1. MeOH, H,O

06 h H

I

LDA = LiN(CPr)z

Scheme 13. Aspartic acid route of Merck, Sharp and Dohme [30, 311.

NaHCO,

2. dimedone.

(l'PhJ4Pd. THF

>

OH

+

" f i ~ 2 N H 3

O

coo-

CGP 31608

Scheme 14. Synthesis of penem CGP 31608 by Ciba-Geigy.

286

A. Synthetic Routes to Different Classes of Natural Products

type (7) with thiocarbonic acids, [33] followed by intramolecular Wittig-Horner phospite cyclisation [34] are mentioned. The last method was used at Ciba-Geigy for pilot synthesis of CGP 31608 (Scheme 14).

-+OSiMe3 H ),.&H2C6H5 oH H

0

' 0

The interesting intramolecular Michael reaction described by Hanessian should also be mentioned here. Camed out under mild conditions, this base-catalyzed addition links the C-2/C-3 bond to the thiazoline ring via a nitroolefin. [9]

-

% H

NH 0

(7/

Y (4):R' = H ( 9 ) : R' = CH,

R.$i

0 C02CH,C,H,

COOH

-0 C02CH, - CH = CH,

Scheme 15. Syntheses of carbapenems via (7) or (8).

FCE 22101

FCE 22891

SUN 5555

SCH 34343

SCH 29482

CGP 31608

Scheme Z6. Selected clinical penem test preparations.

Penems: A New Generation of fi-Lactam Antibiotics

The silyl enol ether, [35] or more recently the boron enolate [36] and tin enolate, [37] routes (Scheme 15), have been used to obtain type (8) intermediate products, which are then used to synthesize carbapenems and @ methylcarbapenems. The main preclinical or clinical test preparations produced using the methods described in this article are shown in Scheme 16. SCH 34343, FCE 22101, CGP 31608, and HRE 664 are p a r e n t e d preparations, and SCH 29482, SUN 5555, and FCE 22891 are metabolisable prodrug esters that can be absorbed orally. A good comparison between in vitro and in vivo data on these preparations with respect to efficacy, pharmacokinetics, stability against /3lactamases, etc. can be found in refs. [38] and [1b, c] . Of the preparations in Figure 15, only CGP 31608 and imipenem are effective against the pyogenic microorganism Pseudornonas aeruginosa. An important advantage of penems over most penicillins and cephalosporins is their efficacy against a large number of anaerobic bacteria. [lb] Of the abovementioned preparations, CGP 31608 and SCH 29482 have already been withdrawn.

The new plactam generation consisting of penems and carbapenems, with their improved spectrum of activity and potentially lower dosage compared with cephalosporins, pose particular problems for development chemists in terms of both economy and environmental impact owing to their unusual @ lactam structure (three stereocenters). Technically feasible, inexpensive, ecologically acceptable, and stereoselective syntheses are therefore needed. The future of penems as broad-spectrum antibiotics able to compete in price with the new-generation cephalosporins, which are already very effective, depends to a large

287

extent on whether a synthesis is found - possibly via plactam building blocks of type (7) that is not too expensive.

References [l] a) D.Hoppe, Nachr. Chem. Tech. Lab. 1982, 30, 24 and 1979, 27, 127; b) S . W. McCombie. A. K. Ganguly, Med. Res. Rev. 1988, 8, 393; c) E.Perrone, Farmaco, Ed. Sci. 1988, 43, 1075; d) T. Nagahara, T. Kametani, Heterocycles 1987,25, 729; e) R.Labia, C.Morin, J . Antibiotics 1984, 37, 1103; f) W.Diirkheimer, J. Blumbach, R. Lattrell, K. H. Scheunemann, Angew. Chem. 1985,97, 183; Angew. Chem. Int. Ed. Engl. 1985, 24, 180; g) R.Kirstetter, W. Diirckheimer, Pharmazie 1989,44, 177. [2] a) B. G. Christensen et al., I. Am. Chem. SOC. 1978,100,6491; b) S. R. Norrby et al., Antimicrob. Agents Chemother. 1983,23,300. [3] R. B. Woodward in RecentAdvances in Chemistry of @Lactam Antibiotics, Spec. Publ. No. 28. (Ed. : J. Elks) Chemical Society, London, W77. [4] D. Seebach, E. Hungerbiihler in Modern Synthetic Methods 1980 (Ed. : R. Scheffold), Salle u. Sauerlander-Verlag, Frankfurt a. M. Aarau, 1980. [5] S. Hanessian in Total Synthesis of Natural Products: The Chiron Approach (Ed.: J. E. Baldwin), Pergamon Press, Oxford, 1983. a) M.Ohno et al., J . Am. Chem. SOC. 1981, 103, 2405 and Tetrahedron Lett. 1983, 24, 217; b) P. Schneider, G. Ramos, J. Bersier, CibaGeigy, E. P.A. 290385,26.4.1988. a) M.Shiozaki et al., Tetrahedron Lett. 1983, 24, 1037; 1981, 22, 5205; b) LEmest, J.Kalvoda, W.Froest1, E.P.A. 126709, 28.ll. 1984; c) M. Shiozaki, N. Ishida, T. Hiraoka, H. Maruyama, Bull. Chem. SOC. Jpn. 1984,57,2135, and references cited therein. B. Hoppe, J. Martens, Chem. unserer Zeit 1984,18,73. S.Hanessian et al., J. Am. Chem. SOC. 1985, 107, 1438. a) J. Kalvoda, I. Ernest, M. Biollaz, E. Hungerbiihler, E. P. A. 181831, 2l.5. 1986;E. P. A. 221846,13.5. 1987; b) M. Altamura, M. Ricci, Synth. Commun. 1988,18, 2129.

288

A . Synthetic Routes to Different Classes of Natural Products

[ll] a) M. Alpegiani, A.Bedeschi, F. Gudici, E.Perrone, G.Franceschi, J. Am. Chem. SOC. 1985,107, 6398; b) A.K.Ganguly et al., J. Antimicrob. Chemother. 1982, 9, Suppl.C, 1; c) G. J. Quallich et al., J. Org. Chem. 1990,55, 367. [12] D.-C.Ha, D.J.Hart, T.-K.Yang, J. Am. Chem. SOC. l984,106,4819; G.I. Georg, Tetrahedron Lett. 1984,25, 3779. [13] D. Seebach, M. A. Sutter, R. H. Weber, M.F.Zueger, Org. Synth. 1985,63, 1. [14] G.I.Georg, J.Kant, H.S.Gil1, J. Am. Chem. SOC. 1987,109, 1129. [15] a) ICI, Marlborough Biopolymers Ltd., Elta House, Yarm Road, GB-Stockton-on-Teese, Cleveland TS 18 3 W G r e a t Britain. Marlborough Biopolymers and Kanegafuchi Chem. Ind. Co. Ltd. also supply (R)-3-hydroxybuteric acid methylester in bulkquantities; b) B. Sonnleitner, E. Heinzle, G. Braunegg, R. M. Lafferty, Europ. J. Appl. Microbiol. Biotechnol. 1979, 7 , 1; see also P.A.Holmes, L. F. Wright, S. H. Collins, ICI, E. P. A. 52459, 26.5.1982.

[16] P.A.Holmes, Phys. Technol. 1985, 16, 32; N. Uttley, Manufacturing Chemist, October 1985, p.63. [17] D. Seebach, M. E Zueger, Helv. Chim. Acta 1982, 65, 495. [18] R. Breckpot, Bull. SOC. Chim. Belg. l923,32, 412. [19] a) G. Sedelmeier, J. Bersier, E. P.A. 279781, 24.8. 1988; b) P. M. Bersier, J. Bersier, G. Sedelmeier, E. Hungerbuhler, Electroanalysis, in print. [20] P. J. Reider, E. J. J. Grabowski, Tetrahedron Lett. l!)82,23, 2293; see also [14]. [21] M.Mori et al., Chem. Express 1989, 4, 89; M.Mori et al., Tetrahedron Lett. 1988, 29, 1409. [22] T. Ohashi, K. Kazunori, I. Soda, A. Miyama, K. Watanabe, E. P. A. 167154/167155, 8.1. 1986; E.P.A. 247378,2.12.1987.

[23] E.Hungerbiihler, E. P. A. 259268, 9.3.1988. [24] G. Schmid, E. P. A. 179318,30.4.1986. [25] Hungerbiihler, E.; Biollaz, M.; Ernest, I.; Kalvoda, J.; Lang, M.; Schneider, P.; Sedelmeier, G. in New Aspects of Organic Chemistry& Yoshida, Z.; Shiba, T., Ohshiro, Y., Eds.; VCH: Tokyo, 1989; p 419. [26] Y. Ito, Y. Kobayashi, S. Terashima, Tetrahedron Lett. 1989,30, 5631. [27] see Ref. l e ) and ref. 128-132 cited therein. [28] M. Miyashita, N. Chida, A. Yoshikoshi, J. Chem. SOC., Chem. Commun. 1982,1354. [29] H. Matsunaga, T. Sakamaki, H. Nagaoka, Y.Yamada, Tetrahedron Lett. l983,24, 3009. [30] a) T.N. Salzmann, R. W. Ratcliffe, B. G. Christensen, F.A.Bouffard, J. Am. Chem. SOC. 1980,102,6163, and E. P. A. 7973; b) R. Labia, C.Morin, Chem. Lett. 1984,1007. [31] F. A. Bouffard, T. N. Salzmann, Tetrahedron Lett. 1985,26, 6285. [32] R.B. Woodward et al., J. Am. Chem. SOC. W8,100, 8214. [33] M. Lang, P. Schneider, R. Scartazzini, W. Tosch, E.A.Konopka, O.Zak, J. Antibiot. 1987,40,217; Helv. Chim. Acta 1986,69, 1576; see also R. M. Cozens, M. Lang, Drugs Future 1988,13, 19. [34] A. Afonso, E Hon, J. Weinstein, A. K. Ganguly, J. Am. Chem. SOC. l982,104, 6138. [35] Y. Sugimura et al., Tetrahedron Lett. 1985, 26, 4739; A.G.M.Barrett, P.Quayle, J. Chem. SOC., Chem. Commun. 1981,1076. [36] L. M. Fuentes, I. Shinkai, T. N. Salzmann, J. Am. Chem. SOC. 1986, 108, 4675; T.Shibata, Y. Sugimura, J. Antibiot. 1989,42, 374. [37] Y.Nagao et al., J. Am. Chem. SOC. 1986,108, 4673; R.Dtziel, D. Favreau, Tetrahedron Lett. 1986,27, 5687; 1989,30, 1345. [38] O.Zak, M.Lang, R.Cozens, E.A.Konopka, H. Mett, P. Schneider, W.Tosch, R. Scartazzini, J. Clin. Pharmacol. 1988,28,128.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Synthesis of 0-Glycosides Herbert Waldmann

Carbohydrates play central roles in numerous biological processes. Therefore, the development of efficient methods for the construction of complex oligosaccharides is of increasing interest. [l,21 For the formation of a glycoside bond a leaving group X, which is attached to the anomeric center of the glycosyl donor A, must be activated to leave the molecule giving rise to the oxonium ion B. This intermediate is then attacked by a hydroxyl group of the glycosy1 acceptor C. For an extension of the carbohydrate chain in both directions the formed disaccharide D must fulfill two demands: (1)it must be deprotectable selectively at a single OH group and (2) it must carry a leaving

group Y that can be activated in a further glycosylation reaction without affecting the already formed glycoside bond. The KoenigsKnorr reaction and its numerous variants, have proven to be efficient methods for this purpose. [la, 2a] However, the glycosyl chlorides and -bromides (A : X = Cl, Br) employed in these transformations are often generated under harsh reaction conditions, they are sensitive to hydrolysis, and are frequently thermally unstable. Furthermore, in most cases expensive and often also toxic silver and mercury salts are needed for their activation. To overcome these disadvantages various leaving groups have been developed and, in particular, the trichloroacetimidates (A : X = 0-C(=NH)CCI,) introduced by Schmidt et al. [lb, 2a] proved to be a viable alternative to the classical techniques. Recently, further new and promising methods for the synthesis of 0-glycosides have been introduced.

pG-bpG-b promotor

X

B

A

Glycosyl Fluorides D X = e.g. CI. Br: promotor: Ag’, Hg” CCI3 : promotor: BF,. OEt,, TMSOTf X= 0

K NH

Glycosyl fluorides, which have already been known for some time, were considered to be too stable to function as glycosyl donors. However, Mukaiyama et al. demonstrated that they can be activated with the catalyst system SnCI2/AgC1O4and they synthesized, for example, the gluco disaccharide (4) in high

AcO

0

(7)

Ac

k?dsF

(7)

0

Btl

+

H

OMe

Piv

(3) R = TMS

P

Bzl

(2) R

PivO

Bzl

-

8 0 : 20

NEb W

OH

Z

z-y-w

R-TUS

SF*, CH&N

a :p

(10)

/

I.

J

*o*o l rB BtlO

-

Scheme 1. Activation of glycosyl fluorides with Lewis acids [3, 41.

F*lrB 6210

R=H SnCiJAgCIO,. ether - 15 “C

0

FJiV

(9)

0 Brl

-

(4)

NH

\

Bz‘

Brl

OMe

:: c

6

0

B

a

t02

Synthesis of 0-Glycosides

yield (Scheme 1). [3] Subsequently several groups studied the application of glycosyl fluorides and investigated the use of various Lewis acid promotors. Noyori et al. showed that (4) can also be obtained from the silyl ether (3) in the presence of gaseous SiF,. [4a] In this and further similar transformations the anomeric configuration of the fluoride (1) does not influence the product ratio, but in ether and acetonitrile complementary cdbselectivity is obtained (Scheme 1). Nicolaou et al. [4b] and Kunz et al. [4c] employed BF3. OEt,, which is a liquid and is, therefore,

1) IS,KIpyridine 2) y-Pd(OH), / C

291

easier to handle in the generation of the intermediary oxonium ions of type B. By this technique, for example, the serine glycoside (6) could be constructed stereospecifically from the pivaloyl-protected carboyhdrate (5). Thiem et al. [4d] reported that the use of the heterogeneous catalyst TiF, in acetonitrile is particularly advantageous. By means of this promotor, for example, the repeating core unit (10) of isohyaluronic acid could be synthesized. To this end, the diaccharide (9) was built up with complete B-selectivity and then transformed into (10) (Scheme 1). In particu-

(13): R = SPh, PG = BzI

3) &O/ pyridine

OR‘ 80 %

R’O

(15)

X (16) R’ = Ac, R‘ = Bz, R3 = Piv, R4 = TBDMS, X = N3

11

e

Bz = -C-C&,

(Gbal

0 R’ = R’ = R3 = R4 = H, X = NHK(CH2)&H3

Piv = (H$)$-C-

R

, TBDMS = SiMe2f Bu

Scheme 2. Synthesis of the globotriaosylceramideby means of glycosyl fluorides according to Nicolaou et al. PCI.

292

A . Synthetic Routes to Different Classes of Natural Products

lar, Nicolaou et al. [4b, 51 and Ogawa et al. [6] employed glycosyl fluorides for the construction of complex glycoconjugates. Thus, to synthesize the biologically relevant globotriaosyl ceramide (Gb,) the perbenzylated galactosyl fluoride (11) and the selectively deblocked acceptor (12) were condensed under Mukaiyama conditions with complete a-selectivity to give the trisaccharide (13) (Scheme 2). [5c] Next, the thioglycoside (13) was converted to the /?-fluoride (14)by treatment with NBS and the HF pyridine complex. [4b] After exchange of the benzyl protecting groups in the terminal galactose unit for acetates (+ (14)) activation of the fluoride with SnCl2/AgC1O4delivers the desired /?-glycoside (16) in 80 % yield. On the one hand, in this step the pivaloyl groups guarantee that only the Fanomer is formed and that competing orthoester formation is suppressed. [7a] On the other hand, the azidosubstituted sphingosine equivalent (15) is the complex alcohol of choice to achieve a high

0

p %

I

yield. [7b] Finally, conversion of the azide to the octadecylamide and the removal of all protecting groups completed the synthesis of Gb3. This glycosylation method also opened routes to the tumor associated Lex-glycosphingolipids [5d] and the complex oligosaccharide part of calicheamyciny,'. [5e] Suzuki et al. described that the hard Lewis acids Cp2XC12(X= Zr, Hf) are efficient promotors for the activation of glycosyl fluorides. [8] In combination with AgC104 these metallocenes rapidly induce glycosylation. They proved themselves, for instance, in the synthesis of the macrolide mycinomycine IV (Scheme 3). To this end the benzoylated mycinolide IV (17) is first coupled with the desosaminyl fluoride (18) to give the glycoside (19). The glycosylation of the second OH-group with 1fluoro-D-mycinose (20) in benzene proceeds with high /?-selectivity. Removal of the acyl protecting functions finally delivers the desired natural product (21).

INOH

0

RO

RO

(17) R = BZ

R' = C-OMe, R2 = Ac II

0

NEh.

(IS) R = Bz4R-

yo/MoH

I-[

R' = R2 = H

= H

OMe _

.

(21)

Scheme 3. Activation of glycosyl fluorides with Hf- and Zr-metallocenes according to K. Suzuki et al. [S].

Synthesis of 0-Glycosides

293

Thioglycosides

2. In subsequent developments Fugedi et at, [lla, b] Paulsen et al. [llc] and Lonn et al. Recently, thioglycosides have been applied in [lld] introduced dimethyl(methy1thio)sulfonumerous cases as glycosyl donors. After nium triflate (DMTST) (23) and the correinitial attempts of several groups to activate sponding tetrafluoroborate (DMTSB) as these thioacetals with thiophilic metal salts superior promotors. Methylsulfenyl bromide (carbohydrates were attached to the aglycon and triflate [12a, b] and phenylselenyl triflate by activation of thioglycosides as early as the [12c] are also advantageous. Furthermore, synthesis of erythromycin A by Woodward et NOBF,, [12d] SO2Cl2/HCF3SO,H[12e] and al.), Lonn [lo] achieved the decisive break- iodonium compounds [12f, g] have been used through. In the synthesis of the trisaccharide successfully for this purpose. In addition, thi(22), a complex hexasaccharide, and a nona- oglycosides can be activated by means of the saccharide the 1-ethylthioethers were alkyl- stable radical cation tris(Cbromopheny1) ated with methyl triflate to give sulfonium ammoniumyl hexachloroantimonate [ 13a] salts that were then attacked by the 0- (24) and electrochemically. [13b, c] Particunucleophiles (Scheme 4). The high stereocon- larly unreactive alcohols and even amides can trol over the anomeric center is guaranteed by be glycosylated if the phenylthioglycosides are the active neighbouring phthaloyl group at C- first converted to sulfoxides that are then acti-

-

NPht

MeO-SO,-CF, ether 72 %

H3c@oBzl OBzl 0

BZlO

NPht = -

N

D

0

0

X'

H3C-S-S-CH3 CH3 (23)

X = CF$03: DMTST

A c O G O A c AcO

f24)

+

OAc (26)

A

CF,SO,SMe,

(25)

N3

S

E

t

X

AcO

c

0

G

OAc

.

l

N3

SEt

DMTST 2-Ser-OM

(30)

87%, a:p = 5 . 3 : l

NHZ

(28)

Scheme 4. Activation of thioglycosides according to Lonn [lo], Fiigedi et al. [lla] and Paulsen et al. [llc].

294

A . Synthetic Routes to Different Classes of Natural Products

vated with trifluoromethanesulfonic acid anhydride. [13d] Finally, the use of anomeric xanthogenates together with the radical cation (24) [13a] and the glycosylation employing 2pyridyl-thioglycosides together with methyl iodide as promotor [14a] should be mentioned. These methods have been applied in a multitude of oligosaccharide syntheses. Two representative examples of the use of DMTST and phenylselenyl triflate involve construction of the glycopeptides (30) and (35). In a synthesis of the core T structure of the mucine 0glycoproteins Paulsen et al. [llc] first attached the peracetylated galactose (26) to the 2azidogalactose thioglycoside (25) (Scheme 4). In this reaction the thioether remained intact.

On treatment with DMTST the sulfonium intermediate (28) is formed, which reacts with 2-serine benzyl ester within one hour to give the glycoside (30) in high yield. If methyl triflate is used as promotor after seven days only 30% product is isolated. Kunz et al. [15a] employed the disaccharide thioglycoside (32) in a synthesis of the P-mannosylchitobiosyl core structure of N-glycoproteins. In the presence of phenylselenyl triflate (32) was coupled in 76% yield to the selectively deprotected glucosamine derivative (33) to give the pmannosyltrisaccharide (34), which was subsequently converted to the desired asparagine (35) (Scheme 5). In this route the installation of the P-configured mannosidic bond, which is F)

Aloc-NH-VH-COOf

BU

A ~AcO O &ACO~ ~ o & T ' o AcO

ACO OAc Aloc =

AcNH

NH

(35)

eol(

Pht = Phthaloyl

0

Scheme 5. Synthesis of the /3-mannosidic core unit of the N-glycoproteins according to Kunz et al. [15].

Synthesis of 0-Glycosides

regarded as being particularly difficult, [15c, d] was elegantly achieved by first building up the P-glucoside (31) and then inverting its configuration at C-2’ via intramolecular nucleophilic substitution (+ (32)) [15b] The use of thioglycosides is particularly advantageous in the chemistry of Nacetylneuraminic acid glycosides. [161 For instance, if the methylthioglycoside (36) is activated with DMTST, a-glycosides of this complex carbohydrate can be built up in high yield and with complete selectivity. [16b] This was demonstrated impressively in the synthesis of the a-(2-3)-linked galactoside (37), which can be obtained by other methods only with great difficulty. Overall, thioglycosides are valuable and advantageous reagents for 0-glycoside synthesis [9] that can be readily synthesized, are stable under a variety of reaction conditions, and that can be easily activated to become reactive glycosyl donors or, alternatively, be converted to glycosyl fluorides [4b] and -bromides. [9, 171

DLClST

HO

47 x V

Electrophile-initiated Cyclizations Glycosyl cations B can also be generated if the leaving group X participates in a cyclization. Fraser-Reid et al. [18,19] discovered this principle and developed the use of pentenyl glycosides to a method by which complex glycosides also become available. [18b, d] If such unsaturated alkyl glycosides, for example (38), are treated with I+-donors like iodonium di-sym-collidine perchlorate (39) or N iodosuccinimide/CF,SO,H [18c] in the presence of glycosylacceptors, for example, (41), via intermediate iodonium ions (e. g. (40)) 2iodomethyltetrahydrofuran (43) (with an enantiomeric excess up to 85 % [20]) and the desired saccharides (e. g. (42)) are formed (Scheme 6). If solvents containing ethers are used in the activation of glycosyl donors carrying alkyl protecting groups the a-anomers predominate, whereas in acetonitrile P-glycosides are formed in excess. If acyl substituents that are active as participating neighbouring groups are present, 1,2-fruns-glycosides are generated as expected. Of particular interest is the observation that in the coupling of (38) and (41) only (38) is activated: the selfcondensation of (41) does not occur. To explain this result the authors assume that ester groups at the 2-position of the carbohydrates reduce the nucleophilicity of anomeric oxygen atoms more than do ether groups. Therefore, 2-acyl substituted glycosyl donors are considered to be “disarmed” towards activation by electrophiles whereas 2-alkyl substituted donors are “armed”. Furthermore, in F the generation of a positive charge at the anomeric center is less favorable than in E. The validity of this rationalization is supported by the observation that “disarmed” pentenyl glycosides can be “armed”. Thus, if in (42) the acetates are replaced by benzyl ethers the monosaccharide unit that could not be activated in the construction of (42) functions as glycosyl donor so that the trisaccharide (44) is readily formed. The “armeddis-

*,,

HO

HO

295

ACO

o

w

II

o AcNH

(47)

a

J

QII

BZlO

(OH

(W

Bzlo OMe

J) (39)/

leoc-Ssr-Ua-Ot&l

+ BdO-

e

4sx

CHI%

0

TuSoTt

p

NPht 65%. only

BzlO BZlO

AcO

(44 62%. a:@ = 1:l

Ac

+

I

(49)

(43) ee 8 0 %

0 Scheme 6. Glycosylation via electrophile-initiated cyclizations according to Fraser-Reid et al. [18, 191, Kunz et al. [21a] and Peter et al. [21d].

TMSOTf = Me3SiO-S-CF3

k

(45)

T ~ O C= CISC-CHZ-0-C-

AcO

60% a$ = 1:l

BrlO

1) w

2) BzlBr. NaH

6

F E

0

a

Synthesis of 0-Glycosides

E

F

297

are being applied at the anomeric center of carbohydrates. For instance, Ley et al. [24] developed 1-imidazolylcarbonyl- and thiocarbonyl- mono- and disaccharides, for example (SO), which were generated from carbohydrates deprotected in the 1-position and carbonyldiimidazole or thiocarbonyldiimidazole . In the presence of ZnBr, or AgC104 as promotors they prove to be efficient glycosyl donors. [24a] This method was applied with great success in the total synthesis of avermectin B1, and allowed the coupling of the bisoleandrose disaccharide (50) and the aglycon (51) to be carried out in 80 % yield.

armed" concept does not only account for the reactivity of pentenyl glycosides. The concept can also be applied to different glycosyl donors (E and F: X = OR, SR; Br, OPent) and electrophiles [12f, 12g, 19b] (Eand F: E = H', I+, Me', Ag', Hal') and may, thus, prove to be a general principle. The generation of glycosyl cations by electrophile initiated cyclizations can also be realized with other glycosyl donors. Thus, Kunz et al. [21a] and Fraser-Reid et al. [21b] investigated the pentenoic acid ester as leaving group at the anomeric center and found that in the presence of glycosyl acceptors and various electrophiles, for example, iodonium compounds and the 1,3-dithianium salt (46), 1-pentenoates form iodolactones and glycoROH AgCIO,, K2W3 sides (Scheme 6). Similarly, anomeric allyic THF. toluene 80 % urethanes can be employed for the same purpose. [21c] Under the mild reaction conditions various protecting groups that are widely used in peptide and carbohydrate chemistry remain intact. Peter et al. [21b] reported that Nacetylglucosaminyl glycosides cannot be synACO thesized from n-pentenyl glycosides, but that Me0 4' 3'-epoxypentenyl glycosides are suitable a:@ = 4 : 1 glycosyl donors to reach this goal. By treatment of the epoxide (47) with TMS-triflate in the presence of the pyranose (48) the GlcNAc glycoside (49) could be synthesized in 49% yield. In addition to these methods a variety of new techniques for the formation of 0glycoside bonds has been developed. [2b] Among these the application of phosphoric acid derivatives and related glycosyl donors ROH [22] as well as heterocycles [23] as leaving groups appear to be particularly promising. Moreover, reagents that are used in peptide chemistry for the activation of carboxylic acids

I

-

OR

c

298

A . Synthetic Routes to Different Classes of Natural Products

[ll] a) P. Fiigedi, P. Garegg, Curbohydr. Res. 1986, 149, C9; b) E Andersson, P. Fiigedi, P. Garegg, M. Nashed, Tetrahedron Lett. 1986,27, 3919; c) a) H. Paulsen, Chem. SOC.Rev. 1984,13, 15; b) H. Paulsen, W. Rauwald, U. Weichert, Liebigs R. R. Schmidt, Angew. Chem. 1986, 98, 213; Ann. Chem. 1988,75, d) S. Nilsson, H. Lonn, Angew. Chem. Int. Ed. Engl. 1986,25, 212; c) T. Norberg, GlycoconjuguteJ. W , 6 , 21. H. Kunz, Angew. Chem. 1987,99,297; Angew. [12] a) F. Dasgupta, P. Garegg, Carbohydr. Res. Chem. Int. Ed. Engl. 1987,26, 294. 1988,177, C13; b) F. Dasgupta, P. Garegg, Cara) K. Krohn, Nuchr. Chem. Tech. Lab. 1987, bohydr. Res. 1990, 202, 225; c) Y. Ito, T. 35, 930; b) K. Toshima, K. Tatsuta, Chem. Rev. Ogawa, Carbohydr. Res. 1990,202, 165; d) V. 1993, 93, 1503. Pozsgay, H. Jennings, J. Am. Chem. SOC. 1987, T. Mukaiyama, Y. Murai, S. Shoda, Chem. 52, 4635; e) E. Kallin, H. Lonn, T. Norberg, Lett. 1981, 431. Glycoconjugate J. l988, 5, 3; f ) G. H. Veenea) S. Hashimoto, M. Hayashi, R. Noyori, Tetman, S. H. van Leeuwen, J. H. van Boom, Tetrahedron Lett. 1984, 25, 1379; b) K. C. Nicorahedron Lett. 1990, 31, 1331; g) P. Konradslaou, A. Chucholowski, R. E. Dolle, J. L. son, U. E. Udodong, B. Fraser-Reid, TetruhedRandall, J. Chem. SOC., Chem. Commun. ron Lett. 1990,31, 4313. 1984, 1155; K. C. Nicolaou, R. E. Dolle, D. P. [13] a) A. Marra, J.-M. Mallet, C. Amatore, P. Papahatjis, J. E. Randall, J. Am. Chem. SOC. Sinay, Synlett 1990, 572; b) C. Amatore, A. 1984,106, 4189; c) H. Kunz, W. Sager, Helv. Jutand, J.-M. Mallet, G. Meyer, P. Sinay, J. Chim. Actu 1985,68, 283; H, Kunz, H. WaldChem. SOC., Chem. Cornrnun. 1990,718; c) G. mann, J . Chem. SOC., Chem. Commun. 1985, Balavoine, A. Gref, J.-C. Fischer, A. Lubi638; d) M. Kreuzer, J. Thiem, Curbohydr. Res. neau, Tetrahedron Lett. 1990, 31, 5761 d) D. 1986,149, 347. Kahne, S. Walker, Y. Cheng, D. Van Engen, J. a) R. E. Dolie, K. C. Nicolaou, J . Am. Chem. Am. Chem. SOC. 1989,111, 6881. Soc. l!M, 107, 1695; b) K. C. Nicolaou, J. L. Randall, G. T. Furst, J. Am. Chem. SOC. 1985, [14] G. V. Redy, V. R. Kulkarni, H. B. Mereyala, Tetrahedron Lett. 1989,30, 4283. 107, 5556; c) K. C. Nicolaou, T. J. Caulfield, [15] a) W. Giinther, H. Kunz, Angew. Chem. 1990, H. Kataoka, Curbohydr.Res. 1991,202, 177; d) 102, 1068; Angew. Chem. Int. Ed. Engl. 1990, K. C. Nicolaou, T. J. Caulfield. H. Kataoka. 29, 1050; b) H. Kunz, W. Giinther, Angew. N. A. Stylianides, J. Am. Chem. SOC. 1990, Chem. 1988,100, 1118; Angew. Chem. Int. Ed. 112,3693; e) R. D. Groneberg,T. Miyazaki, N. Engl. 1988,27, 1086; For new methods for the A. Stylianides, T. J. Schulze, W. Stahl, E. P. synthesis of p-mannosidessee: c) F. Baresi, 0. Schreiner,T. Suzuki, Y. Iwabuchi, A. L. Smith, Hindsgaul, J. Am. Chem. SOC.1991,113, 9376; K. C. Nicolaou, J. Am. Chem. SOC.1993,115, Synlett 1992,759; d) G. Stork, H. Kim, J . Am. 7593. Chem. SOC.1992,114, 1087. [6] a) Y Takahashi, T. Ogawa, Curbohydr. Res. [16] a) T. Murase, H. Ishida, M. Kiso, A. Hase1987, 169, 127; b) Y. Nakahara, H. Ijima, S. gawa, Curbohydr. Res. 1988, 184, C1; b) Sibayama, T. Ogawa, Tetrahedron Lett. 1990, Review: K. Okamoto, T. Goto, Tetrahedron 31, 6897. 1990,46, 5835. [7] a) H. Kunz, A. Harreus, Liebigs Ann. Chem. [17] J. 0. Kihlberg, D. A. Leigh, D. R. Bundle, J. 1982, 41; b) P. Zimmermann, R. Bommer, T. Org. Chem. 1990,55, 2860. Bar, R. R. Schmidt, J. Curbohydr. Chem. 1988, [18] a) B. Fraser-Reid, P. Konradsson, D. R. Moo7, 435. too, U. Udodong, J. Chem. Soc. Chem. Com[8] T. Matsumo, H. Maeta, K. Suzuki, G. Tsuchimun. 1988,823; b) D. R. Mootoo, P. Konradshashi, Tetrahedron Lett. l988, 29, 3567, 3571, son, B. Fraser-Reid, J . Am. Chem. SOC. 1989, 3575. 111, 8540; c) P. Konradsson, D. R. Mootoo, R. [9] Short review: P. Fiigedi, P. Garegg, H. Liinn,T. E. McDevitt, B. Fraser-Reid, J . Chem. SOC., Norberg, Glycoconjugute J . 1987,4, 97. Chem. Commun. 1990,270; d) A. J. Ratcliffe, [lo] H. Lijnn, Carbophydr. Res. 1985,139, 105 and P. Konradsson, B. Frasser-Reid, J. Am. Chem. 115.

References

Synthesis of 0-Glycosides

SOC. 1990,112, 5665; e) Review: B. FraserReid, U. E. Udodong, Z. Wu, H. Ottosson, J. R. Merritt, C. S. Rao, C. Roberts, R, Madsen, Synlett 1992,927. [19] a) D. R. Mootoo, P. Konradsson, U. Udodong, B. Fraser-Reid, J. Am. Chem. SOC. 1988, 110, 5583; b) B. Fraser-Reid, Z. Wu, U. E. Udodong, H. Ottoson, J. Org. Chem. 1990,55, 6068. [20] J. M. Llera, J. C. Lopez and B. Fraser-Reid, J. Org. Chem. 199055,2997. [21] a) H. Kunz, P. Wernig, M. Schultz, Synlett 1990,631; b) J. C. Lopez, B. Fraser-Reid, J. Chem. SOC.,Chem. Commun. 1991, 159; c) H. Kunz, J. Zimmer, Tetrahedron Lett. 1993, 34,

299

2907; d) P.-C. Boldt, M. SchumacherWandersleb, M. Peter, Tetrahedron Lett. 1991, 32, 1413. [22] a) S. Hashimoto, T. Honda, S. Ikegami, J. Chem. SOC., Chem. Comun 1989, 685; b) T. Yamanoi, T. Inazu, Chem. Lett. 1990,849; c) S . Hashimoto, T. Honda, S. Ikegami, Chem. Pharm. Bull 1990,30, 775; d) T. J. Martin, R. R. Schmidt, Tetrahedron Lett. 1992, 33, 6123; e) M. M. Sim, H. Kondo, C.-H. Wong, J. Am. Chem. SOC.1993,115, 2260. [23] W. Broder, H. Kunz, Synlett 1990,251. [24] a) M. J. Ford, S. V. Ley, Synlett 1990, 255, b) M. J. Ford, J. G. Knight, S. V. Ley, S. Vile, Synlett 1990,331.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Carbacyclines: Stable Analogs of Prostacyclines Dieter Schinzer

After the discovery of the prostaglandins in the thirties [l]it took nearly another thirty years until the literature almost exploded and many papers appeared concerning their biolo-

ox

(3) PGH, (X = H)

PGD,

PGEz PGFZ

gical activity and approaches to synthesize these targets. This increase in activity can be explained by solution to the biosynthesis been found in the meantime. The key reaction in

302

A . Synthetic Routes to Different Classes of Natural Products

the biosynthesis is the physiological oxidation of arachidonic acid, the so-called arachidonic acid cascade (Scheme l),with its two enzyme systems. [2] The extraordinary interest in these molecules is explained by their high biological activity. A major drawback for potential medical uses is the high sensitivity to hydrolytic destruction under physiological conditions. Therefore, more stable acyclic molecules like leucotrienes were studied intensively. [3] A further group of related natural products are the prostacyclines because of their remarkable antihypertensive and inhibiting platelet aggregation properties. [4]

In order to overcome the hydrolytic instability analogs were required with potent physiological activity and promising therapeutic properties for treatment of cardiovascular and circulatory disease. Carbacycline, isocarbacycline and various carbacyclic analogs received particular attention as promising therapeutic agents. The following chapter will focus on efficient syntheses for the controlled construction of the bicyclo-octene framework and the regiodefined synthesis of the double bond. An entry to optically active isocarbacycline was published by Korozumi et al. [5] (Scheme 2), who used “N~yori-enone’~ (8) as starting material. [6]

Carbacyclines: Stable Analogs of Prostacyclines

303

Enone (8) was transformed in a short ive protodesilylation of an allylsilane were sequence using Shibasaki's method into the performed as the key steps (Scheme 3). [9] allylic alcohol (13). [7] The em-methylene The precursor (20) for the radical cyclizagroup was introduced by the Lombardo reac- tion was synthesized by the use of a tandem tion [8] to give compund (lo), followed by reaction with the optically active enone (8). hydroboration with 9-borabicyclo[3.3.1] Both functionalized side chains were intrononane to obtain diol (21). The latter was duced in a one-pot procedure. Ketone (16) oxidized under Swern conditions and directly was transformed into the em-methylene transformed by an intramolecular aldol reac- derivative, again by a Lombardo reaction. [8] tion to yield (12). Boronate reduction pro- Hydroboration followed by oxidation yielded vided allylic alcohol (13). Key reaction of the the sensitive aldehyde (18), which gave the asynthesis was a regioselective, direct alkyla- silylated alcohol (19) after addition of a silyl tion of (13) to give (14). cuprate. [lo] The OH-group in alcohol (19) Noyori et al. published a short and very effi- was transformed into a leaving group and phocient synthesis of isocarbacycline (1.5) in which tolyzed to give a ZIE-mixture of the desired a radical cyclization followed by a regioselect- allylsilane (21). Compound (21) was regiose-

304

A . Synthetic Routes to Different Classes of Natural Products

Ikegami et al. approached (33) by a metallectively protodesilylated to yield isocarbacycline (15) in optically active form. The regiose- catalyzed C-H-insertion to give bicyclo-octane lectivity of the endo-double bond was con- system (34) (Scheme 5). [12] The correctly placed ester group allowed trolled by the f3-effect of the silyl group. Nagao et al. described an asymmetric syn- regioselective construction of the lower side thesis of carbacycline using a novel chiral chain using a lead reagent. Finally, isocarbainduction by an asymmetric cleavage of a sym- cycline (15) was approached via ketone (37). metric cyclohexene diester (22) with thiophe- Sulfenylation of the kinetically controlled nolate (Scheme 4). [ll]The product mixture enolate, followed by oxidation, alkylation, was separated by chromatography to yield and reductive elimination, provided (15). In a series of papers Gais et al. published pure asymmetric diester (23). Compound (25) was transformed by con- strategies to synthesize regiodefined the exoventional procedures (Dieckmann condensa- or endo-cyclic double bond. [13-151 Dilithiotion) into (26). After protecting group mani- sulfones were used in a stereoselective cycpulation and oxidative cleavage of the double loalkylation with functionalized cyclopentanes bond a second ester condensation was used to (40) (Scheme 6). construct the bicyclo-octane framework. The The subsequent cuprate addition yielded exocyclic double bond with the functionalized the em-cyclic fragment as a mixture of diasteside chain was introduced by a non-selective reomers (E:Z = 2:1), which is similar to that Wittig reaction to obtain compound (31) as a of other methods used. Considerable progress was achieved with transition metal-catalyzed ZIE-mixture of diastereomers.

(30) Scheme 4

Carbacylines: Stable Analogs of Prostacyclines

305

bf MeCN

(33)

N2

:>

6

d

OSi-t-BuMe, Si-t-BuMe2

(40)

OSi-t-BuMe2

Si- t-BuMe2 (42)

R = CH(Me)OEt

Scheme 6

coupling of optically active sulfoximines (44) (Scheme 7). [14] The starting materials required were obtained by an asymmetric elimination (43) +-(44). The latter was further transformed in

excellent selectivity (99: 1) with the catalyst system MgBr2/NiCI2/Ph2P (CH2)3PPh2and the zinc reagent shown in the scheme into the carbacycline derivative.

A. Synthetic Routes to Different Classes of Natural Products

306

~

~

-

t

-

B

u

P

h

2 1.MN

6 OSi-t-BuMe2 Si-t-BuMez

Scheme 7

(45)

q l J O H

~

2Wg-SH

'2

THPO

8

nip0

OTHP

____, 1. BM. Pyr

2. CISit-BuM.2 DMF

____, KOH. M.OH

1.

2.

M8u

OTHP (47)

(46)

Finally, Gais described an entry - similar to Noyori's approach - to isocarbacyclines by a radical-initiated 5-exo-dig-cyclization. [16] The allylester (50) reacted with a cuprate to the isocarbacycline precursor (51). The -CH2--OH group in the 5-membered ring will be needed later to attach the lower side chain. Gais has developed a microbiological reaction for the asymmetric construction of the 5membered ring (46). [17] The lower side chain was introduced by standard procedures and some protecting group manipulations. The configuration at C-15 was controlled by the use of Yamamoto's reagent (9:l). [18] The epimeric allylic alcohols can be separated by chromotography and (+)-isocarbacycline (15) was isolated after hydrolysis of the methyl ester (Scheme 8). [16] The Schering group used the commercially available Corey lactone (52) as the key intermediate. After reaction with lithiated acetic ester and some additional maneuvers a retroMichael and subsequent Michael addition yielded the desired bicyclo octane (55). The problem of the stereoselective construction of the exocyclic double bond was solved by the

M

&, ,O H

4" 4""' H,

Mezt-BuSiO &, ,

8 THPO

OTHP

A

Me2t-BuSi0 @, , ,

(49)

'2

mpo

(48)

OTHP

Y

A,,.\

" O Q H 1. Nol, AIBN. HSnBu3

2TBK

3. 4 0

&-$

THPO

OTHP

(50)

Carbacyclines: Stable Analogs of Prostacyclines

use of optically active phosphine ligands in the Wittig reaction (Scheme 9). In addition, a microbiological process has been developed by the same group. [4a] The last synthesis in particular has demonstrated that industrial laboratories are using organometallic reactions and newly developed methods to synthesize physiological important molecules by efficient routes. The different strategies to construct the bicyclo-octane framework and the methods to solve the selectivity problems in the endo- or

i( -WSf E" COOEt

1. Silylation 2. LiCHpOOEt 3. TsOH

9

8

4. K,CO,. CH,OH 5.Cr0,. 2 Py

O H& ,

6COPh

Corey-Lacton

2) NoBH,

(5.7)

(54)

>-8 steps s 6CQPh Carbacycline keycoupound (56)

Scheme 9

6H

OH (57)

307

exocyclic double bond were presented with priority. The construction of the lower side chain is almost a routine operation.

References [l] M. W. Goldblatt, Chem. Ind. (London) 1933, 52, 1056. [2] S. M. F. Lai, P. W. Manley, Nut. Prod. Reports l984,1, 409. [3] B. Samuelsson, P. Borgeat, S. Hammarstrom, R. C. Murphy, Adv. Prostaglandine Thromboxane Res. 1980, 6, 1. [4] W. Bartmann, G. Beck, Angew. Chem. 1982, 94, 767. Angew. Chem. Int. Ed. Engl. 1982,21, 751. [4a] W. Skuballa, M. Schafer, Nachr. Chem. Tech. Lab. 1989,37, 584. [5] K. Bannai, T. Tanaka, N. Okamura, A. Hazato, S. Sugiura, K. Manabe, K. Tomimori, S. Kurozumi, Tetrahedron Lett. 1986,27, 6353. [6] R. Noyori, M. Suzuki,Angew. Chem. l984,96, 854. [7] T. Mase, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. W , 2 5 , 5087. [8] L. Lombardo, Org. Synth. 1987,65, 81. [9] M. Suzuki, H. Koyano, R. Noyori, J. Org. Chem. 1987,52, 5583. [lo] I. Fleming, N. K. Terret, J. Organomet. Chem. m, 99, 264. [ll] Y. Nagao, T. Nakamura, M. Ochiai, K. Fuji, E. Fujita, J. Chem. SOC. Chern. Commun. 1987, 267. [12] S. Hashimoto, T. Shinoda, S. Ikegami, J. Chem. SOC. Chem. Commun. 1988,1137. [13] H.-J. Gais, W. A. Ball, J. Bund, Tetrahedron Lett. 1988,29, 781. [14] I. Erdelmeier, H.-J. Gais, J. Am. chem. SOC. 1989,111, 1125. [15] H. Hemmerle, H.-J. Gais, Angew. Chem. 1989, 101, 362. Angew. Chem. Int. Ed. Engl. 1989,28,349. [16] G. Stork, R. Mock, Jr., J. Am. Chem. Soc. 1983,105, 3720. [17] H. Hemmerle, H.-J. Gais, Tetrahedron Lett. 1987,30, 3471. [18] S. Iguchi, H. Nakai, M. Hayashi, H. Yamamoto, K. Maaruoka, Bull Chem. SOC. Japan. 1981,54, 3033.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Synthesis of Mitomycins Herbert Waldmann

Mitomycin A ( I ) , mitomycin C (2) and porfiMiiomycin C romycin (3) are the most important represen(2) tatives of the mitomycins [l] a class of antibiotics found in streptomyces species, which are active against gram positive and gram negative bacteria as well as mycobacteria. Of particular interest is the pronounced activity of mitomycin C (2) against a broad variety of tumors, which renders it one of the most efficient drugs in the clinical chemotherapy of cancer. The cell-destroying activity of mitomycin C is most probably initiated by reductive activation of its quinone subunit. In the course of this reaction an intermediate quinone methide is formed, which then reacts with the amino groups of two deoxyguanidins (+ (5), thereby crosslinking the DNA double strands (4). [2] Due to their clinical importance and their unusual structure the mitomycins have been the subject of numerous synthetic stud- and the aziridine structures present, as well as ies. However, all these endeavors were com- the facile elimination of the methoxy groups plicated by the high reactivity of the quinone at C-9a, so that hitherto only two successful total syntheses could be reported. The first route to (1)- (3)was developed by Kishi et al. [3] (Scheme 1). The synthesis Q starts with the conversion of the ally1 phenyl ether (6) to the alcohol (7) by Claisen rearrangement, epoxidation of the double bond and opening of the oxirane with the anion of 0 s acetonitrile. After oxidation of the alcohol to = H Mitomycin A 1): R' OCH,. the corresponding ketone a crossed aldol reac2): R' = NH2. R2 = H Mitomycin C tion with formaldehyde was carried out, resulting in an intermediate that was con3): R' N H ~ ,R2 C H Porfiromycin ~

-

-

-

4) D I M , 0 %

1 ) M&I.

N&

2) NoH. DMF

AcO

1) Me 0,pyridine 2) Ph~H,-NH,, 150 "C

3) PH-CH,-BI

(75) 1) COCl~PhN(CH& 2) NHJCH,CI,-ioluene/O

"C

3) NaOCH,. CH,OH 4) DMSO, DCCITFA-pyridine

5) HCIO,IPhN(CH,),

R

according to Kishi et al. [3].

>

Synthesis of Mitornycins

verted to the dimethylacetal (8) by means of established methods. Next, Kishi et al. introduced a double bond by phenylselenation, oxidation of the selenide and elimination. Then the nitrile was transformed into the acetylated alcohol (9), which was converted to a mixture of two diastereomeric diols by cishydroxylation with Os04. After chromatographic separation the desired isomer (10) was converted to the aziridine (14) in ten steps. In the course of this synthetic sequence the regioselective methylation of the less hindered OH-group in (10) paved the way to the stereoselective ring closure to the oxirane (11) and its subsequent regioselective opening to the diol (12) via attack of azide at the more accessible carbon atom. Next, both alcohols were mesylated and the primary mesylate was displaced to give the amine (13). On treatment with trimethylphosphite, the azido function in (13) was converted to an amino group, which then attacked the neighbouring carbon atom to the desired aziridine (14). To finish the synthesis of the mitornycins successfully, the aziridine nitrogen had to be protected by a blocking group, which could finally be removed without destruction of the product. The use of acyl functions did not meet this demand, whereas the introduction of the 3-acetoxypropyl group, which can be removed by oxidatiodretro Michael addition, turned out to be the method of choice. After hydrogenolytic cleavage of the benzyl ethers and subsequent oxidation of the aromatic ring to the quinone, conjugate addition of the liberated amino group to the a, @-unsaturated system occurred immediately resulting in formation of the 8-membered quinone (15). On careful treatment with HBF4 this compound underwent a transannular cyclization to give the mitomycin A congener (16), which was formed as a single stereoisomer. The O H group was transformed to the urethane and finally the N-protecting group was removed to liberate mitomycin A (1). On treatment with ammonia [4], this compound can be converted

311

to mitomycin C (2), which delivers porfiromycin (3) on N-methylation with methyl iodide. [4] Overall, the synthetic sequence developed by Kishi et al. includes ca. 40 individual operations and, therefore, does not seem to offer straightforward access to mitomycin analogs with modified physiological activity. A much more practical route to the mitomycins was reported by Fukuyama et al. [5a, b] (Scheme 2). As the central intermediate in this synthesis the chalcone (18) is employed, which was constructed in 13 steps, with an overall yield of 64%, from 2,6-dimethoxytoluene (17). [5c] Compound (18) is then coupled to the silyloxy-substituted furan (19) to give the silylenol ether (20) which, on heating in toluene, undergoes an azide-olefin cycloaddition resulting in the formation of the aziridine (21). This lactone is then reduced to the acetal and the double bond degraded with R u 0 4 to the aldehyde with simultaneous oxidation of the thioether to the corresponding sulfone. After reduction of the carbonyl group and acylation of the alcohol formed thereby to the activated urethane (23), subsequent treatment with ammonia in methanol and NaBH, initiates a reaction cascade that passes throuth the aldehyde (24) and then finally terminates in the formation of the bridgehead semiaminal (25). On treatment with acid in methanol (25) is transformed to the methyl ether (OH -+ OMe), which is then deprotected in the hydroquinone part and oxidized to the quinone (26) (= isomitomycin A ) . Finally, isomitomycin A was treated with ammonia in methanol. In the course of the occurring reaction sequence isomitomycin C (27) is first formed, from which the desired mitomycin C is generated by intramolecular conjugate addition of the pyrrolidine nitrogen to give (28) and a subsequent retro-Michael reaction resulting in the cleavage of the C-N bond to the aziridine nitrogen. By means of this “mitomycin rearrangement” [6] (26) can also be converted to mitomycin A. Although this total synthesis also requires numerous chemical

312

A. Synthetic Routes to Different Classes of Natural Products

13steps

Me0 SnClc CHp.32

64 %

overall yield

-7et

OMe

toluene + 110°C

Me

OMe

1. DIBAH. THF. - 78 "C

Me0

1) NaBH4 5 1 1

Me

Me

* 1) H+.

OAc

2) ci$2-fi-Nco

0

cn30n

2) HdPd-C

3)

NC

CN

1

- 78%

1

l3OoC

CHzOCONHz

Me

H

0 (1)

Me

CH20CONH2

0 (21

Scheme 2. Synthesis of the mitomycins (1)-(3) according to Fukuyama et al. [ 5 ] .

transformations overall it proceeds with high efficiency and makes mitomycin C available from 2,6-dimethoxytoluene with an overall yield of 10 % . Rappoport et al. [7a] succeeded in the construction of a non-racemic aziridinomitosene

(37) (Scheme 3). The key steps in the route followed are the addition of the aziridinopyrrolidine (32) to the dibromoquinone (33) and a Pd-mediated cyclization resulting in the formation of the complete carbon framework. To form (32) in enantiomerically pure form

Synthesis of Mitornycins

313

on

(34)

(36)

(35)

(37)

Scheme 3. Synthesis of the enantiornerically pure aziridinomitosene (37) according to Rappoport et al. [7a, b].

the D-vinylglycine ester (29) (obtained from D- chemical oxidationheduction. [7b] After reoxmethionine) was converted to the aziridine idation of (35) to the quinone (36) the plan(30) by a sequence of reactions that included nedring closure to the enantiomerically pure an epoxidation and suitable inter- and intra- aziridinomitosene (37) can be effected by molecular nucleophilic substitutions. Homo- employing a Pd-mediated cyclization. The logisation of (30) to the Fketo ester (31), fol- absolute configuration at C-1 and C-2 of (37) lowed by selective reduction of the a i d e and is opposite to the structure of the naturally subsequent cyclization, delivers an unsatur- occurring mitomycins, however, starting from ated aziridinopyrrolidine, which is reduced L-methionine, this synthetic route of course with NaCNBH, to the nitrogen base (32). In would make the respective enantiomer availthe following steps (32) is condensed with the able. In addition to the syntheses highlighted, the dibromoquinone (33) to the vinylogous amide (34) which, on irradiation with light, is con- chemistry of the mitomycins has provided a verted to the hydroquinone (35) in a photo- rich and rewarding source of interesting prob-

314

A . Synthetic Routes to Different Classes of Natural Products

lems for numerous research groups. [1,8-101 However, the unusual structure and the pronounced reactivity of these antitumor antibiotics continue to present challenges that by no means are easily met.

References Review: R. W. Franck, Fortschr. Chem. Org. Naturst. 1979,38, 1. a) M. Tomasz, R. Lipman, D. Chowdary, J. Pawlak, G. L. Verdinge, K. Nakanishi, Science 1987,235, 1204; b) J. T. Millard, M. F. Weidner, S. Raucher, P. B. Hopkins, J. Am. Chem. SOC. 1990,112, 3637; c) H. Kohn,Y. P. Hong, J. Am. Chem. SOC. 1990,112, 4596; d) V. Li, H. Kohn, J . Am. Chem. SOC.1991,113, 275-238. a) E Nakatsubo, T. Fukuyama, A. J. Cocuzzo, Y. Kishi, J. Am. Chem. SOC. 19R,99, 8115; b) T. Fukuyama, E Nakatsubo, A. J. Cocuzzo, Y. Kishi, Tetrahedron Lett. 19R, 49, 4295. J. S. Webb, D. B. Cosulich, J. H. Mowat, J. B. Patrick, R. W. Broschard, W. E. Meyer, R. P. Williams, C. E Wolf, W. Fulmor, C. Pidachs, J. E. Lancaster, J. Am. Chem. SOC. 1962, 84, 3185. a) T. Fukuyama, L. Yang, J. Am. Chem. SOC. 1989, 111, 8303; b) T. Fukuyama, L. Yang, J. Am. Chem. SOC. 1987, 109, 7881; c) T. Fukuyama, L. Yang, Tetrahedron Lett. 1986,6299.

[61 Y. Arai and S. Ishii, J. Am. Chem. Soc. 1987, 109, 7224[71 a) K. J . S h W J . R- LUlY, H. RaPPoPofi, J . Org. Chem. 1985, 50, 4515; b) J. R . Luly, H. Rappoport, J. Am. Chem. SOC. 1983, 105, 2859. [8] Aziridinomitosenes and -mitosanes: a) S. Danishefsky, E. M. Bermann, M. Ciufolini, S. J. Etheredge, B. S. Segmuller, J. Am. Chem. SOC. 1985,107, 3891; b) S. J. Danishefsky, M. Egbertson, J. Am. Chem. SOC.1986,108, 4648; c) S. Nakajima, K. Yoshida, M. Mori, Y. Ban, M. Shibasaki, J. Chem. SOC. Chem. Commun. 1990,468. [9] Mitosenes: a) P. A. Wender, C. B. Cooper, Tetrahedron Lett. 1987,49, 6125; b) S. Nakatsuka, 0.Asano, T. Goto, Chem. Lett. 1987, 1225; c) J. Rebek, Jr., S. H. Shaber, Y. Shue, J. Gehret, S. Zimmerman, J. Org. Chem. 1984,49, 5164; d) R. M. Coates, P. A. MacManus, J. Org. Chem. 1982,47, 4822. [lo] a) A. P. Kozikowski, B. J. Mugrage, J. Chem. SOC.,Chem. Commun. l988,, 198; b) W. Verboom, E. 0. M. Oremans, H. J. Berga, M. W. Scheltinga, D. N. Reinhoudt, Tetrahedron, 1986,42, 5053; c) Y. Naruta, N. Agai, T. Yokota K. Maruyama, Chem. Lett. 1986,1185; d) W. Hitsch, P. RuBkamp, Liebigs Ann. Chem., 1985, 1398 and 1422; e) W. Flitsch, P. RUBkamp, W. Langer, Liebigs Ann. Chem., 1985, 1413; f) T. Kametani, T. Ohsawa, M. Ihara, J. Chem. SOC. Perkin Trans. I, 1981,290; g) K. F. McClure, J. W. Benbow, S. J. Danishefsky, G. K. Schulte, J. Am. Chem. SOC. 1991, ll3,8185.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Syntheses of Ergot Alkaloids Thomas Brumby

Ergot alkaloids are pharmacologically important molecules, the most widely known of which is the diethylamide of lysergic acid (LSD). They owe their interesting properties to interaction with the receptors of the neurotransmitters noradrenaline, dopamine and serotonin. The interest of the medicinal chemist is attracted by the fact that selectivity for these receptors can be influenced markedly by structural variation. Thus, it is not surprising that many groups deal with total synthesis as well as variation of ergot alkaloids. The synthesis of lysergic acid was reviewed in this column five years ago [l]. Since then two new total syntheses have been published [2,31. Kurihara et al. [2] started with Kornfeld’s ketone (2) (Scheme l),which was treated with diethyl phosphorocyanidate (DEPC) to yield phosphorylated cyanohydrin (2). Boron trifluoride diethyl etherate catalysed elimination then gave unsaturated nitrile (3). This sequence is generally applicable to aromatic ketones [4]. DiBAH reduction with subsequent benzoylation gave aldehyde (4), which has been used in previous syntheses. The reaction with the enolate of Boc-protected ethyl 3-(methy1amino)propionate (5) to (6) completed the C-frame of lysergic acid. The following steps were carried out without isolation of intermediates: Mesylation and cleavage of the Boc-group gave (7). Unfortunately, the Boc-group was not inert in the mesylation

step: 30 YOof the material is lost as oxazinone (8). The diene (9), generated by treatment of (7) with DBU, cyclized in situ. The isomerisation in position 8 under the basic reaction conditions was expected and (20) was accordingly obtained as mixture of diastereomers. The overall yield from ( I ) was 22 YO nevertheless. The conversion to racemic lysergic acid (22) is known. The second synthesis, which allows 14substitutents to be incorporated [5] follows an unusually interesting strategy [3] (Scheme 2). Haefliger generates the indole-system by his own method at the end of the synthesis, thus avoiding many problems usually associated with the presence of the reactive aromatic system. The synthesis commenced with construction of the D-ring from 5-nitro-tetralone (22) in one step. This reaction was developed by Grob and Renk [6] for ergoline synthesis and allows easy incorporation of 14-substituents into the ergoline via 6-substituted tetralones. Reduction of enamine (13) with sodium cyanoborohydride gave trans-compound (14) in 53 Yo yield; 20 % is lost as the unwanted cisisomer. Catalytic hydrogenation of the nitrogroup, formylation of the resulting amine with formylimidazole and dehydration with phosphorus oxychloride/diisopropylethylamine gave isonitrile (1.5) in excellent yield. LDAtreatment generates a benzyl anion which reacts with the isonitrile to form the indole ring. As in the former synthesis the basic con-

A . Synthetic Routes to Different Classes of Natural Products

316

$CO2Et

N-BOC

+

1. W I / M

2. 1.2NHCI

d 8 Bz‘

(6) I

NH*HCI

2COZEt

,,,t

+

ez’

BZ’

(7)

mc-(8)

& CO2Et

_j

CO$t

y H $ = d

BZ‘

H’

mc-(lO)

mc-(l1)

8u:w-1:2 54%

Bz =

BOC

P’h

&A

MS = -SO+

Scheme 1. Synthesis of racemic lysergic acid by T. Kurihara et al. [2].

Syntheses of Ergot Alkaloids

-

rac (15)

roc-(77)

317

roc-( 16)

rac-( 18)

Scheme 2. Synthesis of racemic dihydro lysergic acid derivatives by W. E. Haefliger [3].

ditions cause equilibration in position 8 and a 1:1 mixture of the 8aL3P-dihydrolysergates (16) (R = Me) is obtained. If one wants to give up the ester functionality (which cannot be regenerated after indol formation) it is possible to reduce (14) and take the THPprotected alcohol through the following reactions. The 14-methoxy-derivatives (17) and (IS) were synthesised in overall yields of 11 and 14 % , respectively; in the case of (18)pure 8P-diastereomer was obtained. An atypical ergot alkaloid is clavicipiticacid (19), the structure of which was determined by X-ray analysis in 1980. [7] Since then the total synthesis and the biosynthesis of clavicipitic acid have interested several groups. [8-131 Some Cluviceps-strains produce clavicipitic acid as a diastereomeric mixture (at C-10 [14]), the &-isomer being predominant. It is believed that a derailment of the normal metabolism after the prenylation of trypto-

phan leads to (19). Ring closure does not take place as in the normal biosynthesis of ergolines between C-10 und C-5, but between C-10 and N-6. The published syntheses of (19) also rely on this strategy. Matsumoto et al. [12] started with 4-cyanomethylindole (20) (Scheme 3). Alkylation with methallyl tosylate gave (21), which was subjected to aerobic oxidation after deprotonation with potassium tert-butoxide. This reaction gave a mixture of ketones (22) and (23). Subsequent deprotection of the indole by basic hydrolysis afforded only conjugated ketone (24), the deconjugated double bond isomerised completely under the reaction conditions. Functionalisation of position 3 by Mannich reaction and condensation with diethyl N-formylamidomalonate gave (26) , which contains all necessary carbon atoms for ring closure. The critical step was the removal of the N-formyl group with consecutive

A. Synthetic Routes to Different Classes of Natural Products

318

(29)

-

roc (30)

(19)

Scheme 3. Synthesis of clavicipitic acid by M. Matsumoto et al. [12].

___, Ts

(3 1)

H

Ts

(32)

______) 2. H2NCH(C02Y.)2/

n-&P

(33)

(34) (35) Scheme 4. Synthesis of clavicipitic acid derivative (35) by D. A. Boyles and D. E. Nichols [13].

Syntheses of Ergot Alkaloids

formation of Schiff base (27). Usually conjugated addition of primary amines to a$unsaturated ketones is observed. In this case, however, only 1,Zaddition was seen, the formation of a nine-membered ring probably being disfavored for steric reasons. The only isolated byproduct (28) is likely formed via a retro aldol reaction. The selective reduction of the imine is possible with catecholborane in

,.ti + .

good yield. Saponification of (29) and decarboxylation completed the synthesis of racemic clavicipitic acid as a cisltrans mixture. To characterise (19), it was converted to the cis-Nacetyl methyl ester (30). The isomerisation of trans-(19) in this reaction was also found by other authors. [8, 91

JO H

H

H

H

(44)

319

(35)

Scheme 5. Synthesis of clavicipitic acid derivative (35) by A. P. Kozikowski and M. Okita [lo].

320

A . Synthetic Routes to Different Classes of Natural Products

This somewhat lengthy sequence can be clised. The cyclization of an analogue of diol shortened considerably, as demonstrated by (37) , another possible precursor of (19) was Boyles and Nichols [13] (Scheme 4). Grignard done in the synthesis of Kozikowski et al. [lo] reaction of 2-methyl-1-propenylmagnesi- (Scheme 5). Protected diol (38), which was um bromide with formylindole (31) gave the synthesized in several steps from 4-ethinylhydroxylated prenylindole-derivative (32). indole, was treated with dimethyl aminomaThe protecting group was removed quantitati- lonateltri-n-butylphosphine. Subsequent revely with sodium amalgam in buffered solu- moval of the silyl group with tetrabutylammotion. The side chain was introduced as in the nium fluoride (TBAF) gave (39), the analog previous synthesis. However, the formyl pro- to (37). Cyclization under Mitsunobu conditecting group proved unnecessary - the Man- tions is highly stereoselective: in addition to nich compound directly condensed with dime- 85% of E-allylalcohol (41), only 3 % Z thy1 aminomalonate and tri-n-butylphosphine isomer (42) was obtained. Probable interto give (34). The final cyclisation with p - mediate in this reaction is compound (40). toluenesulfonic acid in acetonitrile afforded Subjecting model diol (43) to Mitsunobu con(35) in 48 % , the overall yield over five steps ditions, the 31P-resonance of the postulated cyclic phosphorane was observed. The interamounted to an excellent 26 % ! In this reaction an analogue of the postu- mediacy of (40) could be an explanation for lated biosynthetic intermediate (36) was cy- the high stereoselectivity. The sterically less

I

TS (5 1 )

H

-

mc (30)

Scheme 6. Synthesis of racemic N-acetyl clavicipitic acid methyl ester (30) by L. S. Hegedus et al. [ll].

Syntheses of Ergot Alkaloids

demanding of the two possible syn-S~2: transition states leads to the observed product. The formal synthesis was completed by conversion of (41) to the phenyl sulfide (44) and desulfurisation with Raney nickel in DMSO. The last synthesis of clavicipitic acid by Hegedus et al. [ll]reviewed here is remarkable in the consistent use of palladium catalyzed reactions. Bromo-iodo-indole (46) was made available by the authors through an efficient 7 step synthesis in 62% overall yield from 2-bromo-6nitro-toluene (45). Only three palladium catalyzed steps are then necessary to assemble the frame of clavicipitic acid. The first step is the Heck reaction of methyl a-acetamidoacrylate (47) with (46). Only 2-isomer (48) is formed in 60% yield along with 20% deiodinated indole, which can be recycled to (46).The side chain in position 4 is introduced similarly by palladium catalyzed reaction with 2-methyl-3buten-2-01 in 89 % yield. The final cyclization of (49) to (51) is camed out with palladium dichloride in acetonitrile in 95 'YO. However, similar yields can be realised with p toluenesulfonic acid. The originally planned cyclization of saturated compound (SO),which was obtained by homogeneous hydrogenation in 98 YOusing Wilkinson's catalyst, to (30), succeeded neither under acid or basic conditions nor under transition metal catalysis. The authors explain the easy cyclization of (49) by the favorable positioning of the amide function by the 2-geometry of the acetamidoacrylate side chain. The known [9] photoreduction of (51) with simultaneous removal of the tosyl protection group was optimized to give 60 YO pure cis-isomer (30). The overall yield of this elegant 12-step synthesis is 18% ,starting from (45).

321

References

[lo] [11] [12] [13] [14]

J. Mulzer, Nachr. Chem. Tech. Lab. 1984, 32, 721. T. Kurihara, T. Terada, S. Harusawa, R. Yoneda, Chem. Pharm. Bull. B87,35, 4793. W. E. Haefliger, Helv. Chim. Acta 1984, 67, 1942. T. Kurihara, Y. Hamada, T. Shioiri, S. Harusawa, R. Yoneda, Tetrahedron Lett. 1984, 25, 427. Syntheses of 14-substituted lysergic acid derivatives from natural ergolines are not known to date. C. A . Grob, E. Renk, Helv. Chim. Acta 1961, 44, 1531. J. E. Robbers, H. Otsuka, H. G. Floss, E. V. Arnold, J. Clardy, J. Org. Chem. 19&0, 45, 1117. A. P. Kozikowski, M. Greco, Heterocycles PXZ,19, 2269 and J. Org. Chem. 1984, 49, 2310. H. Muratake, T. Takahashi, M. Natsume, Heterocycles l983,20. 1963. A. P. Kozikowski, M. Okita Tetrahedron Lett. 1985,26, 4043. P. J. Harrington, L. S. Hegedus, K. F. McDaniel, J. Am. Chem. SOC. 1987,109,4335. M. Matsumoto, H. Kobayashi, N. Watanabe, Heterocycles 1987,26, 1197. D . A. Boyles, D. E. Nichols, J. Org. Chem. 1988,53, 5128. Stereochemistryat C-5 was not experimentally determined but postulated from investigation of the biosynthesis [7].

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Enantioselective Synthesis of Piperidine Alkaloids Peter Harnmann

Alkaloids represent a large group of plantand animal compounds with a wide variety of activity. The discovery of alkaloids in the last century led to a great surge of interest in natural product chemistry. Alkaloids are not only important pharmacological products, they are also interesting models for the design of new drugs. In addition, as a result of their specific affinity for receptors, they possess great importance for biochemical investigations. Piperidines and pyrrolidines are integral components of countless alkaloids; construction of these fragments is thus frequently a central step in the synthesis of alkaloids. Moreover, simple substituted piperidines and pyrrolidines are often biologically active. Example of piperidines include the pseudodistamines A and B from Pseudodistoma kanoko (cytotoxic), [11 derivatives of desoxyfuconojirimicin (antiviral agent against HIV viruses), [2] the synthetic etoxadrol (phencyclidine agonist), [3] and the 2- or 2,6-substituted compounds (neurotoxic, insecticidal) [4] derived from coniin, pinidine, or solenopsine. In the following account, exemplary examples of piperidine synthesis, which have been developed between 1983 and 1989, will be presented which, in slightly modified form, could also be used for the synthesis of the pyrrolidines. The main objective of the synthesis of piperidine alkaloids directed towards the investigation of their biological activities is the preparation of enantiomerically pure com-

pounds in high yield whereby with modern synthetic concepts both enantiomers should be synthesized, so that these can be individually examined. If the construction of a stereocenter is predictable, then the absolute configuration of a natural product can be clarified by a total synthesis. In particular when X-ray structure analysis cannot be used, because of a lack of suitable crystals of a natural product isolated in only trace amounts, synthesis is obviously the only way to complete the structure determination. To obtain both enantiomers separately, both enantiomers of a chiral reagent, of a chiral building block, or a chiral auxiliary are usually required for an asymmetric synthesis. In many cases one of the two enantiomers is either not available from natural sources or is extremely expensive. An alternative is therefore the selective formation of both enantiomers starting from a single enantiomeric, chiral building block. Stereocontrolled reactions can be performed, for example, by substrate control. In this case an achiral reagent will be converted with a chiral substrate into diasteromers, whereby the chirality is already present in the substrate or can be introduced by connection to a chiral auxilliary. L-Lysine, which is also the starting product for the biosynthesis of several of these compounds, is an ideal chiral substrate for the synthesis of piperidine alkaloids. An efficient method for the cyclization

324

A. Synthetic Routes to Different Classes of Natural Products

/

/c." #w I C02Me

( 1 1)

mlw*

A\\' #OHI

Me (-)Nmethylpseudoconhydrin (12)

Scheme 1. Synthesis of (+)- and (-)-N-methylpseudoconhydrin from L-lysine after Shono.

Enantioselective Synthesis of Piperidine Alkaloids

of L-lysine to the piperidine skeleton involves electrochemical anodic oxidation of Na,NEbis(methoxycarbony1)-L-lysine methyl ester ( I ) (Scheme 1). [5] The intermediate openchain E-N,0-acetal undergoes cyclization to the chiral, cyclic N,0-acetal (2) with retention of the stereocenter of L-lysine. The intermediate (2) is a valuable building block for the synthesis of a multitude of alkaloids. [6, 71 Thus, for example, a propyl group can be introduced diastereoselectively into (3) under the control of the methoxycarbonyl group in the 6position by amidoalkylation [S, 91 of (2) with TiCldallylsilane via a reactive acyl-iminium ion and subsequent hydrogenation. After hydrolysis of the ester the N , 0-hemiacetal (5) is formed from (4) by anodic oxidation and hydrolysis. The reaction probably takes place by way of an anodic decarboxylation and subsequent elimination to give an enamine, which can be anodically diacetoxylated diastereoselectively under the influence of the propyl group. Subsequent reduction of (5) with NaBH, to (6) and then LiAlH, led to the natural (+)-(2S, 5s)-N-methylpseudoconhydrin (7).

The synthesis of the (-)-enantiomer (12) starts with anodic diacetoxylation of (2) to (8). The stereochemistry is controlled by the center at C-6. After reduction and hydrolysis to (9) compound (10) is obtained by anodic decarboxylation. Amidoalkylation with allyltrimethylsilane/TiCl,, hydrogenation, and acetylation gave ( I I ) , which was converted into the unnatural enantiomer (-)(2R,5R))-Nmethylpseudocon-hydrin (12).

325

The strategy for the synthesis of both enantiomers of pinidine (24) and (28) according to Kibayashi is based on the construction of a new stereocenter by diastereoselective hydride addition to a chiral a,/?-bis[(methoxymethyl)oxy]ketone with subsequent cleavage of the original chirality-inducing group. [lo] The starting material is L-tartaric acid diethyl ester (13), [ll] which is converted into the chiral ketone (20) via compounds (14-19) (Scheme 2). [12] Reduction with zinc borohydride gave almost exclusively the antidiastereomer (26) in good yield. Formation of the anti-compound can be explained by acoordination of the zinc atom in the transition state (25), in which the nucleophile attacks the re-side of the carbonyl group (1,2-asymmetric induction). The preference of the a- over the /?-chelate formation can probably be traced to a "crown ether" effect, through which a stable coordination structure is formed from the carbony1 oxygen and the MOM groups with the zinc as central atom. On the other hand, reduction with L-selectride leads predominantly to the syn-diastereomer (22) (91:9). The course of this reaction can be understood either via an open-chain transition state (21a) (Anh-Felkin model) or via P-chelate formation (1,3-asymmetric induction) (21b). As trialkyl borohydrides show only a weak inclination to coordination, as a result of their low Lewis acidity, it is assumed that the reaction takes place via the transitiion state (2Ia) and that the syn-selectivity is only additionally strengthened via P-chelate formation in (21b). Compound (27), which can be converted over six further steps into the natural (-)-(2R ,6R)pinidine (28), can be obtained from (26) with phthalimide under Mitsunobu conditions. The exact reaction sequence from (27) starts with the hydrazinolysis of the phthalimide protecting group and subsequent benzylation of the amino group to give (29) (Scheme 3). Wacker reaction to ketone (30) and hydrogenation gave, after cleavage of the benzyl protecting group and subsequent reductive amination,

326

A . Synthetic Routes to Different Classes of Natural Products

1

1

1

\1

LAH

(tjpinidine (24)

(-)pinidine

(28)

Scheme 2. Synthesis of (+)- and (-)-pinidine from L-diethyl tartrate after Kibayashi.

-

Enantioselective Synthesis of Piperidine Alkaloids

(27)

1)

NWY

21 PhCMBr 81 %

Bn, ,Bn

(29)

WCI, / CuCI, / Oz

"OM

(33)

327

S

Scheme 3. Conversion of the key compound (27) into (-)-pinidine (28).

piperidine (31). Thus, the asymmetric center energy calculations. Regioselective and diasat C-2 controls the diastereomeric course of teroselective reactions are possible, continhydrogenation of the intermediate ketimine. gent on the a-aminonitrile and the aAfter tosylation at the nitrogen atom and aminoether groups on the one hand and on removal of the protecting group to give (32), the chiral auxiliary on the other. If (37) is both original chiral centers in the side chain treated with propylmagnesium bromide in the were converted via the cyclic thiocarbonate presence of AgBF,, the a-aminonitrile group (33) to a trans-double bond. Subsequent reacts regioselectively. As the intermediate cleavage of the nitrogen protecting group gave iminimum ion (38) allows only axial attack of (-)-pinidhe (28). (+)-(2S,6S)-Pinidine (24) is the nucleophile under stereoelectronic conobtained in analogous fashion from (22). trol, the reaction runs strictly diastereoselecAlthough the starting material in this synthe- tively to (39). Reduction of the a-aminoether sis is cheap, the number of steps is relatively group with NaBH, to (40) and cleavage of the high and the eventual moderate overall substituents on the piperidine nitrogen atom yield is only about 2%. In the meantime a gave (-)-(R)-coniin (41). widely used method (CN(RS) method) for the Nue preparation of 2- and 2,6-substituted piperiI dines has been developed by Husson, [13] that, by way of a further cyclization, is also very suitable for the synthesis of indolizidineand quinolizidine alkaloids. [14] The key compound is a chiral2-cyano-6-oxazolopiperidine (37), the synthesis of which was achieved by The position 2 in (37) can, however, also be Robinson-Schopf condensation of glutardialdehyde (35) with the chiral auxiliary electrophilically alkylated after preceeding (+)-norephedrin (34) in the presence of KCN carbanion formation. Reaction with propyl (Scheme 4). The (2S,6R)-configuration was bromide gave (42), which was reduced to (44) determined by NMR measurements and with NaBH, (Scheme 4). As an iminium ion

328

A . Synthetic Routes to DifferentClasses of Natural Products

Scheme 4. Synthesis of (+)- and (-)-coniin using (+)-norephedrin (34) as chiral auxiliary, according to Hus-

son (CN(RS) method).

Enantioselective Synthesis of Piperidine Alkaloids

transition state (43) is also involved here and the nucleophilic hydride anion attacks at the axial side, one obtains at C-2 in (44) the inverted configuration to that in (39). Simultaneously, the a-aminoether group is cleaved under these reaction conditions to give (45). Removal of the substituents at the piperidine nitrogen atom gave (+)-(S)-coniin (46). The potential of this strategy lies in the possibility to attack the electrophilic 6-position regio- and stereoselectively with similar ease

329

and thus to form 2,6-disubstituted piperidines (Scheme 5). If (47), the condensation product from glutaraldehyde (35), (-)-phenylglycinol, and KCN, is alkylated at C-2 to give (48) and subsequently reduced diastereoselectively with AgBFJZnBH., to (49), nucleophilic attack of the Grignard compound at C-6 of the a-aminoether group leads stereoselectively to the cis-product (50). Hydrogenation gave (+)-(2S,6R)-dihydropinidine (51). Alkylation of (47) with methyl bromide gave (52) and

1

70 % AgBF, / B(BH,),

(49)

i

Pd /I$/ HCI

H

(i)-(2S, 6R)dihydropinidine (51)

H

H

(-)(2R, 6S)dihydropinidine (55)

Scheme 5. Synthesis of (+)- and (-)-dihydropinidine with (-)-norephedrin as chiral auxiliary (Husson CN(RS) method).

330

A . Synthetic Routes to Different Classes of Natural Products

subsequent catalytic reduction gave (53). Grignard reaction to (54) and hydrogenation led to the (-)-(2R,6S)-dihydropinidine (55). One recognizes the variability of this method from the number of alkaloids that have been pi synthesized by Husson hitherto. 1141 NeverH theless, the chiral auxiliary cannot be recovered. The use of 0-acyl-glycosylamines as chiral under catalysis by zinc chloride into (60) auxiliaries in the Strecker- and Ugi syntheses (Scheme 6 ) . The high diastereoselectivity of a-amino acids has been demonstrated (97.5:2.5) is of particular significance in that impressively by Kunz. [lS]This strategy has hitherto only a few examples of stereoselecbeen extended to the preparation of piperi- tive Mannich reactions have been described. dines. [16] The conversion of 2,3,4,6-tetra- As delocalization of the C=N-n-electrons into 0-pivaloyl-a-D-galactopyranosylamine (56) the u* orbital of the ring C-0 bond exists, a with butanal gave Schiff base (57). The latter conformation is preferred in (57) in which the could be converted via a stereoselective C-0 bond of the ring is oriented almost tandem Mannich-Michael reaction with orthogonally to the plane of the double bond. 1-methoxy-3-trimethylsilyloxybutadiene (58) The Lewis acid, zinc chloride coordinates with

PiVO

4

piv&

PivO

(W

H2

CH

Piv&

1.

w/-20 oc

Pvo PNO

(57)

H

\

(Stconiin

(46)

Scheme 6. Synthesis of (S)-coniin with an 0-acetyl-protected glycosylamine as chiral auxiliary (after Kunz).

Enantioselective Synthesis of Piperidine Alkaloids

the nitrogen and the carbonyl oxygen of the 2pivaloyl group. The initial step in the Mannich reaction is release of the latent nucleophile of the silyl dienol ether (58). As the required interaction between the chloride ligands on the zinc with the silyl group takes place in front of the plane of the C=N double bond, the (S)-diastereomer (59) is formed, which subsequently undergoes cyclization to the piperidone (60). (S)-Coniin (46) is obtained after reduction of the double bond with L-Selectride to give (61), conversion of the piperidone via the dithiolane, Raney nickel reduction to piperidine (62), and removal of the carbohydrate residue. The cleaved carbohydrate (63) (yield 90 %) can be reconverted to the starting auxiliary (56). Using this synthetic sequence one obtains, starting from (56) and pyridine carbaldehyde (64), the natural (S)-anabasin (68), which possesses the opposite stereochemistry at C-2 to that of (S)-coniin (46) (Scheme 7). Two equivalents of zinc chloride are required, however, for the diastereoselective Mannich reaction. The first equivalent coordinates with the pyridine nitrogen, whilst the second equivalent is responsible for activation of the aldimine bond. The activation of the silyl dienol ether (58) probably results from the Lewis acid at the pyridine nitrogen, whereby attack from the free rear side to give (66) is possible.

331

?\; I--------

P

0

I

H

This hypothesis would explain why the Mannich reaction takes place with the opposite stereochemistry. In analogous fashion to that described for (S)-coniin (46), the compound (66) is converted to (S)-anabasin (68) via (67). In contrast to the results of Husson, Kunz managed to recover the chiral auxiliary. Nevertheless, only one enantiomer is accessible with this route. Of course, stereocontrolled reactions can also be carried out under reagent control, not only under substrate control, as just discussed. In this manner, one obtains enantiomers by reaction of prochiral substrates with chiral reagents. Thus, Tanne [17] used the Sharpless epoxidation with (-)-tartaric acid diethyl ester as the key step in the synthesis of (+)-nitramhe (74) (Scheme 8). Although hitherto only the synthesis of the natural (+)-nitramhe (74) has been reported, in principle synthesis of the unnatural enantiomer

Scheme 7. Synthesis of (S)-anabasine using the Kunz method.

(Skanabasin

. .

(68)

332

A . Synthetic Routes to Different Classes of Natural Products

TS

4 (ID%

"'OH

'"OH

(74

(73)

(+)-nitramine

(74)

Scheme 8. Preparation of (+)-nitramhe according to Tanne, using Sharpless epoxidation as the key step.

could also be considered by the use of (+)diethyl tartrate. Starting from 1-cyclohexene methanol (69) two chiral centers are introduced to (70) under Sharpless conditions with (-)-tartaric acid diethyl ester. The optical purity was determined by 'H NMR measurements with the use of chiral shift reagents as 90-94 '70 ee. Exchange of the hydroxyl group for an amino group to (72) was achieved via the triflate of (70) and reaction with the sulfonamide (71). The latter can be prepared from acrolein according to Pinnick. [18] The spirocyclization by nucleophilic attack of the carbanion formed from attack of butyl lithium on the oxirane gave (73) which can be further converted into (+)-nitramhe (74) with an optical purity of 93 % . The product is diastereomerically but not enantiomerically pure,

tie

which represents a problem for the pharmacological evaluation. Carbohydrates offer themselves as chiral building blocks for an economic synthesis of polyhydroxylated piperidines. In terms of a potential therapy for AIDS, one is currently primarily interested in derivatives of the natural glycosidase inhibitors and less in the unnatural enantiomers. Chiral pool syntheses, starting from carbohydrates, offers the advantage, of starting with the corresponding number of correctly configured chiral centers. The synthetic problem in this case is not the formation of new stereogenic centers, rather more to guarantee regioselective reactions at the hydroxyl groups using appropriate protecting groups. This was nevertheless hitherto possible only in isolated cases with minimal effort.

t'

2 NaNI 8SX

=

1. Pd&

2. CF+XOH

07x

O

X

0

40 83%

H ,O ,Jy

OH H

deoxy-fuconojirimycine

Scheme 9. Chiral pool synthesis of desoxyfuconojirimycin,after Fleet.

(79)

Enantioselective Synthesis of Piperidine Alkaloids

333

The synthesis of desoxyfuconojirimycin (79) azido-2-hydroxypropanal (81) or (84) to (82) by Fleet [19] can be regarded as an example or (85), respectively (Scheme 10). It is not (Scheme 9). Starting from lyxonolactone even necessary to use the pure enantiomers (75) [20] the 2,3-O-isopropylidene-~-lyxono(81) or (84), as the exclusively formed enantilactone (76) is obtained by ketalization with omerically pure diastereomers (82) or (85), acetone. Formation of the azidolactone (77) respectively, can be separated easily. Effenvia the triflate and addition of methyl lithium berger used rabbit muscle aldolase, whereas gave the hemiketal (78). Subsequent hydro- Wong employed a recombinant bacterial genation led to reduction of the azide and fin- aldolase. Hydrogenation of (82) gave (+)-1ally to intramolecular reductive amination. desoxynojirimycin (83) exclusively, and (-)-1Compound (79) was obtained after removal of desoxynojirimycin (86) was formed exclusthe protecting groups. A very elegant route to ively from (85). If the N-protected 3the synthesis of polyhydroxylated piperidines aminopropanal (87) is converted enzymaticwas described first by Effenberger [21] and a ally with (80), one obtains (88), which is conlittle later by Wong. [22] First, a suitable car- verted to fagomin (89) by hydrogenation. bohydrate precursor is constructed with an Similarly, amine (91) is formed from (80) and asymmetric synthesis. The asymmetric induc- 3-(N-butyl)-2-hydroxypropanal (90). Comtion is carried out enzymatically. Both groups pound (91) can be hydrogenated to N-butyl-lused the aldolase-catalyzed aldol addition of desoxynojirimycin (92), [22] which is active dihydroxyacetone phosphate (80) with 3- against the AIDS virus. Nevertheless, in the

aldolase

dbz

&I

H (89)

(88) 1. He&O aldolase

OH (9 1 )

6H

OH

1 Bu (92)

Scheme 10. Synthesis of polyhydroxylated piperidines after Wong and Effenberger with an enzymatic Aldol reaction as the key step.

334

A . Synthetic Routes to Different Classes of Natural Products

long term a synthesis of the corresponding enantiomers will also be required for this series of compounds. The unnatural (-)nojirimycin has proven itself to be a potent inhibitor of Pglucosidases and a-mannosidases. [23] With the methods described herein even complex alkaloids that contain a piperidine or pyrrolidine structure can be prepared enantioselectively. Most advanced here are the investigations of Husson with the CN(RS) method. As adequate amounts of these compounds for biological investigations are now available through synthesis, interesting impulses could be expected for pharmacological research.

[6] K. Irie, K. Aoe, T. Tanaka, S. Saito, J. Chem. SOC. Chem. Commun. 1985,633. [7] T. Shono, Y. Matsumura, K. Tsubata, K. Uchida, J. Org. Chem. 1986,51, 2590. [8] T. Shono, Y. Matsumura, 0. Onornura, M. Sato, J. Org. Chem. 1988,53, 4118. 191 H.-U. ReiBig, Nachr. Chem. Tech. Lab. 1986, 34, 656. [lo] N. Yamazaki, C. Kibayashi, J. Am. Chem. SOC. l989,111, 1396. [ll] H. Iida, N. Yamazaki, C.Kibayashi, J. Org. Chem. 1986,51, 1069. [12] H. Iida, N. Yamazaki, C. Kibayashi, J. Org. Chem. 1986,51, 4245. [13] L. Guemer, J. Royer, D. S. Grierson, H.-P. Husson, J. Am. Chem. SOC. 1983,105, 7754. [14] S . Arsenyadis, P. Q. Huang, H.-P. Husson, Tetrahedron Lett. 1988,29, 1391. [15] H. Kunz, W. Sager, Angew. Chem. 1987, 99, 595; Angew. Chem. Int. Ed. Engl. 1987, 26, 557. References [16] H. Kunz, W. Pfrengle, Angew. Chem. 1989, 101, 1041; Angew. Chem. lnt. Ed. Engl. 1989, [l] M. Ishibashi, Y. Ohizumi, T. Sasaki, H. Naka28, 1067. rnura, Y. Hirata, J. Kobayashi, J. Org. Chem. [17] D. Tanne, H. M. He, Tetrahedron 1989, 45, l987,52, 450. 4309. [2] G. W. Fleet, A. Karpas, R. A. Dwek, L. E. 181 Y. H. Chang und H. W. Pinnick, J. Org. Chem. Fellows, A. S. Tyms, S. Petursson, S. K. Nam1978,43, 373. goong, N. R. Ramsden, P. W. Smith, J. C. Son, 191 G. W. Fleet, S. Peturson, A. L. Campbell, R. F. Wilson, D. R. Witty, G. S. Jacob, T. W. A. Mueller, J. R. Behling, K. A. Bablak, J. S. Rademacher, FEBS Lett. 1988, 237, 128; see Ng und M. G. Scaros, J. Chem. SOC. Perkin also V. A. Johnson, B. D. Walker, M. A. BarTrans. 11989,665. low, T. J. Paradis, T.-C. Chou und M. S. W. J. Humphlett, Carbohydr. Res. 1%7,4, 157. Hirsch, Antimicrob. Agents Chemother. 1989, T. Ziegler, A. Straub und F. Effenberger, 33, 53; D. A. Winkler, G. Holan, J. Med. Angew. Chem. 19118, 100, 737; Angew. Chem. Chem. l989,32, 2084. Int. Ed. Engl. 1988,27, 716. [31 A. Thurkauf, P. C. Zenk, R. L. Balster, E. L. C. H. von der Osten, A. J. Sinskey, C. F. BarMay, C. George, F. I. Carroll, S. W. Mascabas, R. L. Pederson, Y.-F. Wong, C.-H. Wong, rella, K. C. Rice, A. E. Jacobson, M. V. MattJ. Am. Chem. SOC. 1989, 111, 3924. son, J. Med. Chem. 1988,31, 2257. N. Chida, Y. Furuno und S. Ogawa, J. Chem. [41 M. S . Blum, J. R. Walker, P. S. Callahan, A. F. SOC. Chem. Commun. 1989,1230. Novak, Science 1958,128, 306. [5] T. Shono, Y. Matsumura, K. Inoue, J. Chem. SOC. Chem. Commun. 1983,1169.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Taxanes: An Unusual Class of Natural Products Dieter Schinzer

The natural product class of taxanes belongs complex 6-8-6 ring system. The article cannot to an unusual type of terpene: the 6-8-6 ring present all details but will show the principles combination with the rare 1,3-fusion of the of the most important approaches. Worldwide six-and eight-membered ring and - synthetic- more than 20 research groups involved in ally quite difficult - a geminal dimethyl group taxol synthesis. The most striking problem in in the A ring and numerous oxygen functions all these syntheses is the construction of the spread over the skeleton (Scheme 1). The 1,3-annulated ring system containing the enormous variety of challanges required to synthesize the target molecule explains the worldwide interest in this fascinating mole61 cule. Even more important is the high biolo(4) (3) gical activity, especially as an anti-tumor compound. [1]To satisfy the actual clinical need of taxol (ca. 2.5 kg) 12.000 Califorian yew trees had to be felled. [2] These figures show that a flexible approach to taxol is needed: not an easy task, knowing all the problems with this complex structure. The following account will focus on the most important strategies for synthesizing the

%+%

.18

8 PH Th

"O OH

F1

R = C-CH-CH-NHCPh

Scheme 1

Scheme 2

(9)

A. Synthetic Routes to Different Classes of Natural Products

336

geminal dimethyl group. This will be a good test for potential total syntheses. Trost’s group started quite early with the basic construction of a bicyclic 6-%membered ring system, in which an elegant three-carbon ring expansion with a bifunctional reagent is performed (Scheme 2). [3, 41 The geminal dimethyl group is already masked in the exocyclic double bond and the two carbonyl groups contain the required oxygen functionality. Wender’s group uses a Ni-catalyzed bicyclization of compound (12) of a [4+4]cycloaddition. Compound (12) is available from commercial myrcene (10) in four steps. [ 5 , 61 This model system does not contain the geminal dimethyl group. The usefulness of this strategy is the additional approach for the B-C-ring system (Scheme 3). Compound (19) was obtained in 51 % yield by Kraus et al. with

1. MeLk‘ 4

4

____,

TBSO-

2. WH, 3. TBDMSCI, DMF

RIRa (12)

(13a): R’ = OTBDMS. R = H

(136): R’ = H,R = OTBDMS

(1.3:l)

(13)

TBDMSCI

I

= CI-Si

I

; COD = Cyclooctodirnji

a 2-carbon ring expansion (Scheme 4). [7] The precursor (16) is obtained in 3 steps from cyclohexenone by an in situ reaction with electron-rich olefins. Compound (18) can be reductively transformed into bicyclo[5.3.l]undecanone (19). Again, this approach only produced a basic model system.

PhS“

M e 0 OMe

OMe

Me0 OMe

Scheme 4

Considerable progress was made with Blechert’s deMayo approach. [S, 91 The key reaction is a stereoselective[2+2]-photocycloaddition of the bicyclic compound (20) with cyclohexene. The stereochemistry in the cycloaddition can be controlled by the ketal function: attack from the p-face controls the stereochemistry at carbon 8. The benzyl carbonate can be reductively cleaved to the alcohol, which undergoes a retro-aldol reaction to give compound (23) (Scheme 5). This sequence provides, for the first time, the tricyclic skeleton containing the critical geminal dimethyl group. An additional, direct entry to the tricycl0[9.3.l.O~,~]pentadecanesystem uses an intramolecular Diels-Alder reaction with an aromatic C-ring (Scheme 6). [ 101 Intermediate (24) was synthesized from a simple aromatic dibromide, which was transformed under thermal conditions in xylene into the cycloadduct (25) (70%). A new paper from Shea has now solved the problem with the aromatic C-ring. [ll]The

Taxanes: An Unusual Class of Natural Products

337

6 (22)

c&

H O (23)

Scheme 5

(30)

Scheme 8

precursor for the construction of the missing oxygens. Key reaction in this synthesis is a new approach again uses an intramolecular McMuny reaction of dialdehyde (36) in the Diels-Alder reaction yielding compound (29), presence of Ti(0); so far only in low yield which allows the addition of the missing (20 %) (Scheme 9). The cyclization precursor methyl group at carbon 8. The conditions for can be obtained by a Lewis acid-catalyzed the cycloaddition are much milder now aldol reaction: (32) + (33)+ (34). The stereocontrolled synthesis of the 8because Lewis acid catalysis is used. Trienone (28) is easily obtained in four steps from a membered ring system by a Claisen rearrangement of the macrolide (43) was described by cyclic vinylogous ester (Scheme 7). A similar construction of the a tricyclic com- Funk et al. [14] The required lactone (42) was pound has been published by Jenkins et al. synthesized by a short sequence of reactions. Compound (31) already contains the carbonyl The ketene acetal was stereoselectively reargroup at carbon 2 and the angular methyl ranged into compound (45) in 82% yield (Scheme 10). group at carbon 8 (Scheme 8). [12] The first total synthesis of a member of the The first synthesis of a taxane-triene of type (38) was recently discovered by Kende et al. taxane family, taxusine (59), has been [13] Compound (38) represents an excellent reported by Holton et al. [15, 161 The key Scheme 6

"""%

A. Synthetic Routes to Different Classes of Natural Products

338

COOMe

COOMe

Me3Si0 (32)

(33)

HO

0

(34)

1.

OMe

w

2. lBDMSCl

(37)

Scheme 9

v

t-BuOOH;

Ti(O-i-Pr),

OH

@

OTBDMS

(44)

MOM0

MOMCI = CICHZOCH, TBAF = Bu4NF

COZTBDMS

(45)

Scheme 10

(50) BMDA = BrMg-N(iPr)z

Scheme I1

'0

reaction in this synthesis is the fragmentation of epoxy alcohol (46). [15] The missing C-ring is introduced by an intramolecular aldol reaction (48) (49) (Scheme 11). This simple model has been expanded to the total synthesis of taxusine (59), starting with the commercially available optically active P-patchulene oxide (51). An eight-step synthesis leads to compound (52), which is transformed in situ after epoxidation to the 8membered ring (53). The C-ring was built via

Taxanes: An Unusual Class of Natural Products

AcO ( 1 1

aoAc '8.

(59)

MEM = CH20CH2CH20Me

Scheme 12

addition of methoxyvinyl lithium, reduction of the hydroxy ketone (55) with Sm12, and cyclization of the tosylate. A further oxidation and a final olefination (58) + (59) complete the synthesis yielding the natural product in optically active form (Scheme 12). In the meantime taxol (1) has been synthesized by Holton et al. using the strategy described above. [17,18] In this total synthesis terpene alcohol (60) was transformed via an epoxy-alcohol fragmentation into the 1,3annulated bicyclic ketone (61),followed by an aldol addition and closure to (63), which was rearranged to (64) and further transformed to the tricyclic lactone (66). The side chain was ozonized and the lactone cleaved by an intra-

339

molecular Dieckmann condensation to yield (68), which was oxidized to (71). Addition of methyl Grignard, followed by a Burgess elimination yielded (72), which allowed the construction of the sensitive oxetane ring after a short sequence. After several protecting group manipulations an interesting carbonyl shiftoxidation sequence was used to establish the missing oxygen atom in the eight-membered ring (77) + (78). Finally, the side chain in the A Ring was introduced using the Flactam route, followed by deprotection of oxygen functions to give taxol ( I ) in optically active form (Scheme 13). In addition, Nicolaou et al. have synthesized taxol by a flexible strategy using a Shapiro reaction and a McMuny coupling as the key operations to construct the basic skeleton. [19-211 In a straightforward sequence all the oxygens required are maneuvered around the molecule yielding taxol in a 14-step sequence. Nicolaou's synthesis started with compound (81),which is easily available by a Diels-Alder approach. Subsequent transformation into

340

A . Synthetic Routes to Different Classes of Natural Products

1. TESCI, py

epoxyslcohdh3gnent0tion

2. tBuOOH, m(0 CP@4 3. TBSCI

93%

P=TES

(60)

1. LTMP. (+/-)-camphorsulfonyloxaziridine,88% 2. red-Al, alkaline work-up 3. CI,CO, py, 88%

I. 0, MeOH

LTMP = lithielmmethylpiperidii Red-AI = Na+AIH&OC$I,OCl-&~

Scheme 13

2. KMnO,, KyPO,

w

3.

lES = triethylsilyl TBS = tbutyldimethylsilyl

cY%

Tuanes: An Unusual Class of Natural Products

TESO TBSOl'

1. PhSK, DMF

co*Me

2. H+,92%

(69)

TESO 1. BOMCI, EtN@Pr)2 2. LDA. TMSCI

rn

TBSOI*

3. W P B A , 86 % yield at 88% conmion

1. MeMgBr, 95 %

2.Bqess4imimtitm, 63 % MeO$N-SO$J'Et,

D

H+

TESO

mu. toluene, 80-8596

0

(74)

(73) BOM = benzyloxymethyl

DBU = diazabicyclo[5.4.0]undecene-7

Scheme 13.2 cont.

341

342

A . Synthetic Routes to Different Classes of Natural Products

1. LHMDS

-

1. HF,

w

2. H2. Wlchamd, 93 %

TPAP = tetrapropylammoniumperruthenate NMO = N-methylmorpholineN-oxide

Scheme 13.3 cont.

LHMDS = lithiumhexamethyldisilazide

Taxanes: An Unusual Class of Natural Products 1. t-BuMe,SiOTf

(4 eq) 2,Glutidine (4 eq) CDMAP CH,a,. 0 "c, 95%

2. LiAIH, (1 .I eq) Et,O, 0 "C 94%

1 . CSA (0.05 eq) MeOH. CH,CI,. 25 "C, 90% 2. t-BuPh,SiCI (1.5 eq) imidazole (1.6 eq) DMF. 25°C. 92%

3.KH (1.2 eq) Et,O, n-Bu,NI (cat), BnBr (1.2 eq). 25 "C. 87 %

OBn

r 1 <

LiAIH, (3eq) Et,O, 25 "C, 80 %

"'OH

2.2-dimethoxypropane (5 eq) CSA (0.1 eq) CH,CI, 25 "C, 82%

OBn TPAP (0.05 eq) NMO (1.5 eq) CH,CN, 25 "C, 95 '10

(85)

Scheme 14

>

343

voms

A . Synthetic Routes to Different Classes of Natural Products

344

n-BuLi (2.05 eq) THF, - 78 “C. 82 % C%n

NNHS02Ar

(87)

I

Shapiro coupling VO(acac), (0.03 eq), t-BuOOH (3 eq),

4-A MS (cat.), benzene 87%

G

TBSO, LiAIH, (3 eq), Et,O, 78%

(90) (89)

1. KH (3 eq), HMPT/Et,O, COCI, (2 eq), benzene, 48%

2. TBAF (10 eq), THF 80% 3. TPAP (0.05 eq), NMO (3 eq), CH,CN/CH,CI,, 82 %

I

0

fliCl,~-(DME), (10 eq), Zn-Cu (20 eq), DME 23% McMurry coupling

0 (91)

Scheme 14.2 cont.

>

6

\

*

Taxanes: An Unusual Class of Natural Products 1. Ac,O (1.5 eq), CDMAP (1.5 eq), CH,CI,, 95% 2. TPAP (0.1 eq), NMO (3 eq), CH,CN, 93%

od

‘ “ 0

(93)

1. BH,-THF (5 eq), THF, then H,O,, aq. NaHCO,, 55% 2. conc. HCI, MeOH, H,O, 80%

OAc

0

0

(95)

(94)

1. H,. 10% Pd(OH),(C), EtOAc 9 7 % 2. Et,SiCI (25 eq), pyr 85% 3. K,CO, (10 eq), MeOH 9 5 %

v

1. TMSCl(l0 eq), pyr (30 eq), CH,CI,. 96%

0

(97)

345

346

A . Synthetic Routes to Different Classes of Natural Products

0

(98)

-

1. PhLi (5 eq), THF, 78 "C. 80 % 2. PCC (30 eq), NaOAc, celite,

benzene, 75 VO

3. NaBH, (10 eq), MeOH, 83% 4. NaN(SiMe,), (3.5 eq), THF

87% (90% conversion) 5. HF pyr, THF 80 %

.

I tax01 ] CDMAP CSA TPAP NMO TES TBS TPS

4-dimethylaminopyridine camphorsulfonic acid tetra-n-propylammonium perruthenat N-methylmorphonilin-N-oxide Et,Si t-BuMe,Si t-BuPh,Si

Scheme 14.4 cont.

aldehyde (86) provided the coupling partner in the following Shapiro reaction with compound (87). The adduct (88) was further trans-

formed into epoxide (89), which was reductively ring-opened to (90). After several protecting group manipulations and oxidation to the dialdehyde, (91) was ready for the key transformation: McMurry coupling provided compound (92) with almost all oxygen atoms. This intermediate was taken on to construct the oxetane ring using a similar strategy to that used in Holton's synthesis to give (97). A final ally1 oxidation and addition of the side chain in the A ring by the &lactam route provided taxol (I) (Scheme 14). In summary, after many investigations and employment of different strategies taxol has

Taxanes: An Unusual Class of Natural Products

finally been synthesized by two groups using completely different strategies. In addition, success has been made in the isolation of natural taxol from yew trees without felling them. One can only hope that an anti-tumor drug will appear in the near future.

347

[12] R. V. Bonnert, P. R. Jenkins, J. Chem. SOC., Chem. Commun. W ,1540. 1131 A. s. Kende, s. Johnson, P. SanfiliPpo, J. c. Hodges, L. N. Jungheim. J. Am. Chem. SOC. 1986,108, 3513. [14] R. L. Funk, W. J. Daily, M. Parvez, J. Org. Chem. 1988,53, 4143. [15] R. A. Holton, J. Am. Chem. SOC. 1986,106, 5731. [16] R. A. Holton, R. R. Juo, H. B. Kim, A. D . References Williams, S. Harusawa, R. E. Lowenthal, S. Yogai, J. Am. Chem. SOC. 1988,110, 6558. R. W. Miller, J. Nat. Prod. 1980, 43, 425. [17] R. A. Holton, C. Somoza, H.-B. Kim, F. R. W. Miller, R. G. Powell, C. R. Smith, Jr., J. Liang, R. J. Biediger, P. D. Boatman, M. Org. Chem. l98l,46, 1469. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. B. M. Trost, H. Hiemstra, J. Am. Chem. SOC. Suzuki, C. Tao, P. Vu, S. Tang, l? Zhang, K. K. 1982,104, 886. Murthi, L. N. Gentile, J. H. Liu, J. Am. B. M. Trost, M. J. Fray, Tetrahedron Lett. W, Chem. SOC1994,116, 1597. 25,4605. [18] R. A. Holton, C. Somoza, H.-B. Kim, F. P. A. Wender, N. C. Ihle, J. Am. Chem. SOC. Liang, R. J. Biediger, P. D. Boatman, M. 1986,108, 4678. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. P. A. Wender, M. L. Snapper, Tetrahedron Lett. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. WtV, 28,2221. Murthi, L. N. Gentile, J. H. Liu, J. Am. G. A. Kraus, I? J. Thomas, Y.-S. Hon, J. Chem. SOC1994,116, 1599. Chem. SOC., Chem. Commun. 1981,1849. [19] For an excellent review see: K. C. Nicolaou, H. Neh, S. Blechert, W. Schnick, M. Jansen, W.-M. Dai, R. K. Guy, Angew. Chem. 1994, Angew. Chem. W, 96, 903. Angew. Chem. 106, 38. Angew. Chem. Int. Ed. Engl. l994,33, Int. Ed. Engl. 1984,23, 905. 45. R. Kaczmarek, S. Blechert, Tetrahedron Lett. 1986,27, 2845; see also H. Cervantes, D . D. [20] K. C. Nicolaou, C. F. Claiborne, P.G. Nantermet, E. A. Couladouros, E. J. Sorensen, J. Khac, M. Fetizon, E Guir, Tetrahedron 1986, Am. Chem. SOC. 1994,116, 1591. 42, 3491. [21] K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. K. J. Shea, P. D . Davis,Angew. Chem. 1983, G. Nantermet, R. K. Guy, C. F. Claiborne, J. 95, 422; Angew. Chem. Int. Ed. Engl. 1983,22, Renaud, E. A. Couladouros, K. Paulyannan, 419. E. J. Sorensen, Nature 1994,367, 630. K. J. Shea, C. D. Haffner, Tetrahedron Lett. 1988,29, 1367.

~~

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

B. Synthesis of Individual Natural products CC-1065: One of the Most Powerful Anti-Tumor Compounds Dieter Schinzer Apart from taxanes [l]and antibiotics of the calicheamicin- and esperamicin-type [2], a third class of highly potent anti-tumor compounds exists: the antibiotic CC-1065 [3] and some related compounds, which were isolated by the Upjohn group in the U.S. [4]. At the time of its isolation CC-1065 was the most active anti-tumor compound in the world. No name - just a number - already indicates an industrial laboratory, and is probably a good idea: it would not be easy to name this complex molecule using IUPAC nomenclature rules. In this chapter some of the known approaches and the first total synthesis of the natural product (1)will be presented (Scheme 1). Like other interesting target molecules a race was started around the world with several well known groups, recently finished by Boger et al. with a report of the first total synthesis. [5, 61 The antibiotic CC-1065 is twice as active in the L-1210 test with leucemia cells than maytansine. Analysis shows three pyrroloindol units that are connected with amide bonds. From the stereochemical point of view two asymmetric centers (cyclopropane ring in the fragment A) must be created. Most of the research groups involved have first studied the synthesis of the subunits, which will be discussed first. The

u

H

OMe

CC- 1065

Scheme I

C

A

(1)

first synthesis of fragment A was reported by Wierenga et al. (from the Upjohn group), who started from a functionalized aromatic compound (2) and constructed the indol fragment later (Scheme 2). [8] Compound (2) was transformed into a malonic ester derivative. The bis mesylate (4) cyclized after reduction of the nitro group to form the indoline (5). After protecting group manipulation and transformation to the acetate, a modified oxindole synthesis was used to synthesize (8). Demethylation gave (9),the acetate was cleaved, the alcohol transformed into the bromide, and final cyclization with Hiinig base yielded cyclopropane derivative (10). Fragment A of the natural product ( I )

350

B. Synthesis of Individual Natural Products

Scheme 3

CC-1065: One of the Most Powerful Anti-Tumor Compounds

was synthesized over 14 steps with an overall yield of 3 YO. A better result concerning the overall yield was achieved by Magnus, who used a completely different strategy (Scheme 3).[9-111 This synthesis began with an acceptor diene of type (12) as starting material, which was transformed as Michael acceptor with p toluenemethylsulfonyl isocyanate (TOSMIC) to pyrrole (12). It was not possible to use two equivalents, directly thereby forming two rings simultaneously in a one-pot procedure. The strong electron donating effect of the nitrogenatom had to be decreased by transformation into the N-tosylate. This compound generated the desired second pyrrole ring to give (14). Under Mannich conditions (15) was isolated and transformed into the ester (16) after addition of methyl iodide, NaCN, and subsequent hydrolysis of the nitrile in the presence of methanol. Selective ester hydrolysis, followed by the synthesis of the acid chloride, gave the expected phenol (18) under Lewis acid conditions. Reduction of the indol portion with TFA/HSiEt, gave (19), which was

N-acetylated, reduced and transformed under Mitsunobu conditions to give the cyclopropane (20), which represents part A of the natural product (1). A very elegant approach by Kraus et al. used a Diels-Alder reaction as the key transformation. [12] Reaction of the diene (22) and imino quinone (21) gave the Diels-Alder aduct (23) (Scheme 4). After a few transformations the tricycle (26) was generated from the Diels-Alder adduct. The construction of the cyclopropane ring was already designed in this sequence. The mesylate (27) was treated solely with base and (28) was obtained as a protected building block A of (1). A formal total synthesis of CC-1065 was recently described by Rees et al. [13] All subunits of the natural product (the cyclopropane part A and the dimeric pyrrole units B C) have been synthesized by vinyl a i d e chemistry. All six nitrogen atoms of the natural product are formally coming from azide groups, basically from NaN3 (Scheme 5)!

+

+ Ac

1. MBCH

2.w

PhOpS-

351

3.

w,

352

B. Synthesis of Individual Natural Products

This approach is somewhat similar to Wierenga’s approach described earlier. Both use quite accessable aromatic precursors. The bromobenzaldehyde (29) can be prepared on a large scale from isovanillin. A simple condensation with methylazido acetate yielded the desired acyl azide (30),which was thermolyzed to the indole derivative (31). A drawback in the sequence was the transformation of the indole (32) from the ester by reduction and decarbonylation of the aldehyde. The second pyrrole ring was synthesized by a similar strategy: condensation of the aldehyde (33) with methylazido acetate, followed by thermolysis of the product to obtain tricycle (34). The intermediate (34) was used in two ways: 1) Reduction of the indoline system (35); 2 ) Hydrolysis of the ester (34) to the acid, and, finally, coupling of the pieces to the dimer (37) (Scheme 6). The cyclopropane (45) was synthesized in a straightforward way from ketone (38), which was further transformed via the epoxide into the azide (40). Thermolysis gave the indole, which was coupled to the tricycle (43). After a few further operations (45) was obtained (Scheme 7). Both subunits of the natural product were synthesized by this route and can be coupled to the natural product, as already described by Kelly et al. [14]

(35)

+

(36)

CMC __j

OM0

(37)

CMC = 1-Cyclohexyl-3-[2-(4-methylmorpho-

linoethyl]carbodiiminiumtoluene-Gsulfonate

Scheme 6

The first total synthesis of CC-1065 was reported by Boger et al. [15] He used two different strategies with quite interesting new reactions to synthesize the subunits (Scheme 8). As the key reaction in the synthesis of the dimer an intramolecular Diels-Alder reaction

CC-1065: One of the Most Powerful Anti-Tumor Compounds

H

353

354

B. Synthesis of Individual Natural Products

(46) -+ (47) - which resulted directly in the The additional elimination of piperidine indoline (47) - was used. The required precur- gave the required indole derivative (58). Brosor was quite easily obtained - alkylation mination at the 4-position took place at low under Mitsunobu conditions - but had to be temperature, and smooth N-alkylation with optimized by a conformational study in order propargyl bromide followed to yield (60). The to increase the yield in the Diels-Alder reac- latter was cyclized to the tricyclic compound tion. [15] The missing ring was synthesized by (61) by a radical initiated exo-dig reaction in the route of Rees (via the nitrene) yielding the the presence of AIBN and Bu,SnH. The required tricycle (49). The hydroxyl group of desired alcohol (62) was obtained, after the aromatic ring was introduced by a Lewis hydroboration, in racemic form and was acid catalyzed hydroperoxide-rearrangement separated using a procedure developed by of the tertiary alcohol (50). The originally Boger [ 161 yielding the two enantiomers (6%) planned Baeyer-Villiger rearrangement could and (65b) (Scheme 10). The cyclopropanation not be realized. After a few protecting group was the last step after coupling of the fragmanipulations the fragments could be coupled ments, which was carried out using techniques by EDCI. The next operation introduced part developed by Kelly with a derivative of carboA by a radical-induced cyclization as the key diimide. The coupled molecules (66u) and step. In order to manage this step an indole (66b) could be cyclopropanated under basic with the required functionality had to be syn- conditions to give ( I ) in both antipodes thesized. Boger used an unusual nucleophilic (Scheme 11). The syntheses discussed to obtain CC-1065 addition of an enamine (56) to an activated clearly show that know-how developed by difdiimido quinone (55) (Scheme 9). ferent groups could be elegantly combined to make this project a success.

OH

I

CC-1065: One of the Most Powerful Anti-Tumor Compounds

$.-t-p H

OCH2Ph

,.

&N-CO2t-Bu H

~~

2. Hc1

OCH2Ph

&H

H

*

HCI+ &NH

OH

q$&

H

*

HCI

OH

HN 0

(6W

(+)-CC-1065

(1)

CH3

EDCL

(6W EDCl = 1[BDirnelhylamino)propyl~3-ethylcarbodiirnide

Scheme 11

(-)-CC-lQ65

(1)

355

356

B. Synthesis of Individual Natural Products

References D. Schinzer,Nachr. Chem. Tech. Lab, 1989,37, 172. J. Golik, J. Clardy, G. Dubay, G. Groenewold, H. Kawaguchi, M. Konishi, B. Krishnan, H. Okuma, K. Sitloh, T. W. Doyle, J. Am. Chem. SOC. 1987,109, 3462. [31 Review: V. H. Rawal, R. J. Jones, M. P. Cava, Heterocycles 1987,25, 701. [41 L. J. Hanka, A. Dietz, S. A. Gerpheide, S. L. Kuentzel, D. G. Martin, J. Antibiot. 1978,31, 1211. D. L. Boger, R. S. Coleman, J. Am. Chem. SOC. 1988,110, 4796. D. L. Boger, T. Ishizaki, R. J. Wysocki, S. A. Munk, J. Am. Chem. SOC.1989,111, 6461. D. G. Martin, L. J. Hanka, G. L. Neil, Proc. Am. Assoc. Cancer Res. 1978,19, 99.

[8] W. Wierenga, J. Am. Chem. SOC. 1978, 103, 5621. P. Magnus, Y.-S. Or, J. Chem. SOC. Chem. Commun., 1983,26. P. Magnus, T. Gallager, J. Chem. SOC. Chem. Commun. 1984,389. P. Magnus, S. Halazy, Tetrahedron Lett. 1985, 26, 2985. G. A. Kraus, S. Yue, J. Sy, J. Org. Chem. 1984, 50, 284. R. E. Bolton, C. J. Moody, M. Pass, C. W. Rees, G. Tojo, J. Chem. SOC. Perkin Trans. I, 1988,2491. 1141 R. C. Kelly, I. Gebhard, N. Wicnienski, F! A. Aristoff, P. D. Johnston, D. G. Martin, J. Am. Chem. SOC. 1987,109, 6837. 1151 D. L. Boger, R. S. Coleman, J. Am. Chem. SOC. 1987,109, 2717. [161 D. L. Boger, R. S. Coleman, J. Org. Chem. 1988,53, 695.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Syntheses of Morphine Martin Maier

Since drugs have been known, they have been contested in society. This is quite understandable in the light of the misery and the crime caused as a result of unresponsible drug consumption. Nevertheless, it is illusory to dream of a drug-free society and it is questionable whether a repressive drug policy can diminish the problems. [l]For science, however, drugs have proven to be very useful, because they represent important tools for studying the function of the brain. Particularly promising in this regard are marihuana and heroin, or morphine, since in the brain they interact with specific receptors. Thus, they are different from cocaine and other drugs, which merely disrupt certain processes in the brain. In the meantime the receptors for morphine and for tetrahydrocannabinol (THC) have been isolated and cloned. Moreover, for both receptor types the natural (endogenous) ligands are known. While the encephalins and endorphines, which bind to the opiate receptor, are peptides, the anandamides, the ligand for the THC-receptor, is derived from arachidonic acid. [2] An important function of the endogenous ligands is to block pain signals in certain situations. Simultaneously, the endogenous ligands cause a feeling of well-being. Some questions that come to mind are how the corresponding receptors change on consumption of drugs or how they might be manipulated with therapeutics. With this knowledge one hopes to separate the potent anal-

gesic properties from the other, undesired, effects. In both cases the enormous structural differences between endogenous and exogenous ligands are amazing, with structural overlap only in small areas. Possibly, the addicting properties of the exogenous ligands may be explained by a "gain of function" model. [3] This means that only after binding to the receptor is an interaction with other receptors possible via the formation of ternary complexes. Morphine (I) is also an attractive synthetic target because of its complex structure. Despite the fact that the first synthesis dates back almost forty years, its attraction as a synthetic target hardly has diminished. A compar-

Morphine (1)

qBNW

Meo/

0

0

H

358

B. Synthesis of Individual Natural Products

ison of the syntheses also demonstrates to centers that must be established in the course some degree the evolution of synthetic strate- of the synthesis, although in cyclic systems the correct stereochemistry often establishes itself gies and methodologies. Morphine (I) belongs to the class of the automatically or can be easily controlled or morphinanedienone alkaloids; [4] further corrected. In the retrosynthetic analysis it is important representatives of this class of com- important, in the first place, to cut the right pounds are codeine (2), thebaine (3) and bonds, whereby the aim is to get to simpler codeinone (4). The diacetyl derivative of mor- structures, the syntheses of which are obvious. phine is known under the name heroin. The If one does not want to rely on intuition or potency of heroin is about three to five times trial-and-error, a procedure developed by that of morphine and because of its higher Corey is available that allows the determinalipophilicity it is able to cross the bloodbrainbarrier more easily.

Retrosynthesis The polycyclic ring system of morphine represents a great challenge from a synthetic point of view. In addition, there are the five stereo

room-

bond numbers

core bond /

g

arategk bonds in morphine

--

1,Znotstratsgk

3: stxategk

I

U

15

1

2

J

J

4

' (5)

I

8 7 8 9 1 0 J

Nb

5 6

/ J

J

7 J J

Scheme 1. Retrosynthetic analysis of the morphine skeleton.

Syntheses of Morphine

tion of strategic bonds (SB) in polycyclic systerns. [5] Strategic bonds are those, the breaking of which leads to a reduction a) in the number of side chains, b) the number of side chains with chiral centers, c) of the number of medium-sized rings or large rings, and d) of the number of bridged rings. The SB can be

ascertained with the help of six rules, whereby all presuppositions must be fulfilled. In principle an SB is a bond that can be formed very easily. Rule 1: An SB must be part of a primary, four- to six-membered ring. This is connected to the ease of formation of such rings. A pri-

(7 7)

HO

LiAIH,

HO"'

codeine

(2)

Scheme 2. Synthesis of morphine according to Gates.

359

Ir(orphb (1)

360

B. Synthesis of Individual Natural Products

mary ring cannot be represented as a sum (envelope) of two or more rings. The envelope of two annulated or bridged rings is termed a secondary ring. Rule 2: An SB must be ex0 to another ring. If the bond is, however, ex0 to a threemembered ring, it is not considered to be strategic (Rule 2B). Rule 3: An SB must be in the ring that is bridged at the highest number of positions (highest degree of bridging). This or these rings, respectively, is (are) termed the maximum bridging ring (MBR). In addition, the MBR must belong to the set of synthetically significant rings (SSR). The SSRs include primary rings and secondary rings with a size of less than eight atoms. For example, in the ring system (5) there are two secondary rings (D and F, n < 8), besides the three primaries. Ring A is bridged at positions 1 and 3 with B. It should be noted that although atom 2 is a bridgehead atom and is part of ring A , this ring is not bridged to another ring with this atom. Ring C is also bridged at two positions (2 and 4) with other rings. In contrast, ring B is bridged at four positions (1-4) with other rings and is, therefore, the MBR. Rule 4: Bonds common to bridged or fused rings cleavage of which leads to a ring with more than seven atoms are not considered to be strategic. Such bonds are also termed corebonds. If, however, two bridged or fused rings are connected to each other via another bond, even a core-bond is strategic. Rule 5: Bonds in aromatic systems are not strategic, except in a heteroaromatic ring. Rule 6: If rings contain a pair of common atoms (a spiro center, annulated or fused rings), bonds that connect the common atoms are only strategic if the bond path is free of stereocenters. By this rule structures that contain chiral atoms in the side chain are avoided. If, however, only one chiral center is within the chain connecting the two atoms, then the bonds to the chiral center are candidates for strategic bonds because their disconnection

leads to a reduction of chirality (e. g. bonds 1 to 3 in (6)). Moreover, for heterocyclic systems carbonheteroatom bonds are considered to be strategic if they satisfy the requirements of the rules 2B, 4 and 6. This is due to the ease of formation of such bonds. In practice it is recommended to proceed according to the following steps: 1. Identify the primary rings of a polycycle, that is, all rings of size four to seven. 2. Identify the secondary rings. In order to find these rings, all possible ring combinations that share common atoms must be screened. At the same time one can determine whether a secondary ring is synthetically significant and which of the bonds are core bonds. 3. Determine whether

@=p 1

HO

HO

MeO

MeO

\

OH RetiaAne (76)

OH

I

0 OH

OH lrroboldne (79)

0

I m n e (78)

Syntheses of Morphine

an SSR is bridged with another ring and at which positions this is the case. This analysis leads to the MBR. Because this is the most restrictive rule, in the following it is sufficient to check the bonds of the MBR for the fulfillment of the other five rules. 4. Finally, one looks for the carbon-heteroatom bonds that are strategic. If the morphine skeleton is analyzed according to this procedure, one finds five primary rings (Scheme 1). Because the smallest primary ring is a five-membered ring, a synthetically significant secondary ring (n < 8) cannot exist. That is, the analysis is restricted to the bicyclic ring system consisting of the rings B and D because only these two are bridged. [6] The envelope (i.e. (Ri u Rj) (Ri n Rj)) [7] of the rings B and D yields an

361

eight-membered ring, that is bonds 6 and 11 are core bonds and are therefore not strategic. It is appropriate to lay on the bond numbers against the rules, whereby one finds that bonds 7, 10, 12, and 13 are strategic. Actually, one also has to mark bond 15 as strategic, although it is a core bond of rings B and E. Quite often, however, the heterocyclic ring is formed only at the end of the synthesis. That means, in these immediate precursors, bond 15 is not a core bond. Further analysis shows that all of the C-X bonds are strategic.

Hoq J

MeO

Moo'

111

,I

362

B. Synthesis of Individual Natural Products

center at C-14. Certainly, for many of these transformations one would use other reagents or conditions. Still, it is remarkable what can be achieved without using lithium diisopropylamide (LDA), silyl protecting groups, or organometallic chemistry. It should be noted, however, that in those days abundant use was already made of relay syntheses, which was admitted by the authors. Thus, many intermediates, for example (lo), were ultimately prepared from morphine itself. By this chemical correlation, however, the structure of morphine could be established unambiguously. As an aside, most of the subsequent syntheses of morphine lead to intermediates of the Gates Syntheses synthesis. An attractive possibility to approach a synInterestingly, in the first morphine synthesis thesis of a natural product is to follow the bio[9] (Scheme 2) a cycloaddition strategy was synthetic pathway - particularly because the chosen in order to construct the tricyclic sys- retrosynthetic analysis is avoided. The key tem (8). The dienophile (7) was obtained in step of the biosynthesis is the oxidative coupten steps from 2,6-dihydroxynaphtalene.The ling of reticuline (16) to salutaridine (17) attachment of the cyanomethyl side chain by a (ortho-para), whereby bond 15 between the Michael addition is in accordance with the positions that are marked with an arrow, is retrosynthetic analysis. A chemoselective formed. However, it is not easy to realize this reaction with H,/copper chromite resulted in a pathway in an enzyme-free manner, because reductive cyclization with formation of the isosalutaridine (18) (para-para) and isoboline ketone amide (9). The unsaturated amide (10) (19) (ortho-ortho) are formed as major prodwhich was obtained by Wolff-Kishner reduc- ucts. Nevertheless, there have been many tion, N-methylation and amide reduction attempts to direct this reaction in the desired could be transformed to the alcohol (11) by sense. The best result so far was achieved by regioselective hydration of the double bond. Schwartz et al., who succeeded in the cyclizaTwo further steps, which included a selective tion of N-ethoxycarbonylnorreticuline to the cleavage of the methyl ether and an oxidation, corresponding salutaridine derivative in a provided the ketone (12). After introduction yield of 23 % by using thallium trifluoroacetof a double bond, the stereochemistry at C-14 ate. [lo] could be corrected through the sequence douInstead by an oxidative coupling reaction, ble bromination, dinitrophenyl hydrazide bond 15 can also be formed in an acidformation, acid treatment and hydrogenation. catalyzed, intramolecular, electrophilic aroThrough a triple bromination of compound matic substitution. [ll] Although now bond (13) and subsequent treatment with dinitro- formation occurs unambiguously to C-13, the phenyl hydrazine, leading through the inter- wrong regioisomer (OH group points to the mediate (14), the ring system was completed. top) is still favored. The solution to the regioAltogether 28 steps were necessary. Quite chemical problem consists of using a symmetcomplicated is the preparation of the dieno- rical aromatic ring for the electrophilic subphile (7) and the epimerization of the stereo- stitution or to block the position that would Of course, the whole procedure has its limitations and according to the principle “the exception makes the rule” connections of bonds that officially are not strategic can also lead to the target. In particular, synthetic strategies that rely on intramolecular cycloadditions or pericyclic reactions in general are not well recognized. For example, in decalin systems the central bond is a core bond and therefore not strategic, despite the fact that this bond can be formed very efficiently by an intramolecular Diels-Alder reaction. [8]

Syntheses of Morphine

363

lead to the wrong isomer. Thus, Beyermann et build the critical quarternary center of the al. started with compound (20), which by the morphinane skeleton. In a sequence of five way is very easily obtained from the corre- steps, 2-allylcyclohexenone was converted to sponding l-benzyl-1,2,3,4-tetrahydryisochi- the chiral allylsilane (25). The optical activity nolin by Birch reduction ( 8 5 % ) and N- of (25) was secured by an enantioselective formylation. Cyclization of (20) with 80 % sul- reduction of the cyclohexenone derivative furic acid furnished the morphinane derivative with catecholborane in the presence of the (21). Removal of the superfluous OH group to (R)-oxazaborolidine catalyst. Condensation give dihydrothebainone (23) proceeded after of the allylsilane (25) and the aldehyde (24) selective etherification with 5-chloro-l- gave the crystalline (27) via the intermediate phenyl-tetrazole and subsequent hydrogena- (26). The stereochemistry of compound (27) tion. [12] In a variation of this strategy, posi- results from the preferential formation of an tion 1 of the aromatic ring A is brominated, (E)-iminium ion (26) that enters into a stereowhich directs the cyclization to the correct iso- selective iminium ion-allylsilane cyclization. With the iodine atom already in place, the mer. [13] Yet another way to construct bond 15 is problem of regioisomers does not exist in the illustrated in a synthesis of (-)-dihydro- subsequent Heck cyclization of (27) to comcodeinone (29) by the group of Overman. [14] pound (28). The unsaturated morphinane (28) They use an intramolecular Heck reaction to was transformed in four steps to

Me

ow-

[57%from (31)l

MeO

(69%)

OH

(R)-Rsticultne

Scheme 3. Enantioselective synthesis of the morphine precursor (R)-reticuline according to Hirsenkorn.

364

B. Synthesis of Individual Natural Products

(43)

Scheme 4. Morphine synthesis of Evans.

(-)-dihydrocodeinone (29). From this, in turn, functionalization of the diol, the cyclic sulfate (-)-morphine could be obtained in another (32) in 88% ee. [16] Reaction of (32) with methylaminoacetaldehyde dimethyl acetal five steps. Despite the difficulties of controlling the furnished the amino alcohol (33) which (as its regioselective cyclization of reticuline derivat- acetate) cyclized under Pomeranz-Fritsch ives, the biomimetic approach is of particular conditions to compound (35). Hydrogenation interest, because the cyclization to tetracycles of (35) led to (R)-reticuline (16). Although in the synthesis of Evans (Scheme of type (17) necessarily proceeds in a diastereospecific manner. Through asymmetric syn- 4) five C-C bonds (three of them are strategic) theses of l-benzyl-1,2-dihydroisoquinolines, are formed in the course of the synthesis of morphine, or derivatives thereof, would be two rings, the number of steps is nevertheless accessible in enantiomerically pure form. In a rather small. [17] By addition of 2,3very elegant strategy (Scheme 3) stilbene (31) dimethoxylithium to N-methyl-4-piperidone served as starting material, which itself could and acid-catalyzed elimination, the heterobe prepared very easily by McMurry coupling. cyclic olefin (36) is formed. Compound (39) A key step is the enantioselective dihydroxyla- could be constructed in a two-step procedure tion (ADH) of the stilbene (31) according to whereby the allylic anion, which was generthe Sharpless procedure [ 151 providing, after ated by treatment with nBuLi, was alkylated

Syntheses of Morphine

(51) TEOC-

0

62)

A o - ~ ~

Scheme 5. Morphine synthesis of Fuchs.

regiospecifically with the dibromide to provide (38). In the presence of NaI the enamine (38) cyclized to (39). In order to install the missing C-atom for the ring B, the authors made use of a quite remarkable sequence of reactions. The trans-iminium salt, which was formed by acid treatment from (39), can be equilibrated to the desired &-isomer (40). If compound (40) was treated with diazomethane, the aziridinium salt (41) was generated in a diastereospecific manner, which then reacted in a Swern-analogous reaction with

codeinone (4)

I

365

1- N-4

2. BBrS (50%)

Morphine

DMSO to the amino aldehyde (42). Under Lewis acid catalysis, the aldehyde (42) cyclized to the morphinane (43). Reductive removal of the OH-group and oxidative cleavage of the double bond led to the ketone ( 4 4 , a compound that had already passed through in the Gates synthesis (as the 4-OH-free derivative). While the oxygen-containing ring is formed only at the end in the above-mentioned syntheses, Fuchs used this ether bond in a very clever way (Scheme 5) to guarantee an intra-

366

B. Synthesis of Individual Natural Products

1. KN(TMS),

0

,L"TOS

Ph 2. H$W (75%)

MeO-0 (n)

Scheme 6. Morphine synthesis of Tius.

(62)

molecular reaction during the formation of the strategic bond 15. [18] The alcohol (46) was prepared from 1,3-~yclohexanedioneby standard reactions by passing through the intermediate (45). Subsequent Mitsunobu reaction with the functionalized phenol (47) led with inversion of configuration to the trans-ether (48). The key step of this synthesis is a tandem reaction, consisting of a nucleophilic addition of an aryl carbanion (prepared from (48) by treatment with nBuLi) to the vinyl sulfone function. The intermediate car-

banion now reacts in an intramolecular SN2 reaction to the tricycle (49). It took five further steps to convert the ally1 group into a carbamate. Attempts to carry the amino function through the whole synthesis, in the form of an tosyl amide, led to a dead end, because deprotection was not possible without destroying the whole molecule. After enol ether formation the diene (51) was generated by baseinduced elimination of benzene sulfinic acid. Oxidation of the diene (formal abstraction of H-) furnished the dienone (52). Removal of

Syntheses of Morphine

the nitrogen protecting group was followed in the basic medium by addition of the amino function to the dienone with formation of codeinone (4). Besides that, the /3, 'yunsaturated ketone was formed, which, however, could be isomerized to compound (4) without a problem. Reduction of the carbonyl group and cleavage of the methyl ether provided morphine (1). Actually, it is quite logical to incorporate ring A from an aromatic precursor into the target molecule. That it can be done differently was demonstrated in a recent synthesis by Tius et al. (Scheme 6). [19] This synthesis is remarkable because the aromatic ring A is derived from an alicyclic precursor while on the other hand ring C was developed from an aromatic ring! The bonds 11 and 15 are constructed in a Diels-Alder reaction between the diene (53) and the quinone (54). The next steps serve to aromatize ring A. Treatment of (55) with phenylselenyl chloride in methanol induced a selenocyclization with concomitant formation of a hemiaminal structure. Subsequent oxidative elimination and hydrolysis of the ketal yielded compound (56). The introduction of the hydroxyfunction at C-17 was performed with the Davis reagent whereby the rigid ring system, in combination with conformative effects, enable regioselective formation of the required enolate. After hydrogenation of the superfluous double bond and Swern oxidation to the 1,2-diketone7 treatment with Lewis acid caused aromatization by elimination of water. Because of the spatial vicinity of the functional groups a hemiaminal was again formed. Introduction of a double bond, reduction of the carbonyl function, cleavage of the carbamate and regeneration of the carbonyl group led to compound (59). With the use of zinc the dihydrofuran ring could be opened reductively with simultaneous liberation of the amino group, which in one process undergoes a Michael addition to the a,/%unsaturated carbony1 system furnishing (60). Epimerization

367

of pthebainone (61) under acidic conditions finally provided thebainone (62). Although this synthesis seems quite original, it requires, in a addition to the preparation of the starting materials (53) and (54), a large number of steps (24 altogether) many for the aromatization of ring A. In chemistry the direct path is also usually the shortest! Another recent synthesis of morphine by Parker et al. [20] is conceptually identical to the synthesis of Fuchs. The same bonds are constructed in the same order (Scheme 7).

IT-

Me0

'L?-To

%SPh

H

o

d

- (!,,,,.*

1. ArOH, PSy

DEAD

Me

TBSO

Scheme 7. Morphine synthesis of Parker.

368

B. Synthesis of Individual Natural Products

Starting from amine (63) the cis-epoxide (64) was constructed in a conventional and transparent way (Birch-reduction, etc.). Opening of the epoxide provided the cis-diol (65), the sterically less hindered OH group of which could be selectively protected. Subsequent Mitsunobu reaction provided the ether (66). Treatment of (66) with AIBN/Bu3SnH generated a radical that initiates a reaction cascade that ultimately leads to the formation of two C-C bonds. The following ring closure of (68) to give (69) was clearly a stroke of luck. In an attempt to reductively remove the tosyl group, the intermediate nitrogencentered radical or anion added directly to the double bond with the formation of dihydroisocodeine (69). It is evident that with only 11 steps this synthesis defeats that of Fuchs. This synthesis underscores the fact that, besides the strategic concept the experimental execution, that is, the proper choice of reactions, is very important. Moreover, it represents an elegant application of a tandem radical reaction. The syntheses presented here demonstrate that the retrosynthetic analysis of polycyclic systems according to Corey is absolutely useful, although the procedure seems rather complicated at first sight. By implementation of this or similar heuristic procedures using a computer any polycyclic molecule can be retrosynthetically dissected more or less easily. [21] Nevertheless, synthetic chemistry is still an experimental science. A large number of incomplete or failed syntheses provide clear evidence for this fact. [22] The sometimes expressed opinion, that the synthesis of organic molecules is not a problem or a challenge any longer, seems definitely to be wrong. Even today, only a few groups are able to synthesize complex natural products.

References

[lo] [ll] [12]

[13] [14] [15]

See for example, W. Neskovic, Ohne Drogen geht es nicht, in Die Zeit, 1993, no. 25, 40. a) M. Baringa, Science 1992, 258, 1882-1884; b) R. Mestel, New Scientist 1993, July 31, 21-23. M. K. Rosen, S. L. Schreiber, Angew. Chem. 1992, 104, 413-430; Angw. Chem. Int. Ed. Engl. B92,31, 384-400. G. A. Cordell, Introduction to Alkaloids, Wiley, New York, 1981,422-450. E. J. Corey, W. J. Howe, H. W. Orf, D. A. Pensak, G. Peterson, J. Am. Chem. SOC. 1975, 97, 6116-6124. b) E. J. Corey, X. Cheng, The Logic of Chemical Synthesis, Wiley, New York, c) F. Serratosa, Studies in Organic Chemistry 41, Organic Chemistry in Action. The Design of Organic Synthesis, Elsevier, Amsterdam-Oxford-New-York-Tokio, 1990, 168- 184. The numbering of the bonds is arbitrary. u = Element either of the group 1 or 2; n = Elements that belong to both groups. D. Craig, Chem. Rev. 1987,16, 187. M. Gates, G. Tschudi, J. Am. Chem. SOC. 1956, 78, 1380-1393; see also: N. Anand, J. S. Bindra, S. Ranganathan, Art in Organic Synthesis, Holden-Day, San Francisco-LondonAmsterdam, 1970,251-256. M. A. Schwartz, I. S. Mami, J. A m . Chem. SOC. 1975,97, 1239-1240. R. Grewe, W. Friedrichsen, Chem. Ber. 1%7, 100, 1550. H. C. Beyerman, T. S. Lie, L. Maat, H. H. Bosman, E. Buurman, E. J. M. Bijsterveld, H. J. M. Sinnige, Recl. Trav. Chim. Pays-Bas 1976, 95, 24-25. K. C. Rice, J. Org. Chem. 1980,45, 3135-3137. C. Y. Hong, N. Kado, L. E. Overman, J . Am. Chem. SOC. 1993,115, 11028-11029. a) Preparation of ligands for ADH: W. Amberg, Y. L. Bennani, R. K. Chadha, g. A. Crispino, W. D. Davis, J. Hartung, K . 4 . Jeong, Y. Ogino, T. Shibata, K. B. Sharpless, J. Org. Chem. 1993,58, 844-849; b) review, H. C. Kolb, M. S. Van Nieuwenhze, K. B. Sharpless, Chem. Rev. W!M, 94,2483-2547.

Syntheses of Morphine

[16]a) R. Hirsenkorn, Tetrahedron Lett. 1990, 31, 7591-7594; b) R. Hirsenkorn, Tetrahedron Lett. 1991, 32, 175-1778; for further asym-

metric syntheses of l-benzyl-1,2-dihydro isoquinolines, see: a) A. I. Myers, J. Guiles, Heterocycles, 1989, 23, 295-301; b) M. Kitamura, Y. Hsiao, M. Ohta, M. Tsukamoto, T. Ohta, H. Takaya, R. Noyori, J. Org. Chem. 1994,59,297-310. [17]D.A. Evans, C. H. Mitch, Tetrahedron Lett. 1982,23, 285-288; for an alternative synthesis of (39) see: W. H. Moss, R. D. Gless, H. Rapoport, J. Org. Chem. W 3 , 4 8 , 227-238. [18]J. E.Toth, P. R. Hamann, P. L. Fuchs, J. Org. Chem. 1988 53, 4694-4708. [19]M. Tius, M. A. Ken; J . Am. Chem. Sac. 1992, 114, 5959-5966.

369

[20] K. A. Parker, D. Fokas, J. Am. Chem. SOC. 1992,114, 9688-9689. [21] I. Ugi, J. Bauer, K. Bley, A. Dengler, A. Dietz

E. Fontain, B. Gruber, R. Herges, M. Knauer, K. Reitsam, N. Stein, Angew. Chem. 1993,105, 210-239; Angew. Chem. lnt. Ed. Engl. W 3 , 32, 201. [22] See for example: a) M. Chandler, P. J. Parsons., J. Chem. SOC., Chem. Commun. 1984, 322-323; b) J. D.White, R. J. Butlin, H.-G. Hahn, A. T. Johnson, J. Am. Chem. SOC. 1990, 112, 8595-8596; c) T. Hudlicky, C. H. Boros, E. E. Boros, Synthesis 1992, 174-178; d) P. Magnus, I. Coldham, J. Am. Chem. SOC. 1991, 113, 672-673.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Synthesis of Calicheamicin y t Herbert Waldmann

Calicheamicin yl' (I),esperamicin Alb(2),the chromophor (3) of neocarcinostatin and dynemicin A (4) are representatives of the enediyne antitumor antibiotics, which are characterized by a pronounced physiological activity even at very low concentration. The cell-destroying activity of these compounds is caused by a Bergmann cyclization that occurs after an initiation step. In the course of this reaction diradicals like (29) are formed (see

(2) esperamicin A,b:

(7) calicheamyciny!,

R=

Scheme 3) which abstract hydrogen atoms from the deoxyribose units of DNA and thereby initiate strand scissions. [l]In the case of the calicheamicins and the esperamicins this process is triggered by a bioreductive cleavage of the allylic trisulfide (see Scheme 3: (28) -+ (29) (30)). The thiolate thus formed adds intramolecularly to the enone system. Thereby the two acetylenes present are brought into closer contact so that the Bergmann cycliza-

I

R=

H:

(3) chromophor of

neocarcinostatin

R'

h

. I

MS

OM'

OH

Me

2 =OMS O

R' = CH3

HO

0

(4) dynemicinA

372

B. Synthesis of Individual Natural Products

tion proceeds even at room temperature. In the case of dynemicin A the opening of the epoxide initiates the respective reaction cascade and in the case of neocarcinostatin the vinylogous addition of an S- or 0-nucleophile to the epoxide (see (3)) leads to the formation of an enynecumulene intermediate, which reacts further to give an indacene diradical. The hope and expectation to develop less complex and consequently more accessible analogs with similar physiological activity, [11 which might open up new routes for cancer chemotherapy and the challenge to synthesize these complex antibiotics were driving forces initiating numerous research activities. [11 These efforts have recently culminated in the successful total synthesis of enantiomerically pure calicheamicin y.: [2, 71 For the construction of the bicyclo[7.3.l]tridecaenediyne core structure of the aglycon of the calicheamicins three synthetic routes were developed. [l] In each case initially the enediyne was built up from cis-1,2dichloroethylene (5) via Pd(o)-mediated coupling with suitably functionalized copper acetylide [3] in the sense of a Heck reaction. By means of this technique Schreiber et al. [4] synthesized the aldehyde (6), to which a further diene unit was added by nucleophilic addition of a vinyl lithium compound (Scheme 1). After the removal of the silyl protecting group from the terminal acetylene, in a further Pd(o)-catalyzed coupling reaction the authors attached a vinylene carbonate to (7) to give (8),thereby installing the functionality required for an intramolecular Diels-Alder reaction that delivers the bicyclic compound (9). To build up the hydrocarbon framework (10) of the esperamicins the protecting groups were cleaved and after regioselective mesyl-

Scheme I. Construction of the bicyclco[7.3.l]tridecaenediyne core structure of the calicheamicins according to Schreiber et al. [4].

tt

p

1) 120%

2) K,cq

0

Synthesis of Calicheamicin y;

ation an Et2A1C1-inducedpinacol rearrangement was initiated, that was immediately followed by an acyloin shift. Magnus et al. [5a,b] and Tomioka et al. [5c] employed the Pettit-Nicholas reaction and an intramolecular aldol addition, respectively, to effect the decisive ring closure leading to the bicyclic system. The precursors (13) and (14) used for this purpose were built up according to the above mentioned method of successive acetylene couplings (Scheme 2). In the enediyne (11) first the enol ether protecting group was exchanged (MEM +TBDMS) and the sterically less hindered alkyne was converted to the dicobalthexacarbonyl cluster

Sil = TBDMS = -SiMe2tBu MEM = MeO-CH&H&-CHT

373

(13). The cyclization product (15) was formed from (13) in the presence of T iC WAB C O via an intermediate propargyl cation. In the case of the aldehyde (14) the Nicholas reaction was ineffective, although an aldol addition via a boron enolate turned out to be successful. On treatment of the ketoaldehyde (14) with dibutylboron triflate/DABCO the aldol adduct (16) was formed exclusively from which the desired enediyne (17), having the correct relative stereochemistry, was liberated by oxidative decomplexation. The first total synthesis of the racemic aglycon of the calicheamicins (+)-calicheamicinone (28) was reported by Danishefsky et al. [6] For the construction of the bicyclic framework the lithium salt of the enediyne (20) was added chemoselectively to the keto group of the ketoaldehyde (18) , which was obtained from 3,s-dimethoxybenzoic acid. In the coupling of (18) and (20) the aldehyde group was protected in situ by preceeding conversion to the lithium salt (19) (Scheme 3). Subsequent

(12) R = H R=CY

1) W,BBr

I

1

&I,BOTf/ DAkO

2) TBDMSOTf / Mt,

X=

OH

(15) X = H (f6) X = OH

Me' 'Oe

(1 71

Scheme 2. Construction of the bicyclo[7.3.l]tride-

caenediyne core structure of the aglycon of the calicheamicins according to Magnus et al. [5a] and Tomioka et al. [5b].

374

B. Synthesis of Individual Natural Products

(28) calicheamicinone

a Scheme 3. Synthesis of racemic calicheamicinone according to Danishefsky et al. [6].

nucleophilic addition of the potassium acetylide to the aldehyde delivers the desired bicyclic framework. The functionalities introduced thereby then allowed for the installation of the structure of the natural products. After conversion of the enol ether to a ketal the epoxide could be opened by acetolysis and

the respective diol was subsequently oxidized to the ketone (23). In the following steps the vinyl bromide was transformed to the required urethane. After exchange of the bromide by a i d e via a conjugate additiodelimination sequence the authors attached the olefination reagent (24) regioselectively to the secondary

Synthesis of Calicheamicin yl’

alcohol and then elongated the double bond system by an intramolecular Horner-Emmons reaction to give the lactone (25). The extension of the conjugated system was necessary to guarantee the configurational stability of the enamine, which was generated by liberation of the amine function from the azide. After formation of the urethane (26) subsequent treatment with diisobutylaluminum hydride (DIBAH) resulted in the simultaneous cleavage of the carbonate present in (26) and the reduction of the lactone to the ally1 alcohol (27). By means of a Mitsunobu reaction the alcohol could then be converted to the thiol, which, upon treatment with methylphthalimidodisulfide, formed the trisulfide structure present in the natural product. Finally, calicheamicinone (28) was isolated after cleavage of the ketal. For this aglycon of the calicheamicins and related model compounds the authors demonstrated that the cycloaromatization of the enediyne may be triggered by a thiol-mediated reductive cleavage of the trisulfide. On treatment of (28) with benzyl mercaptan and NEt, the diradical (29) is formed,

which is converted to the tetracyclic compound (30) in the presence of 1,4-cyclohexadiene. The first enantioselective total synthesis of enantiomerically pure (-)-calicheamicinone was reported by Nicolaou et al. [7b]. The decisive steps are highlighted in Scheme 4. By means of the diisopinocampheyl borane (32) the lactol (31) was converted to the diol (33), which was formed with >98 % de. This optically active compound was then transformed to the enantiomerically pure isoxazoline (34) employing an intramolecular nitrile oxide cycloaddition as the key step. The stereocenters present in (34) then direct the steric course of the attack of a lithium acetylide to the carbonyl group to give (35),which was further converted to the protected acyclic enediyne (36) in six steps. Subsequently the isoxazole moiety present in (36) was transformed to the protected amino aldehyde (37) via reductive opening of the heterocycle by means of molybdenum hexacarbonyl. Next the ring closure was effected by intramolecular addition of the acetylide generated from (37) to the

gMEM nitrilodde cydoaddilion)

U

(37)

(33)

A N , -

0

Me$i-C=C-Li

cp n

n

n 0 0

0

AcO

0

6 steps

0

+

C02Me

MEMO

Me/MEMO

\

SiMe3

(35)

(34)

(36)

n NPhth toluene. - W C

2) 4 steps

H (37)

375

(38)

Scheme 4. Synthesis of enantiomerically pure (-)-calicheamicinone according to Nicolaou et al.

376

B. Synthesis of Zndividual Natural Products

aldehyde function. Finally, (38) was transformed to calicheamicinone (28) in 11steps. Whereas the unusual reactivity of the aglycon is responsible for the DNA cleaving activity of calicheamicin ,y: the carbohydrate part seems to recognize TCCT tetrades of DNA, thereby allowing for a sequence specific mode of action. [l]Nicolaou et al. [7a] succeeded in

the first total synthesis of this complex oligosaccharide (Scheme 5) and Danishefsky et al. [8a] subsequently described the construction of this aryl tetrasaccharide in a protected form but with reducing terminus. First, Nicolaou et al. linked the saccharide units A and B (see (49)) by coupling of the selectively deprotected fucose (39) and the

then Br,. &I,SnOMe

EtN

OMe

-

t

I,&lutidine

Silo

1) DIEAH

> (45)

(44)

= @-@ O,c/CI

2) 1) toluene, NaSMe, EtSH llO'C

>

t

N 0-"

Meo*e MeO

I

Silo (46)

TES0O -

OTES

(47)

Synthesis of Calicheamicin y j

1-fluorodeoxypentopyranose (40) obtained from L-serine to give the disaccharide (41) (Scheme 5). After removal of the carbonate protecting group the liberated 1,2-diol was oxidized regioselectively to give the a-hydroxy ketone (42), which underwent condensation with the glycosylhydroxylamine(43) to deliver the trisaccharide (44).The correct substitution pattern in the C part was installed by employing a [3,3]-sigmatropic rearrangement as the key step. After exchange of the m-chlorobenzoyl group in (44) into a thionoimidazolide warming in toluene resulted in the formation of the 4-thioester, which was cleaved to give the thiol (46). Nicolaou et al. chose this elegant reaction sequence although an efficient synthesis of the required 4-thiohexopyranose had been developed by Scharf et al. [9] After liberation of the thiol the extension of the aryl oligosaccharide by the

units D and E was achieved by employing the acid chloride (47). After having connected all subunits required, the silyl enol ether in ring C was cleaved selectively with fluoride ion and the ketone generated thereby was reduced stereoselectively with K-selectride. Next the silyl ethers in ring E and the Fmoc group in ring A were removed by treatment with HF/pyridine and HNEt2/THF, respectively. Finally, reduction of the oxime to give the desired hydroxylamine using NaCNBH, in the presence of BF,.OEt, completed the synthesis of the complex oligosaccharide, which was obtained as the methyl glycoside (49). For the construction of the D-E subunit (47) the glycosyl fluoride (50) was used (Scheme 6a). Compound (50) was activated by a method developed by Mukaiyama et al. and reacted with the hexasubstituted phenol (51) to give the phenyl glycoside (52) in high

3 Et3

148)

4)

Fmoc-N Et

OMe

T

1) Bu,W F; then K-selectride 2) HF-pyridine

HO

Ij;cNBnJ BF,

OEt,

EtHN

Fmoc =

377

OMe

O-C( Sil = TBDMS = SiMePtBu TES = SiEtB

Scheme 5. Synthesis of the carbohydrate part of calicheamicin according to Nicolaou et al. [7a].

378

B. Synthesis of Individual Natural Products

yield and with complete stereoselectivity. The glycosylhydroxylamine (43) was built up from the selectively deblocked glycal (53) (Scheme 6b). Directed by the 3-OH group the enol ether was stereoselectively converted into the a) COOMe

"We COOMe

mo I

MeO

AcO

OAc

PhCOO

epoxide, which was immediately attacked by the formed rn-chlorobenzoic acid to deliver the trans-product (54). After silylation of the 3-OH group the alcohol in the 2-position was subjected to Swern oxidation, during which the 4-benzoate was simultaneously eliminated (+ (55)). Stereoselective reduction of the ketone generated the equatorial alcohol, which immediately captured the protecting group at C-1 in the course of an acyl migration. Thereby, the anomeric center in (56) was deblocked and could be used for introduction of the hydroxylamine. For this purpose a Mitsunobu reaction with a hydroxamic acid as monofunctional nucleophile turned out to be particularly suitable. Having gained an access to both the complex oligosaccharide and the aglycon of calicheamicin the Nicolaou group finally succeeded in the first total synthesis of the entire drug [7c] by coupling of the two fragments (Scheme 7). To this end, the enantiomerically pure precursor (57) to calicheamicinone was constructed from the intermediate (38) (see Scheme 4) in seven steps. By analogy to the synthesis of the aryl tetrasaccharide

PhCOO

HO

HO

(54)

(53) WH,h

>

OCOAr

(55)

OCOAr

I

Y

OH (56)

Ar

0

Ar

Scheme 6. Synthesis of the D-E subunit (47) and the glycosylhydroxylamine(43) according to Nicolaou et al. [7a].

Synthesis of Calicheamicin y,'

379

Scheme 7. Final steps in the total synthesis of enantiomericallypure calichearnicin according to Nicolaou et al. [7c].

(40) (see Scheme 5) the respective orthonitrobenzyl glycoside was built up, from which the blocking group at the anomeric center of glycosyl unit B could be removed selectively by photodeprotection. The two complex fragments were then coupled by making use of the trichloroacetimidate method developed by Schmidt. Thus, the oligosaccharide was converted into the glycosyl donor (58), which reacted with the glycosyl acceptor (57) in the presence of BF3 . OEtz to give the desired glycoside in 76% yield. Finally, the complete natural product (59) was constructed in 10 further steps, which were required to install the trisulfide moiety, for the reduction of the oxime bond and for the final deprotections. By this impressive achievement Nicolaou et al. have certainly set a landmark in the total synthesis of complex compounds. It should, however, be noted that Danishefsky et al. also independently succeeded in the coupling of an advanced precursor to calicheamicinone to a protected derivative of the saccharide [8a] and that this group very recently reported the sec-

ond total synthesis of enantiomerically pure calicheamicin by a shorter and more efficient synthetic route. [8b]

References [l] Review: K. C. Nicolaou, W.-M. Dai. Angew. Chem. 1991,103, 1453; Angew. Chem. Int. Ed. Engl. l99l,30, 1387. [2] Review: K. C. Nicolaou, Angew. Chem. 1993, 105, 1462; Angew. Chem. Int. Ed. Engl. 1993, 32, 1377. [3] a) R. D. Stephans, C. E. Castro, J. Org. Chem. 1963, 28, 3313; b) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett 1975, 4467. [4] F. J. Schoenen, J. A. Porco, Jr., S. L. Schreiber, Tetrahedron Lett. 1989, 30, 3765 and references given therein. [5] a) €? Magnus, H. Annoura, J. Harling, J. Org. Chem. 1990,55, 1709 and references given therein; b) €? Magnus, R. T. Lewis, J. C. Huffrnann, J. Am. Chem. SOC. 1988, 110, 6921; c) K. Tomioka, H. Fujita, K. Koga, Tetrahedron Lett. 1989,30, 851.

380

B. Synthesis of Zndividual Natural Products

[6] J. N. Haseltine, M. Paz Cabal, N. B. Mantlo, N. Iwasawa, D. S. Yamashita, R. S. Coleman, S. J. Danishefsky, G. K. Schulte, J. Am. Chem. SOC. M, 113, 3850 and references given therein. [7] R. D. Groneberg, T. Miyazaki, N. A. Stylianides, T. J. Schulze, W. Stahl, E. P. Schreiner, T. Suzuki, A. L. Smith, K. C. Nicolaou, J. Am. Chem. SOC.1993,115, 7593; b) A. L. Smith, E. N. Pitsinos, C.-K. Hwang, Y. Mizuno, H. Saimoto, G. R. Scarlato, T. Suzuki, K. C. Nicolaou, J. Am. Chem. SOC. 1993,115, 7612; c ) K. C. Nicolaou, C. W. Hummel, M. Nakada, K.

Shibayama, E. N. Pitsinos, H. Saimoto, Y. Mizuno, K.-U. Baldenius, A. L. Smith, J. Am. Chem. SOC. 1993,115, 7625. [8] R. L. Halcomb, S. H. Boyer, S. J. Danishefsky, Angew. Chem. 1992,104, 314; Angew. Chem. Int. Ed. Engl. 1992, 31. 338; b) S. A. Hitchcock, S. H. Boyer, M. Y. Chu-Moyer, S. H. Olson, S. J. Danishefsky, Angew. Chem. 1994, 106, 928; Angew. Chem. Int. Ed. Engl. 1994,33,858. [9] K. van Laack, H.-D. Scharf, Tetrahedron Lett. 1989,30,4505.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Total Synthesis of Rapamycin Martin Maier

It is sufficiently known that the discovery of a transition of the cell from the Go to the GInew classes of natural products can influence phase. Within the cell, a kinase cascade is chemistry, biology and medicine. If natural started (kinases are enzymes that catalyze the products interact selectively with biological phosphorylation of substrates), which, among systems, they can serve as important probes other things, induces an increase in the Ca2+for the discovery of hitherto unknown bio- concentration in the cytoplasm. Furthermore, logical processes. Recent prominent examples the calmodulin-dependent phosphatase calcifor such compounds are the ene-diyne antitu- neurin (CaN) is activated. It is assumed that mor antibiotics [ 11 and the immunosuppres- one target of CaN is the cytoplasmatic subunit sives cyclosporin (Csa), FK506 (2), and of the transcription factor NF-AT. This factor, rapamycin (I).Biochemical studies with these which regulates the transcription of the IL2immunosuppressives enable one to determine gene, can, after cleavage of the phosphate how signals from receptors in the cell wall pass groups by CaN, migrate into the nucleus and through the cytoplasm to certain gene seg- take over its regulatory duties. Now the ments in the nucleus. [2] Normally, the bind- activated cell produces IL2 and, in addition, ing of an antigen to the T-cell receptor causes exprimes IL-2 receptors (IL-2R) at the cell

Raparnycin ( I )

FK506 (2)

382

B. Synthesis of Individual Natural Products

surface. The binding of IL-2 to the IL-2R subsequently causes the transition of the cell from the GI- to the S-phase. In a normal signal process, that is, in the absence of the immunosuppressives, this is followed by hyperphosphorylation of the 40s ribosomal protein S6 by two kinases ~ 7 0 ’and ~ ~ ~ 8 5 The ~ ~

OMe A?,,VPh

0

f71)

complete steps of the activation process seem be relatively automatic and proceed according to a time-regulated order, whereby a later step depends on an earlier step. During the complete activation process about 70 moleculs are specifically regulated. [3] It turned out that despite ~ . their structural similarities, rapamycin

Me

Me

(12)

TES = Triethylsilyl TBS = terieutyldimethylsilyl TIPS = Triisopmpylsilyl DEIPS = Diethylisopropylsilyl TBDPS = te/tButyldiphenylsilyl Scheme I. Retrosynthetic disconnection of rapamycin according to Nicolaou. PMB = pMethoxybenzyl

Total Synthesis of Rapamycin

(I) and FK506 (2) influence different signal paths in T-cells. This was the more surprising because in a first step the two compounds bind to the same cytosolic protein, the FKBP12 (FK506 binding protein with a mass of 12 kD). This seemingly strange result could be explained by invoking a so-called dual domain model. That means, FK506 and Rapamycin possess a common binding domain that is responsible for binding to the FKBP. As a result of this complexation these molecules gain, so to speak, a new function and are now able to interact via their efSector elements with different target molecules, whereby at least ternary complexes are formed. [2] The target of the FK506-FKBP-complex is the phosphatase CaN, which is thereby blocked in its activity. In contrast, the rapamycin-FKBP-complex interferes with the signal that originates from the IL-2R. Although the exact binding partner of the rapamycin-FKBP-complex is not yet known, it is established that the ~ 7 (S60 kinase) is deactivated. [4] The activity of the other important S6-kinase, p85S6K,remains unaffected by rapamycin. It is assumed that rapamycin-FKBP activates a hitherto unknown ~ 7 0 phosphatase. ’ ~ ~ That is, ~ 7 would be deactivated by dephosphorylation. [5] In any case these studies underline the enormous significance of phosphate groups for the activity of enzymes. [6] Compounds that are able to inhibit kinases and phosphatases in a cell- and enzyme-specific manner, could also gain medicinal importance. Moreover, these studies demonstrate the importance of multicomponent complexes for the transfer of selectivity in biological systems. In the light of this, it is understandable that these novel macrolides have stimulated enormous synthetic activity. After all, the interesting structural features of these two compounds have contributed to their appeal as synthetic targets. Recent highlights from this area are the total synthesis of rapamycin (1) by several American groups. The short publication intervals show that the synthetic undertaking was

383

like a race. Characteristic structural features of rapamycin include, apart from the triene unit, the asymmetric centers and the tricarbonyl functionality of the molecule. Some of the chiral centers are separated by more than one bond, so that well-established standard procedures for the functionalization of prochiral centers could only be used to a limited extent. In the synthesis of Nicolaou, the molecule is disconnected to give eight small optically active starting materials (Scheme 1). [7] Usually macrolides or macrolactams are assembled from the corresponding seco acids by macrocyclization. Nicolaou instead chose another strategy, namely cyclization by a double Stille coupling. In the final phase of the synthesis bond formation occurs according the numbering given in Scheme 1. The retrosynthetic disconnection of compound (I) proceeds first to the three major fragments (3), (4),and (5). The two large fragments (3) and ~ are~not ~constructed individually from one (4) optically active precursor but rather traced back to four smaller parts. A certain guiding principle of the synthesis is the construction of two stereocenters that bear methyl groups by 0 Evans-aldol ~ ~ reaction ~ an (cf. reagents (10) and (13)). The synthesis of the fragment (3) begins with the preparation of the a, Punsaturated ketone (14)from the vinyl iodide (6) and the Weinreb-amide (7), itself obtained from Lascorbic acid (Scheme 2). With the reagent combination LiAlHJLiI, reduction of the carbony1 group with complete asymmetric induction takes place, whereby chelation of Li’ between the alkoxy- and the carbonyl oxygen controls the formation of the 1,3-syn-product. Four more steps from (15)made available the terminal epoxide (16). This was opened with the iodide (8) derived from (S)-methyl-3hydroxy-propionate. In order to form this C-C bond, (8) is first converted with tBuLi/2thienylCu(CN)Li to a higher order cuprate that reacts with the epoxide. After silylation of the OH-function, the vinyl silane group was

384

B. Synthesis of Individual Natural Producfi Me

WuLirrhienylCuCNLi 2. TlPSOTf (@orb) 3. NIS, THF 4. DDQ 5. swemxidat.

6Me (16) Me-

ph

-

PMBO

-

Me

1.

0 m e "PS

O

0

2.3 steps

(17)

Me

I

OH

10

&Me &TIPS

OH

OH

9

0

(3)

Scheme 2. Synthesis of the acid (3).

converted with NIS to a vinyl iodide and subsequently an aldehyde function was installed at the other end. The aldehyde (17) reacted with the boron enolate of the oxazolidinone (9) to give the syn-aldol product, from which the acid (3) could be obtained after cleavage of the chiral auxiliary and the PMB-protecting group. Control of the stereochemistry at the positions 9 and 10 is not actually necessary because these later become sp2-centers. However, this undoubtedly facilitates the analysis of the spectra of these compounds. [8] The entry to the synthesis of the C-21-C-42 fragment (4) takes place by an Evans-aldol reaction between the oxazolidinone (10) and the aldehyde (11) (Scheme 3). [9] While the aldehyde (11)was prepared in five steps from D-mannitol, (+)-citronelline served as a source for the stereocenter at position 23. Under the chosen conditions (Bu,BOTf,

NEt,), the stereochemical course of the aldol reactions is predictable, namely a synorientation of the residues a and p to the carboxy function, whereby in the depicted rotamer both are anti to the residue in the oxazolidinone. It should be noted that with other conditions other diastereomers are accessible. [lo] Subsequent to the aldol reaction the carboxyl function was converted to a methyl group (cf. compound (19)). In order to liberate the primary hydroxy group, the authors proceed through a p-methoxybenzylidene intermediate (20) that could be opened reductively in a regioselective manner and that therefore provides access to the aldehyde (21). In the other important building block (12) the stereocenters were generated via the addition of a chiral (E)-crotyl borane according to Brown. For the preparation of antzpropionate units this procedure is more

Total Synthesis of Rapamycin

385

PMP OH

Me

Me

1. CpgrHCl

I

oms

o*o Me

OM8

Me

Me

I

PMBO

Me

w e

Me

Me

tile (12)

m e

OMe (21)

1. CrC12, NiC12

2. 12

Me

*

2. TlPSOTf 3. HFlpyridine 4. Swemoxidat

(25)

Scheme 3. Synthesis of the C(21)-C(34) building block of rapamycin by Nicolaou.

practicable than an asymmetric aldol reaction, because the corresponding enolates are not easily accessible. The alkyne (24) was obtained from (23) in several steps. The alkyne in turn allowed preparation of the vinyl iodide (12) by a regioselective hydrozirconation. In the coupling reaction of the two fragments (12) and (21) with chromium(I1)chlo-

ride in the presence of catalytic amounts of nickel (11) chloride, the desired Cram isomer was formed. [ll] Protection of the hydroxy group, selective cleavage of the TBSprotecting group, followed by oxidation furnished the aldehyde (25). Fragment (4) which contains the cyclohexyl part, was obtained from 2-bromocyclohexenone (26). Through a

386

B. Synthesis of Individual Natural Products

5 steps

Aldnl reactinn

(32a) R = Ph (32b) R = Me

(4)

. ntipynoine

HI”‘

I-

4. Swem-oxidat. 5. HF/H2O

Pd(CH,CN),Cr, (28%)

(33)

Scheme 4. Connection of the building blocks to rapamycin with a double Stille coupling as the key step.

Total Synthesis of Rapamycin

catalytic enantioselective reduction an optically active ally1 alcohol could be generated that in a straightforward manner led to the enone (28) via (27). Attachment of the side chain was carried out by an EschenmoserClaisen rearrangement. The aldehyde ob-

387

tained from (29) was condensed with the chiral keto-phosphonate (31) and transformed by hydrogenation to (13). Following the approved principle for the connection of (13) and (25), an Evans-aldol reaction was used, which creates two stereocenters and also pro-

mso 0

0

OPMB

x

HI'''

0

oms Bzi

Scheme 5.Retrosynthetic disconnection of rapamycin by Schreiber.

Me

Me

(41)

388

B. Synthesis of Individual Natural Products

vides the methyl group at C-35. Further steps before the triethylsilyl protecting groups were served to attach N-Boc-pipecolinic acid to removed and the secondary alcohol functions (32), then conversion of the terminal alkene oxidized. The last step before the macrocyclgroup to an alkenyl iodide, and the replace- ization was to cleave the remaining silyl ment of the PMB- for silyl protecting groups. groups. Indeed, the incorporation of the midAfter amide bond formation between (4) and dle olefin with concomitant macrocyclization the acid (3), the a, Fdihydroxy amide func- proved to be successful, although rapamycin tion was first oxidized to the tricarbonyl stage was obtained only in 28% yield (Scheme 4).

Scheme 6. Retrosynthetic disconnection of raparnycin according to Danishefsky.

Total Synthesis of Raparnycin

Besides unreacted starting material (33), a monocoupling product could be isolated that, however, could also be cyclized to give (1). Without counting the steps necessary for the entrance to the synthesis, this route still requires 61 steps. In contrast to the above strategy, Schreiber chose the rather conventional route via formation of the lactam bond for the macrocyclization. [12] Rapamycin (1) is retrosynthetically disconnected by cleavage of one of the double bonds of the triene unit to the two large fragments (34) and (35). The somehow larger building block (35) has its origins in the four chiral fragments (38)-(41) (Scheme 5). In the forward direction an initial connection of the fragments (34) and (35) was performed. Before the macrocyclization (step 3 in Scheme 5 ) could be carried out, a G-building block in form of ethoxyethyl acetate had to be incorporated via an aldol reaction (step 2 in Scheme 5).

PhS

4. H30*, K2C03 allylbrornide

389

In the latest rapamycin synthesis by Danishefsky et al. [13] a further variation of the macrocyclization was introduced. In the crucial step the ring closes via an intramolecular aldol reaction (cf. step 3 in Scheme 6). This conception is remarkable inasmuch that two stereocenters must be formed simultaneously. If, however, this ring closure reaction had failed, there would still have been the option via the classical route, that is, macrolactoneor macrolactam formation would have remained. The building block (46) was synthesized starting from D-glucal. Subsequent transformation of the stereochemical information from position 13 to 11 by a vinylogous substitution of the mesyl group with methyl cuprate is quite interesting. In this SN2'reaction the methyl group attacks anti to the leaving group. [14] The components of the other central building block (43) were developed from 2-deoxy-glucose and (R)-3benzyloxy-2-methyl-propanal (50). [ 151 Im-

3. esterification with (43) 4. Bu4NF

(54)

Scheme 7. Synthesis of rapamycin with a macroaldol reaction as key step.

390

B. Synthesis of Individual Natural Products

portant intermediates are represented by the acid (48) and the cyclohexenol (49). These two fragments were first esterified and then the resulting ester subjected to an IrelandClaisen rearrangement. In preparation for the macrocyclization (Scheme 7), the building block (44) was condensed with the aldehyde (42). With the DessMartin reagent direct oxidation of the asulfonyloxy-phydroxy group to a carbonyl group was feasible. Cleavage of the TBSprotecting group was accompanied by the formation of the pyran ring. In order to prevent rearrangement during the esterification of the alcohol (43) with pipecolinic acid, it was necessary to protect the tertiary O H group of the hemiacetal. Because this protecting group (a TMS ether!) had to survive the liberation of the carboxy function, the Boc-group was first replaced by an allyl-protecting group (cf. compound (53)). From (53) the cyclization substrate (54) could then be obtained. Oxidation of the alcohol at C32was followed by the intramolecular aldol reaction. Using iPrOTiC1, a titanium enolate could be generated that provided the rapamycin precursor in a yield of 11%. In addition, a further ring was formed (22%), which was a stereoisomer of the desired compound. The number of required steps for this route is 82. A comparative evaluation probably will not do justice to these highlights. Clearly, all of them contain a number of standard reactions, nevertheless each of the syntheses is characterized by some remarkable steps. Regarding the ring closure, the syntheses of Nicolaou and Danishefsky are the most original. However, it is striking that in all these syntheses the retrosynthetic disconnections are in similar regions. The characteristic of each synthesis results partly simply from the different sequence of bond formation. In particular, the syntheses demonstrate in an impressive way several modern methods for the creation of stereocenters and they illustrate nicely the skillful application of silyl protecting groups with diverse stability.

References a) H. Waldmann, Nachr. Chem. Tech. Lab. 1991, 39, 211-217; b) K. C. Nicolaou, W.-M. Dai, Angew. Chem. 1991, 103, 1453-1481; Angew. Chem. lnt. Ed. Engl. l99l,30, 1387; c) M. D. Lee, G. A. Ellestad, D. B. Borders, Acc. Chem. Res. 1991, 24, 235-243; d) I. H. Goldberg, Acc. Chem. Res. 1991,24, 191-198; e) K. C. Nicolaou, A. L. Smith, Acc. Chem. Res. 1992,25, 497-503. Reviews: a) M. K. Rosen, S. L. Schreiber, Angew. Chem. 1992, 104, 413; Angew. Chem. Int. Ed. Engl. 1992,31, 384; b) S . L. Schreiber, G. R. Crabtree, Immunology Today, 1992, 13, 136; c) S. L. Schreiber, J. Liu, M. W. W. Albers, M. K. Rosen, R. F. Standaert, T. J. Wandless, P. K. Somers, Tetrahedron W ,48, 2545; d) R. E. Morris, Immunology Today, 1991,12, 137; e) P. J. Belshaw, S. D. Meyer, D. D. Johnson, D. Romo, Y. Ikeda, M. Andrus, D. G. Alberg, L. W. Schultz, J. Clardy, S. L. Schreiber, Synlett 19w,381-392. G. R. Crabtree, Science 1989,243, 355-361. a) C. J. Juo, J. Chung, D. F. Fiorentino, W. M. Flanagan, J. Blenis, G. R. Crabtree; Nature 1992,358, 70-73; b) D. J. Price, J. R. Grove, V. Calvo, J. Avruch, B. E. Bierer, Science 1!)92, 2.57, 973-977. For a short summary, see: S. L. Schreiber, Cell 1992, 70, 365-368. See also: a) E. Krebs,Angew. Chem. 1993,105, 1173; Angew. Chem. Int. Ed. Engl. 1993, 32, 1122, b) E. H. Fischer, Angew. Chem. 1993, 105, 1181;Angew. Chem. Int. Ed. Engl. 1993, 32, 1130. K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, P.Bertinato, J. Am. Chem. SOC. 1993,115, 4419-4420. A. D. Piscopio, N. Minowa, T. K. Chakraborty, K. Koide, P. Bertinato, K. C. Nicolaou, J. Chem. SOC., Chem. Commun. 1993, 617-618. K. C. Nicolaou, P. Bertinato, A. D. Piscopio, T. K. Chakraborty, N. Minowa, J. Chem. SOC., Chem. Commun. B93,619-622. M. Nerz-Stormes, E. R. Thornton, J. Org. Chem. 1991,56, 2489-2498; b) M. A. Walker, C. H. Heathcock, J. Org. Chem. 1991, 56, 5747-5750.

Total Synthesis of Rapamycin

[ll] For an alternative procedure for the construction of such allylic alcohols, see: M. E. Maier, B.-U. Haller, R. Stumpf, H. Fischer, Synlett 1993, 863. [12] D. Romo, S. D. Meyer, D. D. Johnson, S. L. Schreiber, J. Am. Chem. SOC. 1993, 115, 7906-7907. [13] C. M. Hayward, D. Yohannes, S. J. Danishefsky, J. Am. Chem. SOC. 1993, 115, 9345-9346.

391

[14] a) S.-H. Chen, R. F. Horvath, J. Joglar, M. J. Fisher, S. J. Danishefsky, J. Org. Chem. 1991, 56, 5834-5845; b) R. F. Horvath, R. G. Linde, 11, C. M. Hayward, J. Joglar, D. Yohannes, S. J. Danishefsky, Tetrahedron Lett. 1993, 34, 3993-3996. [15] M. J. Fisher, C. D. Myers, J. Joglar, S.-H. Chen, S. J. Danishefsky, J. Org. Chem. 1991, 56, 5826-5834; b) C. M. Hayward, M. J. Fisher, D. Yohannes, S. J. Danishefsky, Tetrahedron Lett. 1993,34, 3989-3992.

Organic Synthesis Highlights I1 Edited by Herbert Waldmann OVCH Verlagsgesellschafi mbH,1995

Subject Index

A acetal cleavage 217 acetate aldol equivalent 117 1,3-acetonides 213 acetyl hypofluorite 244 N-acetylglucosaminyl glycosides 297 N-acetyllactosamine 161 N-acetylmannosamine 151 N-acetylneuraminic acid 151, 158 acid phosphatase 147 (-)-acosamine 81 acyl oxazolidinone 254, 257 O-acyl-glycosylamines 330 C-acylimines 37 N-acylimines 37 N-acylnitroso compounds 43 acyloin condensation - yeast-mediated 152 - enzymatic 152 acylsilanes 129f AD-mix 15 additions - 1,Zadditions 125f - chelation controlled 253, 255 - conjugate 255 - zirconocene-catalyzed 103 aeginetolide 19 AIDS 251 (-)-ajmalicine 195 aldehydes - conjugate reduction of 117 - re-face 29ff, 35 - si-face 30ff - a,/3unsaturated 117 aldol reactions 117, 150, 181, 238, 252, 339, 389

carbene complex anions 83 diastereofacial selectivity 83 diastereoselective 85, 254 enzymatic 333 Evans aldol reaction 384, 388 intramolecular 181, 189, 303, 338 - propionate 34 - retro 336 - stereoselective 118 aldolases - N-acetylneuraminic acid aldolase 151 - 2-deoxyribose-5-phosphate aldolase 151 - fructose-1,6-diphosphatealdolase 147 - fuculose-l-phosphate aldolase 150 - rhamnulose-l-phosphate aldolase 150 - tagatose-l-phosphate aldolase 150 anti-aldols 34, 117 syn-aldols 34 alkaline phosphatase 163 alkaloids - azepine alkaloids 198 - chinolizidine alkaloids 171 - corynanthe alkaloids 196 - daphniphyllium alkaloids 189 - discorhabdin alkaloids 225 - ergot alkaloids 315 - iboga alkaloids 197 - lycopodium alkaloids 187 - piperidine alkaloids 323ff - tetrahydrocarbazole alkaloids 197 - uleine alkaloids 197 alkenyliodonium salts 227 alkinyliodonium salts 227 alkoxycarbene complexes 86 alkyl transfer 32 alkylation - diastereoselective 257 -

394

Subject Index

alkynes 170 allenylstannanes 56 allopumiliotoxine 339 A 196 allosamidin 272 D-allose 232f - synthesis 233 allyl amines 106 allyl boranes 213 allyl silanes 60, 131, 170, 173f, 185, 188, 303,363 allyl stannanes 56, 181f, 185 allyl transfer 29f, 32, 35 allylic alcohols 131 allyltrimethylsilane 255 allylzirconocenes 108f aluminium alcoholates 115 aluminium alkyls - conjugate addition to a,punsaturated carbonyl compounds 115 aluminium enolates 115ff - conjugate reduction via 116 - electrophilic substitution with 116 amides - acrylic 80 amino acid derivatives - chiral glycine 89 amino acid esters 23, 89 - mediators of selectivity 41 amino acids 251ff - pamino acids 278 - functionalization 35 amino alcohols 106 aminocarbene complexes 83ff - a-CH-acidity 83 - acylation 87 - aldol reactions based on 85 - aminocarbene chelate 87 - carbonyl carbene coupling 88f - optically active 88f - photochemical reactions 88f - stereoselective reactions 83 - synthesis 84 - thermal reactions 88ff aminoindene 88 aminoketene complexes 88f - asymmetric protonation 89

aminonaphthol 88 6-aminopenicillianic acid 280 (S)-anabasine 331 anandamides 357 andrimid 272 angiotensinogen 251 anisomycin 271 anomeric effect 216 anthracyclines - nogalamycin 95 - (+)-pillaromycinone 93 anti-Felkin-Anh type conformation 39 anti-Markownikoff hydration 131 antibiotics 371 - antitumor 314 - (-)-hikizimycin 206 - (+)-macbecin I 238 antihypertensivity 302 antitumor antibiotics 314, 371 antitumor compounds 349 L-(-)-arabitol 215 arachidonic acid 302 armed/disarmed concept 297 aryliodonium salts 227 arylpropionic acids 26 asymmetric bisosmylation of C, 15 asymmetric deprotonation 19f asymmetric induction - internal 205 asymmetric intramolecular cycloaddition 38 asymmetric radical reactions 51 asymmetric reactions - coupled 212 asymmetric synthesis 257, 277 avermectin 268 avermectin B1 267, 297 avermectin B,-aglycon - retrosynthetic analysis 270 aza-Diels-Alder reactions 38 - aqueos solution 41 2-azabutadienes 44 azadirachtine 271 azametallacycles 100 aza-substituted dienes 37 aza-substituted dienophiles 37 aziridinium saIt 365

395

Subject Index

aziridinomitosene 313 azomethine ylide - carbonyl ylide-azomethine ylide isomerization 71 B

Baeyer-Villiger oxidation 233, 235 , 280 Baeyer-Villiger rearrangement 129, 131ff, 354 baker’s yeast 152, 278 Baldwin rules 136, 138 Barbier reaction 91 BASF 267 Basta@ 263 Beckmann rearrangement 198 benzene - oxidative fluorination 247 benzocyclobutane 200 benzylidene complex - tungsten 66 (R)-3-benzyloxy-2-methyl-propanal 389 Beret@ 263 Bergmann cyclization 371 bialaphos 263 biaryls 228 bicyclic amino acid esters 37 bicyclization - Ni-catalyzed 336 bilobalide 234 1,l-bimetallic compounds 109 (5’)-BINAP 210 biocatalyzed C-C bond forming reactions 147 biomimetic strategies 192 bioremedation 262 biosynthesis 187, 302 biotechnical processes 263 biotransformations 263 Birch reduction 213 bis(trimethylsily1)acetylene 199 bis-acids 215 bis-epoxide 213 bis-esters 215 bis-olefins 219 bovine serum albumine 154 (+)-brasilenol 19

Brassards diene 38 (+)-exo-brevicomin 149 bromomethyldimethylsilyl chloride 137 bromomethyldimethylsilyl ethers 137 l-bromovinyldimethylsilyl chloride 138 building blocks 231 butenolides 235f, 240

C C,-synthons

- nickel-activated 75ff C,-symmetry 11 C,-symmetric amines 44,49ff C,-symmetric chiral auxiliary groups C,-symmetric diols 24 Cz-symmetricpyrrolidines 53 calicheamicin 349, 371ff - racemic aglycon 373f -calicheamicinone 373 cancer 372 carbacephem 38, 68 carbacyclines 19, 301f, 304f carbapenam - exo-isomer 68 carbapenems 38, 68, 277 carbazomycines 62f carbene - singlet 99 carbene annulation 86f - alkoxycarbene complexes 86 - aminocarbene complexes 86 - aminoindene 88 - aminonaphthol 88 - formation of N-heterocycles 87 - intramolecular 86 carbene complex anions - aldol reactions 83ff - Michael reactions 84 carbene complexes 83ff carbene transfer reactions 65 carbenoids 65ff - C-Hinsertion 67 - cycloaddition 66 carbinols 56 carbohydrate complexes 29ff carbohydrate-derived imines 40

*

49

396

Subject Index

carbohydrates 232 carbon dioxide - activation 75ff carbon-carbon bond formation 227ff - aldolase-catalyzed 163 - diastereoselective 30 - enantioselective 29ff - using C1-synthons 35 - via carbene complexes 83ff - via radicals 93 - with ally1 metal reagents 125 - with group four metallocenes 99 carbonyl compounds - activation 91 carbonyl ylide-azomethine ylide isomerization 71 carbonyl ylides 68f, 71ff, 238 carboxylation 79 carboxylic acids 78 carboxylic esters - triene and tetraene 79 Carroll rearrangement 257 cascade reactions 195 CC-1065 349 cephalosporin 277 cerium trichloride - carbonyl reduction 95 - organocerium(rI1) compounds 94 chelation controlled reaction 255 chemoselectivity 135 chemotherapy 309,372 chiral auxiliary groups - 2,5-dialkoxymethylpyrrolidine 52 - 2,5-dimethylpyrrolidine 49 - cyclohexanediamine 54 chiral bases 209 chiral enol ethers 42, 46 y-chiral enones 84 chiral hetero dienophiles 44 chiral imines 41 chiral lithium amides 24 chiral radicals 51 chiron approach 278 CHIRON 269 chirotopic center 206 1-chloro-1-nitrosomannose 43

a-chloronitroso compounds 43 chlorosulfonylisocyanate 283 chromium carbonyl complexes 226 cinchona alkaloids 10, 25 Claisen condensation 254 Claisen rearrangement 309, 337 clavicipitic acid - isomerisation of 318 - synthesis 317ff cleavage - oxidative 253 CMP-NeuAc 159 CN(RS) method 327 CO, fixation 119 cocaine 357 codeine 358 codeinone 358 cofactor regeneration system 163 compactin 117 q4-complex 59 $-complex 59f complexation - catalytic 63 conduramine A 1 44 conduritol C 17 conduritol E 17 conduritol F 17 (R)-coniin 327 (S)-coniin 327 Corey-Chaykovsky reaction 252 (+)-coriolin 93 coupling reactions - alkene-aldehyde 101 - alkene-alkene 101 - zirconocene-induced 101 cross-coupling 77 cryptone 19 cubane 229 cuprates 108 - addition of 55 Curtius rearrangement 39 2-cyano-6-oxazolopiperidine 327 (R)-cyanohadrin 152 (S)-cyanohadrin 152 cyclizations 135ff, 168, 172f, 177, 181ff, 191, 339,349

Subject Index - ally1 silane cyclization 195, 198 - Bergmann cyclization 371 - a-diazo-pketoester 68

domino Heck cyclizations 201 295 - electrophilic 167, 171, 173, 181 - eado-cyclizations 176 - gem-dialkyl effect 136 - iminium ion-alkaline cyclization 196 - metal-induced 87 - nickel(o) catalysis 206 - of dienes 104 - of diynes 104 - of eneynes 104 - oxidative 60, 62f - palladium catalysis 210 - palladium mediated 313 - polyene cyclization 196 - radical cyclization 137, 303 - radical-initiated 5-exo-dig-cyclization 306 - rhodium catalyzed 65ff - ring size effects 136 - spiro-cyclization 61 - steric effects 136 - with group four metallocene catalysts 103f cycloadditions 136, 142,206, 231ff, 362 - [2+2] 11, 107,235,279 - [3+2] 12, 46 - [4+2] 231,235 - [4+3] 233 - asymmetric intramolecular 38 - 1,3-dipoles - enantioselective 232 - intramolecular 239,375 - nitrile-oxide 239, 375 - oxidopyrilium-alkene 239 - photocycloaddition 336 - stereoselective [2+2] 336 cycloalkylhydrazides 107 cycloaromatization 375 cycloheptenol 234 cyclohexane 206 cyclohexene 233 cyclohexenone 215 cyclopentadiene 206 -

- electrophile-initiated

cyclopentene 210f cyclopentenols 212 cyclopentenones 239 cyclopropanation 354 - enantioselective 65 cyclotrimerization of alkynes - cobalt catalyzed 199 D

DAHP synthetase 151 (-)-damascone 25 daphnilactone A 191 daphniphyllate - methylhomoseco 190 degradation - oxidative 254 dehydropiperdines 40 dehydrothiazine oxides 43 4-demethoxydaunomycine 11 denticulatin A 225 denticulatin B 225 deoxygenation 256 deoxyloganine 195 1-deoxynojirimicin 148 DEPC see diethyl phosphorocyanidate deprotonation - asymmetric 19 - diastereoselective 218 - enantioselective 21 - of meso-ketones 19 desoxyfuconojirimicin 323, 332f Dess-Martin periodinane 224 diacetone glucose complex 29ff 2,5-dialkoxymethylpyrrolidine 52 dialkylzirconocenes 101 diaryliodonium salts 228 diastereoselectivity 59, 135 diastereotopic face selectivity 211 diastereotopic groups 204 - differentiation 213, 216 diazo ketoamides 71 diazo reagents 65 diazoketones 66 DiBAH reduction 315 di-fert-butylsilylacetals 140

397

398

Subject Index

di-tert-butylsilylchlorosilanemonotriflate 140 1,3-dicarbonyl compounds 226ff dicobalthexacarbonyl cluster 373 Dieckmann condensation - intramolecular 339 Diels-Alder reactions 51, 133, 154, 350, 354,367 - asymmetric 41, 236 - aza-Diels-Alder reaction 191 - in aqueous solution 41 - intermolecular 84 - intramolecular 84,336f, 352, 372 - inverse electron demand 84 - Lewis acid mediated 40 - of iminium ions 171 - tandem Knoevenagel-hetero-Diels-Alder reactions 195 - with iminium salts 41 - with Schiff’s bases 40 1,3-dienes 109 - oligomerization 78 dienone 219 dienophiles 232 diethyl phosphorocyanidate 315 diethylaminosulfur trifluoride 243 dihydroactinidiolide 19 dihydrocinchona alkaloids 9 cis-dihydrodiols 16 dihydrooxazines 43 (+)-(2S,6R)-dihydropinidine 329f dihydropyrone 95 dihydroquinidine acetate 10 dihydroquinine acetate 10 dihydroxyacetone phosphate 147 dihydroxylation 9ff, 364 - asymmetric 7 - catalyticcycle 13 - ligand preference 15 - of olefins 14 - with phthalazine-derived ligands 14 diisopinocampheyl borane 375 dimethyl(methy1thio)sulfonium triflate 293 dimethylsilyl acetal 138 diols - 1,3-diols 145, 217

- anti-diols 145 - cis-diols 17 - syn-diols 145

dioxolane 217 dipeptides - isoster 251ff 1,3-dipoles 71 disease - cardiovascular 302 - circulatory 302 divinyl carbinols - epoxidation 211 DMTST 293 DNA 371 - crosslinking 309 domino Heck cyclizations 201 domino reactions 193 dopamine 315

E

ecology 261 elimination - asymmetric 305 - /%elimination 70 - reductive 304 emamectin 267 enantiodifferentiating protonations 24 enantiodifferentiating transfer of protons 19 enantioselective addition of zinc alkyls 55 enantioselective cis-dihydroxylation 15 enantioselective deprotonation 21 enantioselective reactions with transition metals 99ff enantioselectivity 135 - temperature dependence 33 enantiotopic group selectivity 211 enantiotopic groups 204 - differentiation 208f endorphines 357 ene reaction 195, 212f - palladium ene reaction 201 enediyne antitumor antibiotics 371 enolates 252ff - acetate 33 - alkylation 252

Subject Index

- chiral253

- glycine ester

34f - homoenolate 252 - lithium 33 - strategy 252 - titanium 33 enones - 1,Zaddition 94 - 1,4-addition 94 enzyme inhibition 251 enzyme inhibitors 258 enzyme-membrane reactor 151 L-( +)-ephedrine 125 D-(-)-ephedrine 152 epi-bromohydrin 212 epoxidation 338 - asymmetric 3, 6f, 211 - divinyl carbinols 211 - symmetric 5 epoxides - aminoalkyl 252 - electrophilicity 253 - opening 209,256 - regioselective opening 130 ergoline - synthesis 315 ergot alkaloids 315 erythromycin A 293 D-erythrose 17 esperamicin 349, 371 esters L-amino acid 35 anti-/3hydroxy-a-methyl carboxylic 34 conjugate reduction of 117 ester enolates 56 Phydroxy 33 D-syn-phydroxy-a-amino acid 35 D-hydroxy amino acid 34f L-hydroxy amino acid 34f a,Punsaturated estrone 200 ethoxyacetylene 215 etoxadrol 323

F facial selectivity 219 Felkin-Anh model 325 fermentation 263 FK506 215,381 - ClO-C20 fragment 237 - cyclohexyl part 212 fluorination - aromatic ring 245 - reactive anions 245 - selective 243 - with acetyl hypofluorite 244 - with N-fluorosulfonamides 245 fluorine 243ff fluoromethylmalonate 246 N-fluoropyridinium salts 246 N-fluorosulfonamides 245 N-fluorosulfonimides 246 fragmentation 192, 339 anti-Friedel-Crafts acylation 101 frontalin 91 fucose 376 a-fucosidase 158 functional C,-symmetry 49 functional groups - topology 204 furan - as synthetic building block 231ff - cycloaddition with arynes 234 - reaction with dienophiles 232 furfuryl alcohols 236f

Pgalactosidase from E. coli 159 galactosyltransferase 160 GDP-FUC 159 GDP-Man 159 geissoschizine 196 gene technolow 165 gibberellic acid- 271 (+)-gilovaricin M 233 globotriaosyl ceramide 292 D-glucal 256, 389 glucocorticoids 226 glucose

399

400

Subject Index

- 2-deoxy-glucose

389 glufosinate 263 glycinoeclepin 272 glycoconjugates 292 N-glycopeptides 163 N-glycoproteins - core structure 294 glycosidase inhibitors 148 glycosidases 157 C-glycosides 139,233 0-glycosides 289 glycosides 157 - N-acetylneuraminyl glycosides 158 - fucosyl glycosides 158 - phenylselenoglycosides 139 glycosidic bonds 157 glycosyl cations 297 glycosyl donor 289 glycosyl fluorides 157,289, 377 glycosylation 142, 289 - enzymatic methods 165 glycosylhydroxylamine 377 glycosyltransferases 159 Grignard reagent - chiral 254 group differentiating reactions 203 H

haedoxan 272 hafnium complexes 32f halo acetals 137 halolactonization 219 Heck reaction 201, 321, 372 - intramolecular 363 heptadienoic acid 218 herbimycin A 271 hetero Diels-Alder reactions 37, 51 - endo-selectivity 96 - with inverse electron demand 46 hetero olefin complexes 105f heterocumulenes 75ff heterocycles 167, 172f, 181, 185 heterodienophiles 43 hexafluoroantimonates 246 (-)-hexahydrocannabinol 195

Hf-metallocenes 292 (-)-hikizimycin 206f - synthesis 208 HIV 251 Hofmann elimination 243 Hofmann rearrangement 228 homoallyl alcohols 29ff homoenolate 252, 255 - equivalents 254f - synthon 254f homothienamycin 68 homotopic groups 205ff - differentiation 206f Horner olefination 55 Horner-Emmons reaction 375 HPS aldolase 151 (+)-hydantocidin 267 hydride abstraction 59 Phydride elimination 77 hydridosilicates - pentacoordinate 123 trans-hydrindanediones 117 hydroacylation reaction 78 hydroazulene 67 hydroboration 212, 354 cis-hydrogenation 212 hydrometalation reaction 143 hydroperoxide rearrangement 354 hydrosilylation 144, 211 - asymmetric 131 - of olefins 131, 142 hydroxy groups - differentiation 215, 218 - masking 129, 132 - synthetic equivalent 129 hydroxyamination - palladium-catalyzed 81 3-hydroxybutyric acid 281,283 a-hydroxylations 207 - esters 225 - ketones 225 cis-hydroxylations 57, 311 13-/3-hydroxymilbemycin 269 hydrozirconation reactions 108f hypervalent iodine reagents 219,223ff

Subject Index

1, J

ICIA5.504 267 imine complexes 106 iminium ions 37, 167, 170, 172, 185, 188, 191 imipenem 277 imunosuppressives 381 indane derivatives 116 indoles 350f, 354 - 4-bromo-3-iodoindole 321 - 4-cyanomethylindole 317 - 4-ethinylindole 320 - deprotection of 317f, 320 - 4-fomylindole 320 - Heck reaction 321 - Mannich reaction 317 - 3-substituted 228 - synthesis 315ff indoline 351, 354 initiator 173, 176, 181 inosamines 44 insertion in metal-carbon bonds - alkenes 76 - alkynes 77f - carbon dioxide 75ff - isocyanates 76 insertion reactions - of nitriles 100 integrated pest management - active ingredients 261 - biological control methods 261 - degradation times 261 - dose rates 261 - selective mode of action 261 - target-directed placement 261 iodobenzene 223,226 iodolactonization 51 iodonium intermediates 225 iodonium ylides 227 iodosobenzene 225 ionomycin 234 pionone 66f (-)-(S)-ipsenol 33 Ireland-Claisen rearrangement 4, 56, 390 iron complexes

acyloxy 117 aminoacyl 117 chiral 117 $-complexes 59 isocarbacycline 302ff, 306 isocyanates - activation 75ff isohyaluronic acid 291 isomitomycin A 311 2,3-isopropylidene aldehyde isoquinolinium salt 42 isoster - dihydroxyethylene 254 - dipeptide 251ff - hydroxyethylene 251 ivermectin 268 Jones oxidation 280 -

207

K KDO synthetase 151 Kemp’s triacid 25 Pketoester 213 ketone cyanohydrins 152 ketones - a,/$unsaturated 117 - conjugate reduction of 117 kinetic resolution 4, 6 Kitasatosporia phosalacinea 263 Koenigs-Knorr reaction 289 Kornfeld’s ketone 315

L Flactams

68ff, 88f, 283f 68 y-lactams 68 lactic acid esters 26 lactonization 208, 215, 219 - bromo- 257 lanthanides - acetalization 96 - Friedel-Crafts reactions 96 - hetero-Diels-Alder reactions - Lewis acidity 91 - NMR shift reagents 91 - anti-Bredt plactams

96

401

402

Subject Index

- organolanthanides - production 91

91ff

laurenyne 177, 185 LDA see lithium diisopropylamide lead tetraacetate 224 leucotriene 302 leucotriene B5 6 leucotriene D4 21 Lewis acids 123, 126, 173, 176f, 217,337, 350,354 - chiral 232 - optically active 212 Lewis-Langmuir theory 223 Le"-glycosphingolipids 292 liepicidine A 271 ligand accelerated catalysis 13 ligands - heterotopic 204 - homotopic 204 lithium diisopropylamide 362 lithium enolates 115 living polymers 120 Lombard0 reaction 303 LSD see lysergic acid lysergic acid (LSD) 315ff - dihydro derivatives 317 - racemic 316 - substituents 315 - total synthesis 351 L-lysine 323f

M (+)-macbecin I 238 macrocyclization 388 macrolides 383 malonate - alkylation 252 Mannich reaction 56, 317, 350 D-mannose 256 mannostatine A 211 maximum bridging ring 360 maytansine 349 McMurry reaction 337, 339, 346, 364

Meerwein-Ponndorf-Verley-Oppenauer oxidation

91

Meiji Herbiace@ 263 Meldrum's acid 195 l-menthol 235 (-)-menthone 217 metal enolates 115 metal-carbon bond - insertion of alkenes 76 - insertion.of alkynes 77f - insertion of carbon dioxide 75ff - insertion of isocyanates 76 metal-imido complexes 107 metalacycles 101, 106, 143 metalalactones - co-ligands 76 - ferralactones 75ff - nickelalactones 75ff - reactivity 76 metallocenes - group four 99 Pmethoxyacrylates 266 L-methoxyamine 125 methyl transfer 32 methyl triflate 293 ( +)-(2S,5S)-N-methylpseudoconhydrin 324f (-)-(2R,SR)-N-methylpseudoconhydrin 324f methylsulfenyl bromide 293 methylsulfenyl triflate 293 Michael additions 86, 190,206, 236, 306, 362,367 - asymmetric 84 - carbene complex anions 84 - diastereofacial selectivity 84 - intramolecular 286 - retro 132 milbemycins - microbial oxidation 271 - milbemycin A, 269 mitomycin A 309f mitomycin C 309f mitomycin rearrangement 311 Mitsunobu reaction 238, 282, 320, 375, 378 Moffatt reagent 215 molybdenum hexacarbonyl 375 moncerin 272

Subject lndex

morphine 357ff mucine O-glycoproteins 294 mycinomycine IV 292

N natural products 251ff, 261ff acaricides 262 animal parasites 262 for agriculture 262 fungicides 262 herbicides 262 insecticides 262 - production 263 - sales 262 neocarcinostatin 371 NeuAc aldolase 151 nickel complexes 75ff nickel-carbon bond - insertion of alkynes 80 nickelalactones 75ff nikkomycins 271 (+)-nitramhe 331f nitroalkenes 46 nitrosoalkanes 46 (-)-nojirimycin 334 non-steroidal anti-inflammatory drugs noradrenaline 315 norephedrine 328 Noyori ligand 210 nucleophilic addition - of organolanthanides 91 - to Schiff’s bases 117 nucleoside diphosphate 159 nucleoside monophosphate 159 -

0 Olah reagent 243 olefins 245 - differentiation of diastereotopic 218 - enantiotopic 213 oligomerization - 1,3-dienes 78 oligosaccharides 289 - chemoenzymatic syntheses of complex oligosaccharides 161

26

olivanic acids 277 Onchocerca volvulus 268 Oppenauer oxidation 189 organocerium(II1) compounds - transmetalation 94 organocuprates 108, 227 organolanthanides 91ff - nucleophilic addition reactions 91 - reduction reactions 91 osmium 10 Oudemansiella mucida 265 oudemansins 265 7-oxabicyclo[2.2.l]heptJ-ene 231 trans-1,2-oxazines 46 oxazolidinone 55, 81,384 oxet anocin - ring contraction 105 oxidations - biocatalytic 16 - stereoselective 9 oxidative cleavage 129, 131, 253 oxidative degradation 254 oxidatitve demetalation 61 oxiranes 9 oxonium ions 167, 173ff, 177, 185 a-oxygenation 226 - 1,3-dicarbonyl compounds 226 - esters 226 - ketones 226 oxynitrilases - (R)-Oxynitrilase 151 - (S)-Oxynitrilase 151 ozonolysis 213

P palladium catalysis 321 palladium catalyst 81 palladium dichloride 321 pantolactone 26 penems 277,285 penicillin 277 pentamycin 149 pentenyl glycosides 295 peptides - retro-inverso 229

403

404

Subject Index

peptidomimetics 55 perchlorates 246 pericyclic repolarization 141 pesticides 261f phenolic glycosides 163 phenyliodonium acetate 224 N-phenyliodonium amides 229 phenylselenol 138 phenylselenyl triflate 293 phenylsulfonamide 246 philanthotoxins 272 phorbol 239 phosalacine 263 phosphine ligands - electronic properties 75ff - steric properties 75ff (S)-( +)-phosphinothricin 263f phosphoenolpyruvate 119 Pictet-Spengler reaction 195 pig liver esterase 278 (+)-pillaromycinone 93 pinacol - coupling 93 - formation from aldehydes 91 - rearrangement 373 pinidine 325ff (+)-pinit01 17 pipecolic acid esters 37 piperidines 148 plant production 261ff platelet aggregation 302 PLE 279 polycyclization 187 polymerizations - group transfer polymerization 120 - living 120 polyols 212 porfiromycin 309 precursors - chiral 255 propargylstannanes 56 prostacyclines 301f prostaglandin PGE, 17 prostaglandins 108, 301 proteinase - aspartic 251

- HIV 251 protodesilylation 131, 303 protonation - of enolates 23 pseudodistamine A 323 pseudodistamine B 323 Pseudomonas jluorescens 264 D-psicofuranose 267 pyranones 237 pyridinium dichromate 25 2-pyridone 80 pyridyl-thioglycosides 294 a-pyrones 77 pyrroles 87, 35Of pyrrolidines 148 pyrroline 107 pyrrolizidine alkaloids 70f pyrrolnitrin analogs 264f pyrroloindole 349 pyrrolomycin 271

Q querus lactone A 23 D-(-)-quinic acid 215 ortho-quinodimethane 200

R radical reactions 136f rapamycin 381ff reagent control 205 rearrangement 354 - aza-Cope rearrangement 169, 197 - hetero-Cope rearrangement 197 - [3,3]-sigmatropic 167, 377 reductions - catecholborane 318 - chelation-controlled 213 - diastereoselectivity 123 - DiBAH 315 - enantioselective 363, 387 - organolanthanides 91 - sodium amalgam 320 - sodium cyanoborohydride 315 - stereoselective 125 Reformatsky reaction 192

Subject Index

regioselectivity 135 remote stereocontrol 135 renin - inhibitors 251 reserpine 132 resolution 257 restricticidin 271 reticuline 225 retro-inverso peptides 229 retro-Michael reaction 132 retrosynthetic analysis 270, 358, 382, 387 reverse hydrolysis 157 Rhizoctonia solani 264f rhodium carbenoids 65ff rhodium carboxylates 65ff (+)-ribantoin 267f L-ribonolactone 17 rings - annulation 184 - closure 135 - contraction 105 - eight-membered 184, 335, 339 - medium-sized 173, 175, 183 - nine-membered 184 - seven-membered 184 - six-membered 335 rocaglamid 272

S Sakurai reaction 188 salutaridine 225 samarium diiodide - chelate formation 91 - coordination properties 92 - cyclopropanation 93 - electron donor properties 93 - fragmentation reactions 93 - one-electron donor 91 - stereoselective cyclizations 91 Saphire@ 263 secondary orbital interactions 96 L-selectride 325 selenocyclization 367 sequential transformations 193 L-serinal 31

serotonine 315 Shapiro reaction 339, 346 Sharpless epoxidation 3, 9, 331 shingosine 292 sialidase 158 sialyl Lewis' tetrasaccharide 163 sialyltranferase 161 sigmatropic rearrangements - [2,3] 131 - [3,3] 377 sila-Baeyer-Villiger rearrangement 129, 131ff sila-Pummerer reaction 130 silicate intermediate 125 silicon 135ff silicon compounds - pentacoordinate 123, 126f, 131f silicon-carbon bond - oxidative cleavage 129 - temporary 135 siloxanes 137 silylenol ethers 181, 185 Simmons-Smith reaction 93 simultaneous synthesis 204 singlet oxygen 235 SN2reaction - intramolecular 366 soraphen A 271 (-)-sparteine 22, 210 sphydrofuran 149 spiro acetal 137, 215 spiro componds 92f Spodoptera eridiana 267 squaleneoxides 153 statine 251, 255 stereoselective oxidation 9 steroid glycosides 163 steroids - D-ring side chain 76 sterolcyclase 153 Stetter reaction 153 stilbenediamine 56f Stille coupling 383 strand scissions 371 strategic bond 359f Streptomyces avermitilis 268

405

406

Subject Index

Streptomyces hygroscopicus 263, 267 Streptomyces violascens 269 Streptomyces viridochromogenes 263 strigol 271 strobilurin A 265 strobilurin B 266 Strobilurus tenacellw. 265 strychnine 200 substrate control 205 sulfonimide 246 sulfonium ions 167, 181ff sulfonium ylides 70 N-sulfonyldienophiles 37 sulfoximines - optically active 305 sulfoxonium ylides 70 Swern oxidation 378 synthetases - 3-hexulosephosphatge synthetase 151 - 3-deoxy-~-arabino-heptulusonic acid phosphate synthetase 151 - 3-deoxy-D-manno-2-octulusonic acid-8phosphate synthetase 151 - CMP-NeuAc synthetase 163 synthetically significant ring 360 synthon 129ff

T talaromycin A 137 tandem conjugate addition-carbene insertion 228 tandem Knoevenagel-hetero-Diels-Alder reactions 195 tandem radical reaction 368 tandem reactions 195, 231, 366 taxanes 335ff, 349 tax01 4,335, 339ff taxusine 337 TBAF see tetrabutylammonium fluoride Tebbe olefination 144 Tebbe reagent 109, 207 telomerization 79 temporary connections 135ff terminators 174, 181f terpene 335

2,3,4,6-tetra-O-pivaloyl-a-~-

galactopyranosylamine 330 tetrabenzyl glucose 42 tetrabutylammonium fluoride 243, 320 tetrafluoroborates 246 (-)-tetrahydroalstonine 195 tetrahydrocannabinol 357 tetrahydroindanedione 117 (tetrapheny1porphyrinato)aluminium complexes 119 thallium(rI1)-tris(trifluor0acetate) 225 THC see tetrahydrocannabinol thebaine 358 thienamycin 68, 277 thioglycosides 293 threitol 30 threitol complex 33, 35 threonine 279 thrombin inhibitors 37 titanium complexes 29ff titanium-imido complexes 107 titanium reagents 105 titanocenes - dialkyltitanocenes 110 topology 204 TosMIC 265 tosylamide 246 total synthesis 251ff toxicity 261 transannular interactions 136 transform-based strategy 231 transglycosylation 157 transition metals 99ff, 142, 223 transition state 214, 251, 325 - ,,chair-like" 172 - acyclic 126 - chelated 131 - endo-transition state 140 - exo-transition state 140 - ring strain 135 - six-membered cyclic 127 transketolase 149, 152 transmetalation 29, 33, 94, 108 tri-n-butylphosphine 320 trichloroacetimidate 379 trihydroxyheliotridane 17

Subject Index

tungsten benzylidene complex 66 tunicaminyl uracil 138 two-dimensional synthesis 204f, 208, 214, 216 U

UDP-Gal 159 UDP-GalNAc 159 UDP-Glc 159 UDP-GIcNAc 159 UDP-GlcUA 159 umpolung 181, 254 V

validamycins 271 vallesamidine 189 2-vinylindoles 197 vinyl iodide 384 vinyliodonium salts 227 vinylsilanes 130f, 167f, 170, 173, 175f, 181f, 185 vinylsulfone 366 vitamin D3 117 vitamin E 153 Vorbriiggen coupling 267

W

Wilkinson’s catalyst 321 Wittig reaction 136, 266 Wittig rearrangement 51 Wittig-analogous reactions 109ff Wittig-Homer cyclization 286 Wittig-Homer reaction 136, 207, 253 Wolff-Kishner reduction 362

x,y xanthogenates 294 yohimbone 167,196

Z (-)-zeylena 17 zinc alkyls - addition of 55 zirconabicycles 104 zirconacyclopentenes 102 zirconium 99ff zirconium complexes 32f - insertion of nitriles 100 zirconium metallocenes 292 zirconocene-alkene complexes 100 zirconocene-alkyne complexes 100, 102 zirconocene-imine complexes 106 zirconocene methyl chloride 100

407

Organic Synthesis Highlights I11 Edited by Johann Mulzer and Herbert Waldmann

8WILEY-VCH

Further Titles of Interest

Organic SynthesisHighlights I J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig ISBN: 3-527-27955-5 Organic SynthesisHighlights 11 H. Waldmann (Ed.) ISBN: 3-527-29200-4 (Hardcover) ISBN: 3-527-29378-7 (Softcover) Classics in Total Synthesis K. C. Nicolaou, E. Sorensen ISBN: 3-527-29231-4 (Hardcover) ISBN: 3-527-29284-5 (Softcover) Enzyme Catalysis in Organic Synthesis K. Draw, H. Waldmann (Eds.) ISBN: 3-527-28479-6 Two Volumes

Organic Synthesis Highlights I11 Edited by Johann Mulzer and Herbert Waldmann

6BWILEY-VCH

Weinheim . New York * Chichester * Brisbane - Singapore * Toronto

Prof. Dr. Johann Mulzer Institut fur Organische Chemie der Universitat Wahringer StraBe 38 A-1090 Wien (Vienna) Austria

Professor Dr. Herbert Waldmann Institut fur Organische Chemie der Universitat Richard-Willstatter-Allee 2 D-76128 Karlsruhe Germany

This book was carefully produced. Nevertheless, authors, editors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

The cover illustration shows the polycyclic ring system of morphine, surrounded by the primary rings. Strategic bonds determined in a retrosynthetic analysis are highlighted. Library of Congress Card No. applied for A catalogue record for this book is available from the British Library.

Die Deutsche Bibliothek

- CIP-Einheitsaufnahme

Organic synthesis highlights. - Weinheim ; New York ; Chichester ; Brisbane ; Singapore ; Toronto : Wiley-VCH 3. / E d . by Johann Mulzer and Herbert Waldmann 1998 ISBN 3-527-29500-3

0 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 1998

Printed on acid-free and chlorine-free paper All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition: Hagedorn Kommunikation, D-68519 Viernheim Printing: Straws Offsetdruck GmbH, D-69509 Morlenbach Bookbinding: W. Osswald, D-67433 Neustadt/Wstr. Cover design: Graphik & Text Studio Zettlmeier-Kammerer, D-93164 Laaber-Waldetzenberg Printed in the Federal Republic of Germany

Preface

Synthesis maintains its central position in Organic Chemistry and as documented by the rapid preparation of very complex molecules such as taxol or brevetoxin has reached an almost unprecedented power and scope. This progress of organic synthesis over the past eight years could be followed in the two volumes of Organic Synthesis Highlights I and I1 (OSH I and II), which appeared in 1990 and 1995 respectively. In view of the positive response which was met by these two textbooks the third title of this series is now presented. Contrary to the philosophy of OSH I and 11, which were both based on the review section “Synthese im Blickpunkt” of the “Nachrichten aus Chemie Technik und Laboratorium”, the members’ journal of the GDCh, Organic Synthesis Highlights Ill is a selection of the “Highlights” adapted from Angewandte Chemie, volumes 103-107 (1993-97). Compared to the articles in OSH I and I1 these highlights are considerably short-

er and instead of trying to review an entire area, they focus on one subject only. This means that the number of articles and hence different topics (and highlights) has been significantly increased. No less than 56 highlights are presented, all updated by their individual authors to 1997. The basic topics have been maintained and as in OSH I/II particular emphasis is laid on stereoselective reactions and reagents, organometallics and the general synthesis of natural and non-natural products. Following current trends articles on the self assembly of biopolymers and on some aspects of combinatorial synthesis are also included. Based on this general editorial philosophy we hope that the new volume will find a similar acceptance in the scientific community as did its two congeners OSH I and 11. Karlsruhe and Vienna, May 1998 Herbert Waldmann and Johann Mulzer

Contents

Part I. New Methods and Reagents for Organic Synthesis A. Asymmetric Synthesis Catalytic Asymmetric Synthesis Using New Enolato-, Amido-, and Organolithium Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Berrisford, Carlos Horkan, and Matthew L. Isherwood Steric and Stereoelectronic Effects in the Palladium Catalyzed Allylation . . . . . . . . . Oliver Reiser Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary Unexpected Influence of Additives? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Karola Riick-Braun Catalytic Asymmetric Carbonyl-Ene Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Berrisford and Carsten Bolm Chiral 2-Amino-1,3-butadienes: New Reagents for Asymmetric Cycloadditions . . . . . Karsten Krohn Recent Developments in the Enantioselective Syntheses of Cyclopropanes . . . . . . . . Hans- Ulrich Reissig Enantioselective Rhodium(I1) Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henri Brunner Oxazaborolidines and Dioxaborolidines in Enantioselective Catalysis . . . . . . . . . . . . B. B. Lohray, and Vidya Bhushan Enantioselective Catalytic Hydrogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Judith Albrecht and Ulrich Nagel The Sharpless Asymmetric Aminohydroxylation of Olefins . . . . . . . . . . . . . . . . . . Oliver Reiser Epoxides in Asymmetric Synthesis: Enantioselective Opening by Nucleophiles Promoted by Chiral Transition Metal Complexes . . . . . . . . . . . . . . . . . . . . . . . . . Ian Paterson and David J. Berrisford

3

8 15

23 28 35 40 44 51

57 62

VIII

Contents

Asymmetric Deprotonation as an Efficient Enantioselective Preparation of Functionalized Secondary Alcohols and Amino-Alcohols . . . . . . . . . . . . . . . . . . . . Paul Knochel Planar-Chiral Ferrocenes: Synthetic Methods and Applications . . . . . . . . . . . . . . . . Antonio Togni Asymmetric Autocatalysis with Amplification of Chirality . . . . . . . . . . . . . . . . . . . Carsten Bolm, Andreas Seger, and Frank Bienewald Resolution of Racemates by Distillation with Inclusion Compounds . . . . . . . . . . . . . Gerd Kaupp Absolute Asymmetric Synthesis by Irradiation of Chiral Crystals . . . . . . . . . . . . . . Gerd Kaupp and Michael Haak

67 73 79 84 89

B. Organometallic Reagents Cyclopentadienyl Ruthenium Complexes: Valuable Assistents in the Construction of Carbon-Carbon Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Holger Butenschon Transition Metal Catalyzed Synthesis of Seven-Membered Carbocyclic Rings . . . . . . Gerald Dyker [4+4]-Cycloaddition Reactions in the Total Synthesis of Naturally Occurring Eight-Membered Ring Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerd Kaupp “New” Reagents for the “Old’ Pinacol Coupling Reaction . . . . . . . . . . . . . . . . . . . Thomas Wirth Exciting Results from the Field of Homogeneous Two-Phase Catalysis . . . . . . . . . . . Boy Cornils Palladium-Catalyzed Amination of Aryl Halides . . . . . . . . . . . . . . . . . . . . . . . . . Matthias Beller and Thomas H. Riermeier The Metal-mediated Oxidation of Organic Substrates via Organometallic Intermediates: Recent Developments and Questions of Dispute . . . . . . . . . . . . . . . . . . . . . . . . . . Jorg Sundermeyer The Oxofunctionalization of Alkanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Reiser Cooperativity in Rh2 Complexes: High Catalytic Activity and Selectivity in the Hydroformylation of Olefins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Georg Suss-Fink Synthesis of Optically Active Macromolecules Using Metallocene Catalysts . . . . . . . Jun Okuda

96 103 106 113 119 126 133 140 146 153

C. Biological and Biomimetic Methods Discovering Biosynthetic Pathways - A Never Ending Story . . . . . . . . . . . . . . . . . Sabine Laschat and Oliver Temme Peptide Ligases - Tools for Peptide Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . Hans-Dieter Jakubke

156 167

Contents

Synthetic Ribozymes and Deoxyribozymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Petra Burgstaller and Michael Fumulok Enzyme Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anthony J. Kirby Metal-Assisted Peptide Organization: From Coordination Chemistry to De Novo Metalloproteins . . . . . . . . . . . . . . . . . . Heinz-Bernhard Kruatz Artificial Replication Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Siedried H o f i a n n

IX

173 185 192 198

D. General Methods and Reagents LiC104 and Organic Solvents - Unusual Reaction Media . . . . . . . . . . . . . . . . . . . . Uschi Schmid and Herbert Waldmann Reactions in Supercritical Carbon Dioxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerd Kaupp The Selective Blocking of trans-Diequatorial, Vicinal Diols; Applications in the Synthesis of Chiral Building Blocks and Complex Sugars . . . . . . Thomas Ziegler Oxidative Polycyclization Versus the “Polyepoxide cascade”: New Pathways in Polyether (Bio)synthesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ulrich Koert Radical Reactions as Key Steps in Natural Product Synthesis . . . . . . . . . . . . . . . . . Ulrich Koert Light-Directed Parallel Synthesis of Up to 250 000 Different Oligopeptides and Oligonucleotides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Giinter von Kiedrowski Opportunities for New Chemical Libraries: Unnatural Biopolymers and Diversomers . Rob M.J. Liskump Reactive Intermediates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henning Hopf

205 21 1 222 230 235 242 245 250

Part 11. Applications in Total Synthesis Synthesis of Natural and Non-natural Products Pentazole and Other Nitrogen Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rudolf Junoschek New Total Syntheses of Strychnine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uwe Beifuss Total Syntheses of Zaragozic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ulrich Koert The First Total Syntheses of Taxol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . m d P P r A WPvvinhnnn

265

270 282

295

X

Contents

Erythromycin Synthesis - A Never-ending Story? . . . . . . . . . . . . . . . . . . . . . . . . Johann Mulzer Great Expectations for a Total Synthesis of Vancomycin . . . . . . . . . . . . . . . . . . . . Kevin Burgess, Dongyeol Lim, and Carlos I. Martinez The Dimeric Steroid-Pyrazine Marine Alkaloids: Challenges for Isolation, Synthesis, and Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arasu Ganesan New, efficient routes to cyclic enediynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Konig Conocurvone - Prototype of a New Class of Anti-HIV Active Compounds? . . . . . . . Hartmut Laatsch Progress in Oligosaccharide Synthesis through a New Orthogonal Glycosylation Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hans Paulsen Analogues of the Sialyl LewisX Group and of the N-Acetylneuraminic Acid in the Antiadhesion Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Athanassios Giannis Peptidomimetics: Modern Approaches and Medical Perspectives . . . . . . . . . . . . . . . Athanassios Giannis A New Application of Modified Peptides and Peptidomimetics: Potential Anticancer Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R. M. J. Liskamp Mechanically-Interlocked Molecular Systems Incorporating Cyclodextrins . . . . . . . . Sergey A. Nepogodiev and J. Fraser Stoddart Bolaamphiphiles: Golf Balls to Fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gregory H. Escamilla and George R. Newkome Dendrimers, Arborols, and Cascade Molecules : Breakthrough into Generations of New Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andreas Archut, Jorg Issberner and Fritz Vogtle Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches . . . . . . . . . . . . . . . . . Russell N. Grimes Framework Modifications of [60]Fullerene: Cluster Opening Reactions and Synthesis of Heterofullerenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andreas Hirsch

306 3 14 3 18 327 33 1 336 342 354 366 374 382 391 406 4 15

List of Contributors

Prof. Dr. M. Beller Anorganisch-Chemisches Institut Technische Universitat Lichtenbergstralje 4 D-85747 Garching Germany Dr. D. J. Berrisford Department of Chemistry University of Manchester Institute of Science and Technology PO Box 88 Manchester M60 1QD United Kingdom Prof. Dr. C. Bolm Institut fur Organische Chemie der RWTH Aachen Professor-Pirlet-Stralje 1 D-52074 Aachen Germany Prof. Dr. H. Brunner Institut fur Anorganische Chemie Universitat Regensburg D-93040 Regensburg Germany

Prof. K. Burgess Department of Chemistry Texas A & M University College Station, TX 77843-3255 USA Prof. Dr. H. Butenschon Institut fur Organische Chemie Universitat Hannover Schneiderberg 1B D-30167 Hannover Germany Prof. Dr. Boy Comils Hoechst AG Forschungsleitung D- 65926 Frankfurt Germany Prof. Dr. G. Dyker Institut fur Organische Chemie der Universitat-Gesamthochschule Duisburg FB 6, Institut fur Synthesechemie LotharstraSe 1 D-47048 Duisburg Germany

XI1

List of Contributors

Dr. M. Famulok Inst. fur Biochemie der Universitat Munchen Feodor-Lynen-Stral3e 25 D-81377 Munchen Germany Dr. A. Ganesan Institute of Molecular and Cell Biology The National University of Singapore 30 Medical Drive Singapore 117609 Singapore Priv.-Doz. Dr. A. Giannis Institut fur Organische Chemie der Universitat Richard-Willstatter-Allee 2 D-76128 Karlsruhe Germany Prof. Dr. R. N. Grimes Department of Chemistry University of Virginia Charlottesville VA 22901 USA Prof. Dr. A. Hirsch Institut fur Organische Chemie der Universitat Erlangen-Nurnberg HenkestraBe 42 D- 9 1054 Erlangen Germany Prof. Dr. S. Hoffmann Institut fur Biochemie FB BiochemielBiotechnologie der Martin-Luther-Universitat Kurt-Mothes-StraBe 3 D-06120 Halle-Wittenberg Germany

Prof. Dr. H. Hopf Institut fur Organische Chemie der Technischen Universitat Hagenring 30 D-38 106 Braunschweig Germany Prof. Dr. H.-D. Jakubke Institut fur Biochemie Fakultiit fur Biowissenschaften, Pharmazie und Psychologie der Universitat TalstraBe 33 D- 04 103 Leipzig Germany Prof. Dr. R. Janoschek Institut fur Theoretische Chemie Karl-Franzens-Universitat Graz Strassoldogasse 10 A-8010 Graz Austria Prof. Dr. G. Kaupp Fachbereich 9 Organische Chemie I der Universitat Postfach 2503 D-26 111 Oldenburg Germany Prof. Dr. G. von Kiedrowski Lehrstuhl fur Organische Chemie I Ruhr-Universitat Bochum UniversitatsstraBe 150 D-44801 Bochum Germany Prof. Dr. A. J. Kirby Chemical Laboratory University of Cambridge Lensfield Road Cambridge CB2 1EW United Kingdom

List of Contributors

Prof. Dr. Paul Knochel FB Chemie der Philipps-Universitat Marburg Hans-Meerwein-S tralje D-35032 Marburg Germany

Prof. Dr. S. Laschat Institut fur Organische Chemie Technische Universitat Braunschweig Hagenring 30 D-38106 Braunschweig Germany

Prof. Dr. U. Koert Institut fur Chemie der Humboldt-Universitat zu Berlin Hessische Stralje 1-2 D-10115 Berlin Germany

Prof. R. M. J. Liskamp Department of Medicinal Chemistry University of Utrecht P.O. Box 80082 NL-3508 TB Utrecht The Netherlands

Priv.-Doz. Dr. B. Konig Institut fur Organische Chemie der Technischen Universitat Postfach 3329 D-38023 Braunschweig Germany

Dr. B. B. Lohray Vice President, Chem. R & D Dr. Reddy’s Research Foundation Bollaram Road Miyapur Hyderabad-500 138 India

Dr. H. B. Kraatz Department of Chemistry University of Saskatchewan 110 Science Place Saskatoon SK S7N 5C9 Canada Prof. Dr. Karsten Krohn Fachbereich 13, Chemie und Chemietechnik der Universitat-Gesamthochschule Warburgerstralje 100 D- 3309 8 Paderborn Germany Prof. Dr. H. Laatsch Institut fur Organische Chemie der Universitat Tammannstralje 2 D-37077 Gottingen Germany

XI11

Prof. Dr. J. Mulzer Institut fur Organische Chemie der Universitat Wahrringerstralje 38 A-1090 Wien Austria Prof, Dr. Ulrich Nagel Institut fur Anorganische Chemie der Universitat Auf der Morgenstelle 18 D-72076 Tubingen Germany Prof. Dr. G. R. Newkome Center of Molecular Design and Recognition Department of Chemistry, CHE 305 University of South Florida 4202 E. Fowler Ave., ADM 200 Tampa, FL 33620-5950 USA

XIV

List of Contributors

Prof. Dr. J. Okuda Institut fur Anorganische und Analytische Chemie Johannes-Gutenberg-UniversitatMainz J.-J.-Becher- Weg 24 D-55099 Mainz Germany Dr. 1. Paterson Chemical Laboratory University of Cambridge Lensfield Road Cambridge CB2 1EW United Kingdom Prof. Dr. H. Paulsen Institut fur Organische Chemie der Universitat Martin-Luther-King-Platz 6 D-20146 Hamburg Germany Prof. Dr. 0. Reiser Institut fur Organische Chemie der Universitat Regensburg UniversitatsstraBe 3 1 D-93053 Regensburg Germany

Prof. J. F. Stoddart Department of Chemistry and Biochemistry University of California at Los Angeles 405 Hilgard Avenue Los Angeles, CA 90095-1569 USA Dr. Jorg Sundermeyer Fachbereich Chemie der Philipps-Universitat Marburg Hans-Meerwein-Stral3e D-35032 Marburg Germany Prof. Dr. G. Suss-Fink Institut de Chimie UniversitC de Neuchgtel Avenue de Bellevaux 51 CH-2000 Neuchgtel Switzerland Prof. Dr. A. Togni Laboratory of Inorganic Chemistry Swiss Federal Institute of Technology ETH-Zentrum CH-8092 Zurich Switzerland

Prof. Dr. H.-U. Reilig Institut fur Organische Chemie der Technischen Universitat Dresden MommsenstraBe 13 D- 0 1062 Dresden Germany

Prof. Dr. F. Vogtle KekulC-Institut fur Organische Chemie und Biochemie der Universitat Gerhard-Domagk-Strale 1 D-53121 Bonn Germany

Dr. K. Ruck-Braun Institut fur Organische Chemie der Universitat J.-Joachim-Becher-Weg 18-20 D-55099 Mainz Germany

Prof. Dr. Herbert Waldmann Institut fur Organische Chemie der Universitat Karlsruhe Richard-Willstatter-Allee 2 D-76128 Karlsruhe Germany

List of Contributors

Dr. L. Wessjohann Institut fur Organische Chemie Universitat Munchen KarlstraBe 23 D-80333 Munchen Germany Prof. Dr. Th. Wirth Institut fur Organische Chemie der Universitat Basel St. Johanns-Ring 19 CH-4056 Basel Switzerland

Prof. Dr. T. Ziegler Institut fur Organische Chernie der Universitat Koln GreinstraBe 4 D-50939 Koln Germany

xv

Part I. New Methods and Reagents for Organic Synthesis

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

A. Asymmetric Synthesis Catalytic Asymmetric Synthesis Using New Enolato-, Amido-, and Organolithium Chemistry David J. Berrisford, Carlos Horkan, and Matthew L.Ishenvood Organolithium reagents are a cornerstone in the development of modern organic chemistry. Despite the enormous interest in catalytic asymmetric synthesis, [ 1, 21 asymmetric catalytic reactions of organolithium reagents are rare. The complex solution equilibria, [3] so characteristic of lithioanions, often frustrate attempts to render these reactions both asymmetric and catalytic with respect to the chiral ligands. One significant problem is that high background reaction rates are often associated with enolate and alkyllithium chemistry. An asymmetric variant must minimize the extent of reaction occuring by an inevitably racemic OSiMe,

a

1

5

G3

N

-

;I

7

G 3 Y - ' - o M e H

Ye N-

*

NMez

pathway. Given these difficulties, a number of contributions have made valuable advances in this area and are worthy of highlighting. Koga et al. have discovered [4] a remarkable catalytic process for the asymmetric benzylation of lithium enolates derived from silyl enol ethers 1 and 3 (Scheme 1). Previously, stereocontrolled lithium enolate alkylation has been restricted to either diastereoselective processes, [2a,c] requiring the covalent attachment of a chiral auxiliary, or to enantioselective reactions requiring stoichiometric amounts of chiral ligands. [2b] Indeed, this new catalytic reaction is a development of an

dYHZPh (W-2

Me2NwNMe2

6

Scheme 1. Asymmetric benzylation of lithium enolates. a) 1. MeLi, LiBr, toluene; 2. 5 mol% 5, 2 equivs. 6, 10 equivs. PhCHZBr, -45 C, 18 h (76 %, 96 % ee). b) 1. MeLi, LiBr, EtzO; 2. 10 mol% 5, 2 equivs. 6, 10 equivs. PhCHzBr, - 4 5 C, 18 h (52 %, 90 % ee).

4

A. Asymmetric Synthesis

earlier stoichiometric benzylation of 1 which achieved a 92% enantiomeric excess (ee) of 2 using ligand 7. [5] The new process differs from the former stoichiometric procedure in a number of respects. Firstly, the structure of the original chiral ligand 7 has been modified. Furthermore, the chiral ligand must be used in conjunction with an excess of an additional achiral ligand e.g. 6 (Scheme 1). Both polydentate chiral ligands (5/7) are prepared [6] by multistep, but straightforward routes from phenylglycine. The new ligand 5 delivers increased enantioselectivity under stoichiometric conditions (up to 97 % ee for 2) and maintains this performance under defined catalytic conditions. A 96% ee (76% yield) of 2 can be achieved using 5 mol% of 5 in toluene. Lower ligand loading (< 5 mol%) has a deleterious effect on both conversion and enantioselectivity. This study constitutes a further example of how efficient catalytic reactions can be developed despite the presence of complex solution equilibria. Originally, this chemistry was developed in a non-donor solvent rather than using an excess of donor as solvent. By so doing, the critical effects of additives, both chiral and achiral, are more readily appreciated. Indeed, incorporation of lithium bromide and an achiral, bidentate ligand in addition to 5 are essential for selectivity. The effects of these additives are particularly interesting. Tertiary diamines, e.g. 6 and its analogues, [7] substantially accelerate the rate. Without the addition of ligand 6, conversion drops precipitously under catalytic conditions. It is proposed that the achiral additive sequesters [8] the excess of LiBr that is generated as the alkylation reaction proceeds. It is found that an excess of LiBr slows the reaction prohibitively (< 1 % conversion). However, modest amounts of LiBr benefit the enantioselectivity. Under stoichiometric conditions without additional LiBr, the enantiomeric excess increases with time and conversion. The results implicate a kinetically dominant mixed aggregate

comprised of lithium halide, lithium enolate, and chiral ligand. The achiral ligand modulates this aggregate composition. Related halide effects [9, 101 are reported in other enolate reactions. For example, the addition of lithium chloride has a beneficial effect on the asymmetric deprotonation [ 111 of ketones by chiral lithium amides. In the latter case, a lithium amide-lithium chloride aggregate is likely to be the active reagent. [12] This catalytic alkylation reaction is limited as yet to two enolates and a single example of a reactive alkyl halide. The full scope of this process remains to be determined, particularly with respect to the range of compatible substrates and electrophiles. Nevertheless, Koga et al. [4] have discovered a significant example of catalytic lithium enolate chemistry and one that holds considerable promise for future development. Two further contributions illustrate how chiral lithium amides can be used as catalysts in asymmetric deprotonation reactions (Schemes 2 and 3 ) . The first example of catalytic chiral lithium amide chemistry was reported [13] by Asami (Scheme 2). In this process an achiral base, in this case LDA, provides a stoichiometric reservoir of amidolithium reagent. However, deprotonation of the epoxide is affected primarily by the chiral lithium amide 11 rather than the relative excess of LDA. Turnover is possible since the resulting chiral secondary amine 10 can be deprotonated by the remaining reservoir of LDA thus regenerating the chiral base 11. For example, the deprotonation of cyclohexene oxide 8 in the presence of DBU as an additive gives the allylic alcohol 9 in 74 % ee (82 % yield) using 50 mol% of chiral base 11. Using this concept, the Koga group have developed [ 141 catalytic asymmetric deprotonation of 4 -alkylcyclohexanones (Scheme 3 ) . For example, deprotonation of 12 gives silyl enol ether 13 in good enantioselectivity. The reaction is accomplished by combining 30 mol% of chiral lithium amide 15 along

Catalytic Asymmetric Synthesis Using New Enolato-, Amido-, and Organolithium Chemistry

..

excess LDA

5

( lo: X=H

11:X=Li

W N ~

Scheme 2. Asymmetric deprotonation of cyclohexene oxide 8. a) 1.5 equivs. LDA, 0.5 equivs. 11, THF, room temperature, 12 h (82 % yield, 74 % ee).

I

X

OSiMeB 13a: R = Me

a

75% ee

13c: R = t-Bu 79% ee

R

R 16:X=H

15: X = Li

17: X = Li

x

x

Scheme 3. Asymmetric deprotonation of 4-alkylcyclohexanones. a) 1. 2.4 equivs. 17, 30 mol% 15, 2.4 equivs. HMPA, 1.5 equivs. DABCO, hexane/THF, -78 C, 1.5 h; 2. TMSCl(S3-70 %, 75-79 % ee).

with an excess of achiral base 17 and trapping the resulting lithium enolate with trimethylsilyl chloride. Again, the achiral base 17 provides a reservoir of amidolithium reagent to allow catalyst turnover by deprotonation of 14 formed in situ (Scheme 3 ) . Clearly, the kinetics of the reaction are such that deprotonation at the ketone a-carbon by the achiral lithium amide 17 is much slower than deprotonation at the 2" nitrogen of the chiral amine 14. Although the catalytic efficiency is modest, it is remarkable that catalysis of this type can be achieved. Another recent contribution [ 151 by Denmark et al. demonstrates an effective method for promoting the nucleophilic addition reactions [2] of organolithium reagents to imines. [16] The chemistry is a development of earlier methodology. [ 171 The organolithium additions to N-aryl imines 18, are promoted by CZsymmetric bisoxazoline (BOX) ligands, [ 181 e.g. 20, or (-)-sparteine [19] 21 (Scheme 4) with high asymmetric induction.

Notably, BOX ligand 20, which is prepared delivers excellent selectivities for additions to aliphatic imines. Substrate enolization, which is often a problem for aliphatic imines, does not compete to a significant extent. Both methyl- and vinyllithium additions can be promoted by 20 with significant enantioselectivities (19a, R = Me: 91 % ee, Table 1). Using sparteine 21 improves the selectivity of the n-butyl- and phenyllithium additions (19c, R = n-Bu: 91 % ee, Table 1). In both cases the structures of the active organometallic complexes involved remains undefined. In certain cases, it is possible to decrease the ligand loading to a practical 20 mol% and still retain a near maximum ee; below this figure the ee drops significantly. The N-aryl amine products can be deprotected by using published methodology [ 171 to afford the corresponding primary amines. Overall, this chemistry offers alternative syntheses of important amino compounds and is complementary to approaches based [ 181 from tert-leucine,

6

A. Asymmetric Synthesis

!

19a: R =Me 19b: R = CH=CHZ 1 9 ~R: = n - 6 ~

21

:H H

Scheme 4. Asymmetric nucleophilic additions to an aliphatic imine. a) 1. 2 equivs. RLi, toluene, 20 mol% 20, 1 h; b) 2 equivs. RLi, EtZO, 20 mol% 21, 1 h (for yields and conditions see Table 1). Table I . Reaction conditions, yields, and products for the nucleophilic addition of RLi to 18 (Scheme 4). Product

7-(" C)

Ligand (equiv.)

Yield (%)

ee (%)

19a 19a 19b 19b 19c 19c

-63 -63 -78 -7 8 -94 -7 8

20 (1 .O) 20 (0.2) 20 (1.O) 20 (0.2) 21 (1.O) 21 (0.2)

96 81 95 82 90 91

91 82 89 82 91 79

upon catalytic asymmetric hydrogenation [20] of imines and hydrazones. These studies are significant in two respects. Efficient or improving asymmetric methodology is of primary importance, especially in such a fundamental area. Additionally, this work provides new insights [3] into the complex solution behaviour of these commonplace but valuable main group reagents.

References [ l ] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, J. Wiley, New York, 1994; b) Catalytic Asymmetric Synthesis (Ed.: I Ojima), VCH, New YorWeinheim, 1993. [2] a) D. Seebach, Angew Chem. 1990,102, 1363; Angew. Chem. Int. Ed. Engl. 1990, 29, 1320; b) K. Tomioka, Synthesis 1990, 541; c) P. G. Willard in Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 1; d) D.M. Huryn in Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 49. [ 3 ] D. Seebach, Angew Chem. 1988, 100, 1685; Angew. Chem. Int. Ed. Engl. 1988,27, 1624. [4] M. Imai, A. Hagihara, H. Kawasaki, K. Manabe, K. Koga, J. Am. Chem. SOC. 1994, 116. 8829.

Catalytic Asymmetric Synthesis Using New Enolato-, Amido-, and Organolithium Chemistry [5] a) M. Murakata, M. Nakajima, K. Koga, J. Chem. Soc. Chem. Commun. 1990, 1657; b) Y. Hasegawa, H. Kawasaki, K. Koga, Tetrahedron Lett. 1993, 34, 1963. For related chemistry using stoichiometric quantities of chiral ligands see: c) H. Fujieda, M. Kanai, T. Kambara, A. Iida, K. Tomioka, J. Am. Chem. Soc. 1997, 119, 2060; d) M. Uragami, K. Tomioka, K. Koga, Tetrahedron Asym. 1995, 6, 701; e) K. Yasuda, M. Shindo, K. Koga, Tetrahedron Lett. 1996, 37, 6343; f) T. Takahashi, M. Muraoka, M. Capo, K. Koga, Chem. Pharm. Bull. 1995, 43, 1821. [6] R. Shirai, K. Aoki, D. Sato, H.-D. Kim, M. Murakata, T. Yasukata, K. Koga, Chem. Pharm. Bull. 1994, 42, 690. [7] In contrast, addition of ether ligands, e.g. DME, does not accelerate the reaction and has little effect on the ee. Hence, DME can be substituted for toluene as the reaction solvent. Recently, chiral ureas have been used as ligands: K. Ishii, S. Aoki, K. Koga, Tetrahedron Lett. 1997, 38, 563. [8] a) Powerful donors such as HMPA are known to suppress mixed aggregation between MeLi and LiCl; H. J. Reich, J. P. Borst, R. R. Dykstra, D. P. Green, J. Am. Chem. Soc. 1993, 115, 8728. b) For structural characterisation of a 2 amine-enolate complex see: K. W. Henderson, P. G. Williard, P. R. Bernstein, Angew. Chem. Int. Ed. Engl. 1995, 34, 1117; Angew. Chem. 1995,107, 1218. [9] For reviews see: a) A. Loupy, B. Tchoubar, Salt Effects in Organic and Organometallic Chemistry, VCH, Weinheim, 1991; b) E. Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay, M. Simon, D. Seebach, Synthesis 1993, 1271. [lo] a) F. E. Romesberg, D. B. Collum, J. Am. Chem. SOC1994, 116, 9187; b) idem., J. Am. Chem. Soc 1994, 116, 9198; c) J. Corset, F. Froment, M.-F. Lautie, N. Ratovelomanana, J. Seyden-Penne, T. Strzalko, M-C. RouxSchmidt, J. Am. Chem. Soc. 1993, 115, 1684; d) K. W. Henderson, A. E. Dorigo, Q-Y. Liu, P. G. Williard, P. von RaguC Schleyer, P. R. Bernstein, J. Am. Chem. Soc. 1996, 118, 1339.

7

[ l l ] a) B. J. Bunn, N. S. Simpkins, J. Org. Chem. 1993,58, 1847; b) B. J. Bunn, N. S. Simpkins, Z. Spavold, M. J. Crimmin, J. Chem. Soc. Perkin Trans. I 1993, 3113; c) M. Toriyama, K. Sugasawa, M. Shindo, N. Tokutake, K. Koga, Tetrahedron Lett. 1997, 38, 567. F. S. Mair, W. Clegg, P. A. O’Neil, J. Am. Chem. Soc. 1993, 115, 3388. M. Asami, T. Ishizaki, S. Inoue, Tetrahedron Asym. 1994, 5, 793. [14] T. Yamashita, D. Sato, T. Kiyoto, A. Kumar, K. Koga, Tetrahedron Lett. 1996, 37, 8195. [15] S. E. Denmark, N. Nakajima, 0. J-C. Nicaise, J. Am. Chem. SOC. 1994, 116, 8797. [16] For a recent review see: S. E. Denmark, 0. J.C. Nicaise J. Chem. Soc. Chem. Commun. 1996, 999. [17] a) K. Tomioka, M. Shindo, K. Koga, J. Am. Chem. Soc. 1989, 111, 8266; b) I. Inoue, M. Shindo, K. Koga, K. Tomioka, Tetrahedron 1994, SO, 4429, and references therein. [ 181 S. E. Denmark, N. Nakajima, 0. J.-C. Nicaise, A-M. Faucher, J. P. Edwards, J. Org. Chem., 1995, 60, 4884, and references therein. [19] For leading references see: a) D. Hoppe, H. Ahrens, W. Guarnieri, H. Helmke, S. Kolazewski, Pure Appl. Chem. 1996, 68, 613; b) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc. Chem. Res. 1996,29, 552; c) M. Schlosser, D. Limat, J. Am. Chem. Soc. 1995, 117, 12342; d) D. Hodgson, G. Lee, J. Chem. Soc. Chem. Commun., 1996, 1015. [20] For leading references see: a) M. J. Burk, J. P. Martinez, J. E. Feaster, N. Cosford, Tetrahedron 1994, 50, 4399; b) X. Verdaguer, U. E. W. Lange, M. T. Reding, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 6784; c) N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916; d) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Steric and Stereoelectronic Effects in the Palladium Catalyzed Allylation Oliver Reiser

Most of the asymmetric allylic substitution The development of enantioselective-catalyzed reactions has led to great success over processes start from racemic allylic compothe past few years. Numerous chiral metal cata- nents rac-1-R (where for 1-R, R designates lysts have been tested, which have achieved a the general group of the compound, e.g. wide range of selectivities, never thought pos- 1-Me is 1with R = Me), which in the absence sible, for a great number of reactions by using of chiral ligands form meso complexes of the tailored ligands. [ 13 A problem in the catalysis type 2 with palladium(0). Since a nucleophile repertoire was the palladium-catalyzed, enan- can attack at either of the two ends of the allylic tioselective allylic substitution. [2] Elegant component, the enantiomers 3-R and ent-3-R mechanistic investigations have contributed are formed. The degree of the enantioselectito the development of this reaction as a valued vity of a reaction depends on how well a chiral method of synthesis. The understanding of ligand in 2 can direct the attack of the nucleofactors such as the initial conformation of phile (Nu) to one of the two allylic termini. The problem with allylic substitutions, such the allylic component, [3] the nature of its leaving group, [4] the conformation of the interme- as reaction (a), is that a soft nucleophile diate allylic palladium complexes, [ 5 ] the attacks the complexes 2 from the side opposite hardness of the nucleophile, [6] and the elec- to the ligands L; as a result the distance tronic and steric properties of the ligands between the reaction centers and the chiral bound to the palladium center, [7] today inductor is large. Thus, it is not surprising that ligands which allow such substitution reactions to be carried are normally highly selective, such as (+)out with high regio- and diastereoselectivities.

3-R R X = OAc, Halogen, OCOpR, SOpPh, OPO(0R)p

(rac )-1-R

R 2

(ent)-3-R

Steric and Stereoelectronic Effects in the Palladium Catalyzed Allylation

9

Table 1. Enantioselective allylic alkylation of rac-4-R according to Eq. (a) OAc

CH(C02Me)2

I

[Pd(C3H5)CIl2(1 mol%)

*

L (2.5 mol%)

R

5-R

(rac)-4-R

4-R

5-R

L

Yield (%)

% ee

4-Me 4-Me 4-Me 4-Me 4-Et 4-nPr 4-iPr 4-iPr 4-Ph 4-Ph 4-Ph 4-Ph 4-Ph 4-Ph 4-Ph

5-Me 5-Me 5-Me 5-Me 5-Et 5-nPr 5-iPr 5-iPr 5-Ph ent-5-Ph 5-Ph 5-Ph 5-Ph 5-Ph 5-Ph

(+)-DIOP dl 8 17-iPr 17-tBu 17-iPr 17-tBu 17-iPr 17-tBu 6 13 14 16-Se 16-S 17-Ph 17-iPr

66-88 a) 98 b, not reported 98 c, not reported 96 c, not reported 88 a) 85 a) 99 c , 97 c ) 50-84 a) 89 b, 99 b) 74 b)

22 92 56 71 74 69 94 96 96 95 97 95 90 99 98.5

Ref.

a) NaCH(C02Me)z; b, CH2(C02Me)2, Cs2CO3; c, CH2(C02Me)*, BSA, KOAc; dl 100 mol% PdC12, 200 mol% ligand; 0.5 mol% [Pd(CsHs)C1]2, 1 mol% ligand.

DIOP, [8] achieved an enantiomeric excess of only 22% ee (Table 1) for the preparation of 5-Me. [9] Even ligands such as BINAP [8], or Chiraphos [8] have so far only shown a high selectivity for few substrates. [lo] As a result, ligands were developed which can “reach over” to the exo side of the allylic complexes 2, for example the ferrocene 6 designed

’PPh2

6

7

by Hayashi. [ 111 In the allylic complex 7 a flexible hydroxyl group of the phosphane ligand directs the nucleophile. With this ligand 5-Ph was synthesized in up to 96 % ee. A very exciting concept has been developed with the synthesis of ligands which are derived from 2 -(diphenylphosphino)benzoic acid [ 121 or 2-(dipheny1phosphino)aniline. [ 131

10

A. Asymmetric Synthesis

9

8

a:X = CO ,Y=N H b: X = NH, Y = CO 1

r

11

10

8 (78% ee)

9b (88% ee)

Ts

-

(ent)-l2

12

By the coordination of 8 or 9 to palladium a 13-membered ring is formed each time. This chelate ring extension causes an increase of the bite angle B in 2, thus enhancing the depth of the chiral pocket in which the the allylic component is residing. The rneso-ditosylcarbamate 11, which is generated in situ from the diol 10, cyclizes to give the oxazolidinone 12 with up to 88% ee; the highest enantioselectivity for this system obtained so far. Strikingly, with 9b the opposite sense of induction as with 9a is observed. [12, 131 With 8 and 9 also excellent results have been obtained for acyclic substrates, however, with the standard system 4-Ph low yields and only up to 52 % ee are achieved. [14] As a possible explanation it has been suggested that the chiral pocket of these ligand is not large enough to accomodate 4Ph. In agreement with this proposal, smaller

substrates such as 4-Me give selectivities as high as 92 9% ee. This study also revealed the importance of the right choice of base being used to deprotonate the malonate and solvent, optimal results are achieved with the combination of caesium carbonate and THE Cz symmetric, chiral semicorrines [I51 and bisoxazolines [16] have given a great boost to catalysis research over recent years. They have also proven to be efficient ligands in the enantioselective synthesis of 5-Ph and ent-5-Ph, [ 16b] although these ligands neither "attack" the exo side of the complex 2 nor can they increase the bite angle B in the macrocyclic chelate. A selectivity of 95 % ee is achieved for the substitution at 4-Ph with ligand 13 and with 14 even one of 97% ee (see Table 1) in an almost quantitative reaction. For this substitution, instead of sodium dialkylmalonate as nucleophile, the use of a

aN9 7

OR

Steric and Stereoelectronic Effects in the Palladium Catalyzed Allylation

11

RO

13

R = SiMe2'Bu

14 Nu

15

mixture from dimethyl malonate and N,O(bistrimethylsilyl) acetamide (BSA) proved successful. [ 171 These excellent results, supported by an Xray structure analysis of complex 15, could be explained convincingly: [ 181 one benzyl group in the ligand and one phenyl substituent at the allylic terminus repel each other considerably. This steric hindrance is, for example, illustrated by a clear twisting of the oxazoline ring in question and from the lengthening of the corresponding Pd-C bonds. The nucleophile attacks at the allylic terminus which is sterically strained, since in this way, in combination with the rupture of the Pd-C bond, the steric strain can be reduced. If so far the impression was given that the basic condition for an efficient ligand is Cz symmetry, the discovery of new ligands 16 and 17 with S,N [19]-, Se,N [20]- and P,N [21]-coordination at the metal has changed this picture. Especially the ligands 17-R having a triphenylphosphane and a oxazoline unit showed record selectivities (Table 1) for the substitution of 4 -Ph. Initially, malonates were tested as nucleophiles, but later reports

(enf)-3-Ph

16-X

17-R

appeared using nitrogen nucleophiles [22] or nitromethane [23] with spectacular results. Early on it was speculated that a major control element for the effectiveness of these ligands must be centered around stereoelectronic considerations. In an NMR study [24] it was shown that in an allylic palladium complex the carbon atoms of the allylic termini are shifted with increasing acceptor strength of the ligands (e. g., change from nitrogen to phosphorus coordination) to higher field in the 13C NMR spectrum. This effect is particularly marked for the carbon atom in the position trans to the ligand. With the necessary caution required when dealing with the correlation of 13CNMR shifts with charge distributions, this is an indication that the electron density of an allylic carbon atom trans to the

12

A. Asymmetric Synthesis

184

194

phosphane ligand, in comparison to the nitrogen ligand, should be reduced significantly, and consequently being the one which is attacked by the nucleophile. In order to account for these stereoelectronic considerations and the observed stereoselectivity, as the reactive intermediate the palladium complex 19-R was proposed. [21b, 251 However, the original suggestion [25] that this diastereomer should be disfavored on steric reasons compared to 18-R turned out to be incorrect: in most elegant studies [20] using X-ray analysis and nmr spectroscopy Helmchen et al. could demonstrate that of the two complexes 19-R is favored in solution with a ratio of 1 : 8. They identified as the major steric interaction to be avoided the close alignment of the phenyl group in the allyl system with the pseudoequatorial phenyl group of the diphenylphosphino group. The X-ray structure of 19-R revealed that the longer palladium carbon bond is located at the allylic center trans to the phosphorous ligand, thus making this carbon more susceptible for 0

nucleophilic attack. The interconversion of 18-R and 19-R is at least 50 times faster than the reaction with the nucleophile, nevertheless, in light of the experimental evidence and in agreement with a postulate by Bosnich [26] that the more abundant isomer should be the the more reactive one, it seems plausible that 19-R ist the decisive intermediate and that stereoelectronic factors - a concept which should find more use in catalysis [27] - direct the nucleophile. The degree of enantioselectivity therefore seems to depend on the relative reaction rates at the allylic termini in the complexes 18-R and 19-R. NMR studies of the palladium complexes with other allyl substrates revealed that the ratio of 18R increases as the substituents on the allylic termini become smaller. (281 Consequently, these substrates give in parallel lower enantioselectivities. With the chiral ligands such as 8 and 9 and the phoshinooxazolines 17 two powerful and in part complimentary sets of ligands are readily available which allow the effective asymn

Steric and Stereoelectronic EfSects in the Palladium Catalyzed Allylation

metric allylic substitution of a broad range of substrates. Moreover, several useful applications of the substitution products such as the synthesis of a-amino acids, [21] succinic acids, [2b] butyrolactones, [2b, 281 and nucleosides [29] have been reported, demonstrating the practical usefulness of the methodology developed here. Acknowledgement: This work was supported by the Winnacker foundation and the Fonds der Chemischen Industrie.

References [ l ] a) R. Noyori, M. Kitamura in Modem Synthetic Methods (Ed.: R. Scheffold), Springer, Berlin, 1989, pp. 115-198; b) H. Brunner, Top. Stereochem. 1988, 18, 129. [2] Recent reviews: a) B. M. Trost, D. L. Vanvranken, Chem. Rev. 1996, 96, 395-422. b) J. M. J. Williams, Synlett 1996, 705. c) C. G. Frost, J. Howarth, J. M. J. Williams, Tetrahedron: Asymmetry 1992, 3, 1089: d) S. A. Godleski in Comprehensive Organic Synthesis, Vol. 4 (Ed.: B. M. Trost), Pergamon, Oxford, 1991, p. 585: e) B. M. Trost, Angew. Chem. 1989, 101, 1199: Angew. Chem. Int. Ed. Engl. 1989, 28, 1173: f) G. Consiglio, R. Waymouth, Chem. Rev. 1989,89, 257. [3] T. Hayashi, A. Yamamoto, T. Hagihara, J. Org. Chem. 1986,51, 723. [4] a) F. K. Sheffy, J. K. Stille, J. Am. Chem. Soc. 1983, 105, 7173; b) B. M. Trost, N. R. Schmuff, M. J. Miller, ibid. 1980, 102, 5979: c) J. Tsuji, I. Minami, Acc. Chem. Res. 1987, 20, 140: d) N. Greenspoon, E. Keinan, Tetrahedron Lett. 1982, 23, 241. [5] B. Akermark, S. Hansson, A. Vitagliano, J. Am. Chem. Soc. 1990,112,4587. [6] a) J.-C. Fiaud, J.-Y. Legros, J. Org. Chem. 1987,52, 1907; b) N. Greenspoon, E. Keinan, ibid. 1988, 53, 3723: c) B. M. Trost, J. W. Herndon, J. Am. Chem. SOC. 1984, 106, 6835; d) B. M. Trost, T. R. Verhoeven, J. Org. Chem. 1976,41,3215.

13

[7] a) B. Akermark, S. Hansson, B. Krakenberger, A. Vitagliano, K. Zetterberg, Organometallics 1984, 3, 679; b) B. Akermark, S. Hansson, A. Vitagliano, J. Organomet. Chem. 1987, 335, 133. [8] Abbreviations of the ligands: DIOP = 2,3-0isopropylidene-2,3 -dihydroxy-l,4 -bis(dipheny1phosphino)butane; Chiraphos: 2,3-bis(dipheny1phosphino)butane; BINAP 2,2'-bis(dipheny1phosphino)-1,1'-binaphthyl. [9] B. M. Trost, T. J. Dietsche, J. Am. Chem. Soc. 1973, 95, 8200. [lo] M. Yamaguchi, T. Shima, T. Yamagishi, M. Hida, Tetrahedron Lett. 1990, 35, 5049-5052. [ l l ] T. Hayashi, Pure Appl. Chem. 1988, 60, 7. [12] a) B. M. Trost, D. L. van Vranken, Angew. Chem. 1992, 104, 194; Angew. Chem. Int. Ed. Engl. 1992, 31, 228; b) B. M. Trost, D. L. van Vranken, C. Bingel, J. Am. Chem. Soc. 1992,114,9327-9343. [ 131 B. M. Trost, B. Breit, S. Peukert, J. Zambrano, J. W. Ziller, Angew. Chem. 1995, 107, 2577; Angew. Chem. Int. Ed. 1995,34,2386. [14] B. M. Trost, A. C. Krueger, R. C. Bunt, J. Zambrano, J. Am. Chem. Soc. 1996, 118, 6520-6521. [15] a) A. Pfalz in Modem Synthetic Methods (Ed.: R. Scheffold), Springer, Berlin, 1989, pp. 199248; b) Chimica 1990,44, 202. [16] a) D. Muller, G. Umbricht, B. Weber, A. Pfaltz, Helv. Chim. Acta 1991, 74, 232: b) U. Leutenegger, G. Umbricht, C. Farni, P. von Matt, A. Pfaltz, Tetrahedron 1992, 48, 2143: c) C. Bolm, K. Weikhardt, M. Zehnder, T. Ranff, Chem. Bel: 1991, 124, 1173; d) C. Bolm, G. Schlingloff, K. Weickhardt, Angew. Chem. 1994, 106, 1944: e) D. A. Evans, M. M. Faul, M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742; f) S. E. Denmark, N. Nakajima, 0. J.-C. Nicaise, J. Am. Chem. Soc. 1994, 116, 8797; g) T. Fujisawa, T. Ichiyanagi, M. Shimizu, Tetrahedron Lett. 1995,36, 5031; h) A. S. Gokhale, A. B. E. Minidis, A. Pfaltz, Tetrahedron Lett. 1995, 36, 183. i) Recent Review: 0. Reiser, Nachl: Chem. Tech. Lab. 1996, 44, 744. [17] B. M. Trost, S. J. Brickner, J. Am. Chem. Soc. 1983,105,568.

14

A. Asymmetric Synthesis

[18] a) P. von Matt, G. C. Lloydjones, A. B. E. Minidis, A. Pfaltz, L. Macko, M. Neuburger, M. Zehnder, H. Ruegger, P. S . Pregosin, Helv. Chim. Actu 1995, 78, 265-284; b) A. Pfaltz, Acc. Chem. Res. 1993,26, 339. [19] a) J. V. Allen, S. J. Coote, G. J. Dawson, C. G. Frost, C. J. Martin, J. M. J . Williams, J. Chem. SOC. Perkin Trans. I 1994, 2065; b) J. V. Allen, G. J. Dawson, C. G. Frost, J. M. J. Williams, S . J. Coote, Tetrahedron 1994, 50, 799; c) C. G. Frost, J. M. J . Williams, Tetrahedron Lett. 1993, 34, 2015. [20] a) J. Sprinz, M. Kiefer, G. Helmchen, G. Huttner, 0. Walter, L. Zsolnai, M. Reggelin, Tetruhedron Lett. 1994,35, 1523-1526; b) H. Steinhagen, M. Reggelin, G. Helmchen, Angew. Chem. 1997, 109, 2199; Angew. Chem. Int. Ed. Engl. 1997, 36, 2108. [21] a) P. von Matt, A. Pfaltz, Angew. Chem. 1993, 105, 614; Angew. Chem. Int. Ed. Engl. 1993, 32, 566; b) J. Sprinz, G. Helmchen, Tetruhedron Lett. 1993,34,1769-1772; c) G. J. Dawson, C. G. Frost, J. M . J. Williams, Tetrahedron Lett. 1993, 34, 3149-3150; d) J. M. Brown, D. I. Hulmes, P. J. Guiry, Tetrahedron 1994, 50, 4493-4506.

[22] a) P. v. Matt, 0. Loiseleur, G. Koch, A. Pfaltz, C. Lefeber, T. Feucht, G. Helmchen, Tetruhedron Asymmetry 1994, 5, 573; b) R. Jumnah, A. C. Williams, J. M . J . Williams, Synlett 1995, 821. [23] H. Rieck, G. Helmchen, Angew. Chem. 1995, 107, 2881; Angew. Chem. Int. Ed. Engl. 1995,34,2881. [24] B. Akermark, B. Krakenberger, S. Hansson, A. Vitagliano, Orgunometullics 1987, 6, 620. [25] 0. Reiser, Angew. Chem. 1993,105,576-578; Angew. Chem. Int. Engl. Ed., 1993, 32, 547549. [26] B. Bosnich, P. B. Mackenzie, Pure Appl. Chem. 1982,54, 189. [27] T.V. Rajan Babu, A. L. Casalnuovo, J. Am. Chem. SOC.1996,118, 6325. [28] G. Helmchen, S. Kudis, P. Sennhenn, H . Steinhagen, Pure Appl. Chem. 1997,5 13. [29] a) B. M. Trost, R. Madsen, S. G. Guile, A. E. H. Elia, Angew. Chem. 1996, 108, 1666; Angew. Chem. Int. Ed. Engl. 1996, 35, 1569; b) B. M. Trost, Z. P. Shi, J. Am. Chem. SOC. 1996,118, 3037.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary Unexpected Influence of Additives? Karola Riick-Braun

Asymmetric alkylation of carboxylic acid derivatives has been studied intensively for about 20 years. [l] Numerous auxiliaries, tailor-made structures with high steric demands for effective RelSi face differentiation, have been synthesized and their efficiency tested. [ 1, 21 In recent years besides the preparative aspects of enolates, physico-chemical investigations into their structure-reactivity relationships have gained interest. [3] Crystal structure analyses, osmometric measurements, and NMR studies in solution are helpful in the investigation of the factors that may control enolate reactions. [3-51 Recently, Myers et al. described a method for alkylation of amide enolates having D(+)-pseudoephedrine, an industrial product manufactured worldwide in ton quantities, as a chiral auxiliary. [6] Upon treatment with LDA (2 equiv), N-acyl-pseudoephedrine derivatives 1 react with alkyl bromides or iodides efficiently and with high stereoselectivity in the presence of LiCl (6 equiv) (Scheme 1).

Me

0

Even at 0 "C diastereoselectivities of > 94 % de were obtsiined. A wide repertoire of cleavage reactions demonstrates the synthetic potential of the pseudoephedrine amides, providing access to chiral a-branched carboxylic acids, aldehydes, ketones or primary alcohols with recovery of the auxiliary (Scheme 2). Moreover, efficient alkylation reactions utilizing epoxides and epoxide-derived electrophiles open up a route to chiral y-lactones and y-hydroxy ketones. [7] Interestingly, the authors note that the reaction time of the alkylation reaction can be shortened and the conversion increased by addition of LiC1. The concentration of LiCl did not seem to affect the diastereoselectivity of the reaction. Under the same reaction conditions the chiral auxiliary L-(-)-ephedrine [8] led to markedly lower diastereoselectivities. [6, 81 Even in the presence of LiCl the alkylation product from N-propionylephedrine 3 and n-butyl iodide was formed

1.2eq LDA 6eq LiCl

P h \ r , l t .

OH

Me

2.

1

R = Me, Bn, Ph, CI, mBu R'X = Mel, Etl, mBu, BnBr

R'X

Me

OH 2

6'

80 - 99%, 94 - >99% de

Scheme 1. LDA = lithium diisopropylamide.

16

A. Asymmetric Synthesis

1

87-97%, H:SO&Jioxane >95% ee

N-BH<

Li+

80-88%,88-99% ee

Scheme 2. 0

Me

P h d N / l C M e

-

bH

1

3

Me

1. LDNMX THF 2. n-Bul

0

Me

*

P h d N / l C M e 8H

Ae

iBu

4

Scheme 3. Me

0

1. n-BuLi or LDA, LiCI, RX* H O q N H 2 2. NaOH or H20, A

Ph&N&~~2 AH

he

R

(R m-(-)-5

Me

6Li

Me A

0

6

Me

6Li

OLi

Me 0

with a diastereoselectivity of only 70 % de (Scheme 3). Recently, (+)- and (-)-pseudoephedrine-derived glycinamides [9] proved to be suitable building blocks for the synthesis of D- or L-configurated a-amino acid derivatives. [lo] Thus, glycinamides 5, [lob] easily accessible by n-

Scheme 4.

butyl-lithium-promoted condensation of glycine methyl ester with pseudoephedrine in the presence of LiCl, undergo highly diastereoselective alkylation reactions with a wide range of alkyl halides, without protection being necessary for the hydroxyl and amino functionalities present in the molecules (Scheme 4).

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliarj

Apparently, deprotonation performed at -78°C is leading to the 0-, N-dianion A (Scheme 4). Equilibration of the latter to the thermodynamically more stable Z-enolate B (Scheme 4) upon subsequent warming to room temperature seems to be reasonable, due to the C-alkylated products obtained at 0 "C or even at room temperature. In this temperature range N-alkylation, observed at -78 "C, is effectively suppressed. [ 10d] For lithium enolates derived from the glycinamides 5 an influence of lithium halides on rate enhancement and diastereoselectivity is found. [ 101 Thus, in the absence of LiCl a significant decrease in diastereoselectivity is observed in the alkylation of 5 with ethyl iodide (82 % de without LiCl in comparison to 97 % de upon addition of LiCl (6 equiv)). Lithium bromide (6 equiv) was found to accelerate the rate of enolate alkylation, too, but diastereoselectivity was found to be lower (9 1-93 % de). The practical alkylation procedures published, include efficient hydrolysis protocols providing the advantage to prepare either Ntert-butyloxycarbonyl (N-Boc) or N-(g-fluorenyl-methy1oxy)-carbonyl (N-Fmoc) protected proteinogenic and non-proteinogenic Dor L-configurated a-amino acids directly from the alkaline aqueous hydrolysis solution. [lOd] Therefore, and due to the low cost and the availability of the chiral auxiliary employed, the method developed by Myers et al. appears to be competitive even for appli-

i

+

CH2R

-

17

cations in industry. However, the reasons for the high diastereoselectivity observed are neither obvious nor predictable. Considering the investigations of Larcheveque et al., [8] who reported on the alkylation of amide enolates of ephedrine in 1978, one would probably not have been predicted any great success for experiments with pseudoephedrine. Larcheveque and coworkers reported on the deprotonation of N-acyl-ephedrines with LDA in the presence of hexamethylphosphoric acid triamide (HMPA) and subsequent reactions with alkyl halides providing products with diastereoselectivities of c 80 : 20. Only when MgC12 was added, diastereomeric ratios of > 95 : 5 were achieved (Scheme 3). How can the effects brought about by the addition of metal salts be explained? Since the start of investigations into asymmetric reactions with enolates it has been known that the reactivity and selectivity observed in enolate chemistry is influenced not only by the base employed, but also by the use of cosolvents such as HMPA, and the addition of metal salts or Lewis acids. [2-4, 111 Lithium enolates, in particular, tend to form aggregates by self-assembly. [3, 41 Decisive contributions to the explanation of this phenomenon and its consequences have been made by Seebach et al. by crystal structure analyses of crystalline lithium enolates [12] up to suggestions regarding the structure of the complexes in solution (Scheme 5). [3, 4, 131

0 - +

Scheme 5. RCHzY = alkyl halide.

18

A. Asymmetric Synthesis

Scheme 6. R’2N = TMP, R2N = HMDS.

Scheme 7.

The method of choice for structure determination of aggregates in solution is NMR spectroscopy. New investigations are based for instance on 6Li, 15N and 31P measurements with isotopically labeled samples of lithium bases such as lithium hexamethyldisilazane (LiHMDS), LDA, and lithium tetramethylpiperidide (LiTMP). 1141 Thus 6Li-’5N coupling, for example, permits conclusions to be drawn about the degree of aggregation of LiNRz derivatives. Even now, despite its carcinogenicity HMPA is often added to reaction mixtures to increase the reactivity of the lithium compounds. Recently, mixed solvatedaggregates between HMPA and lithium bases (LiHMDS, LiTMS, LDA) were proved (Scheme 6 ) . 115-181 The cosolvent does not break up the aggregates [15] but instead promotes formation of open dimers [16] and “triple ions”. [ 171 In addition, recent spectroscopic studies of Column et al., dealing with the etheral solvation of LiHMDS, revealed no support for the often-cited correlation of reduced aggregation state with increasing strength of the lithiumsolvent interaction. 1191 Moreover, exact spectroscopic data could be obtained for the structures of complexes of lithium bases and salts and their dependence on the concentra-

tion of the added salt (Scheme 7). [14, 15, 201 A mixed aggregate of LDA and LiCl recently was synthesized and the crystal structure analyzed by Mair et al. 1211 Meanwhile, dimeric LDA upon treatment with LiCl is known to form the more reactive mixed aggregate (iPr)*NLi.LiCl. 119, 221 In the light of increasing knowledge about the nature and reactivity of lithium amide/ halide aggregates, information and understanding of lithium enolatehalide aggregates still seem to be rather poor. However, P.v.R. Schleyer’s group recently characterized two aggregates consisting of lithium halides and lithium enolates, identified as heterodimers, by X-ray crystallography. 1231 Besides the question of the constitution and the reactivity of the aggregates being formed, another problem in analyzing the reactions of enolates with electrophiles is the continually changing concentration of base, enolate, and metal salts during the course of the reaction. Stereochemica1 investigations and trapping experiments on the enolization of 3-pentanone 7 with LiTMP in THF impressingly demonstrate the consequences of the structural variety of the aggregates, thus differing in reactivity (Scheme 8). 115, 201 Whereas at 5 % conversion the E/Z selectivity was 30 : 1, at greater

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary

Me&Me

4

OTMS

0

1 .LiTMP/LiCI 2.Me3SiCI

7

OTMS

+

Me

Me&Me

Me

E-8

19

Z-8

LiCl

Scheme 8. TMS-CI = Me3SiC1.

0

I

OSiMe,

I

THF, TMS-CI

’Bu

‘Bu

10

9

I

reaction conditions I

ee of 10

EQ+LiCI

69 23 03

than 80% conversion an EIZ selectivity of only > 10 : 1 was observed. The addition of 0.3-0.4 equivalents of LiCl led to an EIZ ratio of 50 : 1; however, further increase in the amount of LiCl to > 1.0 equivalents produced results identical to those obtained under salt-free conditions. Remarkable improvements in chiral basemediated reactions of prochiral ketones under external quench (EQ) conditions with TMS-C1, furnishing enantiomerically pure enol silanes, were found upon deprotonation in the presence of LiCl. [22, 241 Simpkins et al. studied for instance the conversion of 4 tert-butylcyclohexanone 9 into enol silane 10 by employing the chiral amide base 11 (Scheme 9). [24] Applying the TMS-Cl in situ quench (TMS-Cl-ISQ) protocol a higher level of enantiomeric excess was observed compared to external quench conditions (EQ). However, under external quench conditions in the presence of LiCl (EQ+LiCl procedure) significantly higher levels of asymme-

Scheme 9.

tric induction are observed. Simpkins et al. concluded from the results obtained LiCl to be the reason of the “ISQ effect”. [24] Thus, the internally available TMS-C1 was proposed to be the source for an increasing LiCl concentration during conversion to the enol silane. Indeed, spectroscopic experiments by Lipshutz and coworkers support TMS-C1 to be the supplier of LiCl as the key component of in situ quenching conditions in ketone enolization. [25] Furthermore, the “LiC1 effect” observed upon inclusion of LiCl under external quench conditions was concluded to be caused by conversion to the more selective mixed aggregates already mentioned. [ 19, 22, 231 Exploring “nonstoichiometric effects” [3a, 51 with organolithium compounds since the early 1980s, these days Seebach et al. are investigating the diastereoselective alkylation of polylithiated open-chain and cyclic peptides in the presence of excess lithium salts and bases (Scheme 10). [26, 271 Thus, highly

20

Boc,

A. Asymmetric Synthesis

TH

0

i-

A

1. 6-7 LiEJr THF, -75'C 0

2. 6 BuLi

12

Scheme 10.

functionalized glycine and sarcosine lithium enolates and dilithium azadienolates of peptide lithium salt complexes were alkylated in yields of up to 90 % with diastereoselectivities ranging from 1 : 1 to 9 : 1. The work of Myers et al. [ 6 ] illustrates the synthetic potential of the use of metal salts (instead of HMPA!) in alkylation reactions of enolates, employing easily accessible amide enolates of the chiral auxiliary pseudoephedrine. It is not surprising that the mechanism of chiral induction is not yet fully understood; further investigations are necessary. Nonetheless, unanswered questions in enolate chemistry remain even for tailor-made, well-established auxiliaries, whose asymmetric induction can be explained convincingly by working models on monomer enolate structures, considering chelation control and steric factors. Increasing numbers of striking examples for unusual effects of metal salts other than lithium on various metal enolates were reported in recent years. [28, 291 Thus, we await interesting future results of systematic investigations on the influence of metal salts and, thereby, new applications in supposedly well-known reactions.

References [I] a) D. Caine in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming, G. Pattenden), Pergamon Press, New York, 1991, p. 1; b) D. A. Evans, J. M. Takacs, Tetrahedron Lett. 1980, 21, 4233; c) W. Oppolzer, R. Moretti, S. Thomi, ibid. 1989, 30, 5603; d) K.-S. Jeong, K. Parris, P. Ballester, J. Rebek Jr., Angew. Chem. 1990, 102, 550; Angew. Chem. Int. Ed. Engl. 1990, 29, 555. [2] a) J. D. Morrison, Asymmetric Synthesis, Academic Press, New York, 1984; b) M. Nogradi, Stereoselective Synthesis, 2nd ed., VCH, Weinheim, 1995. [3] Reviews: a) D. Seebach, Proc. Robert A. Welch Found. Con8 Chem. Res. 27: Stereospecijicity in Chemistry and Biochemistry (7.-9. Nov. 1983), Houston, TX, USA, 1984, 93-145; b) D. Seebach, Angew. Chem. 1988, 100, 1685; Angew. Chem. Int. Ed. Engl. 1988, 27, 1624; c) G. Boche, ibid. 1989, 101, 286 and 1989,28, 277. [4] a) L. M. Jackman, T. S. Dunne, J. Am. Chem. SOC.1985, 107, 2805, and references therein; b) P. G. Willard, M. J. Hintze, J. Am. Chem. Soc. 1987, 109, 5539; c) J. Corset, F. Froment, M.-F. LautiC, N. Ratovelomanana, J. Seyden-

Asymmetric Alkylation of Amide Enolates with Pseudoephedrine as Chiral Auxiliary Penne, T. Strzalko, M.-C. Roux-Schmitt, ibid. 1993, 115, 1684. [5] For excellent reviews about “some effects of lithium salts”, see: a) D. Seebach, A. K. Beck, A. Studer, Mod. Synth. Methods 1995, 7, 1 ; b) D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. 1996, 108, 2880; Angew. Chem. Int. Ed. Engl. 1996, 35, 2708 and references cited therein. [6] A. G. Myers, B. H. Yang, H. Chen, J. L. Gleason, J. Am. Chem. SOC.1994,116,9361. [7] A. G . Myers, L. McKinstry, J. Org. Chem. 1996, 61, 2428. Interestingly, attack from opposite z-faces of the pseudoephedrine amide enolates is found for epoxides and alkyl halides. In this context, the lithium alkoxide function of the chiral auxiliary, seems to be the crucial moiety, directing the addition of epoxides and operating as a screen in the case of alkyl halides. [8] a) M. Larcheveque, E. Ignatova, T. Cuvigny, Tetrahedron Lett. 1978, 41, 3961; b) M. Larcheveque, E. Ignatova, T. Cuvigny, J. Organomet. Chem. 1979, 177, 5. [9] a) For the asymmetric alkylation of chiral glycine derivatives, see: R. M. Williams, Organic Chemistry Series, Volume 7: Synthesis of Optically Active a-Amino Acids (Eds.: J. E. Baldwin, P. D. Magnus), Pergamon Press, Oxford, 1989; b) For the role of added salts in enolate alkylation of chiral imines of glycinates, see: A. SolladiC-Carvallo, M.-C. SimonWermeister, J. Schwarz, Organometallics 1993, 12, 3743, and references cited. [ 101 a) A. G. Myers, J. L. Gleason, T. Yoon, J. Am. Chem. SOC. 1995, 117, 8488; b) A. G. Myers, T. Yoon, J. L. Gleason, Tetrahedron Lett. 1995, 26, 4555; c) A. G. Myers, T. Yoon, Tetrahedron Lett. 1995, 26, 9429; d) A. G. Myers, J. L. Gleason, T. Yoon, D. W. Kung, J. Am. Chem. SOC. 1997,119,656. [ l l ] A. Loupy, B. Tchoubar, Salt Esfects in Organic and Organometallic Chemistry, VCH, Weinheim, 1992. [12] a) R. Amstutz, W. B. Schweizer, D. Seebach, J. D. Dunitz, Helv. Chim. Acta 1981, 64, 2617; b) W. Bauer, T. Laube, D. Seebach, Chem. Bel: 1985, 118,764. [13] For the effect of mixed aggregates derived from lithium ester enolates and chiral lithium

21

amides on enantioselective transformations, see: a) E. Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay, M. Simson, D. Seebach, Synthesis 1993, 1271; b) M. Uragami, K. Tomioka, K. Koga, Tetrahedron Asymmetry 1995, 6, 701; c) K. Yasuda, M. Shindo, K. Koga, Tetrahedron Lett. 1996, 37, 6343, and references therein. [14] D. B. Collum, Acc. Chem. Res. 1993,26, 227. [15] a) A. S. Galiano-Roth, Y.-J. Kim. J. H. GilChrist, A. T. Harrison, D. J. Fuller, D. B. Collum, J. Am. Chem. SOC. 1991, 113, 5053; b) Y.-J. Kim, M. P. Bernstein, A. S. GalianoRoth, F. E. Romesberg, P. W. Williard, D. J. Fuller, A. T. Harrison, D. B. Collum, J. Org. Chem. 1991,56,4435. [16] P. L. Hall, J. H. Gilchrist, A. T. Hamson, D. J. Fuller, D. B. Collum, J. Am. Chem. SOC. 1991, 113, 9575. [17] F. E. Romesberg, M. P. Bernstein, J. H. GilChrist, A. T. Harrison, D. J. Fuller, D. B. Collum, J. Am. Chem. SOC. 1993, 115,3475. [ 181 For amine and unsaturated hydrocarbon solvates of LiHMDS, see: a) B. L. Lucht, D. B. Collum, J. Am. Chem. SOC.1996, 118, 2217; b) B. L. Lucht, D. B. Collum, J. Am. Chem. SOC. 1996, 118, 3529; c) B. L. Lucht, M. P. Bernstein, J. F. Remenar, D. B. Collum, J. Am. Chem. SOC.1996, 118, 10707. [19] B. L. Lucht, D. B. Collum, J. Am. Chem. SOC. 1995,117,9863. [20] P. L. Hall, J. H. Gilchrist, D. B. Collum, J. Am. Chem. SOC. 1991,113,9571. [21] F. S. Mair, W. Clegg, P. A. O’Neil, J. Am. Chem. SOC.1993,115, 3388. [22] For solution structures of chiral lithium amides in the presence of lithium halides, see: K. Sugasawa, M. Shindo, H. Noguchi, K. Koga, Tetrahedron Lett. 1996, 37, 7377. [23] K. W. Henderson, A. E. Dorigo, Q.-Y. Liu, P. G. Williard, R. v. R. Schleyer, P. R. Bernstein, J. Am. Chem. SOC. 1996, 118, 1339. [24] a) B. J. Bunn, N. S. Simpkins, J. Org. Chem. 1993, 58, 533; b) B. J. Bunn, N. S. Simpkins, Z. Spavold, M. J. Crimmin, J. Chem. SOC.Perkin Trans. I 1993, 3113; c) P. Coggins, S. Gaur, N. S. Simpkins, Tetrahedron Lett. 1995, 36, 1545, and references cited. [25] B. H. Lipshutz, M. R. Wood, C. W. Lindsley, Tetrahedron Lett. 1995, 36, 4385.

22

A. Asymmetric Synthesis

[26] a) D. Seebach, H. Bossler, H. Griindler, S.-I. Shoda, Helv. Chim. Acta 1991, 74, 197; b) S. A. Miller, S. L. Griffiths, D. Seebach, ibid. 1993, 76, 563; c) H. G. Bossler, D. Seebach, ibid. 1994, 77, 1124. [27] D. Seebach, 0. Bezencon, B. Jaun, T. Pietzonka, J. L. Matthews, F. N. M. Kuhnle, W. B. Schweizer, Helv. Chim. Actu 1996, 79, 588.

[28] K. Ruck, Angew. Chern. 1995, 107, 475; Angew. Chem. Int. Ed. Engl. 1995, 34, 433, references 17-19 cited therein. [29] D. C. Harrowven, H. S. Poon, Tetrahedron Lett. 1996, 37, 4281, and references cited.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Catalytic Asymmetric Carbonyl-Ene Reactions David J. Berrisford and Carsten Bolm

As one of the fundamental bond constructions, the carbonyl-ene reaction - between an aldehyde and an alkene bearing an allylic hydrogen - attracts considerable attention [ 11 from the synthetic community. Given the versatile chemistry of the product homoallylic alcohols, both the intra- and intermolecular versions of asymmetric carbonyl-ene reactions are valuable processes. [2] Within the catalytic field, [3] the continuing development of chiral Lewis acids further advances the utility and scope of carbonyl-ene chemistry. We wish to highlight a number of these developments. Carreira et al. [4] have discovered a titanium-catalyzed asymmetric carbonyl-ene reaction of aldehydes with the cheap commodity chemical 2-methoxypropene (Scheme 1). (13)-I(20mol %), Ti(OPr), (10 mol %)

0 RKH

+

Me

*

R

Using a catalyst prepared in situ from tridentate ligand (R)-1 and Ti(OiPr)4 in a 2 : 1 ratio, the yields and enantioselectivities of the new process are generally high (Table 1). The most encouraging results, up to 98 % ee, are observed with aJ-ynals. Thus, this chemistry provides alternative catalytic syntheses of propargylic alcohols. Unusually for an asymmetric addition process, benzaldehyde gives only modest selectivity - 6 6 % ee. The only a-branched aldehyde reported to undergo addition, cyclohexanecarboxaldehyde, affords a product with 75 % ee. The vinyl ether products obtained from asymmetric ene reactions are valuable precursors for a number of enantiomerically-enriched compounds (Scheme 2). Acid hydrolysis affords the corresponding methyl ketones thus

aoMe 66-98% BB

Scheme I. Asymmetric Ti-catalyzed carbonyl-ene reactions of 2-methoxypropene.

24

A. AsymmetricSynthesis

Table 1. Results of the Ti-catalyzed asymmetric carbonyl-ene reaction. [ 5 ] Aldehyde

% Yielda) % eea)

Ph(CH2)3-C=C-CHO TBSOCH~-CTC-CHO PH-C=C-CHO Ph( CH2)zCHO PhCHO C6Hi lCHO

99 85 99 98

03,CH2ClP/

98 93

R

91 90 66 75

83

79

Me

R = CsFs; 20 mol % of (Rj-2 00% yield, 88% ee

(RJ-2

chiral catalyst molecularsieves

PPh3

R3Me

OH

*

Rd

O

1 OH

OsO,, NMO acetone, H20

a) Isolated and analyzed as the corresponding /3-hydroxy ketones obtained by treatment of the reaction mixture with Et20/2N HC1.

,AH +

7 Et20 I

A

0 M

e

0 O

H

Scheme 2. Synthetic utility of the carbonyl-ene products.

~

R

SPh

R = C02Me; 0.5 mol % of (Rk3 94% yield, 99% ee

(RJ-3:x = CI, y = H (RJ-4:X = Y = Br

providing an alternative method to affect asymmetric methyl ketone aldol additions. [ 5 , 61 Oxidative cleavage of the enol ethers with ozone affords the corresponding phydroxy esters, and osmium-catalyzed dihydroxylation with N-morpholine-N-oxide (NMO) gives ketodiols. Carreira's recent work is an extension of earlier studies [5] in which a titanium(1V) complex, prepared in situ from tridentate ligand (R)-1 and Ti(OiPr)4, was found to catalyze Mukaiyama aldol reactions with high enantioselectivities. The chiral ligand used in both the ene and aldol chemistry is prepared from 3-bromo-5-tert-butylsalicylaldehyde and 2-amino-2'-hydroxy-1,1'-binaphthol. This

Scheme 3. Asymmetric carbonyl-ene reactions of vinyl sulfides with electron deficient aldehydes.

enantiomerically pure amino alcohol is obtained from a convenient oxidative coupling procedure [7] of Smrcina and Kocovsky et al. We expect that this valuable chiral biaryl ligand will prove popular amongst synthetic chemists. Usually, intermolecular ene reactions of simple aldehydes with 1,l-disubstituted alkenes bearing no additional activating substituents require stoichiometric quantities of powerful Lewis acids. [ 11 Therefore, catalytic asymmetric variants using milder Lewis acids have previously been restricted to especially reactive aldehydes in intermolecular processes or to intramolecular reactions. For example, Yamamoto et al. described the use of alumi-

Catalytic Asymmetric Carbonyl-Ene Reactions

lH

25

- 3

(R)-4 (10 mol %)

Me02C

+ &Me

4A MS, ooc, toluene

Me0,C

Me

84% yield, 94:6 syn:anti, syn 89% ee

CIJH

BU0,CJh

+

+

OPh &Me

nPr

A

- aMe

(R)3 (10 mol %) 4A MS, ooc, CH2CIz

O"C,CH2C12D

Ci

OPh 53% yield, 97% ee

Buo2c

67% yield, 9 5 5 E E ,

Z:>99% ee

nium-based chiral Lewis acid (R)-2 in catalyzed asymmetric carbonyl-ene reactions. [8] However, the choice of enophile is limited to highly electron deficient aldehydes such as pentafluorobenzaldehyde and chloral. Both simple 2,2-disubstituted alkenes and vinyl sulfides undergo enantioselective reactions with a maximum ee of 88% even with catalytic quantities (20 mol%) of the Lewis acid (Scheme 3). The scope and utility of asymmetric carbonyl-ene reactions has also been advanced by Mikami et al. [lb, c, el Readily available [TiX2BINOL][9] Lewis acids (X = C1, Br), e.g. (R)-3, catalyze ene reactions of glyoxylates with outstanding enantioselectivities. Recently, it has been demonstrated that equally enantioselective ene reactions can be accomplished using vinylogous glyoxylates [lo] and fluoral [ l l ] as the enophiles. Many of the earlier developments in asymmetric ene chemistry have been thoroughly reviewed. [ l ] However, there are a number of important recent advances worthy of highlighting. [12-181 Even extremely low catalyst loadings (0.5 mol%) are effective in promo-

Scheme 4. Asymmetric [TiX2BINOL]-catalyzed carbonyl-ene reactions.

Scheme 5. An asymmetric catalytic glyoxylate ene reaction of a silyl enol ether.

ting glyoxylate ene reactions with vinyl sulfides and selenides (Scheme 3). [12] Changing the Lewis acid to (R)-4, enables certain trisubstituted alkenes to be used with excellent enantio- and diastereocontrol (Scheme 4). [13] Vinyl ethers, which are more reactive than their thioether counterparts, undergo ene reactions with high enantioselectivities using (R)-3 as catalyst. [14] Thus, addition of 2phenoxybutene to chloroacetaldehyde in the presence of 10 mol% of (R)-3 gives the corresponding ene product in 53 % yield with 97 % ee (Scheme 4). [14] The impressive levels of stereocontrol obtained with this methodology have led to a number of concise syntheses [ l ] of important bioactive targets. Recent studies by the Mikami group include the development of a new synthetic route to insect pheremones using isoprene as the ene component, [15] the preparation of two fragments of the immunosuppressant rapamycin, [ 161 and the synthesis of prostacyclin analogues including isocarbacyclin. [ 171 An ene mechanism is also implicated in the asymmetric "aldol" additions of ketene silyl

26

A. Asymmetric Synthesis

acetals of thioesters to aldehydes [18] and of silyl enol ethers to glyoxylate esters (Scheme 5). [19] The latter process can form part of a novel tandem addition reaction.[l9c] The lack of accompanying silyl transfer is in contrast to other asymmetric Mukaiyama-type aldol reactions. [20] The new methodologies developed by Carreira, Mikami and others widen the scope of asymmetric catalytic ene reactions. Studies on new catalysts [21] often provide the necessary mechanistic insights from which further synthetically-useful developments follow. An excellent example is provided by the recent report [22] of asymmetric catalysis of the glyoxylate ene reaction by a titanium catalyst formed from rucemic [Ti(OiPr)2BINOL] [9] and a catalytic quantity of an enantiopure activator. We are confident that even more practical chiral Lewis acid catalysts, displaying wider substrate tolerance, and requiring lower catalyst loadings, will emerge in the future.

References [ 11 a) B. B Snider in Comprehensive Organic Syn-

thesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 527; Vol. 5, p. 1; b) K. Mikami, M. Shimizu, Chem. Rev. 1992, 92, 1021; c) K. Mikami, M. Terada, S. Narisawa, T. Nakai, Synlett 1992, 255; d) R. M. Borzilleri, S.M. Weinreb, Synthesis 1995, 347; e) K. Mikami, Pure Appl. Chem. 1996, 68, 639. [2] a) S. Sakane, K. Maruoka, H. Yamamoto, Tetrahedron Lett. 1985, 26, 5535; b) idem., Tetrahedron 1986, 40, 2203; c) K. Narasaka, Y. Hayashi, S. Shimada, Chem. Lett. 1988, 1609. [3] a) K. Maruoka, H. Yamamoto in Catalytic Asymmetric Synthesis (Ed.: I Ojima), VCH, New YorNeinheim, 1993, p. 413; b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, J. Wiley, New York, 1994; c) K. Narasaki, Synthesis 1991, 1.

[4] E. Carreira, W. Lee, R. A. Singer, J . Am. Chem. Soc. 1995, I1 7, 3649. [5] a) E. Carreira, R. A. Singer, W. Lee, J. Am. Chem. Soc. 1994, 116, 8837. For an application in total synthesis see: b) S. D. Rychnovsky, U. R. Khire, G. Yang, ibid. 1997, 119, 2058. For extensions to this work see: c) R. A. Singer, E. M. Carreira, ibid. 1995, 117, 12360. [6] Catalyzed Mukaiyama-type aldol reactions of silyl enol ethers or silyl ketene acetals with aldehydes lead to the same products. For recent advances see: a) G. E. Keck, D. Krishnamurthy, J . Am. Chem. Soc. 1995, 117, 2363; b) M. Sato, S. Sunami, Y. Sugita, C. Kaneko, Heterocycles 1995, 41, 143.5, and references therein. [7] a) M. Smrcina, M. Lorenc, V. Hanus, P. Sedmera, P. Kocovsky, J . Org. Chem. 1992, 57, 1917; b) M. Smrcina, J. Polakova, S. Vyskocil, P. Kocovsky, ibid. 1993, 58, 4534; c) M. Smrcina, S. Vyskocil, J. Polivkova , J. Polakova, P. Kocovsky, Collect. Czech. Chem. Commun. 1996,61, 1520. [8] K. Maruoka, Y. Hoshino, T. Shirasaka, H. Yamamoto, Tetrahedron Lett. 1988, 29, 3967. [9] The formulae used in this article merely imply the stoichiometric composition rather than the solution structure. For recent structural investigations of chiral Ti complexes see: a) T. J. Boyle, N. W. Eilerts, J. A. Heppert, F. Takusagawa, Organometallics 1994, 13, 2218; b) E. J. Corey, M. A. Letavic, M. C. Noe, S. Sarshar, Tetrahedron Lett. 1994, 35, 7553; c) K. V. Gothelf, R. G. Hazell, K. A. Jergensen, J. Am. Chem. Soc. 1995,117,443.5. [lo] K. Mikami, T. Yajima, T. Takasaki, S. Matsukawa, M. Terada, T. Uchimaru, M. Maruta, Tetrahedron 1996, 52, 85. [ll] K. Mikami, A. Yoshida, Y. Matsumoto, Tetrahedron Lett. 1996, 37, 8515. [12] M. Terada, S. Matsukawa, K. Mikami, J . Chem. Soc. Chem. Commun. 1993, 327; b) K. Mikami, T. Yajima, N. Siree, M. Terada, Y. Suzuki, I. Kobayashi Synlett 1996, 837. [13] a) M. Terada, Y. Motoyama, K. Mikami, Tetrahedron Lett. 1994, 35, 6693; b) K. Mikami, Y. Motoyama, M. Terada, lnorg. Chim. Acta, 1994, 222, 71.

Catalytic Asymmetric Carbonyl-Ene Reactions [ 141 We thank Professor Mikami, Tokyo Institute of

Technology, for helpful discussions and disclosure of unpublished material. a) K. Mikami, E. Sawa, M. Terada, unpublished data; b) E. Sawa, Master’s Thesis, Tokyo Institute of Technology, 1992. M. Terada, K. Mikami, J. Chem. SOC.Chem. Commun. 1995, 2391. a) K. Mikami, A. Yoshida, Tetrahedron Lett. 1994, 35, 7793. See also: b) K. Mikami, S. Narisawa, M. Shimizu, M. Terada, J. Am. Chem. SOC. 1992,114, 6566; 9242. For a formaldehyde-ene reaction see: K. Mikami, A. Yoshida, Synlett 1995, 29; and reference [ 1 1I. K. Mikami, S . Matsukawa, J . Am. Chem. Soc. 1994, 116, 4077.

27

[19] a) K. Mikami, S . Matsukawa, J . Am. Chem. SOC. 1993, 115, 7039. See also; b) idem., Tetrahedron Lett. 1994, 35, 3133; c) K. Mikami, S. Matsukawa, M. Nagashima, H. Funabashi, H. Morishima, ibid. 1997,38,579. [20] T. K. Hollis, B. Bosnich, J . Am. Chem. SOC. 1995, I 1 7,4570. [21] For new catalysts for asymmetric ene reactions see: a) M. Terada, K. Mikami, J . Chem. Soc. Chem. Commun. 1994, 833; b) D. Kitamoto, H. Imma, T. Nakai, Tetrahedron Lett. 1995, 36, 1861; c) G. Desimoni, G. Faita, P. Righetti, N. Sardone, Tetrahedron 1996, 52, 12019. [22] a) K. Mikami, S. Matsukawa, Nature, 1997, 385, 613. For a related concept see: b) J. W. Faller, D. W. Sams, X. Liu, J . Am. Chem. SOC. 1996, 118, 1217.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Chiral 2-Amino-1,3=butadienes: New Reagents for Asymmetric Cy cloadditions Karsten Krohn

Since its discovery over sixty years ago [ 11 the approach using chiral dienophiles (mostly Diels-Alder reaction has lost none of its derivatives of acrylic esters). [4, 5, 8-10] Chiattraction. [2, 31 It enables, in a one-step ral dienes have been used less frequently, altinter- or intramolecular reaction, the rapid pre- hough Trost et al. in 1980 had achieved an paration of cyclic compounds having a six- attention-riveting result with the ( 1S)-butamembered ring. During the course of the diene derivative 2 [ l l ] (Scheme 1). This [4 + 21 cycloaddition four new stereocenters diene reacted regioselectively with juglone can be introduced directly, and their stereo- (1) to yield a single adduct 3 with 97 % ee! control is a topic of major interest in modern The well-known n-stacking model was devesynthetic chemistry. [4-61 In addition, in loped from this example, although it does not intermolecular reactions, the relative positions appear to be applicable to all reactions. [ 121 of the reaction partners (regiochemistry) must Unfortunately the result obtained by Trost be taken into account. If a concerted reaction et al. remained unique for more than a decade, is assumed, both a cis addition (suprafacial at least in terms of enantioselectivity. The mode) and a preferred endo orientation slow development in the area of chiral dienes (Alder rules) can be expected. But how can may in part be ascribed to the difficulty of prethe absolute configuration of the desired pro- paring these compounds. [4b] Recently, in duct be controlled? There are three basic quick succession and independently of one possibilities: the use of a chirally modified another, the research groups of Enders [I31 diene, a chirally modified dienophile, or a chi- and Barluenga [ 141 reported on the cycloaddiral catalyst. Although the first successes result- tion of chiral 2-aminobutadienes. Inititially, ed from the attractive, but difficult, catalytic the prospects of 2-aminobutadienes in this route, [4b, 71 the majority of the investigators reaction were not promising at all, since the are concerned with the stoichiometric results of MIND03 calculations had indicated

Chirul2-Amino-1,3-butudienes:New Reagents f o r Asymmetric Cycloadditions

that they would not undergo (concerted) Diels-Alder reactions. [ 151 Nevertheless, Valentin et al. in 1977 [16] and later Gompper et al. in 1979 [17] obtained evidence for the cycloaddition of electron-rich methoxy- and amino-substituted dienes. Since then, the research groups of Barluenga in Spain and Pitacco and Valentin [ 181 in Italy have been able to carry out other cycloadditions with activated olefins [ 191, aldehydes [ 19, 201, heterocumulenes [21] (e. g. thiophosgenes [22]), aldimines [23], nitrostyrenes [ 161 or aliphatic nitroolefines. [ 181 The general reactivity depending on the substituents and conformation of the 2-aminobutadienes (e. g. “enamine” reaction versus cycloaddition) was also intensively investigated. [24] The enamine character of 2-aminobutadienes (or dienamines) is clearly demonstrated by non-Lewis acid catalyzed reactions, and open-chain adducts are frequently isolated alongside the cyclic adducts. [21] Nevertheless, in many cases the stereochemistry of the products indicates a concerted reaction. According to Enders et al. the stereochemistry of the final products can be explained equally plausibly by means of a concerted cycloaddition or a sequential series of ionic addition steps, and the authors leave the question of the actual mechanism open. [13] All these investigations also showed a distinct difference from reactions with the highly successful siloxydienes related to the Danishefsky diene. [25, 261 The hydrolysis of the final cycloadducts (enolethers or enamines) affords the preparatively valuable ketones in both cases (vide infra) but the trivalent aminosubstituent allows the attachment of chiral axiliaries at C-2 much more easily

t-BuLi, M F R3

7

than does the silyl ether. This particular aspect is the subject of this overview (for a general review see [27]). The synthesis of 2-aminobutadienes from ketones is somewhat limited due to difficult control of EIZ-stereochemistry. (271 Therefore, the catalytic aminomercuration of 3 alkenyl- 1-ynes 4 was a significant improvement of the synthesis of 2-amino-1,3 -butadienes 5 (yields 49-75%). [28] The catalytic aminomercuration of 4-ethoxy-3 -alkenyl-1ynes even leads to electronrich and highly reactive 1,3-diamino-1,3 -butadiens which undergo a great variety of cycloadditions. [29] Scheme 2 shows the reaction for a general example (for R’ = H two secondary amines can add to the enine 4 to yield 6). The method can easily be extended to the preparation of chiral 2-amino-1,3-butadienes by addition of chiral amines [e. g. (S)-2-methoxymethylpyrrolidine (SMP) [27]]. A novel approach to 2-amino-1,3-butadienes 10 was recently presented by Enders, Hekker and Meyer. [30] The synthesis was accomplished by a two step one pot procedure by coupling the alkenyl lithium compounds 8

R5 R R3

1

w

R2

8

29

R

4

R3

10

Scheme 3.

A. AsymmetricSynthesis

30

pyrrolidine 16 (SMP, review [32a]), obtained from proline, by means of enamine formation. The cycloaddition of 17 with five different nitrostyrenes 18 (R = H, 4-F, 4-OMe, 4-Me, 3,4 -0CH20) proceeded at room temperature without catalysis and yielded labile cycloadducts 19 (enamine substructure), which decomposed on silica gel to form the corresponding ketones 20. [ 131 Careful analysis of the spectra of the products shows that 13 14 the saponification of the intermediate enamiScheme 4. nes 19 (“ketonization”) does not proceed in a (generated by treatment of alkenyl halides 7 completely uniform manner; epimers are forwith 2 equiv. of t-BuLi) with the a-chloro ena- med at the position a to the carbonyl group. mines 9, available from the corresponding For the reaction in diethyl ether, enantioselecamides (Scheme 3). Again, both achiral tivities from 96 to > 99 % ee were obtained for (amine = diethylamino or piperidino) or chiral the main products - record values for cycload(amine = SMP or SDP) dienes were available ditions not catalyzed by Lewis acids. In addition, the reaction is completely regioselective, by this methodology. Barluenga et al. prepared the desired ami- which, in view of the strongly polarized renodienes by Wittig olefination of aldehydes action components, 2 -aminobutadiene and with phosphoranes generated in situ from B- nitrostyrene, is compatible with both the fronenamino phosphonium salts. [31] The proce- tier orbital model for a concerted reaction and dure was extended by Enders et al. to chiral the stepwise ionic course (1,2 - and 1,4-addiproducts by introducing (S,S)-dimethylmor- tion). The two reactions modes can be descripholine as a novel Cz-symmetric chiral auxi- bed by transition states A and B (Scheme 6). liary as shown in Scheme 4 (reactions Scheme ~ 1 3 1 Barluenga et al. have extended the scope of 4, 11 to 14). [32] A variation of the Wittig procedure with the method by reaction with heteroaromatic reversed building blocks served to prepare and aliphatic nitroalkenes and the use of 2the chiral 2-aminobutadiene 17 in good yield aminobutadienes with a protected hydroxymefrom diacetyl 15 and (S)-2-(methoxymethyl)- thy1 substituent at C-4 synthesized by the

& 0

15

.

2. HzC’PPh3

17

SiQ

R

EOWHzO

I9

R 20

Scheme 5.

Chiral2-Amino-1,3-butadienes: New Reagents for Asymmetric Cycloadditions

1”

““&,H3Ar H

Scheme 6.

A

21

31

23

addition of SMP to commercially available enynes. [14, 331 Moreover, open chain compounds can also be obtained with high enantioselectivity and an intramolecular cyclization to chiral substituted furanes takes place after acidic hydrolysis of these products. The Spanish authors also demonstrated two highly interesting reactions which considerably extended the area of application of the new chiral2-aminodienes such as 21. One of these is the hetero-Diels-Alder reaction with N-silylimines (e. g. 22), whose products 23 can be hydrolyzed to provide substituted piperidones 24 with a high degree of enantioselectivity (85 and 95 % ee, Scheme 7). [14, 341 Such piperidones are required for the synthesis of alkaloids and pharmaceuticals. Enders et al. [32] treated azadienophiles such as phenyltriazoledione 26 with (5,5)25 2-(3,5 -dimethylmorpholino)butadiene

24

Scheme 7.

(R = nPr, iPr, cyclohexyl, cyclopentyl, tBu, Ph -C =C ) to form heterocyclic enamines 27 which, after acid-catalyzed removal of the chiral C2-symmetrical amine, yielded the hexahydropyridazines 28 (six examples) with an ee of 90-91 %. The successful use of another chiral amine, [(S,S)-3,5-dimethylmorpholine], gives further indication of the efficiency of asymmetric induction by means of coupling at the C-2 position of the diene. Another example from the Spanish authors [14, 351 is especially interesting, as the cycloaddition leads to the formation of a compound with a seven-membered ring (Scheme 9). The literature shows that in recent years a tremendous amount of effort has been expended in trying to prepare carbocyclic five-membered rings by a route as simple and elegant as the Diels-Alder reaction for the synthesis of sixmembered rings. [4c] Is a counterpart for

32

A. Asymmetric Synthesis

seven-membered rings now in sight? The ami- sis reaction [40] and the preparation of enannodienes were allowed to react with aJ-unsa- tiomerically pure spiro compounds [41] was turated Fischer carbene complexes. [36] The investigated (overview [42]). Interestingly, a reaction consists of two well-known concerted clean [4+2] cycloaddition to 34 occured if reactions which occur sequentially: cyclopro- the corresponding tungsten Fischer carbene panation and a Cope rearrangement of the complexes such as 33 were reacted with the intermediate divinylcyclopropane (e. g. 30). aminodiene 21 (R = SiMe3) instead of their The principle was first demonstrated by chromium counterparts 29. [43] The endoWulff et al. [37] with the reaction of the selectivity is particularly high with complex Danishefsky diene (I-methoxy-3 -trimethyl- 33 (endo : ex0 = 15 : 1) with 81 % ee for the siloxy-l,3-butadiene) and unsaturated car- major endo-product. The tungsten complex bene(carbony1)chromium complexes. The 34 can be hydrolysed and oxidized with ceric Cope-type rearrangement occurs so rapidly ammonium nitrate (CAN) to the lactone 35. What are the advantages of the new chiral with cis-oriented vinyl groups on the cyclopropane that the intermediate usually cannot 2-aminobutadienes? Firstly, as the well-estabbe isolated. Barluenga et al. were recently lished SMP is a commercially available chiral able to show that the analogous reaction with reagent [32a], the chances are good that it will 2-amino-1,3 -butadienes in place of the siloxy- find broad application. Secondly, there are butadiene leads to the formation of seven- established methods for the coupling of SMP membered rings. [35] The decisive advantage with other starting materials to form 2-aminolies, however, in the additional possibility of butadienes. [30-321 Finally, as is shown by using a chirally modified diene component. the examples, especially the nitroolefins, [ 13, [38] The reaction of 21 with the carbene com- 331 good control of the regiochemistry is posplex 29 gave the cycloheptadiene 31 and the sible because of the strong electron donor in hydrolysis product 32 in satisfactory yields the 2 -position. The increased electron density (52-82% for the multistep sequence) with of the diene increases the reactivity (for total regio- and diastereoselectivity and excel- cycloadditions with “normal” electron requilent enantiomeric excesses of 81 and 86 % ee. rements), and the reaction can be extended to More recently, the reaction of chiral 2- compounds with, for example C=N bonds. In amino- 1,3-butadienes with cyclic BF3 adducts addition, the reaction with a$-unsaturated of vinylcarbene complexes [39], the metathe- Fischer carbenes opens the door to the

OMe

30 21

34

I. HCI

2. CAN

-0 M 4& $.e, 0uMe 35

Scheme 9.

Scheme 10.

Chiral2-Amino-1,3-butadienes: New Reagents for Asymmetric Cycloadditions

single-pot, stereoselective synthesis of carbocyclic seven-membered rings. Especially important is the fact that the chiral component can be removed under very mild conditions and can, in principle, be recovered. Decisive, however, is the excellent enantioselectivity of the reaction which can perhaps be further improved by the choice of the reaction conditions.

References

33

[13]D. Enders, 0.Meyer, G. Raabe, Synthesis 1992, 1242-1244. [14]J. Barluenga, F. Aznar, C. ValdCs, A. Martin, S. Garcia-Granda, E. Martin, J. Am. Chem. SOC. 1993,115,4403-4404. [15]L.N. Koikov, P. B. Terent’ ev, 1. P. Gloriozov,

Yu. G. Bundel’, J. Org. Chem. USSR, Engl. Transl. 1984,20, 832. [16]G. Pitacco, A. Risalti, M. L. Trevisan, E. Valentin, Tetrahedron 1977,33,3145-3 148. [17]R. Gompper, R. Sobotta, Tetrahedron Lett.

1979,921-924. [18]M. Mezzetti, P. Nitti, G. Pitacco, E. Valentin, Tetrahedron 1985,41, 1415-1422. [19]J. Barluenga, F. Aznar, M.-P. Cabal, F. H.

[I]0.Diels, K. Alder, Liebigs Ann. Chem. 1928, Cano, M. de la Conceptih, J. Chem. SOC., 460,98. Chem. Commun. 1988,1247-1249. [21 F. Fringuelli, A. Taticchi, Dimes in the Diels[201J. Barluenga, F. Aznar, M.-P. Cabal, c. ValdCs, Alder Reaction, Wiley, New York, 1990. Tetrahedron Lett. 1989,30, 1413-1416. [3]W. Carruthers, Cycloaddition Reactions in [21]J. Barluenga, F. Aznar, C. ValdCs, F. L6pez Organic Synthesis in Tetrahedron Organic Ortiz, Tetrahedron Lett. 1990,31,5237-5240. Chemistry Series, Vol. 8, Pergamon Press, [22]J. Barluenga, C. ValdCs, Synlett 1991, 487Oxford, 1990. 488. 14] a) H.-J’ M’ K’ [23]J. Barluenga, F. Aznar, C. ValdCs, M.-P. Cabal, Krohn, H.-U. Reissig, Organic Synthesis J. Org. Chem. 1993,58,3391-3396. VCH’ Weinheim’ 1991;b, K. [24]J. Barluenga, F.Aznar, M.-P. Cabal, C. ValdCs, Krohn in [4a],pp. 5465;c) K. Krohn in [4a], J. Chem. SOC., Perkin Trans. I 1990, 633pp. 96-103. 638. [51M. J. Taschner, Asymmetric Diels-Alder Reac[251s. J. M. p, DeNinno, Angew. tions (Ed.: T . Hudlicky), JAI Press, London, Chem. 1987, 99, 15-23; Angew. Chem. Int. 1989. Ed. Engl., 1987,26, 15-23. Rev’ 1992’92’ [26]M. Petrzilka, J. I. Grayson, Synthesis 1981, 16] H‘ B. Kagan’ O. Riant’ 1007-1019. 753. [71E. J. cOreY, T.-p. T’ D. Roper, M. D. Azi- [27]0. Meyer, D. Enders, Liebigs Ann. 1996, mioara, M. C. Noe, J. Am. Chem. SOC. 1992, 1023-1035. 114,8290-8292. [28]J. Barluenga, F. Aznar, C. ValdCs, M.-P. Cabal, [8]W.Oppolzer, Tetrahedron 1987,43, 1969. J. Org. Chem. 1991,56,6168-6171. 1984’96’840- [29]J. Barluenga, F. Aznar, M. Fernandez, Tetra19]w‘oppolzer’ Angew. 854;Angew. Chem. Znt. Ed. Engl., 1984,23, hedron Lett. 1995,36,6551-6554. 876-890. [30]D. Enders, P. Hecker, 0. Meyer, Tetrahedron [lo] G. Helmchen, A. Goeke, S. Kreisz, A. Krotz, 1996,52,2909-2924. G. H. Lauer, G. Linz, Cyclopentanoid Natural [31]J. Barlunenga, I. Merino, F. Palacios, TetraProducts via Asymmetric Diels-Alder Reachedron Lett. 1990,31,6713-6716. tions in Studies in Natural Products Chem[321D. Enders, o. Meyer, G. Raabe, J. Runsink, istry (Ed.: Atta-ur-Rahman), Vol. 8,Elsevier, Synthesis 1994,66-72, Amsterdam, 1991,pp. 139-158. [32a]D. Enders, M. Klatt, Synthesis 1996, 1403[ll]B. M. Trost, D. O’Krongly, J. L. Belletire, 1418. Am’ 1980’’02’ 7595-7596’ [33]J. Barluenga, F. Aznar, C. Ribas, C. ValdCs, [12]C. Siegel, E. R. Thornton, J. Am. Chem. SOC. J. Org. Chem. 1997,6746-6753. 1989,I l l , 5722-5728. J’

’‘

34

A. Asymmetric Synthesis

[34] J. Barluenga, F. Aznar, C., ValdCs, C. Ribas, M. FernAdez, M.-P., Trujillo, J. Cabal, Chem. EUK 1996, 2, 805-811. [35] J. Barluenga, I. Merino, A. Martin, S. GarciaGrande, M. A. Salvadb, P. Pertierra, J. Chem. SOC., Chem. Commun. 1993, 319-321. [36] H. K. Dotz, Organometallics in Organic Synthesis: Aspects of a Modern Interdisciplinary Field (Eds.: A. de Meijere, H. tom Dieck), Springer, Berlin, 1988. [37] W. D. Wulff, D. C. Yang, C. K. Murray, J. Am. Chem. SOC. 1988,110,2653-2655. [38] M. ChCrest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968,2199-2204.

[39] J. Barluenga, R.-M. Cantelli, J. Flbrez, S. Garcia-Granda, A. GutiCrrez-Rodriguez, J. Am. Chem. Soc. 1994,116,6949-6950. [40] J. Barluenga, F. Aznar, A. Martin, Organometallics 1995, 14, 1429-1433. [41] J. Barluenga, F. Aznar, S. Garcia-Granda, S. Barluenga, C. Alvarez-Riia, J. Chem. Snc., Chem. Commun. 1998, submitted. [42] J. Barluenga, F. Aznar, M. Fernandez, Chem. EUK 1997, 1629-1637. [43] J. Barluenga, F. Aznar, A. Martin, S. Barluenga, s. Garcia-Granda, A. A. PanequeQuevedo, J. Chem. SOC., Chem. Commun. 1994, 843-844.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Recent Developments in the Enantioselective Syntheses of Cyclopropanes Hans- Ulrich Reissig

The hunt for strained molecules is maintained by the competitive ambition to find the most unusual structures and by the enormous synthetic potential of small-ring compounds. Following the general trend of recent years asymmetric syntheses are at the cutting edge of this research. [l] Despite all advances the synthesis of enantiomerically and diastereomerically pure cyclopropane derivatives remains a considerable challenge, especially when particular functional groups are required. The most

\/

recent years have provided little that is fundamentally new to add to the very elegant procedures based on asymmetric catalysts. [2] In the main, reaction conditions and ligands were optimized, and the scope and limitations were investigated. Most exciting were examples from Doyle's group who reported on the enantioselective synthesis of macrocyclic lactones by means of intramolecular carbene additions. 131 Whereas the expected intramolecular cyclopropanation to a bicyclic y-lac-

43 %, 87 YOee

Scheme 1.

36 0

A. Asymmetric Synthesis 0

variants of the Simmons-Smith cyclopropanation, in particular of allylic alcohols. [7] Although enantioselective catalysis is now developing in this area - with respectable individual successes [8] the auxiliary-controlled procedures are still superior. [9] In general, cyclopropane syntheses controlled by reagent-bound CN auxiliary groups offer a better guarantee of high enantiomeric purity than those using the more elegant asymmetric catalysts. A very impressive new example suitable for the synthesis of highly functionalized cyclopropane derivatives, was discovered by the Hanessian group. [lo] Whereas in most auxiliary-controlled formal [2+l]cycloadditions Scheme 2. 6N [l] the auxiliary group is attached to the olefinic residue, here the chiral information is tone was observed with a chiral rhodium(I1)- carried by a chloroallylphosphonic acid MEPY catalyst with 96% ee (Scheme l), amide, such as 1, which acts as a vinylcarbene with the Evans copper complex containing a equivalent. The reaction of the carbanion bis(oxazo1ine) ligand the macrocyclic lactone derived from 1 with a,p-unsaturated carbonyl was strongly favoured (87% ee). Similar, or compounds such as 2 yields the diastereomerieven higher, regio- and enantioselectivities cally pure bicyclo[3.1 .O]hexanone derivative with astonishingly high yields were also 3 as the endo-isomer (90% yield). By confound in other examples. Thus there is now a trast, the reaction between the cis-chloroallyl new strategy, which will certainly find practi- derivative 4 and 2 yields the epimeric bicyclic cal uses, for the enantioselective synthesis of product 5. Mechanistically this cyclopropanamacrocycles that are otherwise accessible tion is easily understood as resulting from a Michael addition and an intramolecular S N ~ only with difficulty. Pfaltz’s semicorrin copper complexes - a alkylation in which the intermediate 6 could real breakthrough more then ten years ago - account for the observed diastereoselectivity. The method seems to be widely applicable can also be employed for intramolecular [2+ 11-cycloadditions (Scheme 2) and achieve as the examples with other cyclic enones, between 14 and 95 % ee depending on the sub- unsaturated lactones, lactams, and tert-butyl strate. [4] The related, otherwise very succes- esters show (Scheme 3). The diastereoselecful, bis(oxazo1ine) complexes [ 5 ] (see above) tivities are at least 92 : 8 and usually much do not appear to be as effective here though better. only one example has been investigated. It can, however, be said that the ultimate catalyst system for inter- and intramolecular cyclopropanations, which reliably delivers both high enantiomeric excess and good cis/ trans selectivity, and which is also suitable for highly substituted and/or functionalized olefins is still a dream. [6] Advances, but no breakthroughs, can be seen in the several

Recent Developments in the Enantioselective Syntheses of Cyclopropanes

Me

1) BuLi

37

Me

THF,-78 "C 2) 2

Le

C1

4

.

Me 70%

n 5

Formel I .

Formel 2.

After reduction of the carbonyl group with sodium borohydride and protective silylation of the resulting hydroxy group, the auxiliary is removed by ozonolysis of the alkenylphosphonamide group. By this method, or other obvious sequences, the primary products are converted into a series of enantiomerically pure, interestingly functionalized cyclopropane derivatives (Scheme 4), which should find applications as synthetic building blocks. Nevertheless, ozonolysis of the alkenyl substituents destroys some of the preparative potential of the primary products; as vinylcyclopropanes they would be interesting for many other reactions, for example, for 1,3and 3,3 -sigmatropic rearrangements. [ 1 I ] It can be inferred from the footnotes of the report [lo] that a Cope rearrangement of the primary product 8, derived from the hexadienoic acid ester 7 and 1, does actually take place at room temperature with the formation of two isomeric cycloheptadiene derivatives.

No details were given so far about the structure of these compounds. One of the most interesting applications of the method could be the synthesis of enantiomerically pure, highly functionalized cycloheptane derivatives, since divinylcyclopropanes should be obtainable by the appropriate rearrangement of other primary products. On the otherhand, the carbanion derived from the simplier a-chloromethylphosphonamide has been exploited similarly to 1 for the preparation of enantiomerically pure cyclopropane phosphonic acids. [ 121 The results described above represent only the classical developments of organic synthesis extended and perfected; however, a publication on antibody-induced cyclopropanation could be the inauguration of what is, in principle, a new path to asymmetric cyclopropane formation (although the example is one with little preparative interest). [ 131

38

A. Asymmetric Synthesis

n

99: 1

Scheme 3.

Scheme 4.

Recent Developments in the Enantioselective Syntheses of Cyclopropanes

39

0

II

C0,tsu 1

/ / Me

I

55 %

RZp

P

Me

k%,. $\W 8

I

C0,tBu

99 : 1

20°C

2 cycloheptadienes

Formel 3.

References [ 11 Comprehensive survey of diastereoselective

and enantioselective [2+l]cycloadditions covering the literature up to and including 1994: H.-U. Reissig in Stereoselective Synthesis of Organic Compounds /Methods of Organic Chemistry (Houben-Weyl), 4th ed., Vol. E21c (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart, 1995, pp. 3179-3270. [2] M. P. Doyle in Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, Weinheim, 1993, pp. 63-99; M. P. Doyle in Comprehensive Organometallic Chemistry II, Vol. 12 (Ed.: L. S. Hegedus), Pergamon Press, New York, 1995, Ch. 5; V. K. Singh, A. Datta Gupta, G. Sekar Synthesis 1997, 137-149. [3] M. P. Doyle, C. S. Peterson, D. L. Parker, Jr., Angew. Chem. 1996, 108, 1439-1440; Angew. Chem. Int. Ed. Engl. 1996,35, 13341336; see also: M. P. Doyle, M. N. Protopopova, C. D. Poulter, D. H. Rogers, J. Am. Chem. Soc. 1995, 117, 7281-7282; M. P. Doyle, C. S. Peterson, Q.-L. Thou, H. Nishiyama Chem. Commun. 1997,211- 212. C. PiquC, B. Fahndnch, A. Pfaltz, Synlett 1995,491-492. Short review: C. Bolm, Angew. Chem. 1991, 103, 556-558; Angew. Chem. lnt. Ed. Engl. 1991, 30, 542. For the related bis(oxazoliny1)pyridine ligands see: S.-B. Park, N. Sakata, H. Nishiyama Chem. EUKJ. 1996,2,303-306. [6] For a systematic study of several catalyst types employed for the cyclopropanation of silyl enol ethers see: R. Schumacher, F. Dammast, H.-U. Reissig Chem. Eur. J. 1997,3,614-619.

[7] Short review: U. Koert, Nachr. Chem. Tech. Lab. 1995,43,435-442. [8] For a comprehensive introduction to this field see: S . E. Denmark, S . P. O’Connor, J. Org. Chem. 1997, 62, 584-594. For an interesting application to the quinquecyclo-propane fragment of the inhibitor U-106305 see: W. S. McDonald, C. A. Verbicky, and C. K. Zercher, J. Org. Chem. 1997, 62, 1215-1222. [9] Review: A. B. Charette, J.-F. Marcoux, Synlett, 1995, 1197-1207. [lo] S. Hanessian, D. Andreotti, A. Gomtsyan, J. Am. Chem. Soc. 1995, 117, 10393- 10394. [ 111 J. Salaiin in The Chemistry of the Cyclopropyl Group (Ed.: S. Patai, Z. Rappoport), Wiley, Chichester, 1987, pp. 809-878. [12] S. Hanessian, L.-D. Cantin, S. Roy, D. Andreotti, A. Gomtsyan Tetrahedron Letters, 1997, 1103-1106. [13] T. Li. K. D. Janda, R. A. Lerner, Nature 1996, 379, 326-327.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Enantioselective Rhodium(I1) Catalysts Henri Brunner

In the complexes [Mz(OAc)4] (OAc = CH3COO) two metal(I1) cations are bridged by four acetate anions (Fig. 1). In this highly symmetrical framework four oxygen atoms occupy the corners of two ecliptically arranged squares. [ l ] The valencies of the two octahedrally coordinated metal atoms perpendicular to these squares are oriented to the inside and to the outside of the M2(OAc)4 unit. The metal-metal interaction within the M2(0Ac)4 unit depends critically on the electron configuration of the metal atoms. [1] It ranges from a quadruple bond in [Cr2(0Ac)4] (Cr2+ is a d4 system) to a weak interaction in [Cuz(OAc)4] (Cu2+ is a d9 system). Further ligands can be bound, but also catalyses can be carried out at the valencies of the Mz(OAc)4 unit which point outwards. [Rhz(OAc)4] is a green, air-stable compound, which is soluble in organic solvents with the retention of its dinuclear structure. It is prepared from RhCl3 and HOAc/NaOAc in y

3

CH3

Fig. 1.

boiling ethanol. [2] Other carboxylate ions can also be incorporated in place of acetate ions. Anions of fluorinated carboxylic acids afford particularly stable compounds such as [Rh2(00CCF3)4]. [Rh2(OAc)4] and its derivatives have for a long time proven valuable as catalysts for carben(oid) reactions, for example, the formation of cyclopropanes from olefins and diazo compounds or the formation of five-membered rings in intramolecular C-H insertions. [3-61 They are also considered to show anti-tumor activity. [ 11 Recently these dimeric rhodium(I1) compounds have created a furore in enantioselective catalysis. The dimeric rhodium(I1) compounds become enantioselective catalysts if they contain optically active ligands. For this the anions of optically active carboxylic acids seem to be most appropriate. The complex in which the Rh2 unit is clamped by four mandelate anions was synthesized and structurally characterized some time ago. [7] As a catalyst, however, this complex results in only small enantiomeric excesses. [8] The reason for this is probably that the asymmetric centers lie in a plane between the two Rh atoms and are thus too far away from the coordination sites directed to the outside, at which the catalysis occurs. Chiral substituents at the nitrogen atoms of carboxamide anions would be considerably closer to these reaction centers, and

Enantioselective Rhodium(II) Catalysts

indeed on this basis a breakthrough has been achieved recently, which in particular, is linked to the [Rh2(5S-mepy)4] complex (Fig. 2). The name of the optically active ligand has, as usual, been abbreviated, and in this case mepy* stands for the methyl ester of the pyrrolidone-5 -carboxylic acid, which is deprotonated at the nitrogen atom. In the following the complex [Rh2(5S-mepy)4] and its “capacity” for enantioselective catalysis are introduced before finally discussing why complexes of the type [Rh2(5S-mepy)4] are so successful. The introduction of carboxamides instead of carboxylates as bridging ligands is achieved by an exchange reaction between [Rh2(0Ac)4] and the appropriate amides. In this way [Rh2(5S-mepy)4] is prepared from methyl (-)-(S)-pyrrolidone-5 -carboxylate. Similarly, [Rh2(5R-mepy)4] is accessible from methyl (+)-(R)-pyrrolidone-5 -carboxylate so that the catalysts are available in both configurations (5s and 5R). In [Rh2(5Smepy)4] each rhodium atom is in a square-planar environment in which two 0 atoms and two N atoms are arranged cis to each other (Fig. 2). [Rh2(5S-mepy)4] was first used for cyclopropanation. Enantioselective cyclopropanation is industrially important since synthetic pyrethroids, which are used as insecticides, contain substituted three-membered rings, whose configuration is crucial for their biological effect. [9] Enantioselective cyclopropanation has tradition. It was this reaction type which in 1966 opened up the field of enantioselective homogeneous catalysis with transition metal complexes. The copper(I1) complex of the Schiff base from salicylaldehyde and optically active 1-phenylethylamine at that time reached 6 % ee. [lo] With optimized opti-

* The acronym mepy has usually been written in

capital letters. However, according to the IUPAC rules for nomenclature abbrevations for ligands should be written with small letters.

41

cally active amines in the salicylaldimine ligands the industrial group headed by Aratani set early records in the 1970s. [ll] New aspects were forthcoming with the introduction of the cobalt(I1) semicorrin complexes by Pfaltz et al. 1986, [ 12, 131 and more recently with the bisoxazoline ligands from Masamune et al. [14] and Evans et al. [15] The reaction of styrene with (1S,3S,4R)menthyl diazoacetate [Eq. (a)] leads to the incorporation of two new stereocenters into the cyclopropane ring. The cis and trans isomers are formed each consisting of an enantiomeric pair. With the [Rh2(5S-mepy)4] catalyst 86% ee is achieved in the cis series and 48 % ee in the trans series. [ 161 In the catalysis shown in Equation (a) a double stereoselection is involved. The formation of the new asymmetric centers in the cyclopropane ring is influenced by the menthy1 group contained in the substrate (lS,3S,4R)-menthyl diazoacetate and by the mepy ligand contained in the catalyst. The two influences are referred to as substrate and catalyst control, respectively. With regard to the efficiency it has to be noted that whe-

42

A . Asymmetric Synthesis

reas substrate control requires a stoichiometric amount of the reagent, catalyst control requires a substoichiometric amount of the catalyst. For example, in the case of [Rh~(SS-rnepy)4]a catalyst concentration of 1 mol% is sufficient with respect to the substrates. The reaction in Equation (a) is controlled mainly by the catalyst; substrate control by the menthyl group plays only a minor role. This is evident from the fact that with the achiral [Rh2(0Ac)4] catalyst only 9 % ee can be achieved for the cis product and 13 % ee for the trans product. Catalysis with [Rh2(5Smepy)4] was extended from styrene to other prochiral olefins for which similar results were obtained. [ 161 [Rh2(5S-mepy)4] is particularly useful for intramolecular cyclopropanation; in several examples up to 94 % ee was obtained. [17] Highly substituted cyclopropanes are accessible by this reaction; an example is given in Equation (b). With the two enantiomeric catalysts both enantiomeric products can be obtained from the same ally1 diazoacetate. For this intramolecular variant the (2) configuration of the olefin proves superior to the ( E ) configuration.

and enantioselectivity) are shown for the cyclopropenation of propargyl methyl ether with a series of diazo esters in Equation (c). For the ethyl ester (R = Et) the enantiomeric excess is 69%, for the tert-butyl ester (R = tBu) 78 %, and for the (+)-menthy1 ester (R = 1S,3S,4R-menthyl) 98%. The yields of the reactions range between 43 and 73 %. [ 181 MeOCH,-CZC-H

+ N,CHCOOR

-

H,COOR

Metal catalyzed enantioselective C-H insertions of carbenes have so far not been studies in great detail. Copper catalysts are of no use for this type of reaction, rhodium(I1) catalysts, however, allow intramolecular C-H insertions, for example, in the alkyl group of diazoacetates with longer chains. The formation of five-membered rings such as y-lactones is favored. [Rh2(5S-mepy)4] affords 3 -methyl-y-butyrolactone (see Eq. (d)) in 91 % ee and is thus unprecedented for such reactions. [ 191

Eq. (4.

In order to explain the success of [Rh2(5Smepy)4] a general and a specific argument As mentioned before, enantioselective shall be put forward. Generally for enantiosecyclopropanation has been known for a long lective catalysts, a reduction of the conformatime and there are other efficient catalysts for tive variety has a favorable effect on the enanthis reaction apart from dimeric rhodium(I1) tioselectivity. In [Rh2(5S-mepy)4] at each of complexes. This is different to the cyclopro- the two planes of the Rh2 unit which point panation of alkynes with diazo compounds. outwards, a chiral framework is built whose Copper catalysts do not only result in lower rigidity is mainly the result of the incorporaenantiomeric excesses but also poor yields, tion of the amide part into the five-membered since the high temperatures required for the ring. In the case of [Rh2(5S-mepy)4] special reaction favor side and consecutive reactions electronic and steric effects are also involved. such as the ring opening of the primary prod- Model considerations as well as reactivity and ucts. The improvements brought about by the selectivity studies show that during the cleavuse of [Rh2(5S-mepy)4] (with regard to yield age of nitrogen from the diazo compound a

g?

Enantioselective Rhodium(II) Catalysts

43

References

[l] F. A. Cotton, R. A. Walton, Multiple bonds Beteen Metal Atoms, Wiley, New York, 1982. d[2] G. A. Rempel, P. P. Legzdins, H. Smith, G. Wilkinson, Inorg. Synth. 1972, 13, 90. -0 [3] M. P. Doyle, Chem. Rev. 1986, 86, 919. A B [4] M. P. Doyle, Acc. Chem. Res. 1986, 19, 348. [ 5 ] G . Maas, Top. Curr: Chem. 1987, 137, 348. Fig. 3. [6] M. P. Doyle, R e d . Tray. Chim. Pays-Bas 1991, 110, 305. [7] P. A. Agaskar, F. A. Cotton, L. R. Falvello, carbene-rhodium complex is formed whose S. Hahn, J. Am. Chem. SOC. 1986,108, 1214. empty p orbital at the carbene carbon atom [8] H. Brunner, H. Kluschanzoff, K. Wutz, Bull. can be stabilized by interaction with a polar SOC. Chim. Belg. 1986, 98, 63. substituent. [6] Therefore, as shown in Figure D. Arlt, M. Jautelat, R. Lantzsch, Angew. 191 3, the two cis ester groups in [Rh2(5SChem. 1981, 93, 719; Angew. Chem. Int. Ed. mepy)4] fix the carbene ligand in the positions Engl. 1981, 20, 703. A and B, in which the large substituent R of [lo] H. Nozaki, S. Moriuti, H. Takaya, R. Noyori, the carbene adopts the less hindered position. Tetrahedron Lett. 1966, 5239. The attack of the nucleophile at the confor- [ l l ] T. Aratani, Pure Appl. Chem. 1985, 57, 1839. mations A and B occurs from the rear. The [12] H. Fritschi, U. Leutenegger, A. Pfaltz, Angew. Chem. 1986,98, 1028; Angew. Chem. Int. Ed. observed stereochemistry of the products can Engl. 1986,25, 1005. be understood when the preferred orientation of the reaction partners with their C=C, [13] Short review: C . Bolm, Angew. Chem. 1991, 103 556; Angew. Chem. Int. Ed. Engl. 1991, C=C, and C-H bonds in the inter- or intramo30, 542. lecular reactions are taken into consideration. [14] R. E. Lowenthal, A. Abiko, S. Masamune, The article above was written in spring Tetrahedron Lett. 1990, 31, 6005. 1992. Since then the field of enantioselective [15] D. A. Evans, K. A. Woerpel, M. M. Hinman, catalysis with rhodium(I1) complexes contaiJ. Am. Chem. SOC. 1991, 113,726. ning mepy and mepy-like ligands has been [16] M. P. Doyle, B. D. Brandes, A. P. Kazala, R. J. extended appreciably, in particular by the Pieters, M. B. Jarstfer, L. M. Watkins, C. T. Eagle, Tetrahedron Lett. 1990, 31, 6613. group of M. P. Doyle. Thus, the recent references in this field can be found by searching [17] M. P. Doyle, R. J. Pieters, S. F. Martin, R. E. Austin, C. J. Oalmann, P. Muller, J. Am. for the name of the main author M. P. Doyle. Chem. SOC. 1991,113, 1423. The catalysts [Rh2(5S-mepy)4] and [Rh2(5R[18] M. N. Protopopova, M. P. Doyle, P. Muller, mepy)4] have been commercialized (REGIS D. Ene, J. Am. Chem. SOC. 1992, 114, 2755. Chemical Company, Morton Grove, IL [19] M. P. Doyle, A. v. Oeveren, L. J. Westrum, 60053, USA). M. N. Protopopova, T. W. Clayton, Jr., J. Am. Chem. SOC.1991, 113, 8982.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Oxazaborolidines and Dioxaborolidines in Enantioselective Catalysis B. B. Lohray, and Vidya Bhushan

During the last decade, use of oxazaborolidines and dioxaborolidines in enantioselective catalysis has gained importance. [ 1, 21 One of the earliest examples of oxazaborolidines as an enantioselective catalyst in the reduction of ketonedketoxime ethers to secondary alcohols/amines was reported by Itsuno et al. [3] in which (S)-valinol was used as a chiral ligand. Since then, a number of other oxazaborolidines and dioxaborolidines have been investigated as enantioselective catalysts in a number of organic transformations viz a) reduction of ketones to alcohols, b) addition of dialkyl zinc to aldehydes, c) asymmetric allylation of aldehydes, d) Diels-Alder cycloaddition reactions, e) Mukaiyama Michael type of aldol condensations, f) cyclopropanation reaction of olefins.

are easily accessible in both ( R ) and ( S ) forms. Use of CBS reagents in the reduction of ketones afforded alcohols in excellent yields and enantioselectivities (80-99 % ee) under very mild reaction conditions (0-25 "C). The reaction requires both the reagents ; neither catalyst (S)-1 nor THF.BH3 alone is able to reduce the ketone in considerable yield. The active reducing species has been postulated to be an intermediate complex 2 which is formed from (S)-1 and BH3. Mathre et al. [5a] have modified the preparation of (S)-1 and used it in the synthesis of MK047 1, a carboanhydrase inhibitor. [5b]

-

cy* .

R

,B-0

n

.

Ph 151-1

Reduction of Ketones Corey et al. [4] have investigated enantioselective reduction of ketones with THF.BH3 and (S)-diphenyl prolinol-borane adduct as catalyst. They further introduced modification of oxazaborolidines in which R = CH3, nbutyl as catalyst 1 and used along with other Scheme 1. Possible mechanism of the oxazaboroliboranes as reducing agents (Scheme 1). The dine-catalyzed enantioselective reduction of ketocatalysts 1 are known as CBS catalysts and nes with THF.BH3.

Oxazaborolidines and Dioxaborolidines in Enantioselective Catalysis

Later, several oxazaborolidines derived from various amino alcohols have been used for the reduction of ketones [6] and ketoimines. [7] In certain cases, diketones were reduced to optically active diols, [8] a,p-unsaturated ketones to allylic alcohols, [9] etc. in varying degree of enantioselectivities. Of particular interest is the reduction of alkyl trichloromethy1 ketones [lo] which lead to the synthesis of a-amino acids using (S)-1 and synthesis of substituted biaryls by the reduction of substituted 2-pyrones with THF.BH3 in the presence of oxazaborolidines. [ 111 More recently, aliphatic dialkyl ketones have been reduced to secondary alcohols in moderate to high enantioselectivity. [ 121 Quite recently, Corey et al. have reduced achiral a$-ynones using modified oxazaborolidines (Scheme 2) providing highly optically pure propargyl alcohols in excellent yields. [13] Earlier, Corey, and Cimprich had prepared these propargyl alcohols by enantioselective alkynylation process using oxazaborolidines as chiral promoters. ~141

0

R" R1

-fl Cat -1 Catwhoiborane -76 "C 91-100%

1"

HO'b,.,

R1

6

5

Scheme 2. Enantioselective reduction of achiral a,/?-ynones by oxazaborolidines.

f!

Addition of Dialkyl Zinc to Aldehydes In 1989, Brown et al. 1151 suggested that since B-0 and B-N bonds are shorter than metaloxygen and metal-nitrogen bonds, there is a greater chance that boron complex will be a more effective catalyst. In order to substantiate this hypothesis, they carried out enantioselective addition of diethyl zinc to several aldehydes using (4S,5R)-3,4-dimethyl-5 -phenyl-1,3,2-oxazaborolidine as catalyst and achieved very high yield and enantiomeric purity (upto 96 % ee) of secondary alcohols.

Asymmetric Allylation of Aldehydes Yamamoto et al. [16] envisaged that acyloxyboranes might behave as mixed anhydrides because of the electronegative trivalent boron atom and could serve as effective asymmetric catalysts in selected reactions. In the presence of 20 mole% of chiral acyloxy borane (CAB) complex 7 prepared from (2R,3R)-2-0(2,6-diisopropoxybenzoyl)tartaric acid and BH3.THF, various allyltrimethylsilanes react with achiral aldehydes to afford the corresponding homoallylic alcohols in good yield and high enantio- and diastereoselectivity (Scheme 3). The reaction proceeds at -78 "C to furnish predominently erythro homoallylic alcohols (erythro : threo = 80 : 20 to 97 : 3) regardless of the configuration of allylsilanes. These observations were explained based on the re FP

RCOO&COOH

1

OH R'

0 78 (2R,3R)

7b (2S.33

45

6

9

10

Scheme 3. Asymmetric allylation in the presence of 20 mol% 7a. R = 2,6-dimethoxyphenyl.

46

"<

A. Asymmetric Synthesis

OM*

1) PhCHO

2) cat CF3COOH 7 ____)

MeaSiO 17a: Ri = H b: R' = Me

threo

Ph

18

Scheme 5. Asymmetric hetero Diels-Alder reaction catalyzed by dioxaborolidines.

Figure 1. Extended transition state model.

face attack of the nucleophiles on the carbonyl carbon of the aldehyde using an extended transition state model as shown in Figure 1.

Diels-Alder Cycloaddition Reaction The CAB catalyst used in asymmetric allylation reaction has also been found to be equally effective in asymmetric Diels-Alder reaction of a variety of diones with several dienophiles (a$-unsaturated acids and aldehydes) under very mild reaction conditions (-78 "C) (Scheme 4). [ 171 Good to excellent diastereo(99 : 1 to 88 : 12) and enantioselectivities (88 to 97% ee) have been observed in most of the cases. A stable chiral acyloxy borane (CAB) complex 7 is also an effective catalyst for hetero Diels-Alder reaction to produce dihydropyrans in high optical purity. [18] (Scheme 5). Yamamoto et al. [ 191 have further extended these studies to Diels-Alder reactions cataly-

sed by N-arylsulfonyl- 1,3,2-0xazaborolidines 20. The stereoselectivity with these catalysts is relatively inferior to that observed with 7. Similar observations have been reported by Helmchen et al. [20] for the Diels-Alder reaction of cyclopentadiene and methacrolein (exo : endo = 99 : 1 , 6 4 % ee for the ex0 isomer) or crotonaldehyde (ex0 : endo = 3 : 97; 72 % ee for the endo isomer). Use of bulkier aryl substituents such as 2,4,6-triisopropyl and 2,4,6tri-t-butylphenyl had little influence on the diastereoselectivity of the cycloaddition. In contrast, Corey and Loh [21] have reported cycloaddition reaction of cyclopentadiene and 2-bromoacrolein catalyzed by oxazaborolidine derived from N-tosyl-@)-tryptophan in dichoromethane at -78 "C to give a highly diastereo- (exo : endo = 97 : 3) and enantioselective (96 9% ee) reaction leading to the formation of (R)-bromoaldehyde 22 (Scheme 6). It is interesting to know that the stereoselectivity of the adduct using Corey's catalyst is opposite to that normally observed for oxazaborolidines generated from N-tosyl derivative of (S)-valine or hexahydrophenyl alanine.

CHO 13

' 1 9

14

96%16

Scheme 4. Dieis-Alder reactions enantioselectively catalyzed by 10 mol% 7.

Oxazaborolidines and Dioxaborolidines in Enantioselective Catalysis

47

AI

19

23

Scheme 6. Asymmetric Diels-Alder reaction catalysed by oxazaborolidine 20.

25

26

27

Scheme 7. Enantioselective 1,3-dipolar cycloaddition of nitrones with ketene acetals catalyzed by oxazaborolidines.

This methodology has been used for a simple enantioselective synthesis of (lS,4R)-Bicyclo[2.2.l]hept-2-ene-2-methanol.[22] These results suggest a transition state 23 in which the dienophile assumes an orientation parallel to the indole ring because of the n-n donor acceptor interaction leading to an unprecedented (200 : 1) enantioselectivity. [21, 231 Corey et al. [24] have used this oxazaborolidine as an effective catalyst for an efficient synthesis of cassiol and gibberellic acid. Similar high diastereo- (ex0 : endo = 99 : 1) and enantioselectivity (96 : 4) was observed in the cycloaddition reaction of furan with 2-bromoacrolein using oxazaborolidine as catalyst. 1251 Chiral oxazaborolidines 20 derived from various amino alcohols have been used as catalysts in asymmetric 1,3-dipolar cycloaddition reaction of nitrones with ketene acetals to give substituted isoxazoles in high yield and stereoselectivity but in moderate enantioselectivity (upto 62% ee). This method has also been used for the synthesis of P-aminoesters

by hydrogenolysis of isoxazoles (Scheme 7). [261

Mukaiyama-Michael type aldol condensation The chiral acyloxyborane 7 (CAB) has also been found to be an excellent catalyst for asymmetric Mukaiyama-Michael type aldol reaction between silyl enol ethers and aldehydes (Scheme 8). Yamamoto et al. [27] have used 20mol% of CAB in propionitrile at -78°C as a highly efficient catalyst for the condensation of several E and Z silyl enol ethers and ketene acetals with a variety of aldehydes (yields 49-97 %, 80-97 % ee). Interestingly, regardless of the configuration of the enol ethers, the erythro isomer always predominated (erythro : threo = 80120 to > 9 5 k 5). Aromatic and a,p-unsaturated aldehydes always provided higher diastereo- (erythro : threo > 94 : 6) and enantio-

A. Asymmetric Synthesis

48

Rz

OSiMeJ

QSiMq

Ri 9

24

-RZ 30

Scheme 8. Enantioselective MukaiyamaMichael aldol reaction catalyzed by dioxaborolidine.

Rl

31

Arso-/N,B~-siM63 I*

Scheme 9. Enantioselective aldol reaction catalyzed by oxazaborolidine.

selectivities (92-97 % ee) than saturated aldehydes. Polar solvents improved the selectivity by decreasing the association of the catalyst with the formation of oligomers as observed by Helmchen. [20] Corey et al. have used oxazaborolidines as effective catalysts for the enantioselective Mukiayama aldol and aldol dihydropyrone annulation reaction of trimethylsiloxy olefin and diones. [281 Kiyooka et al. [29] and Masamune [30] and coworkers have used oxazaborolidines 32 as catalysts for aldol reactions. The latter have suggested that the initial aldol adduct 33 must undergo ring closure (as indicated by arrow in Scheme 9) to release the final product 31 and to regenerate the catalyst. In many cases, slow addition of the aldehyde to the reaction mixture proved beneficial (which permits enough time for 33 to undergo ring closure) for improving the enantioselectivity of the reaction.

Thus, a,a-disubstituted N-arylsulfonylglycines were used for the preparation of the oxazaborolidine 32 which resulted in catalytic asymmetric aldol processes providing phydroxy esters of > 97% ee from a-unbranched aldehydes (R-CHzCHO) and 84-96 % ee with a-branched aldehydes (RzCHCHO). The reaction proceeds smoothly in propionitrile at -78 "C if the aldehyde is added slowly over 3.5 h affording high yields (68-89 %) of the adduct.

Cyclopropanation Reaction More recently, dioxaborolane derived from (RR)-(+)-N,N,N,'N'-tetramethyltartaric acid diamide has been used as an efficient chiral controller in Simmons Smith cyclopropanation reaction of allylic alcohols to produce substituted cyclopropyl methanols in high

Oxazaborolidines and Dioxaborolidines in Enantioselective Catalysis

34

36 91-94 % ee

I

Bu

49

35

Scheme 10. Enantioselective cyclopropanation of allylic alcohols catalyzed by dioxaborolidines.

enantioselectivities (Scheme 10). [311 This method has been extended for the synthesis of biscyclopropanes [32] and cyclopropanation of polyenes. [33] Using this cyclopropanation strategy, Yamada et al. have stereoselectively synthesized a side chain segment of an antitumor marine steroid, aragusterol. [34] Dioxaborolane derived from dimethyl tartrate has found application in enantioselective epoxidation of unfunctionalized alkenes using TBHP as co-oxidant. [35] The increasing applications of oxazaborolidines and dioxaborolidine derivatives suggest that these class of catalysts will find wide use in synthetic organic and medicinal chemistry to bring about a variety of stereoselective transformations.

References [ 11 Lohray BB, Bhushan, V (1992) Angew Chem Int Ed Engl31 : 729.

[2] (a) Singh VK (1992) Synthesis 605. (b) Wallbaum s, Martens J (1992) Tetrahedron Asymmetry 3 : 1475. (c) Deloux L, Srebnik M (1993) Chem Rev 93 : 763. [3] Itsuno S, Sakurai Y, Ito K, Hirao A, Nakahama S (1987) Bull Chem SOCJpn 60 : 395. [4] (a) Corey EJ, Bakshi RK, Shibata S (1987) J Am Chem SOC 109 : 5551. (b) Corey EJ (1990) Pure Appl Chem 62 : 1209. (c) Corey EJ, Bakshi RK (1990) Tetrahedron Lett 31 : 611. [5] (a) Mathre, DJ, Jones TK, Xavier LC, Blacklock TJ, Reamer RA, Mohan JJ, Jones ETT, Hoogsteen K, Baum MW, Grabowki EJJ

(1991) J Org Chem 56 : 751. (b) Mathre, DJ, Jones TK, Xavier LC, Blacklock TJ, Reamer RA, Mohan JJ, Jones ETT, Hoogsteen K, Baum MW, Grabowki EJJ (1991) J Org Chem 56 : 763. [6] (a) Martens J, Dauelsberg C, Behnen W, Wallbaum S (1992) Tetrahedron Asymmetry 3 : 347. (b) Cho BT, Chun YS (1992) Tetrahedron Asymmetry 3 : 1539. (c) Quallich GJ, Woodall TM (1993) Tetrahedron Lett 34 : 4145. (d) Berenguer R, Garcia J, Gonzalez M, Vilmasa J (1993) Tetrahedron Asymmetry 4 : 13. (e) Kiyooka S, Kaneko Y, Harada Y, Matsuo T (1995) Tetrahedron Lett 36 : 2821. [7] (a) Kawate T, Nakagawa, M, Kakikawa T, Hino T (1992) Tetrahedron Asymmetry 3 : 227. (b) Nakagawa M, Kawate T, Kakikawa T, Yamada H, Matsui T, Hino T (1993) Tetrahedron 49 : 1739. (c) Hong Y, Gao Y, Nie X, Zepp CM (1994) Tetrahedron Lett 35 : 5551. [8] (a) Quallich GJ, Keavey KN, Woodall TM (1995) Tetrahedron Lett 36 : 4729. (b) Prasad KRK, Joshi NN (1996) J Org Chem 61 : 3888. [9] Bach J, Berenguer R, Farras J, Garcia J, Meseguer J, Vilarrasa J (1995) Tetrahedron Asymmetry 6 : 2683. [lo] Corey EJ, Link JO (1992) J Am Chem SOC 114 : 1906. 111 (a) Bringmann G, Hartung T (1992) Angew Chem Int Ed Engl31 : 761 (b) Bringmann G, Hartung T (1993) Tetrahedron 49 : 7891. 121 Berenguer R, Garcia J, Vilarrasa J (1994) Tetrahedron Asymmetry 5 : 165. 131 Helal CJ, Magriotis PA, Corey EJ (1996) J Am Chem Soc 118 : 10938. [14] Corey EJ, Cimprich KA (1994) J Am Chem SOC116 : 3151. [15] Joshi NN, Srebnik M, Brown HC (1989) Tetrahedron Lett 30 : 5551.

50

A. Asymmetric Synthesis

[16] (a) Furuta K, Mori H, Yamamoto H (1991) Synlett 561. (b) Ishihara K, Mouri M, Gao Q, Maruyama T, Furuta K, Yamamoto H (1993) J Am Chem SOC115 : 11490. [17] (a) Furuta K, Miwa Y, Iwanaga K, Yamamoto H (1988) J Am Chem SOC 110 : 6254 (b) Furuta K, Shimizu S, Miwa Y, Yamamoto H (1989) J Org Chem 54 : 1481. (c) Ishihara K, Gao Q, Yamamoto H (1993) J Am Chem SOC 115 : 10412. [18] Gao Q, Maruyama T, Miwa T, Yamamoto H (1992) J Org Chem 57 : 1951. [19] Takasu M, Yamamoto H (1990) Synlett 194. [20] (a) Sartor D, Saffrich J, Helmchen G (1990) Synlett 197. (b) Sartor D, Saffrich J, Helmchen G, Richards CJ, Lambert H (1991) Tetrahedron Asymmetry 2 : 639. [21] Corey EJ, Loh T -P, (1991) J Am Chem SOC 113 : 8966. [22] Corey EJ, Cywin CL (1992) J Org Chem 57 : 7372. [23] Corey EJ, Loh T-P, Roper TD, Azimioara MD, Noe MC (1992) J Am Chem SOC114 : 8290. [24] Corey EJ, Guzman-Perez A, Loh T-P (1994) J Am Chem SOC116 : 3611. [25] Corey EJ, Loh T -P (1993) Tetrahedron Lett 34 : 3979.

[26] Seerden J-P G, Scholte op Reimer AWA, Scheeren HW (1994) Tetrahedron Lett 35 : 4419. [27] (a) Furuta K, Muruyama T, Yamamoto H (1991) J Am Chem SOC113 : 1041 (b) Furuta K, Muruyama T,Yamamoto H (1991) Synlett 439. [28] Corey EJ, Cywin CL, Roper TD (1992) Tetrahedron Lett 33 : 6907. [29] (a) Kiyooka S, Kaneko Y, Komura M, Matsuo H, Nakano M (1991) J Org Chem 56 : 2276. (b) Kiyooka S, Kaneko Y, Kume K (1992) Tetrahedron Lett 33 : 4927. (c) Kaneko Y, Matsuo T, Kiyooka S (1994) Tetrahedron Lett 35 : 4107. [30] Parmee ER, Tempkin 0, Masamune S (1991) J Am Chem SOC 113 : 9365. [31] (a) Charette AB, Juteau H (1994) J Am Chem SOC116 : 2651 (b) Charette AB, Prescott S, Brochu C (1995) J Org Chem 60 : 1081. [32] Theberge CR, Zercher CK (1994) Tetrahedron Lett 35 : 9181. [33] Charette AB, Juteau H, Deschenes D (1996) Tetrahedron Lett 37 : 7925. [34] Mitome H, Miyaoka H, Nakano M, Yamada Y (1995) Tetrahedron Lett 36 : 823 1. [35] Manoury E, Mouloud HAH, Balavoine GGA (1993) Tetrahedron Asymmetry 4: 2339.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Enantioselective Catalytic Hydrogenation Judith Albrecht and Ulrich Nagel

Enantioselective catalysis is one of the most important tools in asymmetric synthesis. [ 1, 21 With its assistence biologically active substances can be prepared in enantiomerically pure form - this purity can be a crucial factor with pharmaceutical products. In the field of crop protection the use of enantiomerically pure compounds provides irrefutable advantages for both economic and ecological reasons. [3,41 Enantioselective transition metal catalyzed hydrogenation has an important place among the methods of asymmetric synthesis. A large range of substrates can be enantioselectively hydrogenated in this way, which is extremely important for the preparation of natural and also nonnatural amino acids, because it enables the directed synthesis of all possible amino acid derivatives from the many prochiral enamides and ketones. Recently great progress has been made in this field. Very high ee values are achieved, and even sterically demanding substrates like p,B-disubstituted enamides are able to be hydrogenated in good optical yield. [5, 61 Since the beginning of the 90's Burk et al. have been exploring the development of novel electron-rich phosphane ligands that give powerful catalysts for enantioselective hydrogenation on complexation with rhodium. [7] The ligands they use each contain

two phospholanes trans substituted in 2,5position, whose phosphorus atoms are linked together through different groups as backbone. The carbon atoms adjacent to the phosphorus atoms are chiral and in these catalysts are situated in the immediate vicinity of the rhodium atoms (Scheme 1). Initially the phospholanes were synthesized by derivatization of homochiral 1,4-diols with mesyl chloride. The dimesylates were then transformed into the 3 3 -disubstituted phenylphospholanes with dilithiumphenylphosphide. The phenyl group was cleaved with pure lithium metal, and the resulting lithium phosphide could then be converted into the bridged system with 1,2-dichloroethane, ethyleneglycoldi-p-tosylate, or 1,3 -dichloropropane. The yields with this synthetic route were moderate and depended strongly on the purity of the lithium metal. [8]

BPE

DuPHOS

Scheme 1. The bisphospholane ligands BPE and DuPHOS; R = Me, Et, nPr, iPr (to give Me-, Et-, nPr-, and iPr-BPE or -DuPHOS).

52

A. Asymmetric Synthesis OH

1 . SOCI,

R

2 . RUCI, , NalO,

OH

R*

c

R+R

0

0 ‘S’

o 4 *o 1 1. n-BuLi

R

2. 1 (2 eq.)

R

3. n-BuLi c

H P

1. n-BuLi 2. 1 (2 eq.) 3. n-BuLi

H2P

PHZ

c

% R

R

Scheme 2. Synthesis of BPE and DuPHOS ligands.

In 1996 Burk et al. also developed a conveA later optimized synthesis also starts from the 1,4-diols. They are then converted into nient method to synthesize chiral a-1 -arylalcyclic sulfates with thionyl chloride on media- kylamines through enantioselective hydrogetion of ruthenium chloride and sodium peri- nation of various enamides using their Meodate. The sulfates are transformed with dili- DuPHOS and Me-BPE ligands, respectively. thiumbis(phosphid0)ethane into bis(phosph0- They consistently achieved from 94 to 97% 1ano)ethane (BPE) ligands or with dilithium- ee. Furthermore their ligands tolerated /hub1,2-bis(phosphido)benzene into bis(phosph0- stituents both in (@- and (a-position. [ 101 In all enantioselective hydrogenations the 1ano)benzene (DuPHOS) ligands. Ring closure to form phospholane is achieved by addi- ability of the substrate to form a chelate ring with the catalyst is extremely important. For tion of nBuLi [9] (Scheme 2). The differently substituted BPE and this reason the enantioselective reductive amiDuPHOS rhodium complexes were applied nation of ketones is always particularly diffiin the hydrogenation of N-acetylenamides. cult, because these compounds usually do Of the BPE ligands, the ethyl-substituted de- not have a structure suitable for the required rivative gave the highest ee values (93 % for chelation. Burk et al. circumvent this problem methyl a-acetylaminocinnamate and 98 % for by reversible derivatization. The ketones are methyl a-acetylaminoacrylate). Higher enan- converted into N-acetylhydrazones, whose tioselectivities were achieved with the structures resemble those of enamides. [ 1I ] DuPHOS ligands. Under optimized conditions The C-N double bond can then be hydrogesome systems afforded ee values of over 99 %. nated by nPr-DuPHOS-rhodium with ee In particular the sterically demanding nPr- values almost as high as those for C-C double DuPHOS gave ee values of 99.8% (enantio- bonds of enamides. The N-acetylhydrazines obtained thus can either be transformed into mer ratio 1000 : 1).

Enantioselective Catalytic Hydrogenation

the free hydrazines by acid hydrolysis or into amines by treatment with samarium diiodide. In this way a large number of ketones can be reductively aminated. [ 121 To hydrogenate prochiral ketones to the corresponding chiral alcohols, Noyori et al. have developed ternary catalyst systems from [RuC12(binap)(dmf),], a chiral diamine, and KOH. [13, 141 By this route methyl(1-naphthy1)ketone can be hydrogenated to 1-(I-naphthy1)ethanol with [RuClz(binap)(drnf),], 1,2diphenylethyldiamine, and KOH in the ratio 1 : 1 : 2 in isopropanol (substrate : catalyst = 500 : 1, 4 bar H2, 28 "C, 6 h) in greater than 99 % yield with 97 % ee. Other sources of hydrogen can be used instead of elemental hydrogen gas. In transfer hydrogenations a secondary alcohol has been employed as hydrogen donor. Noyori et al. have also made advances in this field. They use a catalyst system from [RuCl2($-mesitylene)]z, N-(p-toluenesulfony1)- 1,2-diphenylethylenediamine,and KOH in isopropanol. At room temperature acetophenone can be reduced in 15 h with this complex prepared in situ (substrate : catalyst = 200 : 1) to 1-phenylethanol in 95% yield with an optical purity of 97 %. [15, 161 The

\

CI

R 'c *il

/cI\

53

same system even works better under otherwise comparable conditions when a formic acid-triethylamine mixture is used as hydrogen source (99 % yield and 98 % ee). [17] Catalyst systems with a /3-aminoalcohol as auxiliary are faster, as shown by the reduction of acetophenone to 1-phenylethanol under otherwise identical conditions with [R~C12(1;1~-hexamethylbenzene)]2,2-methylamino-l,2-diphenylethanol,and KOH within as little as 1 h in 94 % yield and 92 % ee [ 181 (Scheme 3). With transfer hydrogenation Noyori et al. were not only able to hydrogenate C-0 double bonds but also the C-N double bonds of prochiral imines. As hydrogen donor they used a formic acid-triethylammonium mixture. With the chiral Ru(I1)-catalyst systems shown in Scheme 4 they achived ee's up to 96 % in hydrogenating various prochiral imines. [ 191 The N-acetylhydrazones used by Burk et al. are ketone derivatives, and their structures therefore correspond to those of the BJ-disubstituted N-acetylaminoacrylic acids. This and the finding that both the (E)- and the (Z)-enamides are hydrogenated with almost the same enantioselectivity by the BPE and DuPHOS

*+w HO

CI

HNCH,

+

i

KOH

A

Scheme 3. Transfer hydrogenation of acetophenone.

54

A. Asymmetric Synthesis

HC0,H-(C,H,),N chiral Ru catalyst

CH30

'C H 3"0

R

'

W

H

N R

Scheme 4. Enantioselective transfer hydrogenation of imines.

complexes prompted them to investigate the ability of the phospholane ligands to enantioselectively hydrogenate @,P-disubstituted Nacetylaminoacrylic acids. [5] Attempts to use the ligands Et-, nPr-, and iPr-DuPHOS, which were most successful for the N-acetylenamides, gave unsatisfactory results: the ee values were 74, 45, and 14%, respectively. In supercritical COz as solvent [20] they improved to 90%. Noyori et al. also used supercritical C02 as solvent for hydrogenations of a$-unsaturated carbolxylic acids. With a Ru(I1)-BINAP complex as catalyst they thereby reached at best 89% ee in hydrogenating tiglic acid at 20"C, 180 atm C02 and 5 atm H2. To enhance the solubility of aromatic compounds in supercritical C02 and the enantioselectivity of the hydrogenation reaction a fluorinated alcohol was added (here: CF3(CF&CH20H). [21] The use of supercritical C02, however, puts a greater demand on the hydrogenation apparatus than conventional conditions, since it must be able to withstand high pressures. The temperature must also be precisely controlled, because in supercricital systems merely a small temperature difference can lead to enormous effects.

The trans chelate ligands developed by Ito et al. are also used for enantioselective hydrogenation of P,P-disubstituted N-acetylaminoacrylic acids. [6] These ligands fall into the class of TRAP ligands (TRAP = 2,2"-bis[l(dialkylphosphino)ethyl]- 1,l' '-biferrocene), with which good ee values are achieved. Methyl a-N-acetylamino-B,/3-dimethylacrylate can be hydrogenated with Bu-TRAP at a catalyst : substrate ratio of 1 : 1000 in 24 h (15 "C, 1 bar H2) to form the corresponding propane carboxylic acid in 88 % ee (Scheme 5). Further progress in the hydrogenation P,Bdisubstituted N-acetylenamides was made with the sterically less hindered Me-DuPHOS-rhodium catalyst. In this system an ee value of 92 % was obtained. [5] The best enantioselectivities till now have been reached with the Me-BPE ligand. With this ligand a large variety of P,P-disubstituted N-acetylenamides were hydrogenated with

y,,M Scheme 5.

R2P

Ito's TRAP ligand.

Enantioselective Catalytic Hydrogenation

55

Scheme 6. Blocked quadrants.

very high ee values of over 99% in some cases. For a catalyst : substrate ratio of 1 : 500 under mild conditions (25"C, 6 bar H2) bmethyl- and /I-ethylphenylalanine derivatives could be prepared from the corresponding p,p-disubstituted N-acetylaminoacrylates in 12-24 hours with optical yields of 99.4 and 99 %, respectively. The Pr-DuPHOS ligand is one of the best ligands for the hydrogenation of sterically less congested substrates, whereas for the sterically more demanding b,p-disubstituted compounds the ligand Me-BPE is the better choice. The astoundingly different behavior of derivatives of these catalysts is hard to predict, yet because of the opportunities for variation in the synthesis of the bisphospholanes, the broadest possible tailoring of the ligands to a problem at hand is assured. An old but graphic picture to explain the enantioselectivities with different ligands is that of the blocked quadrants [22] (Scheme 6). The rigid benzene ring in the backbone of the DuPHOS ligands blocks two diagonally oriented quadrants at the metal atom through the substituents on the phospholane ring. The bulkier the substituent and the more rigidly it is held in its position, the better the quadrants are blocked. For most of the sterically less hindered substrates like p-monosubstituted acetylaminoacrylic acids the optimum is reached with the nPr-DuPHOS ligand. The ligand in the catalyst may not be so bulky that the binding of the substrate is overly restricted. Thus the ee values for hydrogenations with the bulkier iPr-DuPHOS-rhodium catalyst decrease. [9]

In the case of the tetrasubstituted acrylic acids the rigid DuPHOS ligands block both diagonally oriented quadrants so severly that the larger space requirements of these substrates cannot be accommodated. Here the more flexible Me-BPE ligand with its smaller methyl groups performs better.

References [l] R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley & Sons, New York, 1994. [2] J. Ojima (Ed.), Catalytic Asymmetric Synthesis, VCH, Weinheim, 1993. [3] W. A. Nugent, T. V. RajanBabu, M. J. Burk, Science (Washington D. C.) 1993, 259, 479-83. [4] G. M. Ramos Tombo, D. BelluSs, Angew. Chem. 1991,103, 1219-41. [5] M. J. Burk, M. F. Cross, J. P. Martinez, J. Am. Chem. SOC. 1995, 117,9375-6. [6] M. Sawamura, R. Kuwano, Y. Ito, J. Am. Chem. SOC.1995,117, 9602-3. [7] M. J. Burk, J. E. Feaster, R. L. Harlow, Organometallics 1990, 9, 2653-5. [8] M. J. Burk, J. E. Feaster, R. L. Harlow, Tetrahedron: Asymmetry 1991, 2, 569-92. [9] M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow, J. Am. Chem. SOC. 1993, 115, 10125-38. [lo] M. J. Burk, Y. M. Wang, J. R. Lee, J. Am. Chem. Soc. 1996,118,5142-3. [ l l ] M. J. Burk, J. E. Feaster, J. Am. Chem. SOC. 1992, 114, 6266-7. [12] M. J. Burk, J. P. Martinez, J. E. Feaster, N. Cosford, Tetrahedron 1994, 50,4399-428. [13] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. SOC. 1995, 117, 2675-6.

56

A. Asymmetric Synthesis

[14] T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. SOC. 1995, / / 7 , 10417-8. [15] S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 7562-3. [16] K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. 1997, 109, 297-300. [I71 A. Fujii, S. Hashiguchi, N. Uemastu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 2521-2.

[18] J. Takehara, S. Hashiguchi, A. Fujii, S. Inoue, T. Ikariya, R. Noyori, Chem. Comm. 1996, 233-4. [19] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. SOC. 1996, 118, 4916-7. [20] M. J. Burk, Shaoguang Feng, M. F. Cross, W. Tumas, J. Am. Chem. Soc. 1995, 117, 8277-8. [21] J. Xiao, S. C. A. Nefkens, P. G. Jessop, T. Ikariya, R. Noyori, Tetrahedron Letters 1996, 37 2813-6. [22] W. S. Knowles, Acc. Chem. Res. 1983, 16, 106.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

The Sharpless Asymmetric Aminohydroxylation of Olefins Oliver Reiser

“The time has come for me to discover something new, but there is so much chemistry out there!” With these words Barry Sharpless closed the Merck-Schuchhardt lecture 1995 in Gottingen, Germany [l]. After about 10 years of continuous optimization, the asymmetric dihydroxylation (AD) of olefins had developed into one of the most versatile catalytic asymmetric reaction to date [2]. An “obvious” extension of the AD-process would be the asymmetric transfer of heteroatoms other than oxygen to a carbon carbon double bond. Indeed, the osmium catalyzed [3] or palladium mediated [4] aminohydroxylation of alkenes has been known for 20 years. The resulting /3-amino alcohols are an important structural element in biologically active compounds as well as the starting point in the design of many chiral ligands. However, to develop this reaction into a catalytic, asymmetric process several problems had to be overcome. According to the original protocol [3] alkenes can be converted to racemic N-tosyl protected /%amino alcohols in the presence of catalytic amounts of osmium tetroxide using N-chloramine-T as the nitrenoid source and water as the hydroxyl source. However, unlike the AD-process, the aminohydroxylation of unsymmetrical alkenes can lead to two regioisomeric products which was a drawback in

the early stages of its development. Moreover, the direct reaction of osmium tetroxide with the alkene could not be completely surpressed, and diols were sometimes observed as side products. Na’ ‘CI

Formel 1.

oso4 (1%) t

L

J

VNHR R = Ts, Ms,CO,R‘

Although the first, albeit stoichiometric, example of this asymmetric aminohydroxylation reaction had already been observed in 1980 [5], the discovery of the titanium catalyzed asymmetric epoxidation (AE) [6] at about the same time probably also “interfered” with an earlier development of today’s catalytic asymmetric aminohydroxylation (AA) process. Since the discovery of the catalytic AD in 1987, there have been numerous attempts in the Sharpless group to render the old catalytic aminohydroxylation process asymmetric [7]. Until recently, the obvious approach of adding the AD’S chiral ligands, but otherwise staying close to the original protocol [3] led to extremly slow catalyst turnover. The initial breakthrough [8] was not due to a sudden con-

58

A. Asymmetric Synthesis

tected, which is generally difficult to remove. Consequently, the attention of the Sharpless group was directed towards different reagents which could act as the nitrogen source. First, it was discovered that smaller substituents on nitrogen give rise to dramatically improved selectivities [ 101. Thus, N-chloramine-M, transfering a NS02Me group proved to be superior for all cases compared to N-chloramine-T. Nevertheless, the problem of deprotection was still a draw back for synthetic applications, despite some promising developments of easier removable protecting groups of the sulfonamide type [ l l ] . In parallel it was found that N-halo-carbamates are also efficient nitrogen sources [12]. The highest selectivities are observed with N-chloro-ethylcarbamate, followed by N-chloro-benzylcarbamate, offering the great advantage of giving rise to 2-protected amino alcohols, which can be readily deprotected if desired by standard procedures. What types of alkenes undergo this reaction? In contrast to the AD reaction also strongly electron poor alkenes are suitable substrates probably due to the greater polariOAlk' zation of the Os=NR group compared to that of the Os=O group. Thus, acrylates in general Y@\ give good results in the AA, but even dimeOAlk' thy1 fumarate (1) reacts rapidly - 1 is a very PHAL poor AD substrate - to give the 2-hydroxy aspartic acid derivative 2. Cinnamates 3 can be converted to a-hydroxy-b-amino acids 4, giving e. g. a most effective entry to the side chain amino acid of taxol[13]. Paru-substitution of the aryl group in 3 by electron-donating or withdrawing groups is well tolerated, however, meta- and in particular ortho-substitution results in some loss of enantio- and Formel 2. DHQD DHQ regioselectivity. One of the most remarkable Despite these encouraging results, there effects of the chiral ligand is on the regioselecwas much room for improvement of this tivity. In the absence of the ligand the cinnainitial procedure. The obtained selectivites mates 3 give roughly equal amounts of the were not satisfactory in many cases, however, regioiosmers (i. e. 4 plus its 2-NHTs, 3-OH perhaps the most substantial disadvantage was isomer) [3]. While most of the reactions the transferal of the nitrogen being tosyl pro- to date were carried out with 4 mol%

ceptual insight but rather to the luck of making a number of small changes, all of which had been tried before but never in concert. The combination of chloramine-T as the nitrogen source, potassium osmate (4 mol%) and the recently discovered phthalazine ligands (Alk*)2PHAL (5 mol%) as the catalyst, tert-butylhydroperoide as the stochiometric oxidans, and solvent mixtures tBuOH/H20 ( 1 : 1) or CH3CN/H20 (1: 1) proved to be the right recipe. Suddenly the turnover was decent, diol side products were greatly reduced, and good regioselectivity was seen for the first time [7]. Most exciting of all, the products were obtained with moderate to high enantioselectivities, with complimentary discrimination of the enantiotopic faces of the alkene by the two ligands [9], (DHQ)zPHAL and (DHQD)zPHAL. The same sense of asymmetric induction as in the AD is observed, indicating that the chirality transfer occurs by a similar pathway. Moreover, due to the highly crystalline nature of the products they can often be raised to enantiopurity by simple recrystallization.

The Sharpless Asymmetric Aminohydroxylation of Olefins

59

Selectivity [YOeel (yield [%I) Substrate

Product

R

=

NHR CO Me

MeO,C/\;/

Ts

Ms

77 (65)

95 (76)

82 (60)

95 (65)

74 (52)

80 (63)

R' = Et

R' = t-BU

64 (78)

NCOZEt

-

NCOZBn

84 (55)

NCOZt-Bu

-

6H 2

NHR *,+COzMe

ph*CozMe

98 (70) 94 (65)

78 (71)

6H 4

3 /\/CO2R' H3C

NHR H3C%.

co R'

6H

-

-

75 (71)

-

91 (92)

-

-

-

6

5

NHR Ph/\\/

-

Ph

Ph+Ph

6H 8

7 PhX

Ph?

h

50 (57)

6H

Ph

9

P

lo NHR

-

(Regioselectivity) 11

98 (73)

6.6:l

12

0 13

99 (70)

> 1o:i

45 (64)

66 (49)

-

63 (51)

-

14

Scheme 1. AA: RNClNa (3-3.5 eq.), t-BuOHiH2O 1 : 1, n-PrOH&O 1 : 1 or CHsCN/H20 1 : 1, OC or rt, K20~02(OH)4(4.0 mol%), (DHQh-PHAL (5 mol%), (DHQD)z-PHAL leads to the enantiomeric products.

Os/5 mol% ligand, in large scale runs the catalyst amount has been successfully reduced by half, giving similar good results.

Less electron poor alkenes like stilbenes (7 and 9) are also viable substrates. Direct comparison of 8 and 10 also indicates, that

60

A. Asymmetric Synthesis

(E)-alkenes are - in analogy to the AD process better substrates than (Z)-alkenes. Nevertheless, it is already clear at this stage that (Z)-alkenes, and in particular symmetrical (Z)-alkenes, are useful substrates in the AA. A syn-dihydroxyliation of the latter class of olefins leads to meso-diols and is therefore not suitable in relation of the concept of asymmetric dihydroxylation. Cyclic (Z)-alkenes such as cyclohexene (13) also have given promising results, and heteroatoms can be present as long as they are not directly attached to the double bond [7]. 1,3-, 1,4-, and 1,5-dienes as well as certain terminal alkenes also have given encouraging results in the AA, but additional regioselectivity and reactivity problems arise with these substrates. With the discovery of the new nitrogen sources, styrenes such as 11 are converted with excellent enantioselectivity and good regioselectivity to the corresponding amino alcohols. Alkenes which seem to be problematic so far are allylic halides, alcohols and amines, no matter if protected or not. Several allylic acetals have also given poor results [7]. The products obtained by the AA process can be easily transformed into aziridines or into precursors for o$-diamino acids [7]. -

OH

MsCl I NEt3

OMS

theless, the reaction conditions have to be carefully controlled since little changes regarding the nitrogen source, the solvent and the temperature can have a great effect on selectivity and yield of the products. Thanks to the openness with which Sharpless et al. is presenting this discovery to the synthetic community in that not only short communications but simultaneously full papers with detailed experimental procedures have been published, many exciting applications of this reaction should result in the near future. Moreover, there are already two other oxidative amination processes on the horizon, namely allylic amination of olefins and 1,2diamination of 1,3-dienes [14]. Could these useful, but stochiometric transformations be rendered catalytic and perhaps also asymmetric some day? NsN=Se=NNs

R

R

rac

Q

NsN=Se=NNs

* Ns = 2-nitrobenzenesulfonyl

Formel 4.

QNHNS NHNs

rac

P

TsHNAC02R

TsHNACOpR 13

Formel3.

14

15

16

In only very little time the new catalytic process of an asymmetric aminohydroxylation of alkenes has been transformed into a practical method with great synthetic potential. The title reaction is easily being carried out, never-

Acknowledgement: This work was supported by the Winnacker foundation and the Fonds der Chemischen Industrie.

The Sharpless AsymmetricAminohydroxylationof Olefins

61

[9] H. Becker, K. B. Sharpless, Angew. Chem. 1996, 108, 447; Angew. Chem. Int. Ed. Engl. 1996, 35, 448. [l] University of Gottingen, April 28, 1995. The day of the AA discovery has been June 14, [lo] J. Rudolph, P. C. Sennhenn, C. P. Vlaar, K. B. Sharpless, Angew. Chem. 1996, 108, 2991; 1995. Angew. Chem. Int. Ed. Engl. 1996, 35,2813. [2] H. C. Kolb, M. S . VanNiewenhze, K. B. [ l l ] T. Fukuyama, C.-K. Jow, M . Cheung, TetraSharpless, Chem Rev. 1994, 94, 2483. hedron Lett. 1995,36, 6373. [3] a) K. B. Sharpless, A. 0. Chong, K. Oshima, J. Org. Chem. 1976, 41, 177; b) E. Herranz, [12] G. Li, H. H. Angert, K . B. Sharpless, Angew. Chem. 1996, 108, 2995; Angew. Chem. Int. K. B. Sharpless, J. Org. Chem. 1978,43,2544. Ed. Engl. 1996, 35,2837. [4] J . E. Backvall, Tetrahedron Lett. 1975, 26, [I31 G. Li, K. B. Sharpless, Acta Chem. Scand. 2225. 1996, 50, 649. [5] S. Hentges, K. B. Sharpless, J. Am. Chem. [I41 M. Bruncko, T.-A. V. Khuong, K . B. SOC. 1980,102,4263. Sharpless, Angew. Chem. 1996, 108, 453; [6] T. Katsuki, B. Sharpless, J. Am. Chem. SOC. Angew. Chem Znt. Ed. Engl. 1996,35,454. 1980,102,5447. [7] K. B. Sharpless, personal communication. [8] G. Li, H.-T. Chang, K. B. Sharpless, Angew. Chem. 1996, 108, 449; Angew. Chem. Int. Ed. Engl. 1996, 35,451.

References

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Epoxides in Asymmetric Synthesis: Enantioselective Opening by Nucleophiles Promoted by Chiral Transition Metal Complexes Ian Paterson and David J. Berrisford

The turn of the millenium will see the 20th anniversary of the seminal discovery of the asymmetric epoxidation [ 1, 21 of allylic alcohols catalysed by titanium(1V) isopropoxide and tartrate esters. The utility of this transformation largely results from the regio- and stereocontrol possible in subsequent nucleophilic ring opening reactions of the derived epoxy alcohols. Thus, a sequence of asymmetric epoxidation, epoxide opening and further functionalisation leads to a diverse array of molecules in enantiomerically pure form. In comparision, asymmetric epoxidation of unfunctionalised alkenes [3] has yet to match the enantioselectivities which the Ti-tartrate system can deliver with allylic alcohols. The recent discovery of other asymmetric epoxidation reactions [4]suggests that a number of practical options may eventually become available.

A less common strategy for asymmetric synthesis, but one with considerable merit, is the enantioselective opening of meso epoxides (Fig. la) by achiral nucleophiles in the presence of a chiral catalyst. [5] Similarly, the kinetic resolution of rucemic epoxides (Fig. lb), in the best cases, can deliver high enantiomeric excesses in the unreacted epoxide and ring-opened product. Both processes involve initial coordination to a Lewis acidic metal centre, so activating the epoxide to attack by an external nucleophile (Fig. 2, pathway a). The catalyst functions by complexing the epoxide oxygen atom and the ligand environment should allow discrimination of the formally enantiotopic carbon-oxygen bonds by an appropriate achiral nucleophile. Enantioselective opening of meso epoxides by heteroatom nucleophiles [6-111 has been

Nu-

Figure 1. Enantioselectiveopening of meso epoxides (a) and racemic epoxides (b) by achiral nucleophiles.

Enantioselective Opening b y Nucleophiles Promoted by Chiral Transition Metal Complexes

63

L*

M2/L*

"

Pathwaya

L' *

L* Nu

NU-M'

Figure 2. Enantioselective opening of meso epoxides. Pathway a: activation of the epoxide by the chiral Lewis acid (M2XL*2). Pathway b: activation of the stoichiometric nucleophile (NuM') by metathesis with the chiral complex.

investigated by several research groups (Scheme 1). Brown has shown that certain chiral boron Lewis acids display [6] useful levels of asymmetric induction in their stoichiometric reactions with epoxides to give /lhalohydrins. Heterogeneous zinc and copper tartrates catalyse [7] the opening of simple epoxides with n-butyl thiol, trimethylsilyl azide, and aniline with moderate-to-good enantioselectivity. More efficient homogenous catalysts can be derived from titanium alkoxides with chiral ligands. [8,9] For example, the combination of TiClz(0iPr)z with ditert-butyl tartrate catalyses [ 101 the opening of cyclohexene oxide with trimethylsilyl azide giving /l-azido cyclohexanol in 62 % ee. In 1992, Nugent [12] reported a significant advance in the Lewis acid-promoted opening of meso epoxides (Scheme 2). A novel chiral zirconium complex catalyses epoxide opening with hindered silyl azides in excellent ee. The catalyst is derived from zirconium tert-butoxide and the tetradentate C3 -symmetric ligand 1, available by combination of (8-propene oxide with (S)-l-aminopropan-2-01. Al-

though the ligand l possesses C3-symmetry, the active catalyst is likely to display a less symmetrical structure and the complex will certainly be aggregated in solution. The enantioselectivity of the reaction is enhanced by use of bulkier nucleophilic azides and the trifluoroacetate additive is essential for high selectivity. The reaction is simple to carry out, proceeds at either 0 "C or room temperature and affords excellent yields and enantioselectivities. In 1995, Jacobsen [13] reported a further advancement in the nucleophilic opening of meso epoxides. This discovery, which makes use of Cr-Salen catalysts (Scheme 3), is significant for a number of reasons. Firstly, the catalyst delivers high yields and enantioselectivities using only a 2 mol% loading at 0°C with trimethylsilyl azide as the nucleophile. Secondly, kinetic investigations [ 141 reveal that the Cr-Salen complex 4 has an unexpected dual role in the process. Cr-Salen complexes, e. g. 4 and 5, can act as Lewis acids (cf. Fig. 2, pathway a). In addition, the azide is transferred in situ from Si to Cr giving com-

rrBuSH. Zn tartrate

/

0:" 0

CH2C12,25 "C 85% ee (82%)

(-)-lpc,BX

*n-c,Ii,*, -700°C

X = Br 84% ee (82%) X =I

91% ee (89%)

-

1. (+)-DTBT, TiC12(0+Pr)2

TMSN3, CHzCIz, 0 "C

2. 1 N HCI

0;:

62% ee (65%)

Scheme 1. Enantioselective opening of meso epoxides by heteroatom nucleophiles (Ipc = isopinocampheyl; DTBT = di-tert-butyl tartrate).

64

A. Asymmetric Synthesis

Me?

L: (SSS)-1

Me

("

2 [LzrO-t-B~ln

"OH

0

x,

3 [(LZ~OH)~-~-BUOH].

HO'''' Me 3 R'3SiN3(1.04 (8 mol%), equiv),

Me

C F ~ C O ~ S ~(2Mm~o Jl l ) CH2C12,O "C

Me

,P\R

sOSiMe2iPr arMs&r

87% ee (59%)

83% ee (64%)

0;iMq'Pr

Q;;Me2'Pr

93% ee (86%)

89% ee (79%)

Scheme 2. Enantioselective opening of meso epoxides by trialkylsilyl azide catalysed by Zr complex 3.

4 ~

u

-

-

.

(

$

OCOPh

( R , R ) 4 :M = Cr(ll1); X = CI

~

$

~

~

~(R,R)-5: ~ M = Cr(ll1); X = N3

(R,R)8:M = CO(ll)

82% ee (65%)

9

88% ee

Scheme 3. Enantioselective opening of meso epoxides catalysed by chiral Salen complexes.

plex 5.Thus, a second equivalent of the metal complex acts as a chiral nucleophile (cf. Fig. 2, pathway b). The proposed mechanism [14] combines the two possible roles for the metal and requires two Cr-Salen complexes in the turnover limiting step. Azide complex 5, rather than the precatalyst 4, can be used directly in the syntheses [13] of 7 and 8, useful intermediates for prostaglandins and carbocyclic nucleosides. On a practical note, the reactions can be run without solvent and the catalyst can be recycled a number of times. Catalyst recycling involves the potentially hazardous distillation of the neat liquid azides, a procedure which may be incompatible with large scale applications. Further experimentation [ 151 using a variety of metal-Salen complexes has enabled the ring opening of meso epoxides by benzoic acid to give a-hydroxy benzoates. In this case,

the Co-Salen complex 6 affords the highest enantioselectivities; for example, benzoate 9 may be prepared in 98 % ee after recrystallisation. These results give encouragement to chemists to search for other new catalysts which despite apparently similar constitution may possess striking new reactivity profiles. Catalytic kinetic resolution of racemic epoxides [16, 171 has proven to be an elusive goal. The successful implementation of this strategy by Jacobsen [16] is a highly significant achievement (Scheme 4). Complex 5 catalyses the opening of simple terminal epoxides with trimethylsilyl azide with outstanding enantioselectivities. The unreacted epoxides are evaporated, leading to the a-azido silyl ethers 10 in 2 95 % ee and near quantitative yields. The catalyst displays near perfect enantioselection; kinetic resolution [181 often requires a much greater sacrifice of yield to

Enantioselective Opening by Nucleophiles Promoted by Chiral Transition Metal Complexes (R,R)-5 (I rnol%)

R

TMSN3,O"C

0

qR+ H

racemic

65

OSiMe3 N3,,kR IOa:R=Me;97%ee(49%) lob: R = Et; 97% ee (42%) 10 IOc: R = CH,CI; 95% ee (47%)

Scheme 4. Kinetic resolution of terminal epoxides catalysed by chiral Cr-Salen complex 5. 12 (20 rnol%), Ti(O-i-Pr)4 (20 rnol%)

11

/\s+CN

12

F

Scheme 5. Combinatorial screening of ligands for Ti-catalysed enantioselective opening of meso epoxides by trimethyisilyl cyanide.

attain high ee and at > 50% conversion the 13 with 86 % ee. Moreover, this study addresstarting material is returned with the higher ses some pertinent issues with respect to enantiopurity. Given the economy of the pro- screening for asymmetric catalysis by library cess and the ready availability of the epoxide methods. Clearly, library screening offers consubstrates, this discovery is likely to emerge siderable promise in both the discovery and as an established method of asymmetric syn- optimisation of new catalysts. thesis. Taken together, these results for epoxide In 1996, Hoveyda [19] reported an impor- opening promoted by chiral metal complexes tant contribution to catalytic asymmetric [21] illustrate how much there is find out epoxide opening through the use of combina- about asymmetric catalysis by transition torial library screening. All the foregoing metals. These valuable new processes are chemistry in this article concerns heteroatom further proof, if any is required, of the rewards nucleophiles, where the use of carbon nucleo- of searching for new reactivity amongst the philes is noticeably absent. Previous work transition metals. [20] had shown that combinations of early transition metals and Schiff base ligands could act as Lewis acids in the opening of References epoxides with trimethylsilyl cyanide. Using a library of potential ligands 11, prepared by [l] R. A. Johnson, K. B. Sharpless in Catalytic solid phase peptide synthesis, a large number Asymmetric Synthesis (Ed.: I Ojima), VCH, New YorWeinheim, 1993, p. 103-158. of possible catalysts were screened for reac[2] R. Noyori, Asymmetric Catalysis in Organic tivity and enantioselectivity. This led to the Synthesis, Wiley, New York, 1994. discovery of a process capable of delivering [3] For reviews see: T. Katsuki, Coord. Chem. good enantioselectivity for certain meso epoxRev. 1995, 140, 189-214; E. N. Jacobsen ides (Scheme 5). For example, ligand 12 in Catalytic Asymmetric Synthesis (Ed.: combined with Ti(OiPr)4 gives p-cyanohydrin

66

A. Asymmetric Synthesis

I Ojima), VCH, New York/Weinheim, 1993, p. 159-202. [4] V. K. Aggarwal, J. G. Ford, A. Thompson, R. V. H. Jones, M. C. H. Standen, J. Am. Chem. SOC.1996, 118, 7004-7005; D. Yang, X-C. Wang, M-K. Wong, Y-C. Yip, M-W. Tang, ibid. 1996, 118, 11311-11312; Y. Tu, Z-X. Wang, Y. Shi, ibid. 1996, 118, 98069807; C. Bousquet, D. G. Gilheany, Tetrahedron Lett. 1995,36, 7739-7742. [5] I. Paterson, D. J. Berrisford, Angew. Chem. 1992, 104, 1204-1205; Angew. Chem. Int. Ed. Engl. 1992,31, 1179-1 180. [6] M. Srebnik, N. N. Joshi, H. C. Brown, Isr. J. Chem. 1989, 29, 229-237; N. N. Joshi, M. Srebnik, H. C. Brown, J. Am. Chem. SOC. 1988,110, 6246-6248. [7] H. Yamashita, T. Mukaiyama, Chem. Lett. 1985, 1643-1646; H. Yamashita, ibid., 1987, 525 -528. [8] M. Emziane, K. I. Sutowardoyo, D. Sinou, J. Organomet. Chem. 1988,346, C7-C10. 191 C. Blandy, R. Choukroun, D. Gervais, Tetrahedron Lett. 1983,24,4189-4192. [lo] M. Hayashi, K. Kohmura, N. Oguni, Synlett 1991, 774-776. [ 111 H. Adolfsson, C. Moberg, Tetrahedron Asym. 1995,6,2023-2031. [12] a) W. A. Nugent, J. Am. Chem. Soc. 1992,114, 2768-2769; b) W. A. Nugent, R. L. Harlow, ibid. 1994, 116, 6142-6148. [13] L. E. Martinez, J. L. Leighton, D. H. Carsten, E. N. Jacobsen, J. Am. Chem. SOC. 1995, 117, 5897-5898; J. L. Leighton, E. N. Jacobsen, J. Org. Chem. 1996,61,389-390; L. E. Martinez, W. A. Nugent, E. N. Jacobsen, J. Org. Chem. 1996,61,7963-7966.

[I41 K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am. Chem. Soc. 1996, 118, 10924-10925. [15] E. N. Jacobsen, F. Kakiuchi, R. G. Konsler, J. F. Larrow, M. Tokunaga, Tetrahedron Lett. 1997,38, 773-776. [16] J. F. Larrow, S. E. Schaus, E. N. Jacobsen, J. Am. Chem. SOC.1996, 118, 7420-7421; S. E. Schaus, E. N. Jacobsen, Tetrahedron Lett. 1996, 37, 7937-7940. [17] M. Brunner, L. Mussmann, D. Vogt, Synlett 1993, 893-894. [18] E. L. Eliel, S. H. Wilen, L. M. Mander, Stereochemistry of Organic Compounds, WileyInterscience, New York, 1994, p. 395-415. [19] B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A. Harrity, M. L. Snapper, A. H. Hoveyda, Angew. Chem. 1996, 108, 17761779; Angew. Chem. Int. Ed. Engl. 1996, 35, 1668-1671; Angew. Chem. Int. Ed. Engl. 1996,35, 1995. [20] M. Hayashi, M. Tamura, N. Oguni, Synlett 1992, 663-664. For a review of ligand accelerated catalysis see: D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chem. 1995, 107, 1159-1171; Angew. Chem. lnt. Ed. Engl. 1995,34, 1059-1070. [21] N. Oguni, J. Synth. Org. Chem. Jpn. 1996,54, 829-835; M. Hayashi, K. Ono, H. Hoshimi, N. Oguni, Tetrahedron, 1996, 52, 78177832; idem., J. Chem. SOC. Chem. Commun. 1994, 2699-2700.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Asymmetric Deprotonation as an Efficient Enantioselective Preparation of Functionalized Secondary Alcohols and Amino-Alcohols Paul Knochel

The enantioselective preparation of chiral secondary alcohols has been achieved through a number of methods with great success. One pathway that is widely used is the asymmetric addition of organometallic compounds R'M to aldehydes [ 11 (retrosynthetic pathway A of Eq. (1). A disconnection involving inversion of polarity [2] is also possible (retrosynthetic pathway B of [Eq. (l)]. In this case, the secondary alcohol is formed by a substitution reaction of an a-oxygen-substituted carbenoid 1. [3] Although this alternative route has been frequently used for

synthetic applications, the multistep procedures [4] required for the enantioselective preparation of the carbenoids have limited the utility of this approach. Furthermore, to be synthetically attractive, the chiral carbenoid has to be configurationally stable under the reaction conditions, and its reaction with electrophiles has to proceed with a well-defined stereochemistry (retention or inversion). Enantioselective deprotonation reactions have been known for several years and have led to several elegant synthetic applications. [ 5 ] Hoppe found that this method allows OR R'X

OR2

OR2

2: R' = alkyl; R' = Cbx, Cby; R3 = s BuLi R' = alkenyl; R' = Cb;

+

= n BuLi

(9-1.(4-3

RZAM

Eq. (1).

68

A. Asymmetric Synthesis

an expedient access to a wide range of chiral a-oxygen carbenoids 1 (M = Li, Eqs. 1 and 2) [6-121 starting from readily available achiral carbamates 2 and the complex of an alkyllithium compound and (-)-sparteine 3. [131 The deprotonations are complete within a few hours at -78 "C and afford the lithium carbenoid . sparteine complexes (S)-1.(-)-3 with excellent enantioselectivities. [6-121 Whereas sparteine complexes of lithiated secondary allyl and primary alkyl carbamates are configurationally stable below -30 "C, those of primary allyl carbamates such as 4.(-)-3 are not configurationally stable even at -70 "C. It is, however, possible to use these reagents in synthesis, since the preferential crystallization of the S diastereomer in pentanelcyclohexane drives the equilibrium completely to one side. After a low-temperature transmetalation of (S)-4.(-)-3 with an excess of tetraisopropoxytitanium, the allylic titanium reagent (R)-5 is obtained with inversion of configuration. The addition of various aldehydes to (R)-5 furnishes homoaldol adducts of type 6 with high anti diastereoselectivity and very good enantioselectivity (82-90 % ee) (Eq. 3). They can be further converted to lactones as shown in the synthesis of the insect pheromone (+)-eldanolide (92 % ee). [6dJ

A crystal structure analysis of a complex between a lithiated primary carbamate and (-)-sparteine 3 unambiguously established the S configuration of this organometallic intermediate. [ 141 Of considerable interest for synthetic applications are the deprotonations of alkyl carbamates RCH20Cbx or RCHzOCby with s butyllithium . (-)-sparteine, followed by the alkylation with an electrophile. [7] Most electrophiles such as C02, Me3SnC1, Me3SiC1, MeI, MezCHCHO react with retention of configuration to afford protected alcohols of type 7 (Eq. 4). This provides a very general enantioselective synthesis of secondary alcohols. The enantioselectivities of the deprotonations are better than 95 % ee in most cases. These high enantiodifferentiations are kinetic in nature, and MNDO calculations show that the stabilities of the two diasteromeric ion-pairs (+)1.(-)-3 and (-)-1-(-)-3 are comparable. [ 151 Efforts have also been made to determine the structure of the chiral base RLi.(-)-3, but only the structure of the complex (i PrLi)2 . (-)-3 in ether has been determined, by NMR techniques. [ 161 The Cbx- protecting group of 7 can be removed under mild conditions. An acid treatment (MeS03H, MeOH, reflux, 16 h) afford-

Ti(0 iPr)*

inversion of configuration

(9-4. (-)-3

(R)-5

1

r

H "Ti(0 i

OH

6: 90-95 YO:82-90 % ee

RiXOCbx

s BuLi*(-)-3

H H

ether, 5 h,-78 "C

*

E+

(-)-3*L1

R'%OCbx E H 7

Asymmetric Deprotonation as an Efficient Enantioselective Preparation

ing the intermediate carbamate 8 followed by a basic treatment (Ba(OH)2 . 8H20, MeOH, reflux, 4 h) leads to the chiral alcohol 9 (Eq. 5) [7] in excellent yield. Remarkably, this method can be applied to carbamates bearing a functional group in close proximity to the OCbx or OCby group. High enantiomeric excesses are obtained, although chelating groups such as N(CH2Ph)z [8, 111 or an OR [9, 101 group are present. Thus the @-dibenzylaminocarbamate 10 can be deprotonated with high enantioselectivity with s BuLi.(-) -3 (3 equiv; -78 "C, 3 h) and treated with various electrophiles to give almost enantiomerically pure 1,2-aminoalcohols 11(Eq. 6). [8] Interestingly, the presence of a substituent at the a position to the nitrogen functionality strongly influences the rate and controls the enantioselectivity of the deprotonation. This can be clearly seen in the case of the carbamate 12, derived from (S)-N,N-dibenzyl-

leucinol. After the reaction with an electrophile, substrate-controlled deprotonation yields the aminoalcohol derivative 13 (Eq. 7). [81 Interestingly, asparagin acid derivative 14 is deprotonated enantioselectively by s BuLi.(-)-3 in ether (-78"C, 5 h) furnishing after carbonylation and subsequent methylation the ester 15 in 90 % yield (Eq. 8). [ 171 The importance of intramolecular chelation is nicely demonstrated in the lithiation of the glutamic acid derivative 16. With s BuLi.(-)-3 an enantioselective deprotonation is observed at position 5 leading after the carbonylation-esterification sequence to the ester 17, whereas with s BuLi in ether, an intramolecular complexation favors an intramolecular enantio-selective deprotonation at position 1 leading to the ester 18 (Eq. 9). [17] The 1,3-dicarbamate 19 undergoes a stereoselective cyclopropanation after lithiation with s BuLi . (-)-3. Depending on the nature

0

7

9

11

10

s BuLiOTMEDA (3 equiv) t

~ o c , i Pr

-78 "C. 3 h

E O C b y "'LbTMEDA iPr H

E+

X O C b , iPr H

'**

13

12

W OL

O : C NBnz 14

b

y

1) s BuLi (-)-3 -78 "C, 5 h 2) COP,then CHzNz

t

69

CbyOh

-

O

C

b

y

NBn2 C02Me 15: 90 %

E

70

A. Asymmetric Synthesis C02Me

1) s BuLi *(-)-3,ether -78 "C, 5 h

CbyO-OCby

/ 2) CO2, then CH2N2 CbyO-OCby

1) s BuLi (4-3, ether -78 "C, 5 h

knz

16

&n2 17: 81 %

C02Me

*

CbyOLOCby

NBn2

2) COz, then CHzNz

18:61 %

20b: 53 %; 74 % ee

Me Me CbyOAOCby

1) s BuLi*(-)9

5 CbyO-y 3) 2N HCI

COOH

Eq. (9).

Eq. (10).

A 90 "C, 12 h 21: 80 %: >95 % ee

Eq. (11).

n BuLi *(-)-3 be

23:63 %; > 95 % ee

22

Eq. (12).

ether,-78 "C 2) PhzCO

24:91 %; 99 % ee

of the Lewis acid added, the cyclization occurs with retention or inversion of the carbon-lithium leading to the cyclopropanes 20a-b (Eq. 10). [18] Finally, the utility of the method has been demonstrated by Hoppe with a short enantioselective synthesis of (R)-pentolactone 21 (Eq. 11). r91

Eq. (13).

Remarkably, the enantioselective deprotonation with (-)-3 can be extended to various systems. Thus, substituted indenes like 22 can be stereoselectively deprotonated leading to chiral allyllithiums which after reaction with electrophiles furnish chiral 1,3 -disubstituted indenes such as 23 with excellent enantioselectivity (Eq. 12). [191

Asymmetric Deprotonation as an Efficient Enantioselective Preparation

25

26

The lithiation of ferrocenyl amides with n BuLi . (-)-3 proceeds with high enantioselectivity providing after quenching with an electrophile useful new chiral ferrocene derivatives like 24 (Eq. 13). [20] An asymmetric deprotonation of (tert-butoxycarbony1)pyrrolidines 25 has been recently developed by Beak allowing a highly enantioselective synthesis of a variety of 2-substituted pyrrolidines (Eq. 14). [21] Also aminosubstituted benzylic lithiums have been generated with s BuLi.(-)-3 and quenched stereoselectively with electrophiles. [22] The enantioselective deprotonation at the a position to oxygen- or nitrogen-substituted carbamates with RLiSsparteine complexes allows the most practical and efficient synthesis of the corresponding chiral organolithium compounds. The high enantioselectivity of the deprotonation, the high stereoselectivity observed in the course of the reaction of these species with electrophiles, as well as the compatibility with some donating functional groups in the lithium organometallic compound make this methodology a very powerful tool for the construction of nonracemic chiral molecules.

References [ l ] For recent advances in this field see: a) G. SolladiC in Asymmetric Synthesis, Vol 2 (Ed.: J. D. Momson), Academic Press, New York, 1983, pp. 157-200; b) D. A. Evans, Sience 1988,240,420-426; c) R. Noyori, M. Kitamura, Angew. Chem. 1991, 103, 34-35; Angew. Chem. Int. Ed. Engl. 1991,30,49-69; d) B. Schmidt, D. Seebach, ibid. 1991, 103, 1383-1385 and 1991,30, 1321-1323.

27: 55-76 %; 88-99 % ee

71

Eq. (14).

[2] D. Seebach, Angew. Chem. 1979, 91, 259278; Angew. Chem. Int. Ed. Engl. 1979, 18, 239-258. [3] a) H. Ahlbrecht, G. Boche, K. Harms, M. Marsch, H. Sommer, Chem. Ber. 1990, 123, 1853-1858; b) G. Boche, A. Opel, M. Marsch, K. Harms, F. Haller, J.C.W. Lohrenz, C. Thiimmel, W. Koch, ibid. 1992, 125, 22652273. [4] a) W. C. Still, C. Sreekumar, J. Am. Chem. SOC. 1980, 102, 1201-1202; b) V. J. Jephcote, A. J. Pratt, E. J. Thomas, J. Chem. SOC. Chem. Commun. 1984, 800-802; J. Chem. SOC. Perkin Trans.1 1989, 1529-1535; c) J. M. Chong, E. K. Mar, Tetrahedron 1989, 45,7709-7716; d) D. S. Matteson, P. B. Tripathy, A. Sarkar, K. N. Sadhu, J. Am. Chem. SOC. 1989, 111, 4399-4402; e) R. J. Linderman, A. Ghannam, ibid. 1990, 112, 2392-2398; f) J. A. Marshall, W. Y. Gung, Tetrahedron 1989, 45, 1043-1052. [5] For an excellent review see: H. Waldmann, Nachr. Chem. Tech. Lab. 1991, 39,413-418. [6] a) D. Hoppe, 0. Zschage, Angew. Chem. 1989, 101, 67-69; Angew. Chem. Int. Ed. Engl. 1989, 28, 65-67; b) 0. Zschage, J.-R. Schwark, D. Hoppe, ibid. 1990, 102, 336337 and 1990, 29, 296; c) 0. Zschage, D. Hoppe, Tetrahedron 1992, 48, 5657-5666; d) H. Paulsen, D. Hoppe, ibid. 1992, 48, 5667-5670; e) 0. Zschage, J.-R. Schwark, T. Kramer; D. Hoppe, ibid. 1992, 48, 83778388; f) D. Hoppe; F. Hintze; P. Tebben; M. Paetow; H. Ahrens; J. Schwerdtfeger; P. Sommerfeld; J. Haller; W. Guarnieri; S. Kolczewski, T. Hense, I. Hoppe Pure Appl. Chem. 1994, 66, 1479-1486; g) D. Hoppe; H. Ahrens; W. Guarnieri; H. Helmke; S. Kolczewski Pure Appl. Chem. 1996, B 613; h) D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376; Angew. Chem. Int. Ed. Engl. 1997,36, 2282-2316.

72

A. Asymmetric Synthesis

[7] D. Hoppe, F. Hintze, P. Tebben, Angew. Chem. 1990,102, 1457-1459; Angew. Chem. Int. Ed. Engl. 1990,29, 1422-1424. [8] J. Schwerdtfeger, D. Hoppe, Angew. Chem. 1992, 104, 1547-1549; Angew. Chem. Int. Ed. Engl. 1992,31, 1505-1507. [9] M. Peatow, H. Ahrens, D. Hoppe, Tetrahedron Lett. 1992, 33, 5323-5326. [ 101 H. Ahrens, M. Peatow, D. Hoppe, Tetrahedron Lett. 1992, 33, 5327-5330. [ l l ] P. Sommerfeld, D. Hoppe, Synlett 1992, 764766. [12] F. Hintze, D. Hoppe, Synthesis 1992, 12161218. [ 131 (-)-Sparteine has been used as additive in several types of asymmetric reactions with moderate success; see, for example, H. Nozaki, T. Aratani, T. Toraya, R. Noyori, Tetrahedron 1971, 27, 905-913. [14] M. Marsch, K. Harms, 0. Zschage, D. Hoppe, G. Boche, Angew. Chem. 1991,103,338-339; Angew. Chem. Int. Ed. Engl. 1991, 30, 321323.

[151 H.-U. Wurthwein, unpublished results.

[16] D. J. Gallagher, S. T. Kerrick, P. Beak, J. Am. Chern. SOC. 1991,114,5872-5873. [17] W. Guarnieri; M. Grehl; D. Hoppe Angew. Chem. 1994,106, 1815-1818; Angew. Chem. Int. Ed. Engl. 1994, 33, 1734-1737. [18] M. Paetow; M. Kotthaus; M. Grehl; R. Frohlich; D. Hoppe Synlett 1994, 1034-1036. [19] I. Hoppe; M. Marsch; K. Harms; G. Boche; D. Hoppe Angew. Chem. 1995, 107, 2328-2330; Angew. Chem. Int. Ed. Engl. 1995,34, 21582 160. [20] M. Tsukazi; M. Trinkl; A. Rogbuo; B. J. Chapell; N. J. Taylor; V. Snieckus J. Am. Chem. SOC. 1996, 118, 685-686. [21] a) S.T. Kerrick, P. Beak, J. Am. Chem. SN. 1991, 113, 9708-9710; b) D. J. Gallagher, S. Wu, N. A. Nikolic, P. Beak J. Org. Chem. 1995, 60, 8148-8154; c) D. J. Gallagher, P. Beak J. Org. Chem. 1995,60,7092-7093. [22] A. Basu; D. J. Gallagher; P. Beak J. Org. Chem. 1996,61, 5718-5719.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Planar-Chiral Ferrocenes t Synthetic Methods and Applications Antonio Togni

Since its discovery, and because of its stability and the wealth of methods for its derivatization, ferrocene has played an important role in many areas of synthetic and materials chemistry. Thus ferrocene has been incorporated into more complex structures, displaying, e. g., nonlinear optical, liquid crystalline, or ferromagnetic properties [I]. From a stereochemical point of view, however, one of the most important attributes of, e. g., 1,2- or 1,3-disubstituted ferrocenes, such as 1 and 2, is that they are planar-chiral, and thus potentially available in enantiomerically pure form

1

Thus, lithiation of ferrocenylamine (R)-3 with BuLi generates the two possible diastereoisomers of 4 (for simplicity formulated here as monomeric, non-solvated species) in a ratio of 96 to 4. Following the reaction with the electrophile, the diastereoisomeric side-product is usually easily separated by crystallization and/or chromatography. This strategy, involving stereogenic ortho-directing groups, has been further developed in more recent years by several research groups. Thus, sulfoxides (6) [4], acetals (7) [5], and oxazolines (8)[6] have been found to afford high diastereoselectivities. These functional groups, however, are not necessarily those

2

So far, the most relevant method for the preparation of enantiopure (or enantiomerically enriched) planar-chiral ferrocene derivatives relies upon a diastereoselective ortho-lithiation and subsequent reaction with an appropriate electrophile. Still the most prominent example of this methodology is due to the pioneering work of Ugi and co-workers (Scheme 1) [3].

Scheme 1. Diastereoselective ortho-lithiation of Ugi’s ferrocenylamine.

14

A. Asymmetric Synthesis

one may want to incorporate into the final planar-chiral product, i. e., they may need removal or modification. An exception to this observation is the oxazoline fragment in compound 8 which has been demonstrated to fulfil both the purpose of a diastereoselective orthodirecting functionality and of a ligand for transition-metals in homogeneous catalyzed reactions.

Fl

Fe

R

2) M W H I MeOH

-

10 (up to 99% ee)

NHAc

4P 7

11

OH

Fe

6

Fe

14 (up to 94% ee)

t

1) l-paney-Ni

8

Since amines of type 3 (or the corresponding alcohols as synthetic equivalents) still 12 13 (>98%da) remain the most versatile starting materials for diastereoselective lithiation processes, Scheme 2. New syntheses of chiral ferrocenyland because the amino group can easily be amines. substituted in a process occuring with retention of configuration [3a], methods have A completely different approach for the prebeen developed for their enantioselective pre- paration of planar-chiral ferrocenes, represenparation. Recent work includes the aminoal- ting an important development in this area cohol-catalyzed addition of dialkylzinc rea- was reported recently by Snieckus and cogents to ferrocene-carbaldehyde [7], and the workers [ll]. Indeed it was shown that the 1,2-addition of organolithium compounds to enantioselective ortho-lithiation of ferrocenthe corresponding SAMP-hydrazone [8], as ylamides of type 14 is effectively achieved illustratetd in Scheme 2. Further methods utilizing the alkaloid (-)-sparteine as a chiral involve the enantioselective reduction of fer- inducing agent (see example in Scheme 3 ) . rocenylketones using chiral oxazaborolidine The novelty of the method is constituted by borane [9] and lipase mediated desymmetriza- the fact that for the first time it is possible to tion of acetoxymethyl derivatives [lo]. All generate planar-chiral ferrocenes highly selecthese procedures make use of chiral auxilia- tively and without the need of introducing a ries (or catalysts) for the generation of the a- stereogenic directing group. The application stereogenic center bearing a hetero-atom func- of the reagent BuLihparteine in ferrocene tionality. Among these methods those starting chemistry is a welcome extension of the confrom ferrocenylketones are more straightfor- cept of enantioselective deprotonation develward and do not involve, e. g., cumbersome oped inter alia by Hoppe and co-workers in operations for the removal of chiral auxilia- recent years [12]. Despite this impressive ries, or complex work-up and separation pro- result (the phosphine 15 can be obtained in cedures. Therefore, they are anticipated to 90% ee and in 82% yield, whereas other become even more significant in the near electrophiles, e. g. TMSCl or benzophenone future. afford enantioselectivities up to 98 % and

Planar-Chiral Ferrocenes: Synthetic Methods and Applications

2) PPhCl

15 (90% ee)

14

Scheme 3. Synthesis of a planar-chiral fenocenylphosphine using sparteine-mediated enantioselec-

tive ortho-lithiation.

99% ee, respectively), it remains to be seen whether or not the method may be applied so successfully also to ferrocenes bearing substituents other than amides. Furthermore, will there be a chance to overcome the disadvantage of the single enantiomeric form of (-)sparteine? [13] Probably the most important class of planar-chiral ferrocenes accessible by the techniques delineated above is that of chelating ligands for transition-metal-catalyzed asymmetric reactions [I]. Progress in this area is characterized, among others, by ligands of type 16 [14], 17 1151, and 18 [16]. The Cz-symmetric biferrocene 16 has been reported by Ito and co-workers to behave as a trans-spanning chelating ligand. The combination of Cz-symmetry and trans coordination geometry is conceptually new in the field and bears promises for future development. TRAP (the abbreviation for this kind of compounds) affords high enantioselectivities in the Rhcatalyzed asymmetric Michael reaction of 2cyanopropionates 1171, the hydrosilylation of simple ketones [18], the hydrogenation of p,p-disubstituted N-acetylaminoacrylic acid

16

17

75

derivatives 1191 9 as well as the cycloisomerization of 1,6-enynes [20]. The P,N-ligand 17 represents a class of chiral auxiliaries that are amenable to easy steric and electronic tuning, an aspect that is anticipated to play an important role in the further development of asymmetric catalysis. Thus, ligands of this type have been shown to afford the highest so far reported enantioselectivities in the Rh-catalyzed hydroboration of styrenes with catecholborane (up to 98.5 % ee) [15b] and in the Pd-catalyzed substitution of allylic acetates and carbonates with benzylamine (up to > 99 % ee) [15c]. The advantage offered by these ligands is the demonstrated facility of their synthetic modification, relying upon the simple idea of a construction kit [21]. The latter is constituted by 1) the carrier of the chiral information (the amine 3), 2) a set of chlorophosphines (for the generation of the planarchiral phosphine-amine intermediate), and 3) a series of substituted pyrazoles to be used as nucleophiles. The assembly of these three fragment occurs in two consecutive synthetic steps, and allows the ligand to be adapted to the need of a particular reaction in an unprecedented way. The same type of considerations applies to diphosphines of the Josiphos type such as 18 [ 161. This specific compound, containing the bulky t-BuzP group, has been found to be the only ligand affording a very high diastereoface selectivity in the hydrogenation of derivative 19, an intermediate in a new synthesis of (+)-biotin (Scheme 4A) [22]. The analogous achiral starting material containing a benzyl protecting group, instead of a stereogenic phenethyl, affords under the same reaction

18

76

A. Asymmetric Synthesis

20 (99% ds)

19

22

, , J

2

4P

21

23 (80% ee)

24 ((3-Metolachlor)

Catalyst system: Ir(l) / 21 / Iodide/ H2SO4

Substratellr up to 1'OWOOO

Scheme 4. Industrial applications of chiral ferrocenyl phosphines in the asymmetric hydrogenation of C=C and C=N double bonds.

conditions 90% ee. This quite remarkable process, involving the hydrogenation of a fully substituted C=C bond is currently being applied on a commercial scale by LONZA Ltd. A second and probably more important technical application of this type of ligands has recently been disclosed by Ciba-Geigy Ltd (Novartis Ltd.). Derivative 21 constitutes the chiral component of the exceptionally highly active iridium catalyst used for the enantioselective hydrogenation of imine 22, an intermediate in the synthesis of the herbicide (S)-Metolachlor@ (24) [23] (Scheme 4B). The relatively low selectivity obtained in this catalytic reaction (80 % ee) is tolerable for an agrochemical product. Much more important in this specific case are the activity and productivity of the catalyst. Besides a decisive co-catalytic effect of added acids (the exact role of the added iodide salt and of the acid are still unclear), one of the key feature of this large industrial process is the use of ferrocenyl ligand 21 which turns out to be superior to all commercially available chiral chelating diphosphines, with respect to a com-

bination of several important aspects. To our knowledge, the latter two examples constitute the first industrial applications of chiral ferrocenyl ligands and are clear demonstrations of the potential this class of compounds bear. Any improvement of their synthetic versatility will mirror not only their fundamental interest, but shall be welcomed also by the practitioner in the fine-chemical industry who is willing to extend the scope of homogeneous catalysis as a powerful synthetic method. Finally, a completely new use of planar-chiral ferrocenes has been recently disclosed by Fu and co-workers [24]. Compounds of type 25 and 26 were prepared as racemic mixtures and obtained as pure enantiomers via semipreparative HPLC. Derivatives 25, analogues of 4 -(dimethylamino)pyridine, were used as nucleophilic catalysts in the kinetic resolution of chiral secondary alcohols [24a,b]. The aminoalcohol system 26, on the other hand, is an effective chiral ligand for the asymmetric addition of dialkylzinc reagents to aldehydes (up to 90 % ee) [24c]. In conclusion, this brief account summarizing recent development in the field of pla-

Planar-Chiral Ferrocenes: Synthetic Methods and Applications

77

Chem. 1995, 60, 10-11; g) W. Zhang, T. Hirao, I. Ikeda, Tetrahedron Lett. 1996, 37, 4545-4548; h) C. J. Richards, T. Damalidis, D. E. Hibbs, M. B. Hursthouse, Synlett 1995, 74-76; i) C. J. Richards, A. W. Mulvaney, R Tetrahedron: Asymmetry 1996, 7, 141925 26 (R=Me, Ph) 1430; j) K-H. Ahn, C.-W. Cho, H.-H. Baek, J. Park, S. Lee, J. Org. Chem. 1996, 61, 4937-4943. nar-chiral ferrocenes shows the multiplicity of [7] a) Y. Matsumoto, A. Ohno, S. Lu, T. Hayashi, N. Oguni, M. Hayashi, Tetrahedron: Asymactivities in this area and its relevance for synmctry 1993, 4 , 1763-1766. See also: b) thetic and organometallic chemistry at large. L. Schwink, S. Vettel, P. Knochel, Organornetallics 1995, 14, 5000-5001. [8] D. Enders, R. Lochtman, G. Raabe, Synlett References 1996, 126-128. For a second approach utilizing SAMP-derivatives, see: C. Ganter, [I] For a recent overview, see: Ferrocenes. T. Wagner, Chem. Ber. 1995, 128, 1157-1 16 1. Homogeneous Catalysis. Organic Synthesis. [9] a) A. Ohno, M. Yamane, T. Hayashi, N. Oguni, Materials Science (Eds.: A. Togni, T. M, Hayashi, Tetrahedron: Asymmetry 1995,6, Hayashi), VCH, 1995. 2495-2503; b) L. Schwink, P. Knochel, Tetra[2] For a discussion of ferrocene chemistry from a hedron Lett. 1996, 37, 25-28. stereochemical point of view, see the classical: [lo] See, e. g.: G. Nicolosi, R. Morrone, A. Patti, K. Schlogl, Top. Stereochem. 1967, 1, 39. M. Piattelli, Tetrahedron: Asymmetry 1992, [3] a) D. Marquarding, H. Klusacek, G. W. Gokel, 3,753-758. P. Hoffmann, I. K. Ugi, J. Am. Chem. SOC. [ l l ] M. Tsukazaki, M. Tinkl, A. Roglans, B. J. 1970, 92, 5389-5393; b) G. W. Gokel, I. K. Chapell, N. J. Taylor, V. Snieckus, J. Am. Ugi, J. Chem. Educ. 1972,49,294-296. Chem. SOC.1996, 118,685-686. [4] a) F. Rebikre, 0. Riant, L. Ricard, H. B. [12] D. Hoppe, F. Hintze, P. Tebben, M. Paetow, Kagan, Angew. Chem. 1993, 105, 644-646 H. Ahrens, J. Schwerdtfeger, P. Sommerfeld, (Angew. Chem. Int. Ed. Engl. 1993, 32, 568J. Haller, W. Guamieri, S. Kolczewski, 570); b) H. B. Kagan, P. Diter, A. Gref, D. T. Hense, I. Hoppe, Pure Appl. Chem. 1994, Guillaneux, A. Masson-Szymczak, F. Rebikre, 66, 1479-1486, and refs. cited therein. 0. Riant, 0. Samuel, S. Taudien, Pure & Appl. [13] Chiral amines of which both enantiomers are Chem. 1996, 68, 29-36. readily available have recently been used in [5] 0. Riant, 0. Samuel, H. B. Kagan, J. Am. analogous reactions. However, they afforded Chem. SOC.1993,115,5835-5836; b) A. Massignificantly lower enantioselectivities. See: son-Szymczak, 0. Riant, A. Gref, H. B. a) D. Price, N. S. Simpkins, Tetrahedron Lett. Kagan, 1. Organomet. Chem. 1996, 511, 1995, 36, 6135-6138; b) Y. Nishibayashi, 193-197. Y. Arikawa, K. Ohe, S. Uemura, J. Org. [6] a) Y. Nishibayashi, K. Segawa, K. Ohe, S. Chem. 1996,61, 1172-1174. Uemura, Organometallics 1995, 14, 5486- [14] a) M. Sawamura, H. Hamashima, Y. Ito, Tetra5487; b) W. Zhang, Y. Adachi, T. Hirao, hedron: Asymmetry 1991, 2, 593-596; b) I. lkeda, Tetrahedron: Asymmetry 1996, 7, M. Sawamura, H. Hamashima, M. Sugawara, 451-460; c) T. Sammakia, H. A. Latham, J. R. Kuwano, Y. Ito, Organornetallics 1995, Org. Chem. 1996, 61, 1629-1635; d) J. Park, 14,4549-4558. S. Lee, K. H. Ahn, C.-W. Cho, Tetrahedron [15] a) U. Burckhardt, L. Hintermann, A. Schnyder, Lett. 1996,37,6137-6140; e) Y. Nishibayashi, A. Togni, Organometallics 1995, 14, 541 5S. Uemura, Synlett 1995, 79-81; f) T. Samm5425; b) A. Schnyder, L. Hintermann, A. akia, H. A. Latham, D. R. Schaad, J. Org. Togni, Angew. Chem. 1995, 107, 996-998

A. Asymmetric Synthesis (Angew. Chem. Int. Ed. Engl. 1995, 34, 931933); c) A. Togni, U. Burckhardt, V. Gramlich, P. S. Pregosin, R. Salzmann, J. Am. Chem. Soc. 1996, 118, 1031-1037. a) A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert, A. Tijani, J. Am. Chem. SOC. 1994, 116,4062-4066; b) H. C. L. Abbenhuis, U. Burckhardt, V. Gramlich, C. Kollner, R. Salzmann, P. S. Pregosin, A. Togni, Organometallics 1995, 14, 759-766. M. Sawamura, H. Hamashima, Y. Ito, Tetruhedron 1994, SO, 4439-4454. [18] M. Sawamura, R. Kuwano, Y. Ito, Angew. Chem. 1994, 106, 92-94 (Angew. Chem. Int. Ed. Engl. 1994,33, I1 1-1 13). [I91 R. Kuwano, M. Sawamura, Y. Ito, Tetrahedron: Asymmetry 1995, 6, 2521-2526.

[20] A. Goeke, M. Sawamura, R. Kuwano, Y. Ito, Angew. Chem. 1996, 108, 686-687 (Angew. Chem. Int. Ed. Engl. 1996, 35, 662-663). [21] For a discussion of this aspect, see: A. Togni, Chimiu 1996. SO, 86. [22 J. McGarrity, F. Spindler, R. Fuchs, M. Eyer, Eur. Pat. Appl. EP 624587 A2, (LONZAAG), Chem. Abstr: 1995, 122, P81369q. [23 For an account about the successful development of this process, see: F. Spindler, B. Pugin, H.-P. Jalett, H.-P. Buser, U. Pittelkow, H.-U. Blaser. In: Catalysis of Organic Reactions, R. E. Malz, Jr., Ed. (Chem. Ind. Vol. 68), Dekker, New York, 1996, pp. 153-1 66. [24] a) J. C. Ruble, G. C. Fu, J. Org. Chem. 1996, 61,7230-723 1 ; b) J. C. Ruble, H. A. Latham, G. C. Fu, J. Am. Chem. SOC. 1997, 119, 1492-1493; c) P. I. Dosa, J. C. Ruble, C. C. Fu, J. Org. Chem. 1997, 62,444-445.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Asymmetric Autocatalysis with Amplification of Chirality* Carsten Bolm, Andreas Segel; and Frank Bienewald

Asymmetric metal catalysis has been intensively studied in recent years, and some efficient methods for the synthesis of enantiomerically pure compounds have been developed. [ 11 With suitable metal/ligand combinations excellent enantioselectivities and high conversion rates have frequently been achieved. Normally the catalyst must remain unaffected by the continually formed new product in order to achieve a constant, high stereoselectivity. How does it behave, however, when the product itself is a catalyst and, moreover, catalyzes its own asymmetric synthesis? Wynberg recognized very early the great potential of such “asymmetric autocatalysis” for synthesis and as early as 1989 had formulated the challenge that asymmetric autocatalysis could constitute the next generation of asymmetric synthesis. [2] In spite of great efforts the discovery of the first autocatalytic system operating with high enantioselectivity has only recently been made. [3] Important contributions from Soai et al. [3-51 take pride of *We thank the DFG (Graduiertenkolleg at the Philipps-Universitat Marburg), BASF AG, and the Volkswagen-Stiftung for stipends and financial support. We are indebted to Professor H. Wynberg (Groningen, Netherlands) for sending the dissertation by W. M. P. B. Menge.

place here, but before introducing them we will describe some other fundamental studies. Seebach, Dunitz et al. first drew attention to the fact that in stereoselective reactions with organometallic reagents differing diastereoand enantioselectivities could arise because of the formation of various mixed complexes during the course of product formation. [6,7] This led Alberts and Wynberg to investigate the asymmetric additions of organometallic carbon nucleophiles (e. g. ethyllithium) to benzaldehyde (Scheme l), and they showed that the stereochemical course of both stoichiometric and catalyzed reactions were influenced by metal-containing product molecules (here lithium alcoholates). [8] The product itself is not a catalyst but nevertheless ensures that the newly formed product is optically active. Alberts and Wynberg coined the term “enantioselective autoinduction” for this effect. PhCHO

1. (+)-PhC*D(OLi)EtI EtLi 2. H30’

D

phC*H(OH)Et (+ PhC*D(OH)Et)

Scheme 1. Asymmetric addition of ethyllithium to benzaldehyde. [8] Chirality centers are identified by a star.

Danda et al. established that the product powerfully influenced the catalyst in the metal-jree catalyzed asymmetric hydrocyana-

80

A. Asymmetric Synthesis

phodcHo+ (R,Rj-3 (cat.)

HCN

1

I-\

PhO

N

tion of 3-phenoxybenzaldehyde 1 to ( 9 - 2 by the cyclic dipeptide (R,R)-3. [9] In the presence of the product the reactionaccelerating effect of the cyclic dipeptide was enhanced. (R,R)-3 alone showed little catalytic activity at first, and with increasing reaction time the enantiomeric excess of (S)-2 increased. If a small amount of ( 9 - 2 was added to the reaction mixture at the start the product was formed with an almost constant, high ee value. Here (S)-2 itself is not a catalyst and only the interaction between the correct product enantiomer and the cyclic dipeptide leads to better catalysis. In addition asymmetric amplification [ 101 occurred only in the presence of the product. Thus, 2.2 mol% (R,R)-3 with 2 % ee at 43 % conversion yields the cyanohydrin (S)-2 with 81.6 % ee when 8.8 mol% (S)-2 with 92% ee is added at the start of the reaction. If (S)-2 is not added at the start, the conversion and enantiomeric excess are 4 % and 3.4 %, respectively. It is also interesting that in this asymmetric amplification the absolute configuration of the product is not determined by the configuration of the catalyst but by that of the added cy anohydrin. In the examples quoted the product influences the stereoselectivity or has a positive effect on an existing catalysis. [ l l ] Things become especially interesting, however, when the chiral product itself is a catalyst for its own formation from achiral precursors. This area of asymmetric autocatalysis was hardly de-

veloped for a long time, though in 1953 Frank had already formulated a mathematical model that indicated that “spontaneous asymmetric synthesis”, as he called the process, is quite possible. [12] As a natural property of life this could be of fundamental importance in the genesis of asymmetry in nature. [13151 In the scenario described by Frank two achiral substances, A and B, react to form optically active products (R)-C and (S)-C each of which can catalyze its own synthesis (Scheme 2a). This corresponds to the working of conventional autocatalysis. If one imagines that the two enantiomeric catalysts mutually reduce (or destroy) their effects (Scheme 2b), the system would show flip-flop switching properties: even a small statistical fluctuation (for example, if the reaction catalyzed by (R)-C were preferred for a short time) would have the effect of reducing the catalytic activity of (S)-C and new (R)-C would be formed even more quickly. In such an “aggressive” a)

AiB

(R)-C (cat.) /

fR)-C

+

(Sj-c

(S)-C (cat.)

b)

(R)-C

+

(Sj-C

-

[(R)-C * (S)-C] (inactive)

Scheme 2. (a) Model for “spontaneous asymmetric synthesis” according to Frank [12]. (b) Deactivation of the catalytically active chiral product.

Asymmetric Autocatalysis with Amplification of Chirality

system a trace of a chiral substance would be enough to ensure its own production in large quantities by autocatalysis. The inductor does not even need to be enantiomerically pure since the model implies the principle of asymmetric amplification. In his article Frank pleaded for the development and testing of simple autocatalytic systems. [12] The first successful reaction with a “chiral autocatalyst” was reported by Soai et al. in 1990. [16] They found that the pyridinyl alcohol 6 catalyzed its own formation from pyridine-3 carbaldehyde (4) and diisopropylzinc via the isopropylzinc alcoholate 5. With 20 mol% (-)-6 (86 % ee), workup afforded (-)-6 in 67 % yield with an ee of 35 %.

5 I(-)-6 (cat.)

81

(94.8% ee) in the reaction between the corresponding aldehyde 7a and diisopropylzinc led to the formation of (S)-9a in 48 % yield with an ee of 95.7%. The product underwent automultiplication without a significant change in the enantiometric excess. As if this were not enough, Soai et al. [4] also used this system to demonstrate for the first time the asymmetric amplification during autocatalysis that is inherent in the Frank model. Thus 20 mol% of (S)-9b with an ee of only 2 % gave, with autocatalysis, (S)-9b with an ee of 10 %. In further reaction cycles the enantiomeric excess rose from 10 through 57 to 81 and finally to 88 % (Fig. 1). There was a 942-fold increase in the amount of product after four cycles. The asymmetric amplification shown by this simple selfreplicating system behaved, in fact, as predicted by the simple, theoretical Frank model. [ 181

5

4 PH

Similarly, in other enantioselective additions of organozinc compounds asymmetric autocatalyses were also demonstrated, [ 171 though they always gave a product with a much lower ee value than that of the catalyst 0 1 2 3 4 used. Only at the end of 1995 was an im-n portant breakthrough achieved [3,4] when Soai et al. showed that the presence of Figure 1. Increase in the enantiomeric excess of 20 mol% of the pyrimidyl alcohol (S)-9a (S)-9b with the number of reaction cycles n.

(S)-8 / (S)-9 (cat.)

R

a:R=Me

bR=H

R

(8-9

t

R

82

A. Asymmetric Synthesis

1991, 30, 49; b) D. Guillaneux, S.-H. Zhao, 0. Samuel, D. Rainford, H. B. Kagan, J. Am. Chem. SOC.1994, 116, 9430; c) C. Bolm in Advanced Asymmetric Synthesis (Ed.: G. R. Stephenson), Blackie, Glasgow, 1996, p. 9; d) H. B. Kagan, C. Girard, D. Guillaneux, D. Rainford, 0. Samuel, S. Y. Zhang, S. H. Zhao, Acta Chem. Scand. 1996,50, 345. [ I l l Optically active products can also be formed with racemic metal catalysts. With a chiral additive one of the enantiomeric forms of the catalyst is "poisoned" [11 a-g] or activated [11 h] in situ; a) N. W. Alcock, J. M. Brown, P. J. Maddox, J. Chem. SOC.Chem. Commun. 1986, 1532; b) J. M. Brown, P. J. Maddox, Chirality 1991, 3, 345; c) K. Maruoka, H. References Yamamoto, J. Am. Chem. SOC. 1989, 111, 789; d) J. W. Faller, J. Pam, J. Am. Chem. [I] a) R. Noyori, Asymmetric Catalysis in OrSOC. 1993, 115, 804; e) J. W. Faller, M. ganic Synthesis, Wiley, New York, 1994; Tokunaga, Tetrahedron Lett. 1993, 34, 7359; b) Catalytic Asymmetric Synthesis (Ed.: J. f) J. W. Faller, D. W. I. Sams, X. Liu, J. Am. Ojima), VCH, Weinheim, 1993. Chem. SOC.1996, 118, 1217; g) J. W. Faller, [2] a) H. Wynberg, Chimia 1989, 43, 150; b) X. Liu, Tetrahedron Lett. 1996, 37, 3449; J. Macromol. Sci. Chem. A 1989, 26, 1033; h) K. Mikami, S. Matsukawa, Nature 1997, c) W. M. P. B. Menge, Dissertation, University 385, 613. of Groningen 1989. [12] a) F. C. Frank, Biochim. Biophys. Acta 1953, [3] T. Shibata, H. Morioka, T. Hayase, K. Choji, 11,459. See also: b) I. Gutman, J. Sci., Islamic K. Soai, J. Am. Chem. SOC.1996, 118,471. Repub. Iran 1995, 6, 231; Chem. Abstr. 1996, [4] K. Soai, T. Shibata, H. Morioka, K. Choji, 124, 288491k; C) R. D. Murphy, T. M. ElNature 1995,378, 767. Agez, Indian J. Chem. Sect. A: lnorg., Bio[5] a) T. Shibata, K. Choji, H. Morioka, T. Hayase, inorg., Phys., Theor Anal. Chem. 1996, 35A, K. Soai, J. Chem. SOC.Chem. Commun. 1996, 546; Chem. Abstr. 1996,125, 141853s. 751; b) T. Shibata, K. Choji, T. Hayase, [I31 a) J. L. Bada, Nature 1995, 374, 594; b) W. A. Y. Aizu, K. Soai, J. Chem. SOC.Chem. ComBonner, Top. Stereochem. 1988, 18, 1; c) W. J. mun. 1996, 1235. Meiring, Nature 1987, 329, 712; d) P. Decker, [6] D. Seebach, R. Amstutz, J. D. Dunitz, Helv. Nachr. Chem. Tech. Lab. 1975, 23, 167; Chim. Acta 1981, 64, 2622. e) S. Mason, Chem. SOC.Rev. 1988, 17, 347; [7] Review articles: a) D. Seebach, Proc. Robert f) W. A. Bonner, Chem. Ind. 1992, 640; A. Welch Found. Con$ Chem. Res. 1984, g) S. Mason, Nature 1985, 314, 400; g) R. A. 27, 93; b) Angew. Chem. 1988, 100, 1685; Hegstrom, D. K. Kondepudi, Chem. Phys. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624. Lett. 1996, 253, 322. [8] a) A. H. Alberts, H. Wynberg, J. Am. Chem. [ 141 Nonasymmetric molecular replication and Soc. 1989, 111, 7265; b) J. Chem. SOC. autocatalyses: a) L. E. Orgel, Nature 1992, Chem. Commun. 1990,453. 358, 203; b) E. A. Wintner, M. M. Conn, J. [9] a) H. Danda, H. Nishikawa, K. Otaka, J. Org. Rebek, Jr., Acc. Chem. Res. 1994, 27, 198; Chem. 1991, 56, 6740; b) mechanistic interc) J. Am. Chem. SOC. 1994, 116, 8877; d) pretation: Y. Shvo, M. Gal, Y. Becker, A. G. von Kiedrowski, J. Helbing, B. Wlotzka, Elgavi, Tetrahedron: Asymmetry 1996, 7, 911. S. Jordan, M. Mathen, T. Achilles, D. Sievers, [lo] a) R. Noyori, M. Kitamura, Angew. Chem. A. Terfort, B. C. Kahrs, Nachr. Chem. Tech. 1991, 103, 34; Angew. Chem. Int. Ed. Engl. Lab. 1992, 40, 578; e) T. Achilles, G. von

As the mechanism of the reaction and possible intermediates in solution are still unknown, the phenomenon described here cannot yet be used for the targeted development of further reactions. It is, nevertheless, clear that complex formation with the organometallic reagents is essential to autocatalysis with asymmetric amplification. For this reason a deeper understanding of the behavior of chiral compounds during the formation of complexes would be very useful for the design and discovery of new autocatalytic processes.

Asymmetric Autocatalysis with Amplification of Chirality Kiedrowski, Angew. Chem. 1993, 105, 1225; Angew. Chem. Znt. Ed. Engl. 1993,32, 1198. [15] Formation of homochiral crystals from solutions of optically inactive compounds: a) J. Jacques, A. Collet, S . H. Wilen, Enantiomers, Racemates, and Resolutions, Wiley, New York, 1981; b) D. K. Kondepudi, R. J. Kaufman, N. Singh, Science 1990, 250, 975; c) J. M. McBride, R. L. Carter, Angew. Chem. 1991, 103, 298; Angew. Chem. lnt. Ed. Engl. 1991, 30, 293, and references therein. [16] K. Soai, S. Niwa, H. Hori, J. Chem. SOC. Chem. Cornmun. 1990,983.

83

[17] a) K. Soai, T. Hayase, C. Shimada, K. Isobe, Tetrahedron: Asymmetry 1994, 5, 789; b) K. Soai, T. Hayase, K. Takai, Tetrahedron: Asymmetry 1995, 6, 637; c) C. Bolm, G. Schlingloff, K. Harms, Chem. Bel: 1992, 125, 1191; d) S. Li, Y. Jiang, A. Mi, G. Yang, J. Chem. SOC. Perkin Trans 1 1993, 885; e) K. Soai, Y. Inoue, T. Takahashi, T. Shibata, Tetrahedron 1996, 52, 13555; f) for a substituted compound: T. Shibata, H. Morioka, S. Tanji, T. Hayase, Y. Kodaka, K. Soai, Tetrahedron Lett. 1996, 37, 8783. [ 181 Asymmetric autocatalysis with amplification of enantiomeric excess has also been found in reactions with a 3 -quinolylalkanol [5].

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Resolution of Racemates by Distillation with Inclusion Compounds Gerd Kaupp

Chiral drugs and additives are generally not permitted to be used in racemic form (most important exception: DL-methionine) so that unintended side effects and unnecessary environmental hazards are avoided. Larger amounts of enantiomerically pure compounds are economically produced by fermentation or (complete) enzymatic conversion of racemates into the desired enantiomer. Thus, since 420,000 t of L-glutamic acid and large quantities of L-aspartic acid and L-phenylalanine (for the sweetener aspartame) and D-phenylglycine are produced annually, excessive amounts of waste should and can be prevented. [ l ] Absolute asymmetric synthesis, a rapidly developing field, is a simple approach to the synthesis of enantiomerically pure compounds and has low environmental impact; however, enantiomorphic crystals (with a chiral space group) are required, which are not necessarily formed by all compounds with prochiral centers. [2] Enantioselective syntheses with chiral auxiliaries and “without biology” have been fine-tuned most impressively and have a longer tradition, [3] but are still usually very costly and time-consuming. Several approaches to chemical synthesis may be outlined: the synthesis is conducted in chiral media (recently inclusion compounds have been shown to be efficient [4]) or with

chiral catalysts. Alternatively, an optically active starting material is employed in a diastereoselective synthesis, and the portion of the molecule with the initial chiral center is cleaved off afterwards. This can be done with loss of chirality in the auxiliary (e.g. with the Seebach method [3]) or without loss (e. g. with the Schollkopf method [5]); however, recovery of the auxiliary from smallscale reactions does not appear to be very worthwhile. [3] Upscaling for industrial applications is still problematic. [6] Apparently, resolution of racemates following straightforward synthesis remains the most frequently applied method. Fractional distillation after synthesis of volatile amides or esters met with little success, due to low differences in boiling points (4-5 K or < 1 K) and laborious transformations. [7] An early distillation approach using different volatilities of diastereomeric salts of various amines with tartaric acid or its dibenzoyl- (also di-p-toluoyl-) derivatives yielded optical purities of the distillates from 5 to 47 % with a better performance in the case of methamphetamine (56.5-66.5 %). [8] However, probably due to the ban or restrictions with this drug (and most further drugs that might be misused) for use in scientific research by many countries, that publication did not find its due recognition. A further rea-

Resolution of Racemates by Distillation with Inclusion Compounds

85

!tiMe ONMe2

WH Me

1

ONMe2

2

son might be that it did not care for the optical purities of the residues after alkaline extraction. Fortunately supramolecular chemistry introduced new possibilities for optical resolutions that were not restricted to acids and bases; inclusion compounds were systematically examined, and versatile clathrating agents were designed and employed. [9] These findings have been used since the early 1980s to selectively and reversibly include chiral guest molecules in host lattices of chiral molecules. [4] In contrast to the formation of diastereomeric salts, compounds with almost any functional group can be treated. The enantiomerically pure host and the racemic guest (or the racemic host and the enantiomerically pure guest) are dissolved, the inclusion compound composed of the better fitting set of enantiomers is allowed to precipitate, and the crystalline material is removed by filtration. The two enantiomers of the guest (host) are obtained from the filtrate and from a solution of the crystals after the host (guest) is removed by chromatography on SiOz, respectively. The enantiomers (atropisomers) of 2,2'-dihydroxy- 1,l '-binaphthyl (1) do not interconvert at normal temperatures. Thus, if a chiral compound like (R,R)-2 (or N-benzylcinchonidinium chloride) [ 101 is dissolved with ruc-1, only one of the diastereomeric inclusion compounds crystallizes on account of chiral recognition. (-1-1 (and (+)-1) is obtained with > 99% ee (from benzene) and separated from 2 by chromatography on SiO2. The enantiomerically pure host

(-)-1 (and (+)-1) can now be used for a variety of difficult chiral resolutions (> 99% ee) by inclusion crystallization, for example the resolution of racemic sulfoxides like 3, sulfoximines like 4, phosphinates/phosphanoxideslike 5, and aminoxides like 6 and 7. Hundreds of resolutions of very diverse racemic compounds have been reported with a broad range of hosts. [4] Recently an improvement in this separation technique was reported, which seemed to indicate that enantioselective inclusion in the lattices of chiral hosts could be employed on a large scale. [ll] When crystalline hosts such as (R,R)-(--)-8(m. p. 196 "C),[l2] (R,R)-(-)-9 (m. p. 165 "C), [12] and (W)-(-)-lo (m. p. 128 "C) are suspended in hexane or water, chiral guest molecules form the same inclusion compounds as from solution. This is by no means self-evident, since inclusion compounds have different crystal lattices than the pure host crystals. Thus crystalkquid reactions occur, and phase rebuildings analogous to those observed in gadsolid reactions [13] must take place. Yet this suspension technique is more selective and more effective than the initially developed solution technique. Numerous racemic alcohols like 11, p-hydroxy esters like 12, epoxy esters like 13, and epoxy ketones like 14 were stirred a few hours with appropriate hosts (suspensions of 8, 9, and 10) and formed 1 : 1 complexes that could be filtered off in yields of > 85 % and with ee values of > 97 % (the complex of 12 and 9 formed in hexane only; 80% ee in one step). Recrystallization of the inclusion

86

A. Asymmetric Synthesis

HO

compounds is not generally necessary; (-)-11, (+)-12, (+)-13, and (+)-14 are released by heating under vacuum. Hosts 8, 9, and 10 can then be used again in further resolutions. Improvements have been made with stereoselective gas-solid inclusions. Thus, Weber used the host (S)-15 for sorptive stereoselective inclusion of 16-19 and achieved moderate (ee: 8.5-71 %) resolutions. [I41 Further improvements were solid-solid inclusions and slurry techniques using stoichiometric amounts of water. [I51 The reasons for the success have been mechanistically revealed by AFM investigations of the gas-solid resolution of 11 in (R,R)-8 [13,16] and of the solid-solid resolution of (k)pantolactone in 9 and its homolog (32).[I71 The resolution procedures are simple, cheap, and environmentally safe. Of course, as with other resolutions, the undesired enantiomer must be disposed of, or better yet, converted into a racemic mixture and resolved again. Another advantage of the new technique is the possibility of using a stoichiometric amount of the host relative to the racemate (in other words, in excess). The resolution can then be achieved by fractional (Kugelrohr) distillation. For example, 2 mmol of ruc-11 and 2 mmol of crystalline 8 in 1 mL

15

bH

10

18

of hexane were stirred for 1 h at room temperature and the mixture subsequently distilled. At approximately 70 "C uncomplexed (+)-11 was collected with 59 % ee; the distillation of the residue provided (-)-11 in 69 % yield and with 97 % ee at roughly 150 "C. In a similar fashion fractional vacuum distillation of rac-14 and 10 gave (-)-14 (68% ee) and 63 % (+)-14 with 95 % ee. If the process with the enantiomeric host is repeated, both enantiomers of the guest can be isolated in pure form. Since the hosts are not consumed and do not racemize, they can be employed in subsequent separations. Also the amphetamine resolutions by distillation have been pursued by the Hungaryan scientists using an improved acid [(+)-(R)-N-(a-methylbenzy1)phthalic acid monamide] or inclusion by (R,R)-8. [ 181 The real breakthrough of the Toda method required the above (gas)solid-solid techniques without any solvent to be combined with the favorable inclusion properties that allow the non-complexed enantiomer to be distilled off at temperatures far below the melting point of the complex when the antipode is liberated. Thus, chiral recognition leads to ee values between 90 and 100% in many cases by one simple distillation. Sometimes two to four consecutive enantiodiseriminating distillations

'

H

19

Resolution of Racemates by Distillation with Inclusion Compounds

Phb/Et ;,Y 20

xoH XCMI

are necessary for a complete resolution. The non-complexed enantiomer may, of course be enriched by application of the host antipode. For all systems that do not include in present chiral hosts, new ones will have to be developed. However, such endeavors might be highly rewarding, considering the ease of the procedure. At present, about 16 racemates 11-14, 20-30 have been quantitatively resolved by distillation with 5 different chiral hosts 8-10 and the homologs 31-32. [19] The hosts are recovered and used again. Undoubtedly, H bonds play an important role in these enantioselections: IR spectra of the complexes showed broad and shifted bands. [ 191 The diversity of functional groups suggests that many more racemates with other functionalities might be equally resolved. Crystallographic fit is of primary importance. Upscaling of enantioselective distillations for industrial applications is of particular interest and initial tests cannot be far off. The heat transfer to the solid should not present major difficulties up to the kg scale, and technical solutions should be possible for larger scale separations. It can be expected that the

87

Toda procedure for obtaining enantiomerically pure compounds will find broad application very soon. This development could make preparative HPLC with chiral columns obsolete and be applied to distillable amino acid derivatives as well. After all, analytical resolution of amino acids was quite successful by hostfguest complexation chromatography with reversed-phase packings loaded with Cram's chiral 1 ,l'-binaphthyl crown ethers (similar to 1). [20] While distillative separation of enantiomers in contact with optical selectors is the most exciting issue, the separation of isomers or mixtures with very close boiling points by distillation in the presence of structural selectors (that do not need to be chiral for that purpose) is also of high interest, because it again minimizes waste and abuse of energy. Very difficult separations, some of industrial importance, have been performed correspondingly. [21]

References [ 11 Fonds der Chemischen Industrie, Aminosauren - Bausteine des Lebens (Folienserie 11

des Fonds der Chemischen Industrie), Frankfurt, 1993; R. M. Williams, Synthesis of Optically Active a-Amino Acids, Pergamon Press, Oxford, 1989, Chap. 7, p. 2.57; I. Shiio, S. Nakamori in Fermentation Process Development of Industrial Organisms (Ed.: J. 0 . Neway), Marcel Dekker, New York, 1989, p. 133; R. Biegelis in Biotechnology, Vol. 7b (Eds.: H. J. Rehm, G. Reed), VCH, Weinheim, 1989, p. 229. [2] Highlight: G. Kaupp, M. Ha&, Angew. Chem. 1993, 105, 727; Angew. Chem. Znt. Ed. Engl. 1993, 32, 694 see this book on page 99ff; L. Caswell, M. A. Garcia-Garibay, J. A. Scheffer, J. Trotter, J. Chem. Educ. 1993, 70, 78.5. [3] Recent example: S. Blank, D. Seebach, Angew. Chem. 1993, 105, 1780; Angew. Chem. Int. Ed. Engl. 1993,32, 1765, and references therein.

88

A. Asymmetric Synthesis

[4] D. Worsch, F. Vogtle, Top. Curr. Chem. 1987, 140, 22; F. Toda, ibid. 1987, 140, 43; F. Toda in Inclusion Compounds, Vol. 4 (Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol), Oxford University Press, Oxford, 1991, p. 126; F. Toda, Adv. Supramol. Chem. 1992, 2, 141; F. Toda in Comprehensive Supramolecular Chemistry, Vol. 6, Chap. 15 (Eds.: D. D. MacNicol, F. Toda, R. Bishop), p. 465-516, Elsevier, Oxford, 1996. [5] K. Busch, U. M. Groth, W. Kiihnle, U. Schollkopf, Tetrahedron 1992, 48, 5607, and references therein. [6] Of course, this is not true for the diastereoselective reactions of chiral natural products, for example, steroids. [7] E. Fritz-Langhals, Angew. Chem. 1993, 105, 785; Angew. Chem. Int. Ed. Engl. 1993, 32, 753. [8] M. Acs, T. Szili, E. Fogassy, Tetrahedron Lett. 1991,32,7325-8. [9] Comprehensive Supramolecular Chemistry, Vol. 6 (Eds.: D. D. MacNicol, F. Toda, R. Bishop) is devoted to Solid-state Supramolecular Chemistry: Crystal Engineering; Vol. 8 (Eds.: J. E. D. Davies, J. A. Ripmeester) to Physical Methods in Supramolecular Chemistry, Elsevier, Oxford, 1996; early review on clathrates: E. Weber, Top. Cum Chem. 1987, 140, 2. [lo] K. Tanaka, T. Okada, F. Toda, Angew. Chem. 1993, 105, 1266; Angew. Chem. Int. Ed. Engl. 1993, 32, 1147, and references therein. Synthesis of 2 and 3 from tartaric acid: D. Seebach, H.-D. Kalinowski, B. Bastani, G . Crass, H. Daum, H. Dorr, N. P. Duprez, V. Ehsig, W. Langer, C. Niissler, H.-A. Dei, M. Schmitt, Helv. Chim. Acta 1977, 60, 301. [ l l ] F. Toda, Y. Tohi, J. Chem. Soc. Chem. Commun. 1993, 1238; synthesis of 8 and 9: A. K. Beck, B. Bastani, D. A. Plattner, W. Letter, D. Seebach, H. Braunschweiger, P. Gysi, L. La Vecchia, Chimia 1991,45,238,and references therein; synthesis of 10: F. Toda, K. Tanaka, K. Omata, T. Nakamura, T. Oshima, J. Am. Chem. Soc. 1983,105,5151. - Spontaneous inclusion of guests from suspensions of achiral components was only rarely reported: F. Toda, K. Tanaka, G. U. Daumas, M. C. Sachez, Chem. Lett. 1983,1521; H. R. Allcock

in Inclusion Compounds, Vol. 1 (Eds.: J. L. Atwood, J. E. D. Davies, D. D. MacNicol), Oxford University Press, Oxford, 1984, p. 35 1 . [12] The molecule in ref. 1113 (there la, b, c) is shown with the (S,S)-configuration but labeled “(R,R)”. Upon subsequent inquiry the correspondence author replied that “(R,R)-(-)” is correct. The optical rotations in the table apply to this configuration. [ 131 G. Kaupp in Comprehensive Supramolecular Chemistry, Vol. 8, Chap. 9 (Eds.: J. E. D. Davies, J. A. Ripmeester) p. 381-423 + 21 color plates, Elsevier, Oxford, 1996; G. Kaupp, J. Schmeyers, Angew. Chem. 1993, 105, 1656; Angew. Chem. Int. Ed. Engl. 1993, 32, 1587, and references therein. [14] E. Weber, C. Wimmer, A. Llamas-Saiz, C. Foces-Foces, J. Chem. Soc. Chem. Commun. 1992,733. [15] F. Toda, A. Sato, K. Tanaka, T. C. W. Mak, Chem. Lett. 1989, 873. [16] G. Kaupp, J. Schmeyers, M. Haak, T. Marquardt, A. Herrmann, Mol. Cryst. Liq. Cryst. 1996,276, 315. [17] G. Kaupp, J. Schmeyers, F. Toda, H. Takumi, H. Koshima, J. Phys. Org. Chem. 1996, 9, 795. [18] M. Acs, A. Mravik, E. Fogassy, Z. Bocskei, Chirality 1994, 6, 314. [19] F. Toda, H. Takumi, Enantiomer 1996, 1, 29. [20] T. Shinbo, T. Yamaguchi, K. Nishimura, M. Sugiura, J. Chromatogr. 1987, 405, 145, and references therein. [21] H. Takumi, M. Koga, F. Toda, Mol. Cryst. Liq. Cryst. 1996, 277, 79.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Absolute Asymmetric Synthesis by Irradiation of Chiral Crystals Gerd Kaupp and Michael Haak

The formation of enantiopure optically active biomolecules is an important chapter in the history of evolution. The physical phenomena which can generate and augment asymmetry [l] have been known for a long time and a recent report used circularly polarized 190 nm synchrotron radiation in the enantiodifferentiating direct photoisomerization of Ecyclooctene and reached optical purities of 0.12 %. [2] A false claim of achieving absolute asymmetric synthesis in a static magnetic field by Breitmaier et al. [3] was highly acclaimed in Science and even in Chem. Eng. News [4] by several named researchers. That rush occurred despite the clear violation of elementary symmetry principles (an achiral field cannot create chirality) that are taught in first class courses and that were elaborated in great detail also for various field combinations [5] as a response to similarly untenable claims (magnetic and electrical field) in 1975. [6] Even a special seminar chaired by Feringa at Reinhoudt’s Burgenstock Conference 94 did not settle the issue. [7] Thus, the claim was only withdrawn [8] (and its immediate “confirmations” halted) after a fixed-date request to Breitmaier for response to a Correspondence telling the basic principles and the failure to reproduce the published or the “more specified” experiments. [9] Unfortunately this affair caused the cut down

of several then pending research proposals in Germany that were on their ways to apply new mechanistic knowledge for the development of preparatively valuable procedures from hitherto low-yield and low-size solidstate absolute asymmetric syntheses. It is known since 1975 [lo] that crystal chemical reactions can be used in absolute asymmetric synthesis: When achiral molecules crystallize in chiral space groups and the reaction of the crystals leads to chiral products, one speaks justly and correctly of absolute asymmetric synthesis. For this, the use of chiral agents and thus also the “crystal-selecting” human hand must be dispensed with. However, if autoseeding does indeed occur in a system, manipulations by seeding with crystals of a desired chirality must not detract from that term still. Most absolute asymmetric syntheses have been performed photochemically. Some short reviews have appeared. [ 111 Absolute asymmetric [2 + 21 photodimerizations of achiral compounds in crystals have been known since 1982. [12] Achiral compound 1 crystallizes in the chiral space group P21. Crystals of 1 obtained from the melt or from ethanol on irradiation give either (+)- or (-)-2 with enantiomeric excesses (ee values of 0 to 95% and higher). The result varies from crystallization batch to crystallization batch; however, 100 % ee of the (+)- and the

90

A. Asymmetric Synthesis

(-)-enantiomer 2 were also claimed. [ 121 This seems to confirm that the photoreaction occurred stereospecifically (topotactic?; chemical yield and conversion not reported) and that in the batches with low optical yields the preceding crystallization led to mixtures of leftand right-handed chiral crystals. A singlecrystal-to-single-crystal(“topotactic”, though with disintegration of the clear crystals) photolysis was reported for electron-donor-acceptor crystals of 3 and 4 (P21), that provided the adduct 5 with 62 % (40 “C) to 95 % ee (-70 “ C ) from isolated single crystals (size and conversion not reported). [ 131 Unfortunately autoseeding or manual seeding were inefficient here. Most asymmetric [2 + 21-cycloadditions occur with considerably lower optical yields (e. g. < 7 % ee [ 12]), or they are claimed to be dependent on the conversion. [I21 The former result is, however, not surprising, even when only crystals of a single chirality are present, because studies by atomic force microscopy (AFM) [14, 151 have shown that photodimerizations proceed from the surface to the interior of the crystal, during which long-range molecular movements (on the scale of the lattice constants) take place. The degree of the obtainable stereoselectivities clearly depends on the phase rebuilding mechanisms which are necessary for these processes. [14, 151 The fact that relatively often spontaneous asymmetric crystallization of achiral compounds occurs with the formation of either right- or left-handed crystals is the result of autoseeding with the first crystal formed. [12, 161 Thus, in favorable cases all of the supersaturated solution yields only crystals of one chirality (analogously from melts), which, of course, cannot be predetermined. The chirality can only be influenced by manual seeding with selected crystals. Enantioselective syntheses with achiral molecules in host crystals constructed from chiral molecules [17] belong as little to absolute asymmetric syntheses as do intramole-

\

P-

/P

?fN cular photoreactions (di-n-methane rearrangement or p H transfer) following the manual selection of enantiomorphic crystals. [ 18a] However, Scheffer, Trotter et al. [ 18b] developed further their selective di-n-methane rearrangement of diisopropyl dibenzobarrelenedicarboxylate 6 to give the dibenzo-semibullvalene derivative 7 (claim of “quantitative ee” at conversions of a few percent) into an absolute asymmetric synthesis. The AFM-investigation of the diethylester 6 (P212121) yielded very pronounced surface features due to long-range molecular movements (100 nm range) by phase rebuilding. [ 151 These differ on all of its natural crystallographic faces ((011); (110); (010); (001)) and are nicely related to the crystal packing. [ 151 Thus, 6 does not undergo a topotactic reaction and the same is true for the absolute asymmetric synthesis with screwed 8 (P212121) [19] giving equally pronounced AFM surface features, prior to becoming sticky, that again correlate with the crystal structure. [15] We suggested to increase both the chemical and the optical yield by phase-selective parallel irradiation of 6 (R = CzH5) on (110). The AFM features are smaller on that face of 6 (shorter

Absolute Asymmetric Synthesis by Irradiation of Chiral Crystals

movements) than on its other natural faces and the packing is more favorable, which also decreases the disintegration tendency. [20] “Absolute” asymmetric cyclizations (C-H to C=O additions) were performed by Toda et al. [21] Thus, 11 (Ar = Ph) and particularly metu-substituted derivatives of 11 crystallize in chiral space groups and form 12 with nearly quantitative ee at conversions of 74-95 %. As crowded molecules like 11 assume screwed/ helical/spiral conformations [ 11a] it is understandable that the optical yields are much higher at much higher chemical conversions than in the previous cases. Clearly, the common molecular movements and phase rebuilding as well as phase transformation [14, 151 do not immediately (or easily) destroy the helices that were packed during crystallization. Thus, these reactions may gain preparative value after a mechanistic AFM study. While it has not yet been demonstrated that autoseeding is occuring in these cases, the apparently high seeding efficiencies suggest that it would work and that the attribute “absolute” may be appropriate. Toda’s ideas have been taken up and extended by Sakamoto and Scheffer. Thus, meta-substituted 13 give optical active 14 by 4n-cyclization although only at (very) low conversion. [22] Here the rather flat 4nmoiety is part of the chiral helix that induces the chirality. No AFM investigation has been performed in order to use the phase rebuilding

91

mechanisms in these non-topotactic reactions for their major improvement. The same is true for asymmetric cyclobutanol formations. [18] Note, that submicromelting has to be avoided or excluded. [23] The screw/helix/spiral motive [ 11a] has more often been applied. Thus, irradiation of achiral 15, which crystallizes in the chiral space group P212121 yields optically active 16 without external seeding. [24] In seven of ten crystallizations from hexane the (+)-enantiomer 16 predominated, in three cases the (-)-enantiomer 16. The optical yields (10 % ee at O”C, 75 % chemical yield) can be improved by reducing the temperature (40 % ee at -40 “C, 70 % yield; no reaction at -78 “C; however, formation of racemic 16 in solution also at -78°C). This is again a reminder of the necessity of phase rebuilding and finally phase transformation to give the product lattice in solid-state reactions. Both processes are accompanied by extensive molecular movements (on the scale of the crystal lattice constants) in all known cases. [14, 151 Evidently, as a result of these, the chiral conformers 15 have - as in solution - the opportunity for racemization and further conformational alterations. Nevertheless, the

92

A. Asymmetric Synthesis

Figure 1. Top: P212121-unit cell (a = 9.535(2), b = 9.782(2), c = 16.428(3) A) of 15, left- and right-handed arrangement; middle: left-handed (M) and right-handed helix (P)of 15 where M and P are descriptors for helicity (M = minus and P = plus); bottom: (1R,4S)-16 and (1S,4R)-16.

chirality advantage given by the crystal is partly retained. Although, in principle, it is not necessary for the action of an asymmetric crystal environment that the molecules are arranged as uniform chiral conformers, it is essential for the helical compound 15 [24] that the one enantiomorphic type of crystal contains the molecules 15 in the right-handed helix (P),the other in the left-handed helix (M).

As long as the absolute configuration of the products (e. g. 2 or 16) and of the enantiomorphic crystals has not been determined, usually those leading to (+)-products are designated as (+)-crystals and vice versa. Without knowledge of the absolute configurations there is

also no link to the chirality of the crystal and the helicity of the lattice-frozen conformer. To elucidate the principle we arranged the unit cell (P212121) of 15 with the left-handed helix arbitrarily as left handed. Compound (1R,4S)-16 [(-) or (+)I is formed unavoidably from the left-handed helix 15. Correspondingly, (1S,4R)-16 must be formed from the enantiomorphic crystal arranged in the righthanded way. This is represented in Figure 1 on the basis of optimized geometries from semiempirical PM3 calculations. Regardless of whether the adoption of the configurations agrees with reality, it thus becomes clear that the spontaneous asymmetric crystallization determines the chirality of the excess enantio-

Absolute Asymmetric Synthesis by Irradiation of Chiral Crystals

mer 16 exclusively. The energetically most favorable conformer of 15 (Fig. 1; M or P ) is 13 kcal mol-’ less stable than 16 according to our calculations, [25] and thus it should show optimum reactivity. According to the X-ray structure analysis, [24] in the crystal the pitch of the helix is reduced. This is evident from the significantly shortened distances between the reactive centers: the semiempirical calculated distances S-l/C- 6 and C-21 C-5 in 15 are 4.33 and 3.26 A, respectively, (where the numbers refer to the sequence of atoms in the chain starting from S ) ; [25] in contrast, in the crystal they were determined to be 3.59 and 3.11 A, respectively. [24] This compression also contributes to the selectivity of the crystal photolysis. Similarly (+)-crystals or (-)-crystals of 17 giving the (+)- and (-)-products 18 in excess have their opposite helicities. These crystals had to be manually selected even upon seeding, because two different types of racemic crystals coexisted. The two-step reactions consist of 6n-cyclization and hydrogen migration and give 100% yield at 64 % ee. [26]. Further examples using rapidly equilibrating screwed/helical/spiral molecules that happen to crystallize in chiral space groups have been provided by Sakamoto. [ l l c ] These are photochemical formations of chiral oxetanes, 8-lactames, oxazolidine-2,4 -diones, aziridines, oxazolines, phthalides, and 8-thiolactames. [ l l c ] In most cases the ee values had to be improved by going to -78 “C or to “low conversion”. Whereas the latter technique is frequently preferred it is often dubious for the normal selective irradiations (only the educt absorbing the light), if the crystal reacts from its surface down into the bulk, multilayer by multilayer as these become transparent at very advanced local conversions. [14, 151 Thus, no basis exists for assumptions that the optical yield may increase to quantitative values at very low conversions, while the error limits will not allow to secure such claims. Nevertheless, there is the risk that

93

such claims are unduly quoted in the secondary literature. If the products absorb some of the light, extreme milling will be helpful. However, that technique does not help against long-range molecular movements that are connected to the necessary phase rebuilding and that may destroy chiral environments from the beginning. Absolute asymmetric syntheses by irradiation of chiral crystals, now extended to intramolecular reactions, [27] support the assumption of the prebiotic origin of natural chirality. The chemical mechanisms here appear to be so conclusive and efficient that they should in any case be retained besides the complicated physical interpretations. [ l , 21 It must be remembered that of the 230 space groups 65 are chiral and that of these P212121 and P21 belong to the five most frequent in the organic crystals. Regardless of these fundamental findings a wide field has opened up for asymmetric syntheses by approved photochemical reactions. However, in order to make them preparatively useful it will be essential to relate them to the crystal packing by submicroscopic AFM investigations that are easily performed and

94

A. Asymmetric Synthesis

provide an unexpected wealth of kinetic information just by analysis of the far-reaching molecular movements. [14, 151 These are necessary for every non-topotactic reaction to occur. They lead to face-selective surface features regardless of topochemical allowedor forbiddenness and can be related to the crystal packing on the reasonable premise that moving molecules will choose easy ways to do so. [15] Only with that information available many of the known absolute asymmetric syntheses will be enabled to improvement for practical use. Unduly simplifying “topochemica1 considerations” hold only for very rare topotactic reactions. The latter should, of course, also be checked with AFM, if they are not perfect. In short, all use of the experimental phase rebuilding mechanisms will improve the present situation. While these points are certainly more important than the collection of more and more model systems for absolute asymmetric syntheses with selected single crystals it should be pointed out that many polycrystal examples might have remained unrecognized. Far too little attention has been paid to the phenomenon of the spontaneous asymmetric crystallization to date, with the result that the step to the polarimeter or the use of chiral NMR shift reagents after the photolysis has mostly not been taken; otherwise without doubt many a supposed racemate would have turned out to be optically active.

References [l] Origins of Optical Activity in Nature (Ed.: D. C. Walker), Elsevier, New York, 1979; resolution of racemates by crystallization succeeds by Tamura’s “Preferential Enrichment” in the mother liquor: T. Ushio, R. Tamura, H. Takahashi, N. Azuma, K. Yamamoto, Angew. Chem. 1996,108, 2544-2546; Angew. Chem. Int. Ed. Engl. 1996, 35, 2372-2374; R. Tamura, T. Uihio, H. Takahashi, K. Nakamura,

N. Azuma, F. Toda, K. Endo, Chirality, 1997, 9, 220-224; H. Takahashi, R. Tamura, T. Ushio, T. Nakai, K. Hirotsu, F. Toda, Mol. Cryst. Liq. Cryst., in the press and by Collet’s “Entrainment” (selective crystallization): A. Collet, M.-J. Brienne, J. Jacques, Chem. Rev. 1980, 80, 215-230; A. Collet in Comprehensive Supramolecular Chemistry, Vol. 10 (Ed. D. N. Reinhoudt), Elsevier, Oxford, 1996, Chapter 5. Both techniques require particular phase diagram conditions. [2] Y. Inoue, H. Tsuneishi, T. Hakushi, K. Yagi, K. Awazu, H. Onuki, J. Chem. SOC. Chem. Commun. 1996,23, 2627-2628. [3] G. Zadel, C. Eisenbraun, G.-J. Wolff, E. Breitmaier, Angew. Chem. 1994, 106, 460-463; Angew. Chem. Int. Ed. Engl. 1994, 33, 454456. [4] D. Bradley, Science, 1994, 264, 908; Anonymous, Chem. Eng. News 1994, 72(9), 36. [5] C. A. Mead, A. Moscowitz, H. Wynberg, F. Meuwese, Tetrahedron Lett. 1977, 12, 10631064; R. C. Dougherty, J. Am. Chem. Soc. 1980, 102, 380-381; L. D. Barron, J. Am. Chem. SOC. 1986, 108, 5539-5542; M. W. Evans, Chem. Phys. Lett. 1988,152,33-38. [6] P. Gerike, Naturwissenschaften, 1975, 62, 38-39. [7] W. Leitner, Nachl: Chem. Tech. Lab. 1994, 42, 716-717; B. L. Feringa, R. M. Kellogg, R. Hulst, C. Zondervan, W. H. Kruizinga, Angew. Chem. 1994, 106, 1526-1527; Angew. Chem. Int. Ed. Engl. 1994, 33, 14581459. [8] E. Breitmaier, Angew. Chem. 1994,106, 1529; Angew. Chem. Int. Ed. Engl. 1994, 33, 1461 (June 21, 1994). [9] G. Kaupp, T. Marquardt, Angew. Chem. 1994, 106, 1527-1529; Angew. Chem. Int. Ed. Engl. 1994,33, 1459-1461 (June 12, 1994). [lo] B. S. Green, M. Lahav, G. M. J. Schmidt, Mol. Cryst. Liq. Cryst. 1975, 29, 187-200. Bromination of manually selected enantiomorphic single crystals of 4,4’-dimethylchalcone to give optically active products (up to 6 % ee: K. Penzien, G. M. J. Schmidt, Angew. Chem. 1969, 81, 628; Angew. Chem. Int. Ed. Engl. 1969, 8, 608) is incorrectly termed “absolute” asymmetric synthesis; similarly, no autoseeding was described in the bromination of diben-

Absolute Asymmetric Synthesis by Irradiation of Chiral Crystals zobarrelene with reported optical yields of 3 or 8 % using ground single crystals of 20-100 mg: M. G. Garibay, J. R. Scheffer, J. Trotter, F. Wireko, Tetr: Letters 1988, 29, 1485-1488. [ l l ] a) G. Kaupp, M. Haak, Angew. Chem. 1993, 105, 727-728; Angew. Chem. Znt. Ed. Engl. 1993,32,694-695; b) L. Caswell, M. A. Garcia-Garibay, J. R. Scheffer, J. Trotter, J. Chem. Ed. 1993, 70, 785-787; c) M. Sakamoto, Chem. Eur. J. 1997,3, 684-689. [ 121 L. Addadi, J. van Mil, M. Lahav, J. Am. Chem. SOC. 1982, 104, 3422-3429; further example: M. Hasegawa, Y. Hashimoto, Mol. Cryst. Liq. Cryst. 1992, 219, 1-15; Review: V. Ramamurthy, K. Venkatesan, Chem. Rev. 1987, 87, 433-481. [13] T. Suzuki, T. Fukushima, Y. Yamashita, T. Miyashi, J. Am. Chem. SOC. 1994, 116, 2793-2803. [14] G. Kaupp, Angew. Chem. 1992,104,606-609 and 609-612; Angew. Chem. Int. Ed. Engl. 1992,31,592-595 and 595-598. [15] G. Kaupp, Adv. Photochem. 1995, 19, 119177; G. Kaupp in Comprehensive Supramolecular Chemistry (Ed.: J. E. D. Davies) Vol. 8, 381-423 + 21 color plates, Elsevier, Oxford, 1996, Chemie in unserer Zeit, 1977, 31, 129139. [16] J. M. McBride, R. L. Carter, Angew. Chem. 1991, 103, 298-300; Angew. Chem. Int. Ed. Engl. 1991,30,293-295. [17] T. Fujiwara, N. Nauba, K. Hamada, F. Toda, K. Tanaka, J. Org. Chem. 1990, 55, 45324537. [18] a) S. V. Evans, M. Garcia-Garibay, N. Omkaran, J. R. Scheffer, J. Trotter, F. Wireko, J. Am, Chem. SOC. 1986, 108, 5648-5650; b) J. Chen, J. R. Scheffer, J. Trotter, Tetrahedron 1992, 48, 3251-3274; there also absolute configuration of starting conformer and of product; A. D. Gudmundsdottir, G. Rattray, J. R. Scheffer, J. Yang, Tetrahedron Lett. 1993, 34, 35; c) T. Y. Fu, Z . Liu, J. R. Scheffer, J. Trotter, J. Am. Chem. SOC. 1993, 115, 12202-1 2203. [19] A. L. Roughton, M. Muneer, M. Demuth, I. Klopp, C. Krtiger, J. Am. Chem. SOC. 1993, 115,2085-2087. [20] G. Kaupp, M. Plagmann, unpublished.

95

[21] F. Toda, M. Yagi, S.-I. Soda, J. Chem. SOC. Chem. Commun. 1987,1413-1414; A. Sekine, K. Hori, Y. Ohashi, M. Yagi, F. Toda, J. Am. Chem. SOC. 111, 1989, 697-699; F. Toda, H. Miyamoto, J. Chem. SOC. Perkin. Trans. I 1993, 1129-1132; D. Hashizume, H. Kogo, A. Sekine, Y. Ohashi, H. Miyamoto, F. Toda, J. Chem. SOC. Perkin. Trans. 2 1996, 61-66; there also absolute configuration of starting conformer and of product; F. Toda in Comprehensive Supramolecular Chemistry (Ed.: D. D. MacNicol, F. Toda, R. Bishop) Vol. 6, 4655 16, Elsevier, Oxford, 1996. [22] L.-C. Wu, C. J. Cheer, G. Olovsson, J. R. Scheffer, J. Trotter, S.-L. Wang, F.-L. Liao, Tetrahedron Lett., 1997, 38, 3135-3138. [23] G. Kaupp, Mol. Cryst. Liq. Cryst. 1992, 211, 1-15; 1994, 242, 153-169; 1994, 252, 259268; J. Vac. Sci. Technol. B 1994, 12, 19521956. [24] M. Sakamoto, N. Hokari, M. Takahashi, T. Fujita, S. Watanabe, I. Iida, T. Nishio, J. Am. Chem. SOC. 1993,115, 818-820. [25] PM3 according to J. J. P. Stewart (J. Comput. Chem. 1989, 10, 209) with Spartan Version 2.0 from Wavefunction, Inc., Irvine, CA, USA on an IBM RS6000 H32 Workstation calculated with complete geometry optimization. The best boat conformation of 15 (rotation about the C-4/C-5 bond) is about 0.6 kcal mol-' less stable than the helix. Representation of the molecules with Schakal 92/AIX-UNIX version from E. Keller, Universitat Freiburg, on an IBM RS6000. [26] F. Toda, K. Tanaka, Supramol. Chem. 1994,3, 87-88; F. Toda, K. Tanaka, Z. Stein, I. Goldberg, Acta Cryst. 1995, B S I , 856; ibid. 1995, C51, 2722. [27] Absolute asymmetric photodecarboxylation in a mixed crystal: H. Koshima, K. Ding, Y. Chisaka, T. Matsuura, J. Am. Chem. SOC. 1996, 11 8, 12059-12065.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

B. Organometallic Reagents Cyclopentadienyl Ruthenium Complexes: Valuable Assistents in the Construction of Carbon-Carbon Bonds Holger Butenschon Within the last few years a number of papers appeared in an area of increasing importance for organic chemistry: Organoruthenium complexes are now frequently used to form carbon-carbon bonds in a number of ways. Reagents used in this field include cyclopentadienyl complexes like [CpRu(COD)Cl] or [CpRu(PPh)zCl] as well as tetravalent cyclopentadienylruthenium derivatives and others. 111 With respect to cyclopentadienyl metal complexes ligands other than the cyclopentadienyl (Cp) ligand are frequently regarded as less important and are considered to leave the molecule before the critical reaction step at the cyclopentadienylmetal nucleus. It is remarkable that Trost et al. found that reactions involving the 1,5-cyclooctadiene (COD) ligand for the construction of a carbon skeleton are indeed possible. 121 Trost et al. discovered that COD can formally function as a bis-homodiene in metalcatalyzed [4+2]cycloadditions. A 0.1 M solution of the alkyne 1 reacts with 1.1 equivalents of COD in the presence of 5 mol% of chloro(v4-cyclooctadiene)(y5-cyclopentadienyl)ruthenium(I1) [CpRu(COD)Cl] [3] (2) in boiling methanol to give derivatives 3 of tricycl0[4.2.2.O~.~]dec-7-ene(Scheme 1). Yields of between 78 and 100% are achieved in seven out of eight examples. Electron-defi-

Scheme 1. a) 5 % 2, MeOH; R' = Me, Et, CHzOSi(iPr)3, p-CH2C6H40CH3, H; R2 = CHZOH, CHzOSi(iPr)s, CHzCHzOH, pC H Z C ~ H ~ O C HCOzMe, ~, CH2CH2CH2C02Me; 78-100 %.

cient alkynes react particularly slowly, and no reaction takes place with dimethyl butynedioate. Steric hindrance slows down the reaction; 4 is obtained only in 51 % yield after 80 h at reflux. This can, however, be used for the differentiation of triple bonds in alkynes with several triple bonds as shown by the selective formation of 5 in 63 % (Scheme 2). The catalytic cycle proposed by the authors starts from a cationic cyclopentadienylruthenium complex, bearing one COD ligand and one solvent molecule. The latter is displaced by the alkyne, which subsequently reacts

Cyclopentadienyl Ruthenium Complexes: Valuable Assistents in the Construction . . . OH

4

2

/&R

9

10

11

12

5

R /J

Scheme 2.

with a double bond of the COD ligand to give a metallacyclopentene. An intramolecular carbometallation of the remaining double bond of the eight-membered ring with successive reductive elimination leads to products 3; renewed complexation of a COD molecule regenerates the catalytically active species. The authors point out that the reaction is also catalyzed by other coordinatively highly unsaturated ruthenium complexes and finally make the important remark that the ease of the reactions observed by them suggests that a range of other ruthenium-catalyzed reactions may well be possible. They assume that the coordination properties of COD cannot only be derived from the entropic effect of the spatial arrangement of the two double bonds in COD. Possibly electronic effects similar to those in norbornadiene exist in an attenuated form in COD. This is in agreement with the fact that the dienes 6-8 do not undergo the reaction found with COD (Scheme 3). [4]

6

' +

R-

97

7

Scheme 4. a) 5 % 2, dimethylformamide (DMF)/ Hz0 311, 100°C, 2 h; R = Bu, CHzCHzOH, COMe, (CHz)3COzMe; R' = Pr, CHzOTBDMS, COZEt; 60-90 %.

The yields lie between 60 and 90 %, and in most cases the branched isomer 11 is formed preferentially (11 :12 up to 6 : 1). Substituents at the propargyl position of 10 reduce the regioselectivity, and the presence of propargylic oxygen substituents even leads to an inversion of the selectivity in favor of the linear coupling products. The chemoselectivity is impressively underlined by the reaction of 13 with the a,p-unsaturated ester 14 to give exclusively 15 in 70 % yield (Scheme 5 ) . Also in these reaction the authors assume that a cationic cyclopentadienylruthenium complex is the catalytically active species, the only difference here being that in addition to the chloro ligand also the COD ligand is decomplexed and all three free coordination sites are filled by readily displaceable solvent molecules. After the complexation of the alkene component, the latter is transformed

0

Scheme 3.

The ruthenium catalyst 2 was recently used by Trost et al. also for coupling reactions of alkenes 9 with alkynes 10. [ S ] These reactions lead to the branched coupling products 11 as well as the lineaer isomers 12 (Scheme 4).

14

13

&H*h+(O . E' EtO

\

0 15 Scheme 5. a) 5 % 2, DMFMpO 3 : 1, 100°C, 2 h, 70 %.

98

B. Organometallic Reagents

into an allyl ligand and the hydrogen atom released is bound to the metal as a hydrido ligand. After coordination, the alkyne is either intramolecularly hydrometalated or carbome19 20 22 talated starting from the allyl ligand. From both intermediates the reaction product, still coordinated to ruthenium, can be easily fori+R med, which is then released with the regenera0 tion of the above-mentioned catalytically 23 active species. R + 0 Catalyst 2 can also be used in a butenolide synthesis on the basis of a ruthenium cataly21 zed Alder ene type reaction. [6-91 In the course of a reaction sequence directed to the Scheme 7. a) 6 % [(PPh3)2CpRuCl], 10 % NH4PF6, synthesis of acetogenins, Trost et al. coupled IOO'C, 10 h, 44-74%; b) 10% 2, 10-20% I, alkene 16 with propargyl alcohol 17 in the NH4PF6, loooc, 1-2 h; R = C I O H ~ C6H13, R' = Me, iPr, presence of 2 to give butentolide 18 in up to CH(OH)CsHII, C(C~H~)(OH)CSHII; cyclohexyl, CllH23; 51-85 %. 82 % yield (Scheme 6). Several years ago Trost et al. reported on the coupling of terminal alkynes 19 with of alkynes 19 and allyl alcohols 20 in 51allyl alcohols 20 in the presence of ammonium 85 % yields to give y,d-unsaturated ketones hexafluorophosphate. [ 101 This reaction is 22 and 23. 18,131 From the fact that in the reaction catalyzed catalyzed by [(PPh3)2CpRuCl] and leads to the formation of B,y-unsaturated ketones 21 by 2 also internal alkynes 24 can react to (Scheme 7). A mechanistic study reveals that give ketones 25 (Scheme 8), the authors convinylidene complexes are formed as interme- clude that in this case no vinylidene complex diates from the terminal alkynes. 1111 Also acts as an intermediate. Apparently, its formaallyl alcohols can be isomerized with tion is favored by the presence of phosphane [(PPh&CpRuCl] directly to give saturated ligands, and in their absence other reaction ketones. [ 121 Interestingly, complex 2, which paths are followed. The regioselectivity of is different from [(PPh&CpRuCl] only in the reaction as well as its yield can be increathat instead of the two phosphane ligands a sed if a mixture of water and DMF is used as COD ligand is present, catalyzes the coupling solvent. The reaction functions also with alkynes whose triple bond is conjugated to an ester group. The chemoselectivity of the reaction -+ H 5 c 2 0 2 c ~ 0 H was demonstrated by the coupling of a steroid side chain with an allyl alcohol; one a,p-unsaH turated carbonyl functionality present in the 16 17 steroid part remained unaltered. ""

4

R '

R

24 18

Scheme 6. a) 1.4 % 2, CH30H, reflux, 78-82 %.

20 (R' = CHz)

25

Scheme 8. a) 10% 2, 10-20% NH4PF6, 100°C, 1-2 h, R = Bu (45 %), Ph (50 %).

Cyclopentadienyl Ruthenium Complexes: Valuable Assistents in the Construction , . .

The Meyer-Schuster redox isomerization of propargyl alcohols to give a$-unsaturated ketones or aldehydes is a valuable reaction because these compounds can be used in a variety of reactions and because many propargylic alcohols can readily be obtained by addition of acetylide anions to carbonyl compounds. [14] With ruthenium catalyst 26 in the presence of some indium trichloride the reaction becomes possible under mild conditions, allowing for example the formation of the sensitive dienal 28 from 27 (Scheme 9), which is easily prepared by a palladium catalyzed coupling reaction of 1-bromo-2-methylpropene and propargyl alcohol. [15] The authors explain the role of the indium trichloride by suggesting a bimetallic complex with the Lewis acid complexed to the carbonyl oxygen atom. The significance of ruthenium-catalyzed reactions is also emphasized by a publication by Mitsudo et al., [16] who achieved [2+2]cycloadditions of norbornene 29 and norbornadiene 32 with a range of alkynes 30. These reactions are catalyzed by chloro(y4cyclooctadiene)(y5 -pentamethylcyclopentadienyl)ruthenium(II) [Cp*Ru(COD)Cl] (35) and give 31 and 33, respectively, in good yields (Scheme 10). Ruthenium-catalyzed [2+2]cycloadditions of norbornene with butynedioates have been

27

28

Scheme 9. a) 5 mol% 26, 0.25 M solution of 21 in THF, 5 mol% InC13, 5 mol% Et3NHPF6, 1.5 h, 25 "C + reflux, 83 % of 28.

29

32

30

99

31

33

34 (R' = H)

Scheme 10. a) 5 % [Cp*Ru(COD)Cl] 35,80"C, 1520 h, NEt3, R, R' = Me, Et, Ph, C ~ H I ICH(OEt)2, , C02Me, COzEt, CsH17, C I O H ~23-87 ~ , % 33, 1226 % 34 (R' = H).

known for a long time. [17,18] However, what is new is that the reaction, which was successful with other ruthenium catalysts only with butynedioates, now functions with a whole series of different alkynes, and that not only norbornene 29, but also norbornadiene 32 can be used. In this way in the course of the reaction [Cp*RuCl(nbd)] (nbd = norbornadiene) is formed which is more stable than 2. Thus, slightly higher reaction temperatures are required for reactions with norbornadiene. In addition to the adducts 33 to norbornadiene, rnetu-disubstituted arenes 34 are also formed. The use of phenylethyne which is deuterated at the terminal alkyne position reveals that the additional CZ block present in 34 stems from norbornadiene. In accordance with a retro-Diels-Alder reaction, di(cyc1opentadiene) was detected in the reaction mixtures. As a possible mechanism for the reaction the authors propose that 35 releases the COD ligand with the formation of the catalytically active species and the two free coordination

100

B. Organometallic Reagents

t a) or b) sites are then filled by norbornadiene and the Ph-H alkyne. From this a metallacyclopentene is 20 (R' = H) 19 (R = Ph) formed which either reacts by reductive elimination to give the [2+2]cycloadduct or by insertion of a further alkyne molecule forms a metallacycloheptadiene. The latter then releases cyclopentadiene in a retro-Diels-Aler G reaction and is thus transformed into the 36 37 metallacycloheptatriene, the direct precursor of 34. Interestingly, the only difference between Scheme 11. a) 2.5 mmol of phenylethyne, 5 mL of allyl alcohol, 0.125 mmol of [RuC12(q3the catalysts used by Trost et al. (2) and C H ~ C M ~ C H ~ ) ( C S H22~ )h, I , 90°C; b) as for a) Mitudo (35) is that an unsubstituted cyclo- except catalyst [RuC12(q3-CH*CMeCH2)(CsMe~)1. pentadienyl ligand is present is 2 and a pentamethylcyclopentadienyl ligand in 35. The electronic and steric differences of the two 60% and 96%. The proposed mechanism ligands are well known; in light of the papers includes a delicate interchange between the presented here the question arises as to how cyclopentadienyl ruthenium system and a the spectrum of ruthenium-catalyzed reactions corresponding cyclopentadienone complexes. may be extended by the use of a new ligand ~231 recently described by Gassman et al.; [19] the title of the work reads as follows: "1,2,3,4 -Tetramethyl-5 -(trifluoromethyl)cyclopentadienide: A Unique Ligand with the Steric Properties of Pentamethylcyclopentadienide and the Electronic Properties of Cyclopentadienide". The related pentafluorocyclopentadienyl ligand has also found its 38 way into ruthenium chemistry, and pentafluororuthenocene has recently been reported. [20] Scheme 12. More recently, Dixneuf et al. reported the Another interesting coupling reaction was use of Cp*Ru(IV) as catalysts for a coupling of alkynes and allyl alcohols (Scheme 11). Pheny- observed by Werner et al., [24] who coupled lethyne 19 (R = Ph) and allyl alcohol20 (R' = H) the carbene ligand in 39 with ethenylmagnewere transformed to isomeric acetals 36 and sium bromide to obtain allyl complexes 40 37 in 20 % and 60 % yield, respectively, [21] and 41 in up to 65 % yield (Scheme 13). Subin the presence of [RuC1z(r3-CH2CMeCH2)- sequent decomplexation gave the correspond(C5Hs] or [RuC12(q3- C H ~ C M ~ C H Z ) ( C ~ Ming ~ S ] trisubstituted alkenes 42, which were [22]. Remerkably, not only the yield was dif- obtained in quantitative yields. Ruthenium and iron belong to the same ferent with the two similar catalysts, but also the regioselectivity : With the Cp complex the group in the periodic system, and much of 36 :37 ratio was 67 :33, with the Cp* complex their organometallic chemistry is similar. As a special class of ferrocenylphosphines has it changed to 33 : 67. Backvall et al. used ruthenium complex 38 become popular in enantioselective catalysis (Scheme 12) to catalyze an Oppenauer oxida- [25], it was quite obvious to test the corretion of secondary alcohols in yields between sponding ruthenium complexes for catalytic

k

Cyclopentadienyl Ruthenium Complexes: Valuable Assistents in the Construction . . .

39

101

42

41

Scheme 13. a) 0.23 mmol of 39, 5 mL C6H6, 0.47 mmol of HZC=CHMgBr (0.75 M sol. in THF), 45 min, room temp., 63 %, 40 :41 = 1.9 : 1; b) CH3COOH, quant. yield.

activity. Hayashi et al. reported in 1994 that the ring closure of 44 to 45 indeed take place with a high degree of stereoselection with catalyst ligand 43 (Scheme 14). [26] That the Cp*Ru fragment can also be used to break down carbon frameworks was shown by Chaudret et al., [27] who, using an example from steroid chemistry, achieved the elimination of methane from a methyl substituted cyclohexadiene with consequent aromatization.

43

44

45

Scheme 14. a) 0.006 mmol of Pdz(dba)3. CHC13, 0.013 mmol of 43, 0.9 mmol of 44, 0.6 mmol of methyl acetylacetate in 9.0 mL of THF, -20°C under Nz, 48 h, 83 %, ee 83 %.

References [1]B. M. Trost, Chem. Be,: 1996, 129, 13131322. [2] B. M. Trost, K. Imi,A. F. Indolese, J. Am. Chem. SOC.1993,115, 8831-8832. [3] M. 0. Albers, D. J. Robinson, A. Shaver, E. Singleton, Organometallics 1986, 5, 2199-2205. [4] B. M. Trost, personal communication. [5] B. M. Trost, A. Indolese, J. Am. Chem. SOC. 1993,115,4361-4362. [6] B. M. Trost, T. L. Calkins, Tetrahedron Lett. 1995,36,6021-6024. [7] B. M . Trost, T. J. J. Miiller, J. Martinez, J. Am. Chem. SOC.1995,117, 1888-1899. [8] B. M. Trost, A. F. Indolese, T. J. J. Muller, B. Treptow, J. Am. Chem. SOC. 1995, 117, 615-623. [9] B. M. Trost, T. J. J . Muller, J. Am. Chem. SOC. 1994, 116,4985-4986. [lo] B. M. Trost, G. Dyker, R. J . Kulawiec, J. Am. Chem. SOC.1990,112,7809-7811. [ 111 B. M. Trost, R. J . Kulawiec, J. Am. Chem. SOC. 1992, 114,5579-5584. 1121 B. M. Trost, R. J . Kulawiec, J. Am. Chem. SOC. 1993, 115,2027-2036. [13] B. M. Trost, J. A. Martinez, R. J. Kulawiec, A. F. Indolese, J. Am. Chem. SOC. 1993, 115, 10402-10403. [ 141 S. Swaminathan, K. V. Narayanan, Chem. Rev. 1971, 71,429-438.

102

B. Organometallic Reagents

[15] B. M. Trost, R. C. Livingston, J. Am. Chem. SOC. 1995,II7, 9586-9587. [16] T.-A. Mitsudo, H. N a m e , T. Kondo, Y. Ozaki, Y. Watanabe, Angew. Chem. 1994, 106, 595597; Angew. Chem. Int. Ed. Engl. 1994, 33, 580-581. [17] T.-A. Mitsudo, K. Kokuryo, T. Shinsugi, Y. Nakagawa, Y. Watanabe, Y. Takegami, J. Org. Chem. 1979,44,4492-4496. [ 181 T.-A. Mitsudo, Y. Hori, Y. Watanabe, J. Organomet. Chem. 1987,334, 157-167. [19] P. G. Gassman, J. W. Mickelson, J. R. Sowa Jr., J. Am. Chem. Soc. 1992,114,6942-6944. [20] R. P. Hughes, X. Zheng, R. L. Ostrander, A. L. Rheingold, Organometallics 1994, 13, 15671568. [21] S. DCrien, P. H. Dixneuf, J. Chem. Soc., Chem. Commun. 1994, 2551-2552.

[22] H. Nagashima, K. Mukai, Y. Shiota, K. Yamaguchi, K.-i. Ara, T. Fukahori, H. Suzuki, M. Akita, Y. Moro-oka, K. Itoh, Organometallics 1990, 9,799-807. [23] M. L. S. Almeida, M. Beller, G.-Z. Wang, J.-E. Backvall, Chem. Eul: J. 1996, 2, 1533-1536. [24] T. Braun, 0. Gevert, H. Werner, J. Am. Chem. Soc. 1995,117,7291-7292. [25] T. Hayashi in Ferrocenes: Homogeneous Catalysis. Organic Synthesis, Materials Science; A. Togni, T. Hayashi, Ed.; VCH, Weinheim, 1995; pp 105-142. [26] T. Hayashi, A. Ohno, S.-j. Lu, Y. Matsumoto, E. Fukuyo, K. Yanagi, J. Am. Chem. Soc. 1994,116,4221-4226. [27] M. A. Halcrow, F. Urbanos, B. Chaudret, Organometallics 1993, 12, 955-957.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Transition Metal Catalyzed Synthesis of Seven-Membered Carbocyclic Rings Gerald Dyker

The Diels Alder reaction is the most important method for the preparation of functionalized cyclohexenes and is characterized by an almost inexhaustible range of possible variations: numerous functional groups and even heteroatoms can be tolerated and both diastereoselective and enantioselective syntheses are possible. Thus, there has been no shortage of attempts to develop homologous variants and to extend the range of application to the synthesis of seven-membered carbocyclic rings. In specific cases it has been possible to employ vinylcyclopropanes as “homodienes” and to carry out a cycloaddition with appropriate alkenes. [l] However, the mild reaction conditions of the example shown in Scheme 1 are an exception. This special case apparently profits from the fixed, favorable geometry of the heterocyclic-bridged vinylcyclopropane 1 and from the high reactivity of the dienophile 2. The mechanism of this type of reaction was clarified by Klarner et al. performing kinetic measurements at high pressure. [ 1b, c]

For a few combinations of less reactive dienes and dienophiles, transition metal catalyzed variants of the Diels Alder reaction have been developed. An example is the cycloaddition of an unpolar diene and an unactivated alkyne; however, except when the reaction is catalyzed with iron, nickel, cobalt, or rhodium(1) complexes, the temperature required often causes competing decomposition, even for the intramolecular version. [2] Wilkinson’s catalyst [3] - tris(tripheny1phosphane)rhodium(1) chloride - frequently used for hydrogenations and for decarbonylations, permits the cyclization of 4 to the annelated cyclohexadiene 5 in excellent yield in only 15 minutes at 55 “C in trifluoroethanol as solvent (Scheme 2). [2c] Recently, Wender, Takahashi, and Witulski [4] found that this rhodium complex also catalyzes the homologous Diels-Alder reaction [5] of vinylcyclopropanes with alkynes, leading to formation of cyclohepta-1,4 -dienes. By this method, hitherto used exclusively as an

4 1

2

3

Scheme I . a) CHzC12, 20 “C,quantitative yield.

5

Scheme 2. a) 10 mol% [(PPh&RhCl], trifluoroethanol, 55 “C, 15 min, yield 96 %.

104

B. Organometallic Reagents

7

6

Scheme 3. R = H, Me, Ph, trimethylsilyl (TMS), C02Me: a) 10 mol% [(PPh3)3RhCl], toluene, llO°C, 1.5 h, yield 50-88 %.

8

9

10

Scheme 4. Metallacycles as possible reactive intermediates of the reaction in Scheme 3. L = ligand.

12

11

Scheme 5. a) 10 mol% [(PPh3)3RhC1], 60 "C, yield 84 %.

ao

AcO&TMS

a)

+

13

14

15

% 0

16

17

18

Scheme 6. a) 5 mol% Pd(OAc)2, P(OiPr)3, benzene 80 "C, yield 70 %; TMS: b) NaI, Cu, CH3CN, 4 h, 50 "C, yield 4 0 4 8 %.

intramolecular process, annelated and functionalized seven-membered carbocycles such as 7 have been synthesized simply and efficiently (Scheme 3). Acceleration of the reaction has been achieved by the use of the polar solvent trifluoroethanol and also by the addition of silver triflat; thus, it can be assumed that cationic rhodium complexes act as the active catalyst. Eight-membered metallacycles such as 9 are probably key intermediates. [6] Cyclopropylsubstituted five-membered metallacycles 8 and homoallyl complexes 10 can be considered as precursors of 9 [7] (Scheme 4). Rhodium catalysis is also of crucial importance in the conceptually new type of synthesis of cyclohepta-2,4-dien-l-ones(e. g. 12) by Huffman and Liebeskind. [8] The rearrangement of 4-cyclopropyl-2 -cyclobutenones such as 11, which are accessible in a few steps from squaric acid, [9] is similarly achieved with Wilkinson's catalyst (Scheme 5). This concept is particularly flexible in that the corresponding reaction of 4-cyclobutyl-2-cyclobutenones opens a route to eightmembered carbocyclic rings. The new rhodium-catalyzed processes appear as competition to known and thoroughly tested methods for the synthesis of seven-membered carbocyclic rings, such as [4+3] cycloadditions catalyzed or induced by transition metals (Scheme 6). According to Trost et al., [lo] trimethylenemethane palladium complexes, which undergo cycloaddition with suitable dienes, can be prepared from the allylsilane 14 under catalytic conditions. Thus, the bridged cycloheptene 15, containing an exocyclic methylene group, is obtained from a-pyrone 13. Binger et al. [ lOc] found that methylenecyclopropane can be an advantageous reagent for the palladium-catalyzed synthesis of seven-membered rings from dienes. Cycloheptanones such as 18 can be prepared according to Hoffmann [ 1la-c] with a,a'-dibromoketones as coupling component. [ 11d, el The preparative potential

Transition Metal Catalyzed Synthesis of Seven-Membered Carbocyclic Rings

of such compounds for the diastereoselective synthesis of highly functionalized cycloheptanes and also of open-chain compounds has been demonstrated impressively quite recently. [12] It will be interesting to see whether the new rhodium-catalyzed processes also offer opportunities for enantioselective induction. [13,14]

105

P. P. Patel, J. J. Matasi, S. U. Turner, J. J. Harp, M. D. Reid, J. Am. Chem. Soc. 1991, 113,7508-7509. [7] Topical examples of ring opening of cyclopropyl-substituted transition metal complexes with formation of homoallyl metal compounds: a) R. I. Khusnutdinov, U. M. Dzhemilev, J. Organomet. Chem. 1994, 471, 1-18; b) I. Ryu, K. Ikura, Y. Tamura, J. Maenaka, A. Ogawa, N. Sonoda, Synlett 1994, 941-942; c) S. Braise, A. de Meijere, Angew. Chem. 1995, 107, 2741-2743; Angew. Chem. References Int. Ed. Engl. 1995,34, 2545-2547. [8] M. A. Huffman, L. S . Liebeskind, J, Am. [ l ] a) R. Herges, I. Ugi, Angew. Chem. 1985, 97, Chem. Soc. 1993,115,4895-4896. 596-597; Angew. Chem. Int. Ed. Engl. 1985, [9] L. S. Liebeskind, R. W. Fengl, K. R. Wirtz, 24, 594-596, and references therein; b) F.-G. T. T. Shawe, J. Org. Chem. 1988, 53, 2482Kliirner, D. Schroer, Chem. Ber: 1985, 122, 2488. 179-185; c) T. Golz, S. Hammes, F.-G. [lo] a) B. M. Trost, S. Schneider, Angew. Chem. Klamer, Chem. Ber: 1993,126,485-498. 1989, 101, 215-217; ; Angew. Chem. Int. Ed. [2] a) P. A. Wender, T. E. Jenkins, S . Suzuki, Engl. 1989, 28, 213-215; b) B. M. Trost, J. Am. Chem. Soc. 1995, 117, 1843-1844; J. Am. Chem. Soc. 1987, D. T. MacPherson, b) L. McKinstry, T. Livinghouse, Tetrahedron 109, 3483-3484; c) P. Binger, H. M. Buchi, 1994, 50, 6145-6154; c) R. S. Jolly, G. Top. Cum Chem. 1987,135,77-151. Luedtke, D. Sheehan, T. Livinghouse, J. Am. Chem. SOC. 1990, 112, 4965-4966; d) P. A. [ l l ] a) H. M. R. Hoffmann, Angew. Chem. 1984, 96, 29-48; Angew. Chem. Int. Ed. Engl. Wender, T. Jenkins, ibid. 1989, 111, 64321984, 23, 1-32; b) ibid. 1973, 85, 877-894 6434; e) I. Matsuda, M. Shibata, S. Sato. Y. and 1973, 12, 819-835; c) M. R. Ashcroft, Izumi, Tetrahedron Lett. 1987, 28, 3361H. M. R. Hoffmann, Org. Synth. 1978, 58, 3362; f ) K. Mach, H. Antropiusova, L. Petru17-23; d) R. Noyori, Acc. Chem. Res. 1979, sova, F. Turecek, V. Hanus, P. Sedmera, 12, 61-66; e) J. Mann, Tetrahedron 1986, 42, J. Schraml, J. Organomet. Chem. 1985, 289, 461 1-4659. 331-339; g) H. tom Dieck, R. Diercks, a) M. Lautens, S. Kumanovic, J. Am. Chem. [12] Angew. Chem. 1983, 95, 801-802; Angew. Soc. 1995, 117, 1954-1964; b) M. Lautens, Chem. Int. Ed. Engl. 1983, 22, 778-779; Pure Appl. Chem. 1992,64, 1873-1 882. h) J. P. Genet, J. Ficini, Tetrahedron Lett. [13] For other recent contributions to the synthesis 1979, 1499-1502; i) A. Carbonaro, A. Greco, of seven-membered carbocyclic rings, see: G. Dall’Asra, J. Org. Chem. 1968, 33, 3948a) H. M. L. Davies, Tetrahedron 1993, 49, 3950. 5203-5223; b) A. Padwa, S. F Hornbuckle, [3] L. S. Hegedus, Organische Synthese mit UberG. E. Fryxell, Z. J. Zhang, J. Org. Chem. gangsmetallen VCH, Weinheim, 1995. 1992, 57, 5747-5757; c) P. A. Wender, H. Y. [4] P. A. Wender, H. Takahashi, B. Witulski, J. Am. Lee, R. S. Wilhelm, P. D. Williams, J. Am. Chem. SOC. 1995, 117,4720-4721. Chem. Soc. 1989, 111, 8954-8957; d) K. E. [ 5 ] The cycloaddition of norbornadiene with alSchwiebert, J. M. Stryker, ibid. 1995, 117, kynes to give deltacyclenes has also been 82758276. described as a homo-Diels-Alder reaction: M. Lautens, J. C. Lautens, A. C. Smith, [14] For a detailed review on transition metal mediated cycloaddition reactions, see: M. J. Am. Chem. Soc. 1990, 112, 562775628, Lautens, W. Klute, W. Tam, Chem. Rev. 1996, [6] For an eight-membered metallacycle as reac96.49-92. tive intermediate in the formation of a cycloheptadiene, see J. W. Herndon, G. Chatterjee,

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

[4+4]-Cycloaddition Reactions in the Total Synthesis of Naturally Occurring Eight-Membered Ring Compounds Gerd Kaupp

Eight-membered rings can be obtained by [4+4]-cycloadditions of 1,3-dienes [11 via diradicals or other intermediates. Synthesis of such compounds has been achieved by thermal, [2] photochemical, [3] and by metal-catalyzed [4] processes: these reactions have been the subject of extensive mechanistic [5] and theoretical [5c] studies. Their strategic applications in natural product synthesis have been reviewed. [5d] The thermal version has generated little interest, except in orthoquinodimethane dimerizations and in cycloreversions; the Cope rearrangement of 1,2-divinylcyclobutanes [3] is more commonly used. [4+4]-Cycloadditions are also used with 1,3dipoles or mesoionic heterocycles for the synthesis of six- and seven-membered rings. Sometimes also [6+4]-cycloadditions are

competing. [2b] Good yields can be obtained with the photolytic reaction when the 1,3diene is fixed in the s-cis configuration. Such is the case for, amongst others, condensed arenes, a-pyrones, and 2-pyridones. Two coupled, linear [4+4]-cycloadditions lead to tenmembered rings. [2c] Catalysis by NiO is the obvious method of choice for open-chain 1,3-dienes, favorable coordination (template effect) apparently solving the difficult problem of bringing the terminal groups of the bis-1,3-diene into contact. The choice of typical examples given in Scheme 1 shows that one, two, or four eight-membered rings, which are not connected by zero bridges, can be formed by [4+4]-cycloadditions. Cyclooctanoids (eight-membered ring compounds) can also be found among biologically

[4+4]-CycloadditionReactions

active natural products such as sesqui-, di-, and sesterterpenes, as well as non-terpenoids. The total synthesis of such compounds has been a challenge for many research groups for years. Most prominent was the more than 20 years old race for a total synthesis of the cancer chemotherapeutic taxol 20. [6-81 All of these syntheses did not use [4+4] or other cyclovinylogous additions that could have saved steps in their long reaction sequences. Nevertheless, cycloaddition approaches in cyclooctanoid syntheses are of lasting value beyond total syntheses of taxol20. More practical partial syntheses of taxol have been patented. Also less highly functionalized analogues of taxol, which inhibit the depolymeri-

(2.2)

107

zation of tubulin, [9] have longer been prepared. Some of the best known naturally occuring cyclooctanoids include fusicoccin A (l),ophiobolin A (2), vinigrol (3), epoxybasmenone (4), kalmanol (5), (+)-asteriscanolide (8), crispolide, ceroplastin, vulgar olide, cotylenin, variecolin, pleuromutilin, taxusin, 7deoxytaxol, 12,13-isobaccatin among more than 100 naturally occurring taxanes. Strategies have been developed for the synthesis of these compounds, in some cases successfully, that do not depend on cycloadditions for formation of the eight-membered ring. The concern, unjustly, [3-41 was that the control of the regio- and stereoselectivity would not be possible and that cross-dimeriza-

(1.01

Scheme 2.

108

B. Organometallic Reagents

6

7

tion with substituted 1,3-dienes would lead to poor yields. It was not until 1986 that Wender et al. showed [lo] that it was possible to conduct stereoinduced Nio-catalyzed [4+4]-cycloadditions, even in the presence of oxygencontaining substituents (Scheme 2). Thereafter, the same group achieved the enantioselective synthesis of (+)-asteriscanolide 8, a sesquiterpene. [I I] With this approach they also planned on exploring further possibilities for the synthesis of cyclooctanoid diterpenes of the taxane series, such as 20. [I21 The key step in the synthesis of 8 was the Nio-catalyzed intramolecular [4 + 41-cycloaddition of 6 (accessible in 11 % yield from acrolein in nine steps) to give 7 in 67 % yield (leading to a 36% yield of 8 in three further steps): a satisfyingly short and elegant total synthesis. Presumably stimulated by the success of template-controlled syntheses, Sieburth et al. hoisted the flag for tether guided photochemical [4+4]-cycloadditions. [ 131 This case requires, of course, that two s-cis-constrained dienes are connected to each other. The choice thus fell on 2-pyridones. Target molecules are fusicoccin 1 and the cancer chemotherapeutic agent taxol 20 (cf. [9]). The 3,6-bis(2pyridone) 9, used as the racemate but undoubtedly separable into the enantiomers, provides favorable prerequisites for the [4+4]-photocycloaddition. The nitrogen atoms, the carbonyl groups, and the double bonds are so arranged that further reaction to give 1 by standard methods appears to be possible. Indeed, the epimers 10 were formed by photolysis in good yield (66 and 75 %). Moreover, suitable choice of solvent (protic or aprotic) even allowed preferential formation of one of the epi-

mers. Extension of this work to 11 opens the way to fusicoccines 1. 12 is the only product in methanol and 13 is the only product in benzene, the difference almost certainly arising from two intramolecular hydrogen bridges in the aprotic solvent. [ 141 The bis-N-methylated derivative of 11 yields only the trans isomer. A systematic study of the photodimerizability and stereoselectivity in tethered pyridones has been performed [ 151 and extended to regioselection and intermolecular examples. [ 161 Of particular interest is, however, a thermal-photochemical cycle to increase the yield of trans-cycloadduct, as shown with 14 to give 15. The by-product 16 experiences thermal Cope rearrangement to give 17, which upon photolysis provides 14. Two cycles increase the initial 2 : 1 ratio of 15 and 16 to 18 : 1. [ 171 Sieburth et al. also photolyzed the racemic 3,6-bis(2-pyridone) 18, in which the two rings are connected by a four-membered chain, obtaining both epimers of the secondary alcohol 19 (2 : 3, 63 %). A certain resemblance to taxol 20 is clearly present, but there is still a long way to go. This interim result must be compared with that by Wender et al. in 1987, in which the [4+4]-cycloaddition was catalyzed with Ni'. [I21 Using conversion of 21 to 22 and 23 to 24 as model reactions allows the eight-membered ring and each of the two six-membered rings to be constructed, although not simultaneously. A starting compound such as 25, in which both possibilities are combined, and from which conversion to 20 is feasible with standard reactions after treatment with Nio, is not yet known. However, 25 contains the skeleton of cembrene (14-isopropyl-3,7,11trimethyl-1,3,6,10-cyclotetradecatetraene), a

[4+4]-Cycloaddition Reactions

U

9

10

M

TBS= t er t-bu t y Id ime t h y 1 s i 1y 1

109

”-

12

widespread diterpene, though with all four double bonds 1,3 -shifted. Cembrene is synthesized in nature by cyclization of geranylgeraniol pyrophosphate, it is a possible precursor (or side product) in taxane biosynthesis and it has been suggested to use its isomer cembrene B for closing the taxane A- and Crings, though separately. [ 181 A starting material similar to compound 23 with a methyl group at C4 and the tert-butyldimethylsiloxy group at C7 was used to initiate a crispolide synthesis: the [4+4]-cycloaddition succeeded with 74% yield. [19] But neither this “model” nor 23 is suitable for the synthesis of taxol20, of course. After the first total synthesis of taxol by Holton et al. [6] Sieburth pursued his approach with a photolysis of 26 and approached taxol more closely (an additional quaternization with a 2-hydroxypropyl group was not possible). Labile 27 was quantitatively obtained and could be selectively hydrogenated at the disubstituted double bond. The residual double bond could be stereospecifically epoxidized followed by ad-

dition of methanol. [15] However, recently it was possible to fully functionalize the eightmembered ring to give 28 with 65 % yield. [ 141 Thus, Sieburth et al. have come pretty close to taxol (20) and fusicoccin (1) in an elegant way. Their results have provided vital new impetus for the total synthesis of naturally occurring cyclooctanoids, many of them exhibiting mitotic inhibition that is so typical for this class of compounds. It should always be attempted, by means of stereoselective cycloaddition, to save steps in a total synthesis. The foundation for the application of [4+4]cycloadditions [5b] for the most vaned experimental conditions already exists and has been adopted now to natural product syntheses. That event has also stimulated further synthetic work. [20] One should also not forget, that cyclovinylogous additions [Sb] contain still further ideas for saving synthetic steps that have been used previously and adopted recently. For example, eight-membered rings can also be constructed by [2+2]-cycload-

110

B. Organornetallic Reagents

I

18

dition of cyclobutenes or of alkynes to (hetero)cyclohexenes or arenes followed by further ring expansion. [3a, 211 Diels-Alder reactions between components connected by a bridging group with six carbon atoms lead to cyclooctanone-annelated cyclohexenes, [22] homo-Diels-Alder ([4+3]-) [23] and [6+2]-additions [24] provide bridged cyclooctanoids. Further perspectives for the synthesis of natural products are opened up by the cyclovinylogous [6+4]- [2b, 5b, 241 (for tenmembered rings, see 3, 20, pleuromutilin), [6+6]- [25] and [4+4+4]-additions [4] (twelve-membered rings, see 5, 20) and are often investigated in parallel with the [4+4]additions. Thus, synthesis strategies aimed at the largest ring present containing no zero bridges should definitely also be considered. The work of Wender [lo-12,191 and Sieburth [13-171 appears to illustrate a renaissance of cycloaddition reactions of polyenes, with very promising potential.

References [ l ] H. Bouas-Laurent, J. P. Desvergne, Stud. Org. Chem. (Amsterdam) 1990,40, 561-630. [2] a) J. Wagner, J. Bendig, A. Felber, A. Sommerer, D. Kreysig, Z. Chem. 1985, 25, 64; b) W. Friedrichsen, W. D. Schroer, T. Debaerdemaeker, Liebigs Ann. Chem. 1980, 1850-1 858; W. Friedrichsen, H.-G. Oeser, ibid. 1978, 1161-1186; c) S. A. Ali, M. I. M. Wazeer, J. Chem. SOC. Perkin Trans. 2 1986, 1789-1792; J. Thesing, H. Mayer, Chem. Ber: 1956, 89, 2159-2167; J. Basan, H. Mayr, J. Am. Chem. SOC. 1987, 109, 65196521; H. Meier, U. Konnert, S. Graw, T. Echter, Chem. Ber: 1984, 117, 107-126; d) [6+2]-cycloadditions with 1,5-dipoles: P. A. Wender, J. L. Mascarenas, J. Org. Chem. 1991, 56, 6267-6269; e) A. Katritzky S. I. Bayyuk, N. Dennis, G. Musumarra, E.-U. Wiirthwein, J. Chem. SOC. Perkin Trans 1 1979, 2535-2541 (classified there as an “allowed’ photoreaction).

[4+4]-Cycloaddition Reactions [3] a) G. Kaupp, Methoden Org. Chem. (HoubenWeyl)4th Ed. 1975, Vol. 4/5a, p. 278ff.; 360ff.; E. Leppin, ibid., p. 476ff.; 484ff.; V. Zanker, ibid. p. 586ff.; 616ff.; b) Y. Nakamura, T. Kato, Y. Morita, J. Chem. Soc. Perkin Trans. I 1982, 1187-1191. [4] G. Wilke, Angew. Chem. 1963, 75, 10-20; Angew. Chem. Int. Ed. Engl. 1963, 2, 105115; P. Heimbach, P. W. Jolly, G. Wilke in Advances in Organometallic Chemistry, Vol. 8 (Eds.: F. G. A. Stone, R. West), Academic Press, New York, 1970, p. 29ff.; P. W. Jolly, G. Wilke, The Organic Chemistry of Nickel, Vol. 2, Academic Press, New York, 1975. [5] a) J. Saltiel, R. Dabestani, K. S. Schanze, D. Trojan, D. E. Townsend, V. L. Goedken, J. Am. Chem. Soc. 1986, 108, 2674-2687, and references cited therein; b) G. Kaupp, E. Teufel, Chem. Ber: 1980, 113, 3669-3674; G. Kaupp, H.-W. Grtiter, E. Teufel, ibid., 1983 116, 630-644; G. Kaupp, D. Schmitt, ibid., 1981, 114, 1567-1571; 1980, 113, 1458-1471; G. Kaupp, H.-W. Griiter, ibid, 1980, 113, 1626-1631; Angew. Chem. 1979, 91, 943-944; Angew. Chem. Int. Ed. Engl. 1979, 18, 881-882; G. Kaupp, Liebigs Ann. Chem. 1973, 844-878; c) M. J. Bearpark, M. Deumal, M. A. Robb, T. Vreven, N. Yamamoto, M. Olivucci, F. Bernardi, J. Am. Chem. Soc. 1997, 119, 709-718; d) G. Kaupp, Angew. Chem. 1992, 104, 435-437; Angew. Chem. Int. Ed. Engl. 1992, 31, 422424; S. M. Sieburth, N. T. Cunard, Tetrahedron 1996, 52, 625 1-6282. [6] R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J. Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile, J. H. Liu, J. Am. Chem. Soc. 1994,116, 1597-1598; 1994,116, 1599-1600 (submitted Dez. 21, 1993). [7] K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature 1994, 367, 630-634 (submitted Jan. 24, 1994); K. C. Nicolaou, R. K. Guy, Angew. Chem. 1995, 107, 22472259, Angew. Chem. Int. Ed. Engl. 1995, 34, 2079-209 1.

111

[8 J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, S . J. Danishefsky, Angew. Chem. 1995, 107, 1886-1888, Angew. Chem. Int. Ed. Engl. 1995,34, 1723-1725. [9 S . Blechert, A. Kleine-Klausing, Angew. Chem. 1991, 103, 428-429; Angew. Chem. Int. Ed. Engl. 1991, 30, 412-414; F. Gueritte-Voegelein, D. Guenard, F. Lavelle, M. T. LeGoff, L. Mangatal, P. Potier, J. Med. Chem. 1991,34,992-998. [lo] P. A. Wender, N. C. Ihle, J. Am. Chem. SOC. 1986, 108, 4678-4679; Tetrahedron Lett. 1987,28, 245 1-2454. [ l l ] P. A. Wender, N. C. Ihle, C. R. D. Correia, J. Am. Chem. Soc. 1988,110,5904-5906. [12] P. A. Wender, M. L. Snapper, Tetrahedron Lett. 1987, 28, 2221-2224; M. L. Snapper, Stanford University, Diss. Abstr: Int. B 1991, 52,248-249. [13] S. M. Sieburth, J.-L. Chen, J. Am. Chem. Soc. 1991,113,8163-8164. [14] S . M. Sieburth, Private Communication, March 22, 1997. [15] S. M. Sieburth, J. Chen, K. Ravindran, J.-L. Chen, J. Am. Chem. Soc. 1996, 118, 1080310810. [I61 S. M. Sieburth, B. Siegel, J. Chem. Commun. 1996, 2249-2250; S . M. Sieburth, C. H. Lin, Tetrahedron Lett. 1996, 37, 1141-1 144. [17] S. M. Sieburth, C. H. Lin, J. Org. Chem. 1994, 59, 3597-3599. [18] T. Frejd, G. Magnusson, L. Pettersson, Chem. SCK 1987, 27, 561-562; L. Pettersson, T. Frejd, G. Magnusson, Tetrahedron Lett. 1987, 28, 2753-2756; Acta Chem. Scand. 1993,47, 196-207. [19] P. A. Wender, M. J. Tebbe, Synthesis 1991, 1089-1094; the reaction conditions for the conversions 6 -+ 7 from ref. [11] and 23 -+ 24 from ref. [12] are not given here for comparative purposes. [20] F. G. West, C. E. Chase, A. M. Arif, J. Org. Chem. 1993,58,3794-3795. [21] J. G. Atkinson, D. E. Ayer, G. Buchi, E. W. Robb, J. Am. Chem. Soc. 1963, 85, 22572263; D. Bryce-Smith, A. Gilbert, J. Grzonka, J. Chem. Soc. Chem. Commun. 1970, 498499; W. C. Agosta, W. W. Lowrance, J. Org. Chem. 1970, 35, 3851-3856; G. Kaupp, M. Stark, Angew. Chem. 1977, 89, 555-556;

112

B. Organometallic Reagents

Angew. Chem. Int. Ed. Engl. 1977, 16, 552553, and literature cited therein; G. Kaupp, U. Pogodda, A. Atfah, H. Meier, A. Vierengel, Angew. Chem. 1992, 104, 783-785; Angew. Chem. Int. Ed. Engl. 1992, 31, 768-770; cf. also P. A. Wender, C. J. Manly, J. Am. Chem. Soc. 1990, 112, 8579-8581 (synthesis oftenmembered rings). [22] K. Sakan, D. A. Smith, S. A. Babirad, F. R. Fronczek, K. N. Houk, J. Org. Chem. 1991, 56, 2311-2317; J. S. Yadav, R. Ravishankar, Tetrahedron Lett. 1991, 23, 2629-2632; R. V. Bonnert, P. R. Jenkins, J. Chem. SOC. Perkin Trans. 1 1989,413-418.

[23] M. Harmata, S. Elahmad, C . L. Barnes, J. Org. Chem. 1994,59, 1241-1242. [24] J. H. Rigby, Acc. Chem. Res. 1993, 26, 579585. [25] See, for example L. A. Paquette, J. H. Barrett, D. E. Kuhla, J. Am. Chem. SOC. 1969, 91, 3616-3624; G. Kaupp, E. Teufel, H. Hopf, Angew. Chem. 1979, 91, 232-234; Angew. Chem. Int. Ed. Engl. 1979, 18, 215-217, and references therein for the synthesis of paracyclophanes via para-quinodimethanes.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

“New” Reagents for the LLOld9’ Pinacol Coupling Reaction Thomas Wirth

An old-timer in the history of chemistry, the pinacol coupling, was first described nearly 140 years ago in a publication on the synthesis of pinacols. [ 1a] Today this reaction is still a versatile tool for chemists. This ‘‘longevity’’ can be explained by the continuous development of improved reagents and by the intrinsic elegance of the method for the preparation of 1,2-diols (pinacols) by the reductive coupling of carbonyl compounds. [ l ] Starting with two carbonyl functionalities a carbon-carbon bond is formed and two new adjacent stereocenters created. 1,2-Diols are versatile intermediates in synthesis; for example, they can be used for the preparation of ketones by the pinacol rearrangement or alkenes with the McMuny reaction (Scheme 1). Whether the reductive coupling of carbonyl compounds leads to 1,2-diols or to the deoxygenated or rearranged products is dependent on the oxygen affinity of the reducing agent

-

employed. The McMurry-reaction uses lowvalent titanium compounds, which under certain reaction conditions can transform the 1,2-diol intermediates into alkenes by rapid deoxygenation (Scheme 1). When this reaction was performed on the surface of reduced titanium dioxide, the intermediate 1,2-diols could be isolated. [2] Reducing agents suitable for the synthesis of pinacols must allow the reaction to be stopped at the 1,2-diol stage. One of the first practical reductants for pinacol coupling reactions was the Mg/MgIz system reported by Gomberg and Bachmann. [3] More recently these reducing agents have been extended by a magnesium-graphite system, which is competitive with other currently available reductants. [4] Different low-valent titanium compounds have proved to have similar efficiency for pinacol coupling reactions. [5] They have been used for intramolecular couplings as

pinacol rearrangement

/ *,

. .

*

.

-w McMurry reaction

*.

..___.. :*

.-..--.-. . *

Schemel.

114

B. Organometallic Reagents

well as for the formation of unsymmetrical pinacols, and have demonstrated their potential in several key steps of natural product syntheses. [6] Recent developments show that low-valent titanium, manganese, as well as zinc reagents can be used in the pinacol coupling reaction in aqueous media. [7] Also with catalytic amounts of low-valent titanium reagents the highly diastereoselective synthesis of coupling products is possible. [8] Typical mechanisms for pinacol couplings are shown in Scheme 2. In the first reduction step a ketyl radical is formed which can dimerize (path A) or add to a second carbonyl group, forming a C-C bond. In path B a second one-electron reduction must then follow. For pinacol coupling reactions mediated by transition metals the insertion of a carbonyl group into the metal-carbon bond of initially formed metal oxiranes has been proposed (path C). Pinacol coupling reactions can lead to either the syn- or anti-diols. The stereochemical course of the reaction depends on the reducing agents and, of course, on the structure of the carbonyl compounds. Recent studies employing reagents that form the C-C bond according pathways B and C have met with success.

Previously, tin-ketyl radicals have been added to alkenes only in an intramolecular fashion. [9] In recent publications, however, pinacols and amino alcohols have been prepared by cyclisation of dicarbonyl compounds [ 101 or keto-oximes [ 111 with tributyltin hydride. Cyclisation of 1,5-ketoaldehydes 1 and 1 3-dialdehydes with tributyltin hydride yields cis-diols 2 with excellent stereoselectivities, whereas the keto-oxime 4 with four benzyloxy-substituents affords a 58 : 42 (cis : trans) mixture. The trans-product was transformed in two more steps to the potent glycosidase inhibitor 1-deoxynojirimycin (6). [ l l b ] The reversibility of both the addition of the tributyltin-radical to the carbonyl group and the intramolecular radical C-C bond formation is believed to be responsible for the high selectivity in the formation of 2. In the cyclisation of lS-pentanedial the unhydrolyzed coupling product 3 could be isolated, therefore providing evidence for a new mechanistic variant of the pinacol reaction, in which only 1.2 equivalent of the reducing agent are necessary. 1,6-Dicarbonyl compounds can also be converted into the corresponding pinacols. Tributyltin hydride can again be used as an efficient reducing agent, this time for the ste-

t.

Scheme 2.

“New” Reagents for the “Old” Pinacol Coupling Reaction

1

2

R = CH@TBS

3

62% (cis :trans) (>95:5)

R’‘’y#,,R Rx OCH,

I

H / m 3

Bu3SnH

Rp R

++HOY),,

HO

OH

OH

R

R=OCl+Ph

H

HO N

+

4

1 15

6

68% (cis:tms) (58:42)

reoselective synthesis of 7. [lo] Other well established pinacol forming reagents such as low-valent titanium compounds [lb, c] or samarium diiodide [ 121 can cyclize 1,n-dicarbony1 compounds with comparable stereoselectivities to give 1,2-diols. X-ray crystal structures of a samarium ketyl complex and a samarium pinacolate are further evidence of the reversibility of the coupling reaction under appropriate conditions. [ 131 An excess of samarium diiodide was used as pinacol coupling reagent for the synthesis of the optically active inositol derivative 8 [12b] or in the highly threo selective coupling of tricarbonylchromium complexes of benzaldehydes. [ 12d] An acceleration of the pinacol coupling with samarium diiodide is possible by addition of trimethylsilyl chloride. [ 141 Even catalytic amounts of samarium diiodide are sufficient for the pinacol coupling reaction, when magnesium is employed as reductant for the conversion of samarium(n1) to samarium(I1). 1151 Low-valent compounds of other early transition metals were shown to be effective reagents for the pinacol coupling. Zirconium,

6

Scheme 3.

niobium, and ytterbium [16] reagents form metal oxiranes with carbonyl compounds; however, the mechanism of the recation with vanadium compounds is not clear at present. The mechanism of the pinacol coupling via metal oxiranes is supported by X-ray structure analysis of an intermediate. [ 171 Vanadium and niobium compounds seem to be particularly attractive reagents for intermolecular pinacol coupling reactions. The vanadium complex [V2C13(thf)6]2 [Zn2Cl6] (Caulton’s reagent) [181 is suitable for the intermolecular coupling of functionalized aldehydes which bear further coordination sites, for example amino aldehydes. [19] The formation of a bidentate or tridentate metalaldehyde complex is proposed to be the origin of the threo selectivity observed in this reaction. The coupling products like 9 are interesting target structures because they are potential inhibitors of HIV-proteases. They can even be synthesized on the kg-scale with good yields. [ 19b] Improvements were reported in the synthesis of Caulton’s reagent avoiding the highly air-sensitive VCl3(thf)3. [19c] Efficient pinacol cross coupling

B. Organometallic Reagents

116

& \ /

Bu.$nH

53 Yo

+

(cis :trans ) (95:s) 7

Sml,

+

60%

(cis : trans )

(93:7)

Scheme 4.

8

Ph

-

g

Jh

NbCI,( dme)

Ph

0

6-73 %

(tbreo :erytbro)

(75 25)- (87 13) '

PhHQ

reactions are possible with this reagent [20] and even first catalytic systems with low-valent vanadium species have been reported. [21] The niobium reagent [NbC13(dme)] can be used to couple imines with carbonyl compounds giving amino alcohols such as 10, although generally lower stereoselectivity is observed. [6] In analogy to reactions with other early transition metals the mechanism is believed to proceed via a niobaziridine, which adds to the carbonyl functionality. The relative and absolute stereochemistry in pinacol coupling reactions, for instance in the natural product syntheses mentioned earlier, [6] is always controlled by the stereocenters

1o

55-76 Yo (three0 : erythro) (85: 15)-(90 : 10)

OH

'

Scheme 5.

of the substrates. Very little work has concentrated on the control of the absolute stereochemistry in pinacol coupling reactions. [ lb, 231 Because of the potential of the reagents presented here, the development of chiral coupling reagents will no doubt be reported in the near future.

“New” Reagents for the “Old” Pinacol Coupling Reaction

117

References [ l ] a) R. Fittig, Justus Liebigs Ann. Chem. 1859, 110, 23-45; b) review: G. M. Robertson in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M. Trost, I. Fleming, G. Pattenden), Pergamon, Oxford, 1991, p. 563; c) A. Furstner, Angew. Chem. 1993, 105, 171-197; Angew. Chem. Int. Ed. Engl. 1993, 32, 164189; d) T. Wirth, ibid. 1996, 108, 65-67 and 1996,35,61-63. [2] K. G. Pierce, M. A. Barteau, J. Org. Chem. 1995,60,2405-2410. [3] M.Gomberg, W. E. Bachmann, J. Am. Chem. SOC. 1927,49, 236-257. [4] A. Furstner, R. Csuk, C. Rohrer, H. Weidmann, J. Chem. SOC. Perkin Trans. I 1988, 1729-1734. [ 5 ] J. E. McMurry, Chem. Rev. 1989, 89 15131524. [6] a) E. J. Corey, R. L. Danheiser, S. Chandrasekaran, P. Siret, G. E. Keck, J. Gras, J. Am. Chem. SOC. 1978, 100, 8031-8034; b) C. S. Swindell, W. Fan, P. G. Klimko, Tetrahedron Lett. 1994, 35, 4959-4962; c) K. C. Nicolaou, Y. Zang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F, Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature 1994,367,630-634; d) C. S. Swindell, W. Fan, Tetrahedron Lett. 1996, 37, 23212324; e) C. S. Swindell, M. C. Chander, J. M. Heerding, P. G. Klimko, L. T. Rahman, J. V. Raman, H. Venkataraman, J. Org. Chem. 1996, 61, 1101-1108; f) C. S. Swindell, W. Fan, ibid. 1996,6I, 1109-1118; g) X. Yue, Y. Li, Synthesis 1996, 736-740. a) M. C. Barden, J. Schwartz, J. Am. Chem. SOC. 1996, 118, 5484-5485; b) C. Li, Y. Meng, X. Yi, J. Ma, T. Chan, J. Org. Chem. 1997, 62, 8632-8633; c) T. Tsukinoki, T. Kawaji, I. Hashimoto, S. Mataka, M. Tashiro, Chem. Lett. 1997, 235-236. a) A, Gansauer, Chem. Commun. 1997, 457458; b) A. Gansauer, Synlett 1997, 363-364. [9] B. Giese, B. Kopping, T. Gobel, J. Dickhaut, G. Thoma, K. J. Kulicke, F. Trach in Organic Reactions, Vol. 48 (Ed.: L. A. Paquette), Wiley, New York, 1996, p. 301. [lo] a) D. S. Haysm G. C. Fu, J. Am. Chem. SOC. 1995, 117, 7283-7284; b) T.-H. Chuang,

J.-M. Fang, W.-T. Jiaang, Y.-M. Tsai, J. Org. Chem. 1996,61, 1794-1805. [ l l ] a) T. Naito, K. Tajiri, T. Harimoto, I. Ninomiya, T. Kiguchi, Tetrahedron Lett. 1994, 35, 2205-2206; b) T. Kiguchi, K. Tajiri, I. Ninomiya, T. Naito, H. Hiramatsu, ibid. 1995, 36, 253-256; c) J. Tormo, D. S. Hays, G. C. Fu, J. Org. Chem. 1998,63, 201-202. [12] a) J. L. Chiara, W. Cabri, S. Hanessian, Tetrahedron Lett. 1991, 32, 1125-1128; b) J. L. Chiara, M. Martin-Lomas, ibid. 1994, 35, 2969-2972; c) J. P. Guidot, T. Le Gall, C. Mioskowski, ibid. 1994, 35, 6671-6672; d) J. L. Chiara, N. Valle, Tetrahedron: Asymmetry 1995, 6, 1895-1898; e) J. L. Chiara, J. Marco-Contelles, N. Khiar, P. Callego, C. Destabel, M. Bernabi, J. Org. Chem. 1995, 60, 6010-6011; f) N. Taniguchi, N. Kaneta, M. Uemura, ibid. 1996, 61, 60886089. [13] a) Z. Hou, T. Miyano, H. Yamazaki, Y. Wakatsuki, J. Am. Chem. SOC. 1995, 117, 4421-4422; b) Z. Hou, A. Fujita, H. Yamazaki, Y. Wakatsuki, J. Am. Chem. Soc. 1996, 118,7843-7844. [14] T. Honda, M. Katoh, Chem. Commun. 1997, 369-370. [15] R. Nomura, T. Matsuno, T. Endo, J. Am. Chem. SOC. 1996,118, 11666-11667. [16] a) Y. Taniguchi, K. Nagata, T. Kitamura, Y. Fujiwara, D. Deguchi, M. Maruo, Y. Makioka, K. Takaki, Tetrahedron Lett. 1996, 37, 34653466; b) Y. Makioka, Y. Taniguchi, Y. Fujiwara, K. Takaki, Z. Hou, Y. Wakatsuki, Organometallics 1996, 15, 5476-5478. [17] Z. Hou, H. Yamazaki, Y. Fujiwara, H. Taniguchi, Organometallics 1992, 11, 271 1-2714. [18] R. J. Bouma, J. H. Teuben, W. R. Beukema, R. L. Bansemer, J. C. Huffman, K. G. Caulton, Inorg. Chem. 1984,23,2715-2718. [19] a) A. W. Konradi, S. J. Kemp, S. F. Pedersen, J. Am. Chem. SOC. 1994, 116, 1316-1323; b) B. Kammermeier, G. Beck, D. Jacobi, H. Jendrella, Angew. Chem. 1994, 106, 719721; Angew. Chem. Int. Ed. Engl. 1994, 33, 685-687; c) B. Kammermeier, G. Beck, W. Holla, D. Jacobi, B. Napierski, H. Jendralla, Chem. Eur: J. 1996, 2, 307-315;

d) M. E. Pierce, G. D. Hams, Q. Islam, L. A. Radesca, L. Storace, R. E. Waltermire, E. Wat, P. K. Jadhav, G. C. Emmett, J. Org. Chem. 1996, 61, 444-450; e) M. T. Reetz, N. Griebenow, Liebigs Ann. 1996, 335-348. [20] a) Y. Kataoka, I. Makihira, M. Utsunomiya, K. Tani, J. Org. Chem. 1997,62, 8540-8543; b) S. Torii, K. Akiyama, H. Yamashita, T. Inokuchi, Bull. Chem. SOC. Jpn. 1995, 68, 2917-2922; c) M. Kang, J. Park, S . F. Pedersen, Synlett 1997, 41-43.

[21] T. Hirao, T. Hasegawa, Y. Muguruma, I. Ikeda, J. Org. Chem. 1996, 61, 366-367. [22] E. J. Roskamp, S. F. Pedersen, J. Am. Chem. SOC.1987,109,6551-6553. [23] a) R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi, P. Giaroni, J. Org. Chem. 1992, 57, 782-784; b) M. Shimizu, T. Iida, T. Fujisawa, Chem. Lett. 1995,609-610.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Exciting Results from the Field of Homogeneous Two-Phase Catalysis Boy Cornils

With the advent of two-phase catalysis, the last and in fact inherent disadvantage of homogeneous catalysis relative to its heterogeneous counterpart appears to have been swept away. This break-through has been achieved by arranging the process such that, at least when reaction is complete, the organometallic complex serving as a catalyst on one hand, and the reaction product (and residual starting material) on the other, are located in different phases, so a simple phase separation is sufficient for isolating the product from the catalyst (which may then be introduced immediately into another catalyst cycle). [ 11 The catalyst is situated in a mobile phase which, because it is confined whithin the reactor, also serves as an immobilization medium. Interestingly, quite atypically, the principle itself was implemented on a large (approx. lo6 tonnes per annum) scale in industry in the Shell higher olefins process (SHOP), as well as the RuhrchemieRhGne-Poulenc 0x0 process even prior to the onset of comprehensive scientific investigation, initiated later by a number of academic research groups. [2] Some of these later studies have been pursuing unusual course: The work undertaken by Chaudhari et al. [3], which deserves much credit (for introducing a systematic approach) assumes, for instance, that it is possible to manage without quotations from the pioneers

of the biphase technique (Job and Ruhrchemie). An indication of the significance of the process as far as the scientific world is concerned is the fact that the “standard ligand” for aqueous two-phase catalysis, triphenylphosphine trisulfonate (TPPTS), now appears in the Aldrich Catalogue of Fine Chemicals. The elegant approach to catalyst separation has in turn led to intense preoccupation with possible laboratory and industrial applications of two-phase catalysis, as well as extension of the process into new areas. A series of important contributions to the literature has recently cast a rather bright spotlight in this direction. Not surprisingly the ideal form of the process is aqueous biphase catalysis, in which the organometallic two-phase catalyst resides in a stationary aqueous solution in the reaction system. This is not only the most convenient arrangement on both the laboratory and industrial scale, but also the optimal modification wich respect to cost and environmental considerations. Use of water as the second phase has its limitations however, especially when the water solubility of the starting materials proves too low, preventing adequate transfer of organic substrate into the aqueous phase or at the phase boundary, and consequently reducing the reaction rate to such an extent that it becomes unacceptable. Cases

120

B. Organometallic Reagents

like this can be dealt with by introducing a of higher olefins > C 6 (a challenge not yet surfactant (or by using ligands that confer sur- met) it must of course be noted that the suggefactant properties), but other alternatives stion by Chaudhari et al. of adding a promoter include addition of a solvating agent that pro- ligand once again raises the problem of a duces a quasi “mechanical” effect, or use per- “foreign substance”, with the resulting need haps of a cosolvent, two measures that presu- for a costly separation step. Nevertheless, mably increase either the mutual solubility of these experiments do suggest that a search the components or mobility across the phase for ligands with carefully matched hydrophilic boundaries. The effectiveness of additives of and hydrophobic characteristics may lead to a this type has been the subject of much contro- solution to the problem, provided the electroversy in the literature, and it depends heavily nic characteristics of the 0x0 catalyst can be on such specific factors as the ligands and optimized simultaneously. From among the their purity, the nature and behavior of the large number of relevant papers, reference substrate, the presence of miscibility gaps, may be made here to suggestions by Fell on and precise reaction conditions. From an eng- ligands of matched hydrophilicity and lipoineering and economic standpoint it is also philicity for converting raw materials used in important to remember that any “foreign” fat chemistry [5], the paper by Purwanto and additive will inevitably increase the difficulty Delmas on hydroformylation in the presence and cost of purification, thereby mitigating of externally added solvents [ 6 ] ,that by Hanthe clear advantages associated wich two- son on surface-active ligands or special spectator cations [7] (supplementing earlier studies phase catalysis in its purest form. Chaudhari et al. [4] were the first to suggest by Ruhrchemie AG [8]) or that by Montflier introducing “promoter ligands” soluble exclu- and Mortreux on the two-phase hydroformylasively in the organic phase, thus altering the solubility of the complet internally. These 600 authors were able to show through hydro51 I formylation of the extremely water-insoluble l-octene (equilibrium solubility in water at 298 K: 2.408 x kmol m-3; cf. propene, with a solubility of approx. 7 X kmol m-3) with [HRh(CO)(TPPTS)3] as catalyst that addition of triphenylphosphine to the TOFx 10‘ l-octene increases the reaction rate by a factor of 10-50. Ligand exchange during the course of the reaction leads to the formation of isolable mixed-ligand complexes of the type [HRh(CO)(TPPTS)3-,(TPP),I (x = 0-3). These display activities somewhat greater than is observed for catalysts modified only with Figure 1. Two-Phase hydroformylation of l-octene. TPPTS, though still inferior to the activity Turnover frequencies (TOF) obtained under three different operating conditions: Column 1 : Hydroobtained by simple physical addition of TPP formylation with [HRh(CO)(TPPTS)3]. Column 2: alone, a result that indicates the importance of Addition of 3.33 x lo3 kmol TPP per m3 of organic as yet unexplained effects at the boundary sur- phase to TPPTS. Column 3: [HRh(CO)(TPPTS)3.x faces of the two reaction phases (cf. Fig. 1). (TPP),]. The TOF values indicate how many With respect to the development of an kmol of product per kg rhodium are forme4 per industrial process for the hydroformylation second [4].

Exciting Results from the Field of Homogeneous Two-Phase Catalysis

tion of water-insoluble olefins with the aid of molecular recognition with functional b-dextrines [9]. The various possibilities from a process engineering viewpoint for catalyst recycling in two-phase processes and hence also on the necessary circulation of any auxiliaries or solvents have been dealt with by Behr [lo]. The foreign additive problem is avoided in an approach suggested by Jin, Fell, et al. [ l l , 121 who have proposod a two-phase hydroformylation of higher olefins (up to 1-dodecene) based on replacing the ligands in [HRh(C0)4] with ethoxalated tris(p-hydroxypheny1)phoshines of the structure indicated in 1. / P

6

0 T C H 2 - CH,O),,-

H

O T C H 2 - CH:O),,-

H

XF+

\

0

CH,-

CH20),,- H

1, n > 6-8

121

sired higher aldehydes) as an independent phase. Since the agent responsible for the merger and subsequent separation of the phases is the appropriately custom-designed ligand itself, there is no call for investing extra effort in the removal and recycling of a foreign additive, and this must therefore be regarded as a promising avenue for further exploration on a commercially realistic scale. Results reported in two other papers by Bergbreiter et al. [13] and Wan and Davis [14] take advantage of similar effects. Bergbreiter et al. applied the designation “smart ligands” in describing certain phosphorus bound poly(a1kylene oxide) oligomers that together with rhodium precursors form complexes with the structure 2, complexes that display both hydrogenation and 0x0 activity. Here again, an inverse temperature dependency of the complex catalyst’s solubility leads at high temperature to single-phase behavior and correspondingly increased reaction rates.

The corresponding Chemical Abstracts entry fails to provide any indication of the Wan and Davis combined the possibilities real novelty involved in the Chinese work, but the German version of the paper makes it inherent in the supported liquid phase catalyclear that this particular 0x0 catalyst takes sis (SLPC) and supported aqueous phase cataadvantage of a temperature dependent “cloud lysis (SAPC) techniques with a modified point” associated wich the phosphorus bound water-soluble (and thus hydrophilic) ruthepoly (alkylene glycol ether) ligands. Thus, nium catalyst dissolved in ethylene glycol in above the cloud point the ligand (and thus their demonstration of an enantioselective the complex catalyst) loses its hydration hydrogenation of 2 -(6’-methoxy-2‘-naphthyl) shell, just as in the case of other compounds acrylic acid (3). The reaction leads to (S)of this type, causing the two-phase reaction naproxene (4) with ee values as high as mixture normally obtained when olefin is 96 %. Ligand modification was accomplished added to the catalyst solution to merge into a with tetrasulfonated BINAP [2,2’-bis(diphesingle phase, thereby initiating a rapid trans- ny1phosphino)-1,1’-binaphthyl], which in conformation that is no longer impeded by mate- junction with ruthenium chloride generates the rial-transport problems. Subsequent lowering active hydrogenation complex [Ru(BINAP-4 of the temperature causes the hydration shell SO&a)(C6H6)C1]C1 (Scheme 1). The substrate is dissolved in the hydrophoto be reversibly restored, inducing the complex catalyst solution once again to separate bic solvent mixture cyclohexanekhloroform. this time from the reaction product (the de- This combination forms a second phase in

122

B. Organornetallic Reagents FH2

+

H,CO ~

c \ c o o ’ lRu 3

H2

cat.

cH\coo“

*H,CO’ 4

Scheme 1. Homogeneous hydrogenation of the acrylic acid derivate 3 to give (S)-naproxene (4).

the presence of the highly polar supportedcatalyst solution, which is in turn immiscible with organic liquids. Wan and Davis attempted in this way to achieve a double “heterogenization” or “immobilization” of a complex catalyst that would otherwise be homogeneous: Deposition on the selected support CPG (controlled-pore glass) causes the catalyst to become heterogeneous, and the two-phase technique results in its further immobilization. The success reported in conjunction with this remarkable experiment is quite astounding. It will certainly be worth waiting a bit to see if the success proclaimed [ 151 can be confirmed with other substrates, and whether the indirect “proofs” cited for localized retention of the ruthenium catalyst in fact withstand closer scrutiny. Given all the previous experience with liquid-solid phase catalysts and their susceptibility to “leaching” this would seem somewhat unlikely. Another approach to two-phase catalysis and the immobilization of homogeneons catalysts has been suggested by Horvith and Ribai at Exxon. Following preliminary conference reports [ 161 and a paper in Science [ 171 the corresponding European Patent application has now been published as well [ 181. Horvith and Ribai discuss their new “fluorous biphase system” (or “fluorous multi-phase system” as it is characterized in the broader set of claims constituting the patent application) also in the context of the hydrofonmylation reaction as an illustrative example. Thus, a modified 0x0 catalyst bearing partially fluorinated ligands bound via phosphorus, such as that illustrated in structure 5, is introduced into certain perfluoro (or partially fluorinated)

solvents with which ordinary organic substrates and solvents are immiscible

Proper “tailoring” of the ligands is said to be extraordinarily important. For example, the methylene group located between the phosphorus atom and the perfluoro end group in 5 is alleged to be responsible for controlling the influence of the electron withdrawing end groups (“fluorous ponytails” [19]) and finetuning their effect to the appropriate level. The two-phase mixture consisting of catalyst phase and olefin becomes homogeneous at higher temperature, causing the catalytic process itself to occur with a correspondingly high rate of reaction in a single phase. The system is subsequently cooled, permitting one to take advantage of a thermally defined miscibility gap in order to separate the reaction product from the catalyst, which then becomes available for immediate reuse. The practical applicability on an industrial scale of this rather exotic two-phase system remains to be demonstrated. Doing so will require a clarification of such basic issues as activity, cost, catalyst lifetimes (and thus catalyst life and economic feasibility), toxicity, concerns regarding the ozone depletion potential (ODP) and greenhouse warming potential (GWP) values of the corresponding fluorinated compounds, etc. There is also the possibility of competitive extraction of fluorinated hydrocarbons by the aldehyde phase in the 0x0 reaction (leading to potential problems in subsequent hydrogenation to the plasticizer

Exciting Results from the Field of Homogeneous Two-Phase Catalysis

123

alcohols that are in fact the desired products). There now exists evidence for the extension Some other work describe the environmental of two-phase catalysis into a new area, sugadvantages of the “classical” aqueous biphase gesting interesting possibilities in an entirely systems [20]. different field of application. Gassner and The professional world will also follow Leitner [23] have described a hydrogenation with some interest the future course of of carbon dioxide to formic acid [Eq. (l)] Exxon’s patent application itself and the pos- that is accompanied by astonishingly high sibility that there may be appeal, since at turnover values in aqueous solution in the least part of the basic idea underlying the presence of TPPTS-modified rhodium cataExxon process was described previously in lysts. This potentially relevant process will a 1991 dissertation by M. Vogt (under certainly generate considerable interest if it Keim’s supervision) entitled “Zur Anwen- proves feasible to carry out a selective transdung perfluorierter Polyether bei der Immo- formation of “technical grade” carbon dioxide bilisierung homogener Katalysatoren” (On (i.e. without prior purification) at “industrial the Application of Perfluorinated Polyethers concentrations” (meaning a COZ content in in the Immobilization of Homogeneous Cata- the range of a few percent). The high specilysts). [21] Vogt was attempting to develop ficity associated with two-phase processes ligands based on hexafluoropropene oxide makes rapid progress in this regard appear (HFPO) oligomers for subsequent complexa- likely as well. tion with appropriate cobalt or nickel precursors, and to exploit the latter for oligomerization or polymerization reactions. It did The specificity of biphase catalyst systems indeed prove possible in principle to bind HFPO oligomers to homogeneous transition (in conjunction with activities comparable to metal catalysts, confemng upon the modified those anticipated with single-phase systems) complexes the solvophobic properties charac- has been illustrated in an elegant way by teristic of this class of compounds. The result Mortreux et al. [24] In a regioselective hydrowas a two-phase reaction procedure con- formylation of methyl acrylate to give alphaducted in a perfluoropolyether medium facili- formylpropionic acid with the catalyst tating separation of the product from the [HRh(CO)(TPPTS)3], these authors observed an aldehyde yield comparable to that achieved catalyst. The current enthusiasm for biphase cata- with TPP, as well as an alphabeta product lysts will also benefit work being undertaken ratio of the expected order of magnitude and with ionic liquids. According to Chauvin et an even higher turnover frequency (TOF) al. [22] olefins in particular can be dimerized (Scheme 2). A [HRh(CO)(TPPTS)3]catalyst of the SAPC with this special form of biphasic reaction in molten salt media (e. g. the Dimersol@process type on SiOz led to TOF values that were higher still, exceeding those obtainable with of dimethyl butenes). 0

0

6methyl formylpmpionate

Scheme 2. Hydroformylation of methyl acrylate.

a-

124

B. Organometallic Reagents

the homogeneous single-phase [HRh(CO) (TPP)3] system by a factor of 200 depending on experimental conditions. This is impressive evidence of the fact that it is dangerous to make predictions about reaction rates with biphasic catalyst systems, and that the nature of the associated substrate must always be taken into account. The same applies to results of Chaudhari et al. [25], who proved that, in the hydroformylation of ally1 alcohol, the two-phase form of reaction affords special advantages through the reduced level of catalyst inactivation and a more effective circulation. What are also exciting are the many and varied methods by which the field of homogeneous two-phase catalysis can be expanded. Following on from biphasic carbonylation and the Heck reaction, two highly promising approaches pioneered by Beller, new results now suggest that Wacker oxidation [26] and Suzuki coupling [27] also have great potential.

References [ l ] Introduction to the topic: (a) B. Cornils, W. A. Herrmann, Aqueous-Phase Organometallic Catalysis - Concepts and Applications, VCH, Weinheim, 1998; (b) W.A. Herrmann, C. W. Kohlpaintner, Angew. Chem. 1993, 105, 1588; Angew. Chem. Int. Ed. Engl. 1993,32, 1524. [2] A NATO Advanced Research Workshop was held in AugustEeptember 1994 on the subject “Aqueous Organometallic Chemistry and Catalysis” (Debrecen, Hungary); followed by other workshops on this topic, such as the symposium “Catalysis in Multiphase Reactors”, Dec. 1994 in Lyon (France), Spring ACS Meeting in Anaheim (CA) in April 1995 and the Fall Meeting in Las Vegas, Scp. 1997. [3] R. V. Chaudhari, A. Bhattacharya, B. M. Bhanage, Catalysis Today 1995, 24, 123 [4] R. V. Chaudhari, B. M. Bhanage, R. M. Deshpande, H. Delmas, Nature 1995, 373, 501.

[5] B. Fell, C. Schobben, G. Papadogianakis,

J. Mol. Catal. A: 1995,101, 179; S . Kanagasabapathy, Z. Xia, G. Papadogianakis, B. Fell J.Prakt. Chem./Chem.-Ztg. 1995, 337, 446. P. Purwanto, H. Delmas, Catalysis Today 1995, 24, 135. H. Ding, B. E. Hanson, J. Mol. Catal. A 1995, 99, 131; T. Bartik, H. Ding, B. Bartik, B. E. Hanson, J. Mol. Catul. A 1995, 98, 117. The appropriate patents of Ruhrchemie AG are described in detail in J. Organomet. Chem. 1995,502, 177. [9] E. Montflier, G . Fremy, Y. Castanet, A. Mortreux, Angew. Chem. 1995,107, 2450. [lo] A. Behr, Henkel-Referate 1995, 31, 31. [Ill Y. Yan, H. Zhuo, Z. Jin, Fenzi Cuihua 1994, 8(2), 147, Chem. Abstr. 1994, 121, 111.875a. [12] Z. Jin, Y. Yan, H. Zhuo, B. Fell, J. Prakt. Chem./Chem. Ztg. 1996,338, 124. [13] D. E. Bergbreiter, L. Zhang, V. M. Mariagnanam, J. Amel: Chem. SOC. 1993,115,9295. [14] K. T. Wan, M.E. Davis, Nature 1994, 370, 449. [I51 J. M. Brown, S . G. Davies, Nature 1994, 370, 418. [16] NATO Advanced Research Workshop (cf. Ref. PI, p. 35). [17] I. T. Horvith, J. Ribai, Science 1994,266, 72. [18] Exxon Res. Eng. Comp. (I. T. Horvith, J. Ribai), EP-Appl. 0.633.062 (1994). [19] J. A. Gladysz, Science 1994, 266, 5 5 . [20] a) B. Cornils, E. Wiebus, Recl. Trav. Chim. Pays-Bas 1996, 115, 211; (b) G. Papadogianakis, R. A. Sheldon, New J. Chem. 1996, 20, 175. [21] M. Vogt, Dissertation, Technische Hochschule Aachen, 26. August 1991. [22] Y. Chauvin, H. Olivier in Applied Homogeneous Catalysis with Organometallic Compounds (Eds. B. Cornils, W. A. Herrmann), Vol. 1, p. 258, VCH, WeinheidGermany, 1996; Y. Chauvin, H. Olivier-Bourbigou, CHEMTECH 1995, (9), 26; Y. Chauvin, S. Einloft, H. Olivier, Znd. Eng. Chem. Res. 1995,34, 1149. [23] F. Gassner, W. Leitner, J. Chem. SOC. Chem. Commun. 1993, 1465; W. Leitner, Angew. Chem. 1995,107,2391.

Exciting Results from the Field of Homogeneous Two-Phase Catulysis [24] G. Fremy, E. Montflier, J.-F. Carpentier, Y. Castanet, A. Mortreux, Angew. Chem. 1995, 107, 1608; Angew. Chem. Znt. Ed. Engl. 1995,34, 1474. [ 2 5 ] R. M. Deshpande, S. S. Divekar, B. M. Bhanage, R. V. Chauhari, J. Mol. Catal. Letter 1992, 75, L19.

125

[26] E. Montflier, S. Tilloy, E. Blouet, Y. Barbaux, A. Mortreux, J. Mol. Catal. A 1996, 109, 27. [27] Hoechst AG (S. Haber), DE-Appl. 19527118 A1 (1997)

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Palladium-Catalyzed Amination of Aryl Halides Matthias Beller and Thomas H. Riermeier

“The discovery of truely new reactions is likely to be limited to the realm of transitionmetal organic chemistry, which will almost certainly provide us with additional ‘miracle reagents’ in the years to come”, was predicted by D. Seebach in 1990. [l] No other area of classic synthetic chemistry today still offers such innovative possibilities as metal-catalyzed processes. Transition metal-catalyzed reactions are becoming increasingly more significant not only for the synthesis of complex building blocks, but also for structurally simpler, industrially important intermediates. Since the inception of the Wacker-Hoechst oxidation [2] and the Heck reaction, [3] palladiumcatalyzed processes, in particular, have aroused the interests both of the synthetic chemist in the laboratory and also of the industrial chemist. Based on the almost unique range of catalytic transformations of palladium complexes, whose use however is often limited by low selectivities and deactivations during the reactions, a multitude of palladium supported syntheses were discovered or developed further in the last few years. [4] So far, most of the research has focussed on methods for C-C coupling. Because of the significance of unsymmetrically substituted ethers and amines in organic synthesis, the transferability of catalysis by palladium complexes of C-C couplings to the equally impor-

tant C-0 and C-N couplings is of general interest. In this respect, new methodic developments for hetero Heck reactions leading to aromatic amines, which are important substructures in natural products as well as industrial chemicals are noteworthy. Palladium-catalyzed C-N bond-forming coupling processes were first reported by Migita and coworkers [5]. Unfortunately the original procedure applies toxic and air sensitive tributyl-N,N-diethylaminostannane as transamination reagent (Scheme 1). According to investigations by Hartwig et al. [6a] the actual catalytically active species in the amination reaction seems to be a palladium(0)-bis(tri-o-tolylphosphine) complex. The catalytic cycle starts with an oxidative addition of the palladium(0) complex into the aryl-halogen bond. Then the resulting arylpalladium(I1) complex reacts with the tin amide under transmetalation; this step is postulated

0 Br I

+ B&SnNEtz

R

[‘dl

100 “C

0 PEt

+ B&SnB

R

Scheme 1. [Pd] = PdC12[P(o-tolyl)3]2. R = H, 2-CH3, 3-CH3,4-CH3, 4-OCH3,4-COCH3, 4-NO2, 4-N(CH3)2.

Palladium-Catalyzed Amination of Aryl Halides

127

to be rate determining. The subsequent reduc- shortly afterwards the first catalytic aminative elimination leads back to the palladium(0) tions of aryl bromides with free amines. The catalyst. Recent investigations show that in ad- palladium-catalyzed reactions occur in the dition to tri-o-tolylphosphine complexes, sim- presence of stoichiometric amounts of a steripler arylpalladium(I1)-bis(tripheny1phosphine) cally hindered base such as NaOtBu in toluene complexes also react with alkali metal amides or tetrahydrofuran at temperatures of 65to form amido complexes, which give access 100°C (Scheme 3). More recently Buchwald et al. have been able to expand this reaction to arylamines by reductive elimination. [7] By clever coupling of a transamination protocol to aryl iodides. [lo] reaction of tributyl-N,N-diethylaminostan- The arylamines are generally formed in nane with higher boiling amines with palla- good yields (Table 1). Dehalogenation products dium catalysis, Buchwald and Guram suc- are the only by-products observed, which proceeded in extending the method (Scheme 2). baly arise from base-induced p-hydride elimi[6b] It was shown that secondary aliphatic nation of the amido arylpalladium complex and aromatic amines react with substituted and subsequent reduction. Interestingly, the aryl bromides to afford the corresponding ary- base employed has a decisive influence on lamines in good yields. As in the classic Heck the course of the reaction. In the amination reaction, depending on the substitution pattern of 1-bromo-4-n-butylbenzene with free amiof the arene, electron acceptor substituents nes in the presence of silyl amides as base in contrast to the coupling with tin amides promote the reactivity of the aryl bromide. Clearly, the use of stoichiometric amounts the rate-determining step in the catalytic of organo tin compounds is the main disad- cycle is the oxidative addition of bis(trivantage of this type of C-N coupling reaction o-tolylphosphine)palladium(O) to the aryl both for ecological reasons and with regard to halide. However, when LiOtBu is used as practicability. Thus, from an industrial point base, the formation and reductive elimination of view the aim was to replace the tin amides of the amido arylpalladium complex is deciby simpler amino sources, ideally the amines sive for the rate of the reaction. In the prethemselves. Again independently, Buchwald sence of NaOtBu both reaction steps seem to et al. [8] and Hartwig et al. [9] reported take place at similar rates. [9]

Rn

80 "C

Scheme 2. [Pd] = PdCl:![P(o-tolyl)3]2. R = 4-CH3,3-CH3,4-CF3,3-OCH3,4-C02Et; R' = CH2C&, C6H5; R = H, CH3.

b X

R

+ HNRR" + NaOBu

-

NRR

[Pdl

+

65- 100°C

NaX

+

t-BuO'H

R

Scheme 3. [Pd] = PdC12[P(o-tolyl)3]2. X = Br, I; R = 4-CdH9, 4-CF3, 4-OCH3, 4-CsH5, 4-(CH&N; R' = C6H5, C6H13; R = H, CH3; R'-R = H ~ C ( C H ~ ) ~ C H ~ZC, C H Z N ( C H ~ ) C H ~ C H ~ .

128

B. Organometallic Reagents

As can be seen from Table 1 sodium tert- research groups - appeared in the literature: butoxide gives similar results compared to Zhao et al. (Roche Bioscience) demonstrated lithium amides as base (entries 1 and 2). elegantly the synthetic potential of the aminaBoth are superior to lithium tert-butoxide tion reaction for the synthesis of various N(entries 3 and 4). Since NaOtBu is easier to arylpiperazines. [ 111 In the case of piperazine handle it seems to be the base of choice for itself, the appropiate choice of reaction stoithis reaction, With tri-o-tolylphosphine as chiometry leads to either a symmetrical ligand the procedure is limited to secondary N,N’-bisarylpiperazine or N-monoarylpiperaamines. Nevertheless, some application of zine in good yield. Amination reactions with this new method - mainly from industrial C-substituted unsymmetrical piperazines proTable I . Palladium-catalyzed reactions of aryl bromides and iodides with (o-tolyl)3P palladium complexes. Entry

Aryl halide

Base

Amine

/o”‘

nBu

B

u

e

N

3

5

89

NaOtBu

n

B

u

e

N

3

5

89

LiN( SiMe3)2

40

LiOtBu

<2

NaOtBu

88

NaOtBu

89

NaOtBu

79

flBr

nB

nBr

Ph

/o”‘

m‘ PhOC

Yield [%]

n

flBr

flBr

mol% Pd

LiN(SiMe&

nBu

nB

Arylamine

F3cuB‘

9

NaOtBu

67

NaOtBu

79

a‘wB

Me

Me’

Go

Me0

NaOtBu

M

e

O

G

N

c

O

1

66

Palladium-Catalyzed Amination of Aryl Halides

ceeded with high regioselectivity, allowing facile preperation of several novel arylpiperazines. Two other research groups, Ward et al. (Boehringer Ingelheim Pharmaceuticals) and Willoughby et al. (Merck Research Laboratories) succeded in expanding the amination protocol to the solid phase synthesis of aryl amines. [12] Thus, this new reaction was already added to the tools of combinatorial synthesis. Extending the intermolecular coupling, dihydroindoles (Scheme 4), dihydroquinolines, and other N-heterocycles were successfully synthesized by simple intramolecular trapping reactions, starting from alkylamino substituted aryl bromides. [8] Intramolecular amination can be achieved in the presence of tetrakis(tripheny1phosphine)palladium as catalyst and stoichiometric amounts of base in toluene. Here, best results are obtained with mixtures of NaOtBu and potassium carbonate. The catalysts used for the aforementioned aminations - usually 1 to 5 mol% palladium - contained monodentate triarylphosphines especially tri-o-tolylphosphine as ligands. In case of tri-o-tolylphosphine the steric bulk leads to superior reactivity by favoring low coordination numbers at the metal center. Studies from the groups of Buchwald [13] and Hartwig [14] of late-transition metal amido complexes led to new second-generation aryl halide amination catalysts based on chelating bisphosphine ligands. While Hartwig used a 1,1'-bis(dipheny1phosphino)ferrocene ligand Buchwald employed BINAP as ligand. As shown in Table 2 the new catalyst system works efficiently for the cross coup-

129

ling of a variety of primary amines and secondary amines with both aryl bromides as well as aryl iodides. More recently, the aryl amination methodology was extended to the use of aryl triflates using chelating ligands. [ 15a, b] Because of the diversity of available phenols this extension of the reaction protocol is of synthetic value on laboratory scale. Noteworthy, are the superior yields for coupling of amines with ortho-substituted halides and halopyridines. [15c] In case of the synthesis of aminopyridines the improved catalyst activity is explained by the ability of chelating ligands to prevent formation of bispyridyl palladium complexes that terminate the catalytic cycle. Interestingly, electron rich aryl bromides (entry 2) gave similar high yields as electron poor aryl halides (entry 1). The sterically hindered aryl bromide 1bromo-2,5 -dimethylbenzene can be coupled with N-methylpiperazine even in the presence of just 0.05 mol % palladium (entry 4). Thus, catalyst turnover numbers up to 2000 were realized for the first time. When primary amines are used, just small ammounts of double arylated products were detected. Although the reported method give high yields for aminations of aryl bromides and aryl iodides, clearly, an extension of the methodology towards chloroarenes as starting materials is of high interest due to their availability and low cost. Thus, we studied the coupling reaction of 4-trifluoromethyl-1-chlorobenzene with piperidine in the presence of new palladium catalysts (palladacycles, e. g. trans-dib-acetate)-bis[o(di-o-toly1phosphino)benzyl]dipalladium(lI)) and additional bromide ions as co-catalysts [16] as model reaction (Scheme 5 ) [17]. Crucial for the success of the C-N bond forming reaction is the use of potassium tert-butoxide as base and reaction temperatures > 120 "C. Turnover numbers up to 900 and yields up to 80 % have been obtained for the amination of 4 -trifluoromethyl-1-chlorobenzene. Small amounts of the meta-regioisomere are observed. This is explained by aryne

rNHBn Pd(PPh3h

Br

NaOBu, KzC03 toluene

\

Bn

Scheme 4. Intramolecular palladium-catalyzed amination of aryl halides.

130

B. Organometallic Reagents

Table 2. Aminations of aryl bromides and iodides catalyzed by palladium complexes with chelating ligands ( ‘second-generation catalysts’).

Entry

Aryl halide

1 NC

2

&

mol% Pd

Yield [%I

NaOtBu

0.5

98

NaOtBu

0.5

95

Amine

Base

nHexNH2

nHexNH2

kr @

6

H

o

M

e

NaOtBu

7

D’ Jyr QJBr

H2N-Ph

NaOtBu

HzN-Ph

NaOtBu

nBuNH2

DBr

PhOC

9

94

Me

5

92

DNHPh 5

94

5

96

5

84

Ph

NaOtBu PhOC

PhOC

8

Q”’ DMPh 0.05

Me

Me

Ph

94

Me

Me

5

VPh 0.5

NaOtBu

Hb(Ph Me

Me

4

Lit.

Me0

Me0

3

Arylamine

nN”r

/BuNHz

NaOtBu

H

NaOtBu

1

87

NaOtBu

1

75

C

O

PhOC

QBr

10

intermediates which can be formed under the conditions. Apart from the aforementioned results the usefulness of palladium-catalyzed aryl aminations is shown by applications in natural product synthesis. [18] In this regard the total synthesis of the toad poison dehydrobufetenine is

of particular interest. Here, the key step of the synthesis is the intramolecular amination of an aryl iodide (Scheme 6). In conclusion, the palladium-catalyzed amination of aryl halides, discovered by Migita et al. and developed by Buchwald at al. and Hartwig et al. is now a powerful1 tool for or-

a'' +

R

aNR'R'' Palladium-Catalyzed Amination of Aryl Halides

palladacycle 135°C

H( R' ~

~

'

1

KOtBu

131

+ KCI + HOfBu

R

Scheme 5. Palladacycle: trans-di~-acetato)-bis[o(di-o-tolylphosphino)benzyl]dipa~ladium(II);R = CF3, COPh; R' = C4H9, C6H5; R = C4H9, CH3; R ' - R = H2C(CH2)3CH2, H ~ C C H Z O C H ~ C H ~ .

qBr OMe

H Dehydrobufotenine

1

1. BBr3 2. Me1 50%

10 mol% Pd(PPh&

M e O d N H M e toluene, K2CO3, NEt3 200 "C CO7Et

CO2Et 81 %

Scheme 6. Total synthesis of dehydrobufotenine by Buchwald et al. [181

ganic synthesis. The availibility of a variety of nometallic chemistry and catalysis offers secondary and primary amines together with manifold possibilities. the broad range of aryl halides - even aryl chlorides - allows the synthesis of complex arylamines. First applications of this method, References both by research groups from industry as well as universities, showed the importance [I] D. Seebach, Angew. Chem. 1990, 102, 1363; Angew. Chem. Int. Ed. Engl. 1990, 29, 1320. such C-N coupling reactions. [2] J. Tsuji in Comprehensive Organic Synthesis, Interestingly, a first successful extension of Vol. 7 (Eds.: B. M. Trost, J. Fleming, S . V. the amination to oxygen nucleophils has Ley), Pergamon, Oxford, 1991, p. 449. been reported very recently. [19] Still at the [3] Recent reviews: a) R. F. Heck, Palladium beginning, this discovery opens the door to Reagents in Organic Synthesis, Academic C-0 coupling reactions for the synthesis of Press, London, 1985; b) R. F. Heck in B. M. arylethers, including oxygen heterocycles. Trost and I. F l e m i n g (Eds.), Comprehensive It becomes evident that there is still a need Organic Synthesis, Vol. 4 , Pergamon Press, for practical catalytic methods also for apparOxford, 1991, p. 833; c) W. Cabri and I. Canently simple molecules such as arylamines. diani, Acc. Chem. Res 1995, 28, 2; d) The future will show that in this respect orga-

132

B. Organometallic Reagents

J. Tsuji, Palladium Reagents and Catalysts Innovations in Organic Synthesis, Wiley, ChiChester, UK, 1995; e) W. A. Herrmann, in B. Cornils and W. A. Henmann (Eds.), Applied Homogeneous Catalysis, VCH, Weinheim, 1996, p. 712; f) A. de Meijere, F. Meyer, Angew. Chem 1994, 106, 2437; Angew. Chem. Int. Ed. Engl. 1994,33, 2379. [4] Recent examples: a) H. M. R. Hoffmann, A. R. Otte, A. Wilde, Angew. Chem. 1992,104,224; Angew. Chem. Int. Ed. En$. 1992, 31, 2379; b) T. I. Wallow, B. M. Novak, J. Org. Chem. 1994, 59, 5034; c) T. Ohishi, J. Yamada, Y. Inui, T. Sakaguchi, M. Yamashita, J. Org. Chem. 1994, 59, 7521; d) G. Dyker, Angew. Chem. 1994, 106, 117; Angew. Chem. Int. Ed. Engl. 1994, 33, 117; e) E. Drent, J. A. M. van Broekhooven, M. J. Doyle, J. Organomet. Chem. 1991, 417, 235; f) L. F. Tietze, R. Schimpf, Angew. Chem. 1994, 106, 1138; Angew. Chem. Int. Ed. Engl. 1994, 33, 1089; g) Y. Sato, S. Nukui, M. Sodeoka, M. Shibasaki, Tetrahedron 1994, 50, 371; h) Y. Ben-David, M. Portnoy, D. Milstein, J. Am. Chem. SOC. 1989, 111, 8742; i) W. Oppolzer, Pure Appl. Chem. 1990, 62, 1941; j) S. C. A. Nefkens, M. Sperrle, G. Consiglio, Angew. Chem. 1993, 105, 1837; Angew. Chem. Int. Ed. Engl. 1993, 32, 1719; k) B. M. Trost, Angew. Chem. 1995,107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259; 1) C. CopCret, S. Ma, E. Negishi, Angew. Chem. 1996,108, 2255; Angew. Chem. Int. Ed. Engl. 1996, 35, 2125; m) L. F. Tietze, T. Nobel, M. Spescha, Angew. Chem. 1996, 108, 2385; Angew. Chem. Int. Ed. Engl. 1996, 35, 2259; n) M. Brenner, G. Mayer, A. Terpin. W. Steglich, Chem. Eu. J. 1997, 3, 70; 0)A. Heim, A. Terpin, W. Steglich, Angew. Chem. 1997, 109, 158; Angew. Chem. Int. Ed. Engl. 1997, 36, 155. [S] M. Kosugi, M. Kameyama, T. Migita, Chern. Lett. 1983, 927.

161 a) F. Paul, J. Patt, J. F. Hartwig, J. Am. Chem. SOC. 1994, 116, 5969; b) A. S. Guram, S. L. Buchwald, J. Am. Chem. SOC. 1994, 116, 7901. [7] M. S. Driver, J. F. Hartwig, J. Am. Chem. SOC. 1995,117, 4708. [8] A. S. Guram. R. A. Rennels, S. L. Buchwald, Angew. Chem. 1995, 107, 1456; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348. [9] J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609. [lo] J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1996,6I, 1133. [ l l ] S. Zhao, A. K. Miller, J. Berger, L. A. Flippin, Tetrahedron Lett. 1996, 37, 4463. [12] a) Y. D. Ward, V. Farina, Tetrahedron Lett. 1996, 37, 6993; b) C. A. Willoughby, K. T. Chapman, Tetrahedron Lett. 1996, 37, 7 181. [13] J. P. Wolfe, S. Wagaw, S. L. Buchwald, J. Am. Chem. SOC.1996, 118,7215. [14] M. S. Driver, J. F. Hartwig, J. Am. Chem. SOC. 1996,118,7217. [15] a) J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, 62, 1264; b) J. Louie, M. S. Driver, B. C. Hamann, J. F. Hartwig, J. Org. Chem. 1997, 62, 1268; c) S. Wagaw, S. L. Buchwald, J. Org. Chem. 1996, 61, 7240. [16] a) W. A. Henmann, C. BroBmer, K. Ofele, C.-P. Reisinger, T. Priermeier, M. Beller, H. Fischer, Angew. Chem. 1995, 107, 1989; Angew. Chem. lnt. Ed. Engl. 1995, 34, 1844; b) W. A. Herrmann, C. BroBmer, C.-P. Reisinger, T. H. Riermeier, K. Ofele, M. Beller, Chem. Eus J. 1997, in press. [17] M. Beller, T. H. Riermeier, C.-P. Reisinger, W. A. Henmann, Tetrahedron Lett. 1997, 38, 2073. [18] A. J. Peat, S. L. Buchwald, J. Am. Chem. SOC. 1996, 118, 1028. [19] a) M. Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. SOC. 1996, 118, 10333; b) G. Mann, J. F. Hartwig, J. Am. Chem. SOC. 1996,118, 13109.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

The Metal-mediated Oxidation of Organic Substrates via Organometallic Intermediates: Recent Developments and Questions of Dispute Jorg Sundermeyer

The complex-catalyzed oxyfunctionalization of organic substrates is of fundamental importance, for example in chemical processes of nature, in the synthesis of fine chemicals, and in the production of commodity chemicals. [ 11 Regardless of the results achieved in this interdisciplinary area of research, there is still a great lack of experimental evidence that could help to settle very controversial debate [2] about the mechanism of the metalmediated C-0 bond formation. The catalytically active complexes are usually differentiated on the basis of their mechanisms. [le] Thus, there is a group of metal complexes that catalyzes the homolytic cleavage the 0-0 bond of peroxides and triplet oxygen, a second group that induces its heterolytic cleavage, and a third that has at its disposal polarizable and transferable 0x0 functions such as M-06-, M=O, and M=O". The first group includes low- and high-spin complexes of Fe, Co, Ni, Mn, Cu, and other biologically relevant metals, which, for example, form "oxen" complexes [M=O] with transferable oxygen atom [ 11 and control the radical chain initiations as well as the propagation and inhibition of autoxidation reactions. In contrast, do complexes of the second category (e.8. those of Ti, V, Mo, W, and Re) are diamagnetic and strong Lewis acids. These compounds activate H202 or alkyl hydroperoxides by formation of reac-

tive d-block metal peracids [M-OOH], peroxides [M(q2-02)], or peracid esters [M-OOR], that is, they polarize the 0-0 bond for nucleophilic attack of the substrate at the peroxidic oxygen atom. In contrast, electron-rich transition metals (Rh, Ir, Pd, Pt) cause an inverse polarization, which makes an electrophilic attack at the peroxy function more favourable. The group of reactive do 0x0 complexes includes, for example, [Mn0&, Ru04 and OsO4 well-established for hydroxylations. Not so long ago the suggestion that organometallic intermediates might participate in polar oxygen-transfer reactions would have been refuted and considered as unrealistic. The knowledge accumulated over the last few years about 0x0 and peroxo complexes functionalized with organometallic co-ligands demonstrates that, in particular, the relatively nonpolar M-C bonds in complexes of molybdenum(VI), tungsten(VI), and rhenium(VI1) can be stable under catalytic conditions (protic medium, hydroperoxides, 02), and that they are sometimes essential for the activity and lifetime of a catalyst. In this respect the oxidation catalyst methyltrioxorhenium (MTO)/ H2OzltBuOH developed and intensely studied by Herrmann et al. should be considered a breakthrough in homogeneous oxidation catalysis. [3] They have succeeded in bridging the gap between the Mimoun reagents of the type

134

B. Organometallic Reagents

1 (L = HMPA, DMF, etc.) [4] well established for epoxidations, and the classic Milas reagent Os04/H202/tBuOH [5] for the catalytic syn hydroxylation of olefins. The isolation and complete characterization of the catalytically active species 2, R = CH3, [3b] in the catalyst system RRe03/H202/tBuOH is noteworthy and stimulates comment. Compounds 1 and 2 have the same pentagonal-bipyramidal molecular structure; [3b, 4c] however, the equatorial [do-Mo-L] building block in 1 is replaced by the isoelectronic [do-Re-R] fragment in 2. The symmetry and relative arrangement of all frontier orbitals should be similar in the two compounds. This relationship between 1 and 2 is reflected in the similar reactivity of the two compounds, particularly in the anti hydroxylation of alkenes by means of the opening of epoxides formed as intermediates. However, it is already apparent that the Herrmann reagent excels as a result of higher reactivity (oxyfunctionalization of certain alkynes, similar as OsO4 [5d]) and high catalytic activity, whereas the readily prepared Mimoun reagent has proved successful primarily for stoichiometric reactions. [2a, 41 0

0

1

2

Why has it taken a period of more than twenty years since the discovery of Mimoun type complexes that the quality of isoelectronic rhenium 0x0 complexes for catalytic 0transfer reactions has been recognized and proven? The key to success with 2 lies in its organometallic functionality. More polar ReX groups (X = OR, NR2, C1, etc.) are generally more rapidly protolyzed to give catalytically inactive compounds than the relatively nonpolar Re-R unit in 2, which is stable

under catalytic conditions (weakly acidic, protic medium). The hydrolytic instability of the peroxidic function [Re(v2-02)] in absence of an organyl group at the rhenium center is clearly demonstrated by the peroxo perrhenic acid { Re0(02)2(H20)}2(1(-0) [3c] which is structurally related with 2. This remarkable peroxo complex catalyses the same oxidation reactions as Re0(02)2(H20)(CH3), but water, the reaction product from H202 strongly inhibits the catalytic cycle due to the formation of the catalytically inactive hydrolysis product perrhenic acid Re03(0H). The MTO/H202 system has been successfully used not only for epoxidations [3a] but for many other oxidations, the most prominent being the arene oxidation [3d], the Baeyer-Villiger oxidation [3e] and the oxidation of carbonyl complexes [3c]. Other organometallic compounds have also proven their value as catalyst precursors in the activation of hydroperoxides. For example, Trost and Bergmann have reported [6] that molybdenum complex 3 catalyzes the epoxidation of olefins with alkyl hydroperoxides ROOH. In sharp contrast to 2, 3 is not capable of activating H202, conversely 2 cannot activate alkyl hydroperoxides. The catalytically active species in the ROOH/3/olefin system has not been characterized unambiguously as yet; the authors report, however, that the surprisingly catalytic inactive peroxo complex 4 forms from 3 and ROOH or H202 in a deactivating side reaction. Complexes with a [(q5-C5Me5)Mo(v2-O0R)] building block could be considered as a plausible organometallic intermediate for the oxygen-transfer step.

U

3

4

5

The Metal-mediated Oxidation of Organic Substrates via Organometallic Intermediates:

6

Y

+-\\u

Y

135

U

7

followed by a 1,3-dipolar cycloinsertion with the formation of a metalladioxacyclopentane and its cycloreversion (steps B-D in Scheme 1). P a l The question of whether the metal center adopts only the activating role of a n-acidic substituent, analogous so that of a -I, -M substituent in percarboxylic acids or persulfonic acids, or whether in an equilibrium on account of unoccupied metal acceptor orbitals it forms weak interactions [lo] with the olefin to be oxidized, remains a point of controversal debate. However an increasing number of recent experimental and theoretical studies support the idea of direct nucleophilic attack of the olefin HOMO into a low-lying U*O-O orbital (LUMO) of an q2-metal-bonded peroxidic function [ 113. The oxenoid [ 121 character of the two coordinate oxygen atom in three membered rings [M(q2-00E)] is strongly enhanced by an electron withdrawing substituent E+ on the adjacent peroxidic oxygen atom. This substituent is polarizing the nonpolar 0-0 bond of the less reactive oxenoid [M(q2-02], thus faciliating a reaction of S N ~ type centred at the less substituted oxygen the [M(q2-OOE)] moiety [ l l ] . The polarizing substituent E+ may be a proton [S], an alkyl group R+ [12], an acyl group or the Lewis acidic metal center of a second coordinatively unsaturated transition metal peroxide as found in complexes with [M@,q2-02)M] functionality. [ 131 How easily well-established mechanistic ideas about the metal-mediated oxyfunctionalization of organic substrates can begin to falter and consolidate again is also illustrated in a kinetic study by Gobel and Sharpless on Scheme 1. Mechanistic alternatives for polar oxy- the influence of the reaction temperature on the enantioselectivity of the asymmetric syn gen-transfer reactions of peroxo complexes.

The stability of M-C bonds in the presence of hydroperoxides could also be confirmed for the structurally related alkyl complexes 5 (M = Mo, W; R = CH3, CH2SiMe3). [7] An intramolecular [1,2] shift of the alkyl groups to one of the peroxidic oxygen atoms similar to that which occurs in the tantalocene complexes, for example 6, investigated in detail by Bercaw et al. [S] does not appear to be a preferred reaction pathway in analogous complexes of Mo, W, and Re. However, Bercaw et al. were able to show that the rearrangement of 6 into the alkoxy complex 7 does not take place either spontaneously or according to a first-order rate law, but is initiated by the attack of an electrophile (e. g. H+) at the per0x0 group which leads to substantial polarization of the 0-0 bond. In spite of intensive efforts, the knowledge accumulated to date about polar oxygen-transfer reactions on peroxo, hydroperoxo, and alkylperoxo complexes is not yet sufficient to decide whether to agree with the direct attack of the olefin at the positively polarized oxygen center [9] (“butterfly mechanism” without an organometallic intermediate, step A in Scheme 1) discussed by Chong and Sharpless, or with the mechanism postulated by Mimoun based on an olefin coordination,

136

B. Organornetallic Reagents

hydroxylation of olefins with chirally modified alkaloid-0s04 complexes. [ 141 The Eyring plots for several olefin/alkaloid combinations provide indications of a multistep mechanism with at least two diastereoselective steps. [14a] Thus, a concerted [2+31 addition mechanism (pathway A in Scheme 2) should be ruled out, a fact which can be considered as evidence for but not proof of the two diastereomeric oxametallacyclobutanes discussed as intermediates by Sharpless (step B in Scheme 2) [14b] and their stereoselective [1,2] rearrangement into the glycolate complexes 8 (step C in Scheme 2).

Scheme 2. Mechanistic alternatives for syn hydroxylations of olefins with OsO4 complexes.

A few model reactions known from the literature also support the idea of an oxametallacyclobutane intermediate such as the formation of the irida(II1)oxetane 10 modeling the metal-mediated transfer of oxygen to a coordinated olefin (step B). This reaction is explained by autoxidation of the iridium(1)-cyclooctadiene complex 9 via the plausible dinuclear oxoiridium(II1) intermediate. [ 151 A model reaction related to step C in Scheme 2 is the photochemically induced [ 1,2] migratory insertion of metal bonded aryl groups to a metal 0x0 group in hydrido trispyrazolylborato rhenium(V) complexes. [ 161

,Ph (HBpz,) R e x 0

\c,

pz = I-pyrazolyl

/

PY

(HBpz,) Re-OPh \

CI

There is also theoretical evidence supporting oxametallacyclobutanes as intermediates in a two step (B and C) mechanism as they are minima and not too high in energy on the potential energy surface. [17] Very recently however, three more detailed and independently performed theoretical studies [ 181 clearly demonstrate, that activation barriers for a two step [2 + 21 addition/[ 1,2] rearrangement mechanism are definitively too high in energy. This again together with experimentally kinetic isotope effects observed by Corey et al. [I91 suggests that osmylation reactions proceed by a more or less concerted [ 3 + 2 ] pathway as originally suggested by Boseken [20a] and Criegee. [20b] This point is still a topic of ongoing debate [21]. A third class of mechanistically not well understood oxidation reactions, that might involve organometallic intermediates is the allylic oxidation of olefins, technically realized in the important catalytic oxidation of propene to acrolein by molecular oxygen on a heterogeneous bismuth molybdate contact (SOH10 process). According to Grasselli et al. [22] a Bi(V)-0 functionality is believed to be responsible for the allylic hydrogen abStrdCtion from propene while a high valent molybdenum oxide site is believed to be responsible for the redox 0-transfer reaction with the allyl radicals initially formed. The key step of C-0 bond formation could be rationalized by direct attack of the allyl radical at the oxygen atom of a d’ metal 0x0 species (step A in Scheme 3).

V-,ir (p3o9) 9

hv. pyridine

10

The Metal-mediated Oxidation of Organic Substrates via Organometallic Intermediates:

Scheme 3. Mechanistic alternatives for allylic oxidation of olefins, e.g. propene, at a Mo03Bi203 catalyst site.

On the other hand a coordinatively unsaturated paramagnetic d’ metal center could oxidatively add the allyl radical at the metal center to form a labile do n-ally1 0x0 species as organometallic intermediate (step B). The latter may rearrange via a a-ally1 intermediate to a d2 allyloxy species (step D). The latter is believed to convert to acrolein and a reduced metal center via an /3-hydrogen abstraction by the metal center. In an attempt to gain insight into fundamental reactions involved in this catalytic cycle, some authentic do allyl 0x0 complexes of rhenium [23] and tungsten [24] have been prepared. So far reactivity studies of these could not yet accumulate any proof for an [ 1,2] allyl migration to terminally bonded 0x0 group (step D). However these and other unsaturated organometallic compounds prooved to be interesting substrates in selective photooxygenation reactions with singlet oxygen. [24b] Whereas there is still an immense lack of knowledge whether organometallic intermediates play a crucial role in 0-transfer reactions of metal 0x0 and peroxo complexes, our understanding for the mechanisms that control oxidation reactions of authentic organometallic compounds, e. g. intermediates in organic synthesis, was put into more precise terms in recent years. In this respect a combined theoretical and experimental study of Boche et al. [12] provided good evidence that lithiation [12, 251 and titanation [26] of an alkyl hydroperoxide leads to an increase of the electrophilic character of the formally anionic oxygen atom thus making it a better

137

oxenoid than the protonated parent. It is known for a long time and even of technical importance [27] that alkylhydroperoxides and alcohols are products from autoxidations of reactive organometallic intermediates. It was suggested that alkylperoxy species, the formal insertion products of 0 2 into the M-C bond, are preferably formed on radical chain pathways and that they may act as oxygen transfer reagents to the remaining part of polar M-C bonds within the reaction mixture. Progress in this field arises from a better understanding for this second oxygen transfer step. It can be envisaged as polar S N type ~ of reaction centred at the formally anionic oxygen atom of the oxenoid [M(q2-00R)] (M = Li, Al, Mg, Ti etc.) rather than as an electron transfer/recombination sequence. The configuration of the attacking carbon nucleophile is retained. The attack is directed into the low-lying @O-O orbital of the oxenoid. [11, 12, 251 Progress from a synthetic point of view has been achieved in the selective oxidation of alkyl zinc reagents with oxygen in perfluorohexane solutions to give good yields of either hydroperoxides or alcohols. [28] As many zinc organometallics are easily obtained from olefins via a hydroborationhoron-zinc exchange sequence or by a nickel catalyzed hydro- or carbozincation reaction, this method may proof its synthetic potential in the future development.

References [ l ] See also the Highlight from C. Bolm, Angew. Chem. 1991, 103, 414-415; Angew. Chem. Int. Ed. Engl. 1991, 30, 403-404. Reviews: a) R. H. Holm, Chern. Rev. 1987, 87, 14011449; b) K. A. Jargensen, ibid. 1989, 89, 431-458; c) B. Meunier, ibid. 1992, 92, 1411-81456; d) H. Mimoun in Comprehensive Coordination Chemistry, Vol. 6 (Eds. G. Wilkinson, R. D. Gillard, J. A. McCleverty),

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B. Organometallic Reagents

368, 45-56; e) G. Parkin, J. E. Bercaw, Pergamon, Oxford, 1987, 317-410; e) R. A. Polyhedron 1988, 7, 2053-2082. Sheldon, J. K. Kochi, Metal-Catalyzed Oxida[8] a) A. van Asselt, M. S. Trimmer, L. M. Hention of Organic Compounds, Plenum, New ling, J. E. Bercaw, J. Am. Chem. SOC. 1988, York, 1981; f) G. Strukul, Catalytic Oxidations with Hydrogen Peroxide as Oxidant, 110, 8254-8255. [9] A. 0. Chong, K. B. Sharpless, J. Org. Chem. Kluwer Academic Publishers, Dordrecht, 1992. 1977, 42, 1587-1590; for q2-alkyl peroxides both reaction pathways can also be formulated. [2] a) H. Mimoun, Angew. Chem. 1982, 94, 750766; Angew. Chem. Int. Ed. Engl. 1982, 21, [ 101 pn+ d, Charge transfer interactions between ligand and metal center in do electron con734-750; b) K. A. JGrgensen, B. Schiott, figuration, without participation of metal Chem. Rev. 1990, YO, 1483-1506. d, +pn backbonding; spectroscopic indi[3] a) W. A. Herrmann, R. W. Fischer, D. W. Marz, cations: W. A. Nugent, J. Org. Chem. 1980, Angew. Chem. 1991,103, 1706-1709; Angew. Chem. Int. Ed. Engl. 1991, 30, 1638-1641; 45,4533-4534. b) W. A. Herrmann, R. W. Fischer, W. Scherer, [Ill Review: R. Curci, 0. E. Edwards in ref. [If], M. U. Rauch, Angew. Chem. 1993,105,120945-9s. 1212; Angew. Chem. Int. Ed. Engl. 1993, 32, [12] G. Boche, F. Bosold, J. C. W. Lohrenz, Angew. Chem. 1994, 106, 1228-1230; Angew. Chem. 1157-1160; c) W. A. Herrmann, J. D. G. CorInt. Ed. Engl. 1994, 33, 1161-1163, and reia, F. E. Kiihn, G. R. J. Artus, C. C. references cited therein. Romiio, Chem. EUKJ. 1996, 2, 168-173; d) W. Adam, W. A. Herrmann, J. Lin, C. R. [13] L. Salles, J.-Y. Piquemal, R. Thouvenot, C. Saha-Moller, R. W. Fischer, J. D. G. Correia, Minot, J.-M. BrCgeault, J. Mol. Catal. 1997, 117, 375-387. Angew. Chem. 1994, 106, 2545-2546; Angew. Chem. Int. Ed. Engl. 1994,33, 2475- [14] a) T. Gobel, K. B. Sharpless, Angew. Chem. 1993, 105, 1417-1418; Angew. Chem. Int. 2477; e) W. A. Herrmann, R. W. Fischer, J. D. G. Correia, J. Mol. Cat. 1994, 94, 213Ed. Engl. 1993, 32, 1329-1330; b) K. B. 223. Sharpless, A. Y. Teranishi, J.-E. Backvall, J. Am. Chem. Soc. 1977,99, 3120-3128. [4] a) H. Mimoun, I. Seree de Roch, L. Sajus, Bull. Soc. Chim. 1969, 1481-1492; b) H. [15] V. W. Day, W. G. Klemperer, S. P. Lockledge, Mimoun, I. Seree de Roch, L. Sajus, D. J. Maine, J. Am. Chem. Soc. 1990, 112, 203 1-2033. Tetrahedron 1970, 26, 37-50; c) P. J.-M. Le Carpentier, R. Schlupp, R. Weiss, Acta [16] S. N. Brown, J. M. Mayer, Organometallics 1995,14,2951-2960. Crystallogv. Sect. B 1972, 28, 1278-1288; d) Lit. [le], p. 93 f. [17] A. Veldkamp, G. Frenking, J. Am. Chem. SOC. 1994,116,4937-4946. [5] N. A. Milas, S. Sussman, J. Am. Chem. Soc. 1936, 58, 1302-1304; ibid. 1937, 59, 2345- [18] a) U. Pidun, C. Boehme, G. Frenking, Angew. 2347; b) N. A. Milas, S. Sussman, H. S. Chem. 1996, 108, 3008-3011; Angew. Chem. Int. Ed. Engl. 1996, 35, 2817-2820; b) S. Mason, ibid. 1939, 61, 1844-1847; c) R. Dapprich, G. Ujaque, F. Maseras, A. Lledbs, Criegee, Angew. Chem. 1937, 50, 153-155; D. G. Musaev, K. Morokuma, J. Am. Chem. ibid. 1938, 51, 519-520; d) Review: M. SOC.1996, 118, 11660-11661; c) M. Torrent, Schroder, Chem. Rev. 1980, 80, 187-213. L. Deng, M. Duran, M. Sola, T. Ziegler, [6] M. K. Trost, R. G. Bergman, Organometullics Organometallics 1997, 16, 13-19. 1991, 10, 1172-1178. [7] a) P. Legzdins, E. C. Phillips, S. J. Rettig, [19] E. J. Corey, M. C. Noe, M. J. Grogan, Tetrahedron Lett. 1996,37,4899-4902. L. Sinchez, J. Trotter, V. C. Yee, Organometallics 1988, 7, 1877-1878; b) P. Legzdins, [20] a) J. Boseken, Recl. Trav. Chim. 1922, 41, 199-207; b) R. Criegee, B. Marchand, H. E. C. Phillips, L. Shnchez, ibid. 1989, 8, Wannowius, Justus Liebigs Ann. Chem. 1942, 940-949; c) J. W. Faller, Y. Ma, ibid. 1988, 550,99-133. 7, 559-561; d) J. Organomet. Chem. 1989,

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[21] a) P.-0. Norrby, H. Becker, K. B. Sharpless, [24] a) J. Sundermeyer, J. Putterlik, H. Pritzkow, J. Am. Chem. SOC.1996, 118, 35-42; b) The Chem. Ber: 1993,126,289-296; b ) W. Adam, J. Putterlik, R. Schuhmann, J. Sundermeyer, controversy about the mechanism of the Jacobsen-Katsuki epoxidation has recently Organometallics 1996, 15, 4586-4596. been highlighted, while this manuscript was [25] G. Boche, K. Mobus, K. Harms, J. C. W. in print: T. Linker, Angew. Chem. 1997, 109, Lohrenz, M. Marsch, Chem. Eur: J. 1996, 2 , 2150-2151; Angew. Chem. Int. Ed. Engl. 604-607. 1997,36,2060-2062. [26] G. Boche, K. Mobus, K. Harms, M. Marsch, J. Am. Chem. SOC. 1996, 118, 2770-2771. [22] a) R. K. Grasselli, J. Chem. Edu. 1986, 63, 216-221; b) J. D. Bumngton, C. T. Kartisek, [27] The AlEt3 catalyzed oligomerization of ethene followed by an stoichiometric autoxidation R. K. Grasselli, J. Catal. 1984, 87, 363-380; with molecular oxygen leads - via Al(OR)3 c) L. C. Glaeser, J. F. Brazdil, M. A. Hazle, to even-numbered primary alcohols used in M. Mehicic, R. K. Grasselli, J. Chem. SOC., production of PVC plasticizers and biodegraFaraday Trans. I 1985, 81, 2903-2912. dable detergents. [23] W. A. Henmann, F. E. Kiihn, C. C. RomBo, H. T. Huy, J. Organomet. Chem. 1994, 481, [28] 1. Klement, H. Liitjens, P. Knochel, Tetrahedron Lett. 1995,36,3161-3164; b) I. Klement, 227-234. P. Knochel, Synlett 1995, 1113-1114.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

The Oxofunctionalization of Alkanes Oliver Reiser

The selective oxidation of alkanes remains a challenge in organic synthesis. The development of economical processes for the functionalization of hydrocarbons is of tremendous technical importance. In nature such reactions are mediated efficiently by various enzymes. The systems related to cytochrome P-450, which for example detoxify lipid-soluble compounds in the human liver, [l] have received the most attention. The fundamental problem in the functionalization of saturated hydrocarbons is that their components, carbon and hydrogen, do not have lone electron pairs, and the molecules do not have orbitals of sufficient energy that are easily accessible. Thus, very reactive reagents and/or extreme reaction conditions are typically required, for example for the oxidation of alkanes. However, the initial products are almost always more reactive than the starting compounds, and undesired side reactions may occur. Other complications arise if the molecule to be oxidized contains different types of C-H bonds. Since formation of tertiary radicals and carbenium ions is favored and they are also more stable than their secondary and primary analogues, functionalization processes that proceed via these intermediates generally have the selectivity for C atoms in the order tertiary > secondary > primary. For steric rea-

sons, however, the attack of bulky reagents at primary C atoms may be preferred; the best example known is the oxidative addition of transition metal complexes. The metal-mediated oxyfunctionalization of organic compounds, of olefins in particular, is becoming increasingly important. [2] Research on metal catalysts that activate elemental oxygen and make it usable as a selective oxidizing agent is therefore especially worthwhile. Inspired by the enzyme cytochrome P-450, in which the active center is an 0x0iron(1V) unit, researchers have examined numerous iron-containing reagents for the oxidation of alkanes. For example, the so-called Gif systems [3] developed by Barton et a]., which consist essentially of air, catalytic amounts of iron andlor zinc, acetic acid (HOAc), pyridine (py), and water, oxidize adamantane (1) to give adamantanone (2) as the major product along with 2- (3) and 1-adamantanol(4) as side products.

g 1

oxidation-

go+ goH+ OH

2

3

4

The oxidizing species are postulated to be [Fe11Fe11120(0Ac)6(py)3.~] [4] and heteroaromatic N-oxide radical cations, [5] in keeping with the necessity of a nitrogen base compo-

141

The Oxofunctionalization of Alkanes

nent such as pyridine. Apparently these species attack C-H bonds on secondary C atoms in marked preference to those on primary and tertiary C atoms. Mechanistic studies suggest that the oxidation yielding ketones like 2 does not proceed via the corresponding alcohols 3 and 4. Turnover rates of over 3000 and almost quantitative reactions have been achieved with several Gif reagents. One disadvantage is that the reactions can be conducted only up to 10-15 % conversion to avoid considerable amounts of side products. The allotropic form of oxygen, ozone, can also be employed for the oxidation of saturated hydrocarbons. The reactivity of ozone without additional reagents is not sufficient for the preparative functionalization of alkanes in solution; however, its reactivity is increased substantially by the addition of iron(II1) chloride [6] or antimony pentafluoride. [7] The dry ozonation variant [8] of Mazur et al. [9] by which alkanes are hydroxylated at tertiary C atoms with high selectivities and yields, was shown to be especially useful. According to this method, silica gel is coated with roughly 1 wt% of the substrate, cooled to -78”C, saturated with ozone, and subsequently allowed to warm to room temperature within 0.5-2 h. Adamantane (1) is converted almost quantitatively into 1-adamantanol (4) in this way (Table l), and this method of oxyfunctionalization has been applied successfully even on certain steroids. [ 101 The selective oxidation of hydrocarbons by dry ozonation is not restricted to reaction at tertiary C atoms: the CH2 groups adjacent to a cyclopropane ring are smoothly converted into carbonyl groups. This “cyclopropyl activation” can be explained by the well-known ability of the cyclopropyl group to effectively stabilize a neighboring R3C+ center. Although in the oxidation of alkanes with ozone the first intermediate, the hydrotrioxide, [ 111 does not arise from carbenium ions, the effect of polarity upon attack of the electronegative ozone molecule, either as a radical or by 1,3-dipolar

addition, at the C-H bond certainly leads to development of a positive charge on the pertinent C atom. [ 111 Dry ozonation was the first efficient method for the a-functionalization of cyclopropylidene hydrocarbons and served as the key step in a synthesis of [6]rotane [ 121 (7) via the tetraspiro hydrocarbon 5 . [ 131 The ketonation of cyclopropylidene hydrocarbons with ruthenium tetraoxide (generated in situ from RuC13 and NaI04 in CH3CNI CCWaqueous phosphate buffer) [ 141 proved to be more convenient and better suited for large-scale reactions. This oxidation of organic substrates originally developed by K. B. Sharpless et al. [ 151 for the oxidative cleavage of alkenes can also be applied for the selective hydroxylation of tertiary C-H groups; [ 14c, d] for example, adamantane (1) is converted into 1- adamantanol (4) in 75 % yield. [14d] 0

5

6

7

Since the development of a handy, even large-scale method for the generation of dimethyldioxirane (9a), [16] it has become known best as a reagent for the epoxidation of double bonds. [17] Its application for the selective hydroxylation of C-H bonds at tertiary C atoms is less well known. For example, the reaction of 1 with 9a as the oxidizing agent provides 4 with only minor amounts (< 3 %) of side products. [18]

Oa: R = CH3

9a: R = CH,

0b: R = CF3

9b: R = CF,

Oxidations with 9a proceed stereoselectively with retention, as the reactions with cis-decalin (10) and trans-decalin (12) de-

142

B. Organometallic Reagents

monstrate. Remarkably, the oxidation of 10 is faster than that of 12: after a reaction time of 17 h 11 had been formed in 84 % yield, 13 in only 20 %. This indicates that the oxidation of equatorial positions is preferred to that of axial positions (Table 1). oxidation-

& H

10

11

+-& oxidation

H

H 12

13

An oxidizing agent up to 7000 times more reactive than 9a is methyl(trifluoromethy1)dioxirane (9b), which not only hydroxylates tertiary C-H positions (Table 1) but also converts secondary C-H groups into carbonyl functions. As an illustration, the oxidation of cyclohexane at -22 "C afforded cyclohexa-

none in yields of over 98 % in only 18 min. [19] With this reagent not only the monohydroxylation of adamantane (1) providing 4 proceeds in excellent yield, but also the two-, three-, and even four-fold hydroxylation of the bridgehead positions of adamantane. [20] Remarkably, 9b is stable towards acids like trifluoroacetic acid, trifluoromethanesulfonic acid, and sulfuric acid. Based on this observation, Asensio et al. employed 9b for the oxidation of tertiary C-H positions in the presence of amino groups. [21] Their trick was protecting the amino group as an ammonium tetrafluoroborate by treatment with tetrafluoroboric acid. In the subsequent reaction with 9b, the C-H bond at a tertiary C atom, which must be at least two C atoms removed from the ammonium group, is converted into a hydroxyl or acetamido function in excellent yield. C-H bonds on secondary C atoms in acyclic amines such as 14 (R = Me, Et, Pr) may also be oxidized in this way to afford the corresponding ketones 15; the oxygen insertion takes place exclusively at the E-

Table I . Comparison of reagents for the oxidation of adamantane (1) and decalins 10 and 12.

Substrate

Oxidation agent

Product

t [hl TWI

Yield

1 1 1 1 1 1 1 1 10 10 10 10 10 12 12 12 12

031Si02 RuC13lNaI04 9a 9b F2lH201CH3CN hdTCB102 19a 19b 03/Si02 9a 9b 19a 19b 03/Si02 9a 9b 19a

4 4 4 4 4

0.51-78 to 25 3-7/90 18/22 11-22

99 75 87 92 80 60118 90 90 99 84 91 85 88 72 20 61 73

412 4 4 11 11 11 11 11 13 13 13 13

-10

-I-< 1125 < 1125 0.51-78 to 25 11/22 02-22 few125 few125 0.51-78 to 25 17/22 0.11-22 many125

[%I

The Oxojknctionalization of Alkanes HBF4 R-NH2

CH3CN

'

9b

Na2C03

CH2CI2, O"C, 8h

CH,C12,25"C, 5h

143

c

14

15

16

methylene group. The authors explain the excellent selectivity by the coordination of 9b to the ammonium group by hydrogen bonding. Recently, the scope of the reagent 9b could be considerably broadened in that hydroxylations of secondary and even primary C-H bonds were achieved. [22] The innovation is to carry out the oxidation in the presence of trifluoroacetic anhydride, which acylates the alcohols being the primary reaction products. For example, cyclohexane is converted in quantitative yield to the trifluoroacetate of cyclohexanol. Very exciting results for the oxyfunctionalization of alkanes were also obtained using photoinduced SET reactions as the key step. [23] The principle applied here is that after electron tranfer oxidation of the alkane 18 the aciditiy of the C-H bonds of the resulting radical cation 20 is dramatically increased. Thus, deprotonation to the radical 23 occurs, which then can be trapped by oxygen. For example, if 1 is irradiated in an oxygen saturated acetonitrile solution in the presence of 1,2,4,5-tetracyanobenzene (TCB), 4 is obtained as the main product. Changing from TCB to 2,3,5,6-tetrachloro-p-benzoquinone (Chl) the radical 23 is further oxidized to the cation 26, which in turn can now also be trapped by acetonitrile leading to amidated products 24. Hydroxylation of C-H bonds on tertiary C atoms can be conducted with solutions of fluorine in aqueous acetonitrile. [24] This

+

Oxidant

RH

17a:TCB 17b: Chl

hv

21

RNCOMe

-

-

[Oxidant

10

+ [,HIo

19

10

ROH

24

ROO 22

a

R-N=CMe 25

1

20

- 02

-Ha

R.

I -

23

CH3CN

17b

Ra

26

reagent appears particularly attractive for the synthesis of 180-labeled compounds; for example, [180]-1-adamantanol ([180]-4) is prepared in over 80% yield by using a solution of F2 in acetonitrile and H2I80. Another promising reagent for the oxyfunctionalization of hydrocarbons are the di(perfluoroalky1)oxaziridines 29, [25] which can be synthesized from commercially available tri(perfluoroa1kyl)amines 27 on a large scale [25b] in two steps. The reaction of 27 with antimony pentafluoride produces a-fluoroketimines 28, which are then epoxidized with rn-chloroperbenzoic acid (MCPBA) to give

27

28

29

144

B. Organometallic Reagents

29. Compound 29 can be purified by vacuum distillation and stored indefinitely at room temperature. Solutions of hydrocarbons such as 1, 10, and 12 in chloroform, carbon tetrachloride, or trichlorofluoromethane are readily monohydroxylated at their tertiary C atoms with only minimal amounts of side products. In addition to the high selectivity for tertiary C atoms over secondary, 29 shows a marked preference for the oxidation of equatorial over axial positions and a high stereospecificity for retention of configuration of the C atoms oxidized (Table 1). The authors propose the concerted 0 insertion into a C-H bond as the mechanism, since in the reaction of 19 with 1 in CC14 no chlorine-containing trapping products are formed from 1 via intermediate radicals, as is observed for the oxidation of 1 in CC14 with ozone. 29 has proven to be useful also for the epoxidation of alkenes, [26] and for the oxidation of sulfides to sulfoxides or sulfones, [27] pyrdines to the corresponding N-oxides, [28] or trialkylsilanes to trialkylsilanols, the latter occurs with retention of configuration. [29] As these examples show there has been considerable progress in achieving the goal of finding efficient methods to selectively oxidize alkanes. There have been also several promising reports on transition metal complexes which are able to insert into non activated C-H bonds at very low temperatures. [30] All these developments give rise to optimism that in the near future general methods for the functionalization of non activated molecules will become available. This was supported by the Winnacker foundation and the Fonds der Chemischen Industrie.

References [ 11 H. L. Holland, Organic Synthesis with Oxida-

tive Enzymes, VCH, New York, 1991. [2] See also J. Sunderrneyer, Angew. Chem 1993, 105, 1195-1197; Angew. Chem. Int. Ed. Engl. 1993, 32, 1144-1146, and references therein. [3] D. H. R. Barton, E. Csuhai, N. Ozbalik, Tetrahedron 1990, 46, 3743-3752, and references therein. [4] a) D. H. R. Barton, M. J. Gastiger, W. B. Motherwell, J. Chem. Soc. Chem. Commun. 1983,731-733. b) G. Balavoine, D. H. R. Barton, Y. V. Geletii, D. R. Hill in The Activation of Dioxygen and Homogeneous Catalytic Oxidation; D. H. R. B. et. al., Ed.; Plenum Press: New York, 1993; pp. 225-242. [5] a) Y. V. Geletii, A. E. Shilov in The Role of Oxygen in Chemistry and Biochemistry; W. Ando Y. Moro-oka, Ed.; Elsevier: Amsterdam, 1988; 33, pp. 293-300. b) E. M. Koldasheva, Y. V. Geletii, A. F. Shestakov, A. V. Kulikov, A. E. Shilov, New. J. Chem. 1993, 421-24. [6] T. M. Hellman, G. A. Hamilton, J. Am. Chem. SOC. 1974, 96, 1530-1535. [7] a) G. A. Olah, G. K. S. Prakash, J. Sommer, Superacids, Wiley, New York, 1985, p. 315ff, and references therein; b) N. Yoneda, T. Kiuchi, T. Fukuhara, A. Suzuki, G. A. Olah, Chem. Lett. 1984, 1617. [8] Reviews: a) A. de Meijere, NachK Chem. Tech. Lab. 1979, 27, 177-182; b) E. Keinan, T. H. Varkony in The Chemistry of Peroxides (Eds.: S . Patai), Wiley, New York, 1983, p. 649ff. [9] Z. Cohen, E. Keinan, Y. Mazur, T. H. Varkony, J. Org. Chem. 1975,40, 2141-2142. [lo] Z. Cohen, E. Keinan, Y. Mazur, A. Ulman, J. O m" . Chem. 1976,41, 2651-2652. [11] a) M. Zarth, A. de Meijere, Chem. Bel: 1985, 118, 2429-2449; b) A. de Meijere, F. Wolf, Methoden erg. (-hem. (Houben-Weyl) 4th ed., Vol. E13, 1988, pp. 971-990, and references therein. [12] L. Fitjer, Angew. Chem. 1976, 88, 804-5; Angew. Chem. Int. Ed. Engl. 1976, 15, 762.

The Oxofunctionalization of Alkanes

1131 a) E. Proksch, A. de Meijere, Angew. Chem 1976, 88, 802-803; Angew. Chem. Znt. Ed. Engl. 1976, 15, 761-762; b) Tetrahedron Lett. 1976, 4851-4854. [14] a) T. Hasegawa, H. Niwa, K. Yamada, Chem. Lett. 1985, 1385-86, and references therein; b) B. Waegell, J.-L. Coudret, S. Zollner, A. de Meijere, unpublished; J.-L. Coudret, Ph. D. thesis 1995, Universite d’Aix Marseille 111; c) A. Tenaglia, E. Terranova, B. Waegell, Tetrahedron Lett. 1989, 30, 5271-5274; d) H. J. Carlsen, Synth. Commun. 1987, 17, 19-23. [ 151 P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981, 46, 39363938. [16] W. Adam, J. Bialas, L. Hadjiarapoglou, Chem. Bel: 1991,124,2377. [ 171 a) W. Adam, L. P. Hadjiarapoglou, R. Curci, R. Mello in Organic Peroxides (Ed.: W. Ando), Wiley, New York, 1992, pp. 195-219ff, b) R. Curcin in Adv. Oxygenated Processes, (Ed.: A. L. Baumstark), JAI, Greenwich, CT, USA, Vol. 2, 1990, pp. 1-59. [18] R. W. Murray, R. Jeyaraman, L. Mohon, J. Am. Chem. SOC. 1986,108,2470-2472. 1191 R. Mello, M. Fiorentino, C. Fusco, R. Curci, J. Am. Chem. SOC. 1989,111,6749-6757. [20] R. Mello, L. Cassidei, M. Fiorentino, R. Curci, Tetrahedron Lett. 1990, 31, 3067-3070. [21] G. Asensio, M. E. Gonzalez-Nunez, C. B. Bernadini, R. Mello, W. Adam, J. Am. Chem. SOC. 1993,115,7250-7253.

145

1221 G. Asensio, R. Mello, M. Elena, M. E. Gonzaleznunez, G. Castellano, J. Corral, Angew. Chem. 1996, 108, 196-8; Angew. Chem. Znt. Ed. Engl. 1996,35, 217-218. [23] M. Mella, M. Freccero, A. Albini, J. Chem. SOC.Chem. Commun. 1995,41-42. [24] S. Rozen, M. Brand, M. Kol, J. Am. Chem. SOC..1989, I l l , 8325-8326. [25] a) D. D. Desmarteau, A. Donadelli, V. Montanari, V. A. Petrov, G. Resnati, J. Am. Chem. SOC. 1993, 115, 4897-4898; b) V. A. Petrov, D. D. DesMarteau, J.0rg. Chem. 1993, 58, 4754-4755. c) A. Arnone, M. Cavicchioli, V. Montanari, G. Resnati, J. Org. Chem. 1994, 59, 5511-5513. (d) V. A. Petrov, G. Resnati, Chem Rev 1996, 96, 1809-1823. [26] A. Arnone, D. D. Desmarteau, B. Novo, V. A. Petrov, M. Pregnolato, G. Resnati, J. Org. Chem. 1996,61, 8805-8810. [27] a) D. D. Desmarteau, V. A. Petrov, V. Montanari, M. Pregnolato, G. Resnati, J. Org. Chem. 1994, 59, 2762-2765. (b) M. Terreni, M. Pregnolato, G. Resnati, E. Benfenati, Tetrahedron 1995, 51, 7981-7992. (c) J. P. Begue, A. Mbida, D. Bonnetdelpon, B. Novo, G. Resnati, Synthesis Stuttgart 1996, 399. [28] a) C. Balsarini, B. Novo, G . Resnati, J. Fluorine Chem. 1996, 80, 31-34. b) R. Bernardi, B. Novo, G. Resnati, J. Chem. SOC. Perkin Trans 1 1996,2517-2521. [29] M. Cavicchioli, V. Montanari, G. Resnati, Tetrahedron Lett. 1994, 35, 6329-6330. 1301 Review: W. A. Herrmann, B. Cornils, Angew. Chem. 1997,109, 1074-1095.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Cooperativity in Rhz Complexes: High Catalytic Activity and Selectivity in the Hydroformylation of Olefins Georg Siiss-Fink

Several important steps forward in the search is an excellent hydroformylation catalyst for for catalytically active polynuclear metal olefins such as propylene, 1-hexene and 1complexes have been made over the last octene, combining high activity with high years by George G. Stanley’s group: By reac- regioselectivity. Up to 12000 turnovers (10 tion of a novel tetraphosporus ligand L, which cycles per minute) were achieved in a single exist in the R,R, S,S, and R,S forms and which batch run without observing any ligand degracan be separated into the racemate (R,R/S,,S)dadtion reactions. The conversion of olefin to and the meso form (R,S) [l], with the nor- aldehyde for 1-hexene is 8 5 % , the n/i ratio bornadiene (C7HS) complex [Rh(y4-C7Hs)2] being 96.5 : 3.5. [2] The combination of high [BF& the new dinuclear complex cations activity with high selectivity can be explained ruc-[Rh2(y4-C7Hs)2(y2:y2-L)2I2+ (ruc-1) and by cooperativity between both metal centers meso-[Rh2(y4-C7H&(y2:y2-L)2l2+(meso-1) in the catalytically active dinuclear complex. The hydroformylation of olefins is the were obtained and isolated as the tetrafluoroborate salts (Scheme 1). [2] The racemic com- world’s most important homogeneous cataplex roc-1, whose structure was determined lytic industrial process with more than six by a single-crystal X-ray structure analysis, million tonnes of 0x0 products produced per

1

rac-(R,FUS,S ) I

/PEtZ

Et2p\

PheP

*Ph rac-I

meso-(R, S)-L

Scheme I . The tetraphosphorus ligands rac-L and meso-L, and the hydroformylation active dirhodium complex rac-1.

Cooperativity in Rhz Complexes

147

R-Ch,-CH,-CH=O n-aldehyde

R-CH=CH2

+

CO

+

HP R-CH(CH=O)-CHs i-aldehyde

year. [3] Besides the problem of chemical selectivity, the hydroformylation of olefins raises the question of regioselectivity depending on whether the formyl group is added to the terminal or to the internal carbon atom of the double bond. This results in the ratio of linear to branched product (di ratio of the aldehyde formed) (Scheme 2). The industrial processes are all based on mononuclear cobalt or rhodium complexes. Ever since transition metal clusters have been discussed as catalysts, [4] there have been many attempts to develop catalytically active polynuclear complexes in which the metal centers interact during the formation of the target molecule (“cooperativity”) to control activity and selectivity of the catalytic process. In this way, a highly selective hydroformylation catalyst for propene was found in the cluster anion [HRu3(CO)11]- (linear to branched product ration of butyraldehyde 98.6 : 1.4), however, its activity is very low with only 57 cycles in 66 h. [5] The high selectivity and low activity suggest the catalytic process to occur via a sterically demanding, intact trinuclear structure, for which there is experimental evidence. [6] In contrast to [HRu3(CO)11]- , the tetranuclear neutral cluster [Rh4(C0)12] was reported to yield high catalytic conversions (84000 cycles) for the hydroformylation of 1-hexene, the selectivity, however, is unfavorable (n/i 54 :46). [7] Accordingly, evidence for a catalytic route via mononuclear rhodium fragments was found. [8] The higher hydroformylation activity of the mixed-metal cluster [Co2Rh2(CO)121 as compared to those of either the parent clusters

Scheme 2. The hydroformylation of terminal olefins and the regio-

selectivity problem.

[Co4(CO)12] and [Rh4(CO),,], originally interpreted by cooperativity between Co and Rh centers in the bimetallic catalyst, [9] was later shown to be simply due to the more facile fragmentation of the mixed-metal cluster into reactive [HRh(C0)4] species. [ 101 The catalyst rac-1 described by Stanley et al. is the only polynuclear system as yet which compares favorably with the hydroformylation catalysts used industrially. Stanley et al. explain the combination of high selectivity with high activity of their catalyst by bimetallic cooperativity in the form of an intramolecular hydride transfer which assists in the elimination of the aldehyde from an intermediate containing the RCHzCHzCO fragment as a ligand at one Rh centre and the H ligand at the other Rh center. This interpretation is supported by the lack of catalyst fragmentation and the fact that mononuclear model complexes [Rh(y4-C7Hs)(y2-diphos)][BF4] (diphos = Et2PCH2-CH2PEt2, Et2PCH2CHzPMePh,Et2PCH2CH2PPh2, Ph2PCH2CH2PPh2) generate, under the same conditions as for rac-1, extremely poor hydroformylation catalysts for 1-hexene from both activity and selectivity viewpoints. [2] Further persuasive evidence for this interpretation came from a systematic investigation of well-designed dinuclear model systems in which the central methylene group (with respect to complex 1) has been replaced by propylene (2) or para-xylylene (3) groups (Scheme 3). These “spaced” precursors 2 and 3 (although comparable to rac-1 both electronically and sterically) are only poor hydroformylation catalysts as compared to rac-1,

148

B. Organometallic Reagents

12+

2

12+

3

Scheme 3. The model "spacer" complexes 2 and 3.

being in line with the cooperativity concept: 4), accessible from ruc-1 and allylmagnesium Unlike in ruc-1, an intramolecular hydride bromide. Surprisingly, ruc-4 turned out to be transfer is not possible in 2 or 3, since both a rather slow and poorly selective hydroformylation catalyst (with respect to ruc-1). [12] Rh atoms are kept apart by the spacers. [2] In the face of these confusing results, StanThe most internally self-consistent check, however, is the dramatic decrease in both activ- ley and co-workers decided to initiate an ity and selectivity by using the R,S diastereo- extensive series of in situ spectroscopic studmer meso-1 as hydroformylation catalyst (as ies to understand what was occurring under compared to the racemic R,R/S,S diasteromers hydroformylation conditions with the neutral ruc-1). The higher rate of the rucemic system and dicationic precursor complexes ruc-1 was thought to arise from its ability to form a and ruc-4, why they give such dramatically double-bridged hydrido-carbonyl interme- different catalytic results, in marked contrast diate (or transition-state) which favors the to mononuclear hydroformylation catalyst. In intramolecular hydride transfer. The meso a recent book on catalysis by di- and polycatalyst can do an intramolecular hydride nuclear metal complexes, edited by R. D. transfer, but cannot form a double-bridged Adams and F. A. Cotton, George G. Stanley H/CO situation facilitating the hydride trans- gives a detailed account of this fascinating fer, since the terminal CO ligand at the acyl- story which reads as exciting as a detective bound Rh center is unfavorably oriented with novel. [12] In situ FT-IR studies showed that the respect to the other Rh atom. [2] The mechanism proposed in the original neutral complex ruc-4 reacts under CO paper, [2] however, proved to be inconsistent atmosphere with carbon monoxide through with further mechanistic studies by Stanley the intermediacy of ruc-[Rh2(CO)2(y3et al.: The original catalytic cycle was based C3H5)2(q2:r2-L)] (ruc-5) to give ruc(ruc-6). on neutral dinuclear rhodium intermediates, [Rhz{q1-C(0)C3H5}~(C0)4(r2:r2-L)] the first of which, the neutral hydrido-carbo- Under syngas conditions (CO/Hz), ruc-6 nyl complex ruc-[Rh2(C0)z(rZ:r2-L)], was is converted into a zwitterionic Rh(-I)believed to form from the dicationic ruc-1 (Rh+I) species ruc- [Rh2(C0>2@2-CO)(r3:r under syngas (CO/Hz) conditions with libera- L)] (ruc-7), for which the crystal structure tion of H+ and norbornadiene. In order to analysis revealed the tetraphosphine ligand L model the intermediacy of this neutral species, to be unsymmetrically coordinated (with 3 P Stanley et al. designed the neutral ally1 (C3H5) atoms to one Rh center and with one P to the analogue ruc-[Rh~(q~-CgH5)2(~~:r~-L)] (ruc- other Rh center). [ 111

'

Cooperativity in Rhz Complexes

12+ rac-8

149

12+ tX-9

v(C0) 2058s, 2006s

v(C0) 2095s, 2 0 4 4 2018w ~

12+

v(C0) 2076m, 2038s, 1832m,1818w

6('H) - 9.0,'J(Rh-H) 164 Hz, 'J(f3h-H) 15 Hz)

Scheme 4. Interpretation of the in situ spectroscopic studies on the reactivity of the dicationic complex rac-8 towards CO and H2.

In situ FT-IR and NMR studies on rac-1, could be identified by its IR, 'H and 31P however, revealed the catalytically active NMR data as being ruc-[Rh2H2(C0)2(112species to be a dicationic Rh(+II)-Rh(+II) C0)2(q2:y2-L)l2+(rac-12) (Scheme 4). [ 131 complex: The dicationic percursor rucComplex ruc-12 is now proposed, based on [Rh2(C0)4(v2:r2-L)l2+ (rac-8), which gene- the in situ spectroscopic studies, to be the rates under hydroformylation conditions the catalytically active species in the olefin hydrosame active species and gives identical formylation using rac-1 as catalyst precursor. spectroscopic results as ruc-1, was shown to In contrast to the original hypothesis [2], react, under CO atmosphere, with carbon the active species now is dicationic and conmonoxide to give rac-[Rh2(CO)~(y2:y2-L)l2+ tains a Rh-Rh bond: rac-12 is believed to (rac-9).Under syn gas (COM2) atmosphere, be a electron-precise 34e Rh(+II)-Rh(+II) rac-9 takes up molecular hydrogen to give, complex with an edge-sharing bioctahedral with elimination of CO (and presumably structure. [ 131 The current proposed hydrothrough the intermediacy of uncharacterized formylation mechanism is depicted in species rac-10 and r m - l l ) , a complex which Scheme 5 .

B. Organometullic Reagents

150

12+

1

2’

rac-l

rac%

\

+6CO

1

- 2 C7Ha

/+

2 CO

2i

+2co R-CH&H&H=O

//

12+

1

A\

2+

rac-10

rac-15

1

R

I

.+

1

0

2+

rac-11 rac-I4

\

/

1

1

2+

rac-13

2+

- co

rac-12

Scheme 5. The catalytic cycle proposed for the hydroformylation mechanism with ruc-1 as catalyst precursor. The two intramolecular hydride tran\fer processes reflect the “cooperativity” of the two rhodium centers.

Cooperativity in Rhz Complexes

151

In a brilliant systematic study, Stanley et al. The facile loss of CO from rac-9, formed from the precursor rac-1 (or rac-8), opens up have demonstrated that their dinuclear rhoa vacant coordination site allowing the oxi- dium hydroformylation catalyst is radically dative addition of H2 to give rac-10 which is different from anything previously observed considered to be a Rh(+I)-Rh(+III) 18e/16e for this industrially important process: It comspecies. Here the first cooperative step takes bines high activity with high chemo- and place with the rearrangement of rac-10 by regioselectivity and, provided the pure enanan intramolecular hydride transfer via the tiomers are employed, with excellent enantiobridged intermediate rac-11 to the metal- selectivities. It is not exaggerated to consider metal bonded Rh(+II)-Rh(+II) 34e complex these results as a breakthrough in the developrac-12. Dissociation of CO in rac-12 provides ment of tailor-made homogeneous catalysts. entry for an olefin ligand to give rac-13 which Fixing two or more cooperating metal centers forms, by migratory insertion, the alkyl spe- in the geometry required for a particular catacies rac-14. CO addition gives rac-15 and lytic process by means of a suitable ligand finally, with reductive elimination of the alde- matrix, with the aim of controlling activity hyde via another intramolecular hydride and selectivity of the catalyst, is now in reach. transfer, rac-9 with which the cycle started. Despite the modification of the original hypoReferences thesis, [2] the cooperativity concept still holds in the current proposed cycle. [ 121 [ I ] S. A. Lanernan, F. R. Fronczek, G. G. Stanley, Furthermore, Stanley and co-workers have J. Am. Chem. Soc. 1988,110,5585. also been able to resolve the racemic tetra[ 2 ] M . E. Broussard, B. Jurna, S. G. Train, W.-J. phosphorus ligand into the enantiomerically Peng, S. A. Laneman, G. G. Stanley, Science pure compounds R,R-L and S,S-L by prepa1993,260, 1784. ratory HPLC using a Chiralcel OD column. [ 3 ] K. Weissermel, H . - J . Arpe, Chimie organique industrielle, lkre dition, Masson, Paris, 1981, From these, they prepared the chiral catalyst p. 113; Industrielle Organische Chemie, precursors R,R-[Rhz(r4-C7H&(r2:r2 -L)2I2+ (R,R-1) and S,S-[Rhz(r4-C7H~)2(r2:r2-L)2I2+2 . Auflage, Verlag Chemie, Weinheim, 1978, p. 120. (S,S-1).These turned out be excellent asymB. F. G. Johnson, J. Lewis, Pure Appl. Chem. metric hydroformylation catalysts for non-ste1975, 44, 43; E. L. Muetterties, Bull. SOC. rically hindered substrates such as vinyl esters Chim. Belg. 1975, 84, 959; Science 1977, (Scheme 6). Enantioselectivities of 85 % (ee 196, 839. 85 %) and regioselectivities of 80 % ( d i ratio G. Suss-Fink, G. F. Schmidt, J. Mol. Cutul. 4 : 1) have been achieved for vinyl acetate at 1987,42, 361. 85 "C and 6.2 bars of CO/H2 (1 : l), the turn[h] G. Suss-Fink, G. Herrmann, J. Chem. SOC. Chem. Commun. 1985,735. over frequency being 476 cycles per hour. [7] R . Lazzaroni, P. Pertici, S. Bertozzi, G. ~ 4 1 Fabrici, J. Mol. Catal. 1990, 58, 75. 0 [ X I C. Fyhr, M . Garland, Organometallics 1993, n \ o 12, 1735. [(I] A. Ceriotti, L. Garlaschelli, G. Longoni, M. C.

Scheme 6. The asymmetric hydroformylation of vinyl acetate, a key step in the synthesis of D- or L-threonine.

Malatesta, D. Strumolo, A. Fumagalli, S. Martinengo, J. Mol. Catal. 1984, 24, 309. [ I 0 1 M. Garland, Organometallics 1993, 12, 535. [ l I ] W.-J. Peng S. G. Train, D. K. Howell, F. R. Fronczek, G. G. Stanley, J. Chem. SOC., Chem. Commun. 1996,2607.

152

B. Organometallic Reagents

[ 121 G. G. Stanley, “Bimetallic Homogeneous

[ 141 G. G. Stanley, “Bimetallic Hydroformylation

Hydroformylation”, in: R. D. Adams, F. A. Cotton (editors), Catalysis by Di- and Polynuclear Metal Complexes, VCH, New York, to be published in 1997. [13] R. C. Matthews, D. K. Kowell, W.-J. Peng, S. G. Train, W. D. Treleaven, G. G. Stanley, Angew. Chem. 1996, 108, 2402; Angew. Chem. Int. Ed. Engl. 1996, 35, 2253.

Catalysis: The Uses of Homobimetallic Cooperativity in Organic Synthesis”, in: M. G. Scaros, M. L. Prunier (editors), Catalysis of Organic Reactions, Marcel Dekker, New York, 1995, p. 363.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Synthesis of Optically Active Macromolecules Using Metallocene Catalysts Jun Okuda

Although Nature is capable of efficiently producing monodisperse, optically active macromolecules from functional monomers, the rational synthesis of high molecular weight polymers having a well-defined microstructure, a narrow molecular weight distribution, and variable architectures remains a significant challenge. One of the goals in synthetic chemistry therefore is the development of structurally characterized complexes which can efficiently catalyze the polymerization of unsaturated monomers in a controlled or living fashion and, in the case of prochiral monomers, in a stereoselective manner. Several years ago, the cocatalyst methylalumoxane was found to increase the activity of Ziegler catalysts derived from group 4 metallocenes dramatically. [ 11 Shortly thereafter the fundamental possibility of controlling the tacticity of polypropylene through the molecular structure of the transition metal catalyst was reported. [2] Since the pioneering work by Turner et al. [3a], Jordan [3b], and others it has been established in a plethora of studies that cationic 14-electron alkyl [CpzMR]+ is the active site for chain propagation. [31 Elegant kinetic studies recently performed by the teams of Brintzinger et al. [4a] and of Bercaw et al. [4b] have proved the decisive role of a-agostic inter-

action of the growing chain with the transition metal center. At present intense effort worldwide is concentrating on evaluating the critical parameters for the strereoregularity of a-olefin polymerization and finding a transparent relationship between ligand properties of the catalyst and polymer structure. [5] Thus, the use of racemic Cz-symmetrical zirconocene rac-[ 1,l '-ethylenebis(4,5,6,7-tetrahydro-1-indenyl)]zirconium dichloride (1) developed by Brintzinger leads to highly isotactic polypropylene. Here an enantiomorphic site control is proposed to be operative on the basis of defects within the polymer chain. [2b] On the other hand, the achiral titanocene derivative CpzTiPh2 gives isotactic block polymer that is formed via chain end control. [2a] Finally the Cs-symmetrical metallocene complex 2 with a bridged cyclopentadienyl-fluorenyl ligand system yields syndiotactic polypropylene [6]. Recently Waymouth and Coates have demonstrated that it is also possible to produce an optically active polyolefin using a chiral non-racemic metallocene catalyst of the Brintzinger type. [7] Although optically active oligomers can be obtained in the presence of a resolved metallocene complex according to the above mentioned procedure [8], high molecular weight isotactic as well as syndiotactic polypropylene generally con-

154

B. Organometallic Reagents

2

tain mirror planes and are therefore achiral (“cryptochiral”). [91 Waymouth and Coates employed the homogeneously catalyzed cyclopolymerization of 1 3-hexadiene giving poly(methy1ene-l,3 cyclopentane) as previously developed in his group in order to utilize the stereoselectivity of the monomer insertion for the construction of a polymer with main-chain chirality. The cyclopolymerization is a remarkable chain growth reaction during which a conventional

insertion of a vinylic function into the transition metal-carbon bond is followed by an intramolecular insertion resulting in a cyclization. [lo] Thus from 1 3-hexadiene, a polymer chain is obtained in which methylene and 1,3cyclopentanediyl fragments are arranged in a strictly alternating sequence (Scheme 1). By modifying the catalyst’s ligand sphere, control over the diastereoselectivity could be achieved ([CpzZrClz] leads to trans, [Cp*~ZrC12]to cis connection of the cyclopentane fragments). An analysis of possible stereoisomers shows four structures of maximum order of which all but the racemo-diisotactic polymer are achiral. The latter does not contain a mirror plane and is chiral due to configurationally determined main-chain stereochemistry. The Stanford group recognized that by using a chiral catalyst the enantioselective cyclopolymerization of 1S-hexadiene would be possible. The catalyst used was chiral [ 1,1’-ethylenebis(4,5,6,7-tetrahydro- 1-indenyl)]zirconium 1,l ’-binaph-tholate (3) which had been prepared according to Brintzinger [ 111 by reacting the racemic dichloro derivative 1 with optically active (R)- or (8)-1,l’-binaphthol. Poly(methy1ene-l,3 -cyclopentane) synthesized in the presence of (-)-(R,R)-3 and methylalumoxane revealed a molar optical rotation of [@12’405 = +51.0” (c 8.0, CHCb), whereas the polymer analogously prepared using the enantiomer (+)-(S,S)-3 showed a value of [@912’405 = -51.2” (c 8.0, CHC13). These findings are consistent with the formation of polymers with main-chain chirality. [9a1

Scheme 1. [Zr] = zirconocene fragment, -@ = polymer chain.

Synthesis of Optically Active Macromolecules Using Metallocene Catalysts

In summary, Waymouth and Coates have for the first time realized the enantioselective synthesis of an optically active polymer starting with an achiral monomer by using an optically active, structurally well-defined metallocene catalyst. Their results are promising, since the synthesis of organic polymers in a more rational way through modification of the transition metal catalyst seems within reach. In addition, this study emphasizes that knowledge of well-characterized organotransition metal complexes offers an unprecedented opportunity for the design of novel polymerization reactions.

References [ l ] H. Sinn, W. Kaminsky, Adv. Organomet. Chem. 1980,18,99. [2] a) J. A. Ewen, J. Am. Chem. SOC. 1984, 106, 6355; b) W. Kaminsky, K. Kulper, H. H. Brintzinger, F. R. W. P. Wild, Angew. Chem. 1985, 97, 507; Angew. Chem. Int. Ed. Engl. 1985, 24, 507. [3] a) G. G. Hlatky, H. W. Turner, R. R. Eckman, J. Am. Chem. SOC. 1989, 111, 2728; b) R. F. Jordan, J. Chem. Educ. 1988, 65, 285; Adv. Organomet. Chem. 1991,32, 325. [4 a) H. Krauledat, H. H. Brintzinger, Angew. Chem. 1990, 102, 1459; Angew. Chem. Int. Ed. Engl. 1990, 29, 1412. H. H. Brintzinger in Organic Synthesis via Organometallics (Eds.: K. H . Dotz, R. W. Hoffmann), Vieweg, Braunschweig, 1991, p. 33; b) W. E. Piers, J. E. Bercaw, J. Am. Chem. SOC.1990, 112, 9406. [5] a) For some recent reviews, see: P. C. Mohring, N. J. Coville, J. Organomet. Chem. 1994, 479, 1. H. H. Brintzinger, D. Fischer, R. Miilhaupt, B. Rieger, R. M. Waymouth, Angew. Chem. 1995, 107, 1255; Angew. Chem. Int. Ed. Engl. 1995, 34, 1143. Ziegler Catalyst, Recent Scientifc Innovations and Technological Improvements (Eds.: G. Fink, R. Miilhaupt, H. H. Brintzinger), Springer, Berlin, 1995; b) G. Erker, R. Nolte, Y.-H. Tsay, C. Krtiger, Angew. Chem. 1989, 101,

155

642; Angew. Chem. Int. Ed. Engl. 1989, 28, 628. G. Erker, Pure Appl. Chem. 1991, 63, 797. G. Erker, C. Fritze, Angew. Chem., 1992, 104, 204.;Angew. Chem. Int. Ed. Engl. 1992, 31, 619728; c) W. Roll, H. H. Brintzinger, B. Rieger, R. Zolk, Angew. Chem. 1990, 102, 339; Angew. Chem. Int. Ed. Engl. 1990, 29, 279; d) W. Spaleck, M. Antberg, V. Dolle, R. Klein, J. Rohrmann, A. Winter, New. J. Chem. 1990, 14, 499; e) T. Mise, S. Miya, H. Yamazaki, Chem. Lett. 1989, 1853; f) J. A. Bandy, M. L. H. Green, I. M. Gardiner, K. Prout, J. Chem. SOC, Dalton Trans. 1991, 2207. [6] J. A. Ewen, R. L. Jones, A. Razavi, J. D. Ferrara, J. Am. Chem. SOC.1988, 110,6255. [7] G. W. Coates, R. M. Waymouth, J. Am. Chem. SOC. 1991, 113, 6270; idem, ibid. 1993, 115, 91. G. W. Coates, A. Mogstad, R. M. Waymouth, J. Macromol. Sci., Chem. 1992,31,47. [8] P. Pino, P. Cioni, J. Wei, J. Am. Chem. SOC. 1987, 109, 6189. W. Kaminsky, A. Ahlers, N. Moller-Lindenhof, Angew. Chem. 1989, 101, 1304; Angew. Chem. Int. Ed. Engl. 1989, 28, 1216. [9] a) G. Wulff, Angew. Chem. 1989, 101, 22; Angew. Chem. Znt. Ed. Engl. 1989, 28, 21; b) M. Farina, Top. Stereochem. 1987, 17, 1. [lo] a) L. Resconi, R. M. Waymouth, J. Am. Chem. SOC. 1990, 112, 4953; b) G. B. Butler, Acc. Chem. Res. 1982, 15,370. 111 F. R. W. P. Wild, M. Wasiucionek, G. Huttner, H. H. Brintzinger, J. Organomet. Chem. 1985, 288, 63.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

C. Biological and Biomimetic Methods Discovering Biosynthetic Pathways A Never Ending Story Sabine Laschat and Oliver Ternmc There is an increasing interest in the study of biosynthetic reactions due to the fact that a detailed understanding of biosynthetic and metabolic pathways eventually enables us to control malfunctions which often lead to severe health disorders and diseases. In addition, biosynthetic reactions have largely improved synthetic organic methodology. This is especially true for the biomimetic reactions, which proceed highly chemo-, regioand stereoselective under extremely mild (and often neutral) conditions in an aqueous environment without the requirement of protecting groups. The following chapter deals with several biosyntheses, which have been investigated recently. Pericyclic reactions, that is one-step processes that proceed through cyclic transition states under control of orbital symmetry, represent an important tool for the synthetic organic chemist. A large number of pericyclic key steps occur also in biological systems [l]. The classical example, which led Woodward and Hoffmann to establish the rules of conservation of orbital symmetry, is the formation of vitamin D3 from 7-dehydrocholesterol by a photochemically induced, conrotatory cycloreversion of the steroid B-ring, followed by a thermally allowed [1,7]-sigmatropic H-shift . Claisen rearrangements are found as well in natural systems. The [3,3]-sigmatropic

Claisen rearrangement of chorismic acid 1 to prephenic acid 2 (Scheme l), which is catalyzed by the enzyme chorismate mutase, can be considered as the key step in the biosynthesis of aromatic compounds, that is the so-called shikimic acid pathway. The chair-like transition state geometry 3 was proved by double isotope-labeling experiments [ 2 ] . However, in the laboratory this particular reaction can be accelerated not only by enzymes but also by catalytic antibodies [3]. For the generation of such antibodies haptenes such as 4 were used, that is, molecules whose structure is very similar to the transition state of the particular reaction and which are tightly bound by the antibody.

&

-o*g

Chorismat-mutase /

on

co; OH 2

1

4

Scheme 1.

0'

Discovering Biosynthetic Pathways - A Never Ending Story

Besides Claisen rearrangements many other types of reactions can be catalyzed by antibodies. Reduction of diketone 5 with NaBH4 yielded the hydroxyketone 6 in 95 % (96 % ee) (Scheme 2) [4]. This remarkable regioselectivity was achieved, because the reduction of the p-nitrobenzyl-substituted carbonyl group is 75 times faster than the reduction of the corresponding rn-methoxybenzyl-substituted carbonyl group in the presence of the catalytic antibody 37B.39.3, which was raised against the haptene 7. In the absence of the catalytic antibody no kinetic preference for one of the carbonyl group was observed. In the case of antibody-catalyzed Diels-Alder reactions an additional problem has to be tackled with, that is the product inhibition resulting from the close structural similarity between the transition state (or haptene respectively) and the product. In order to avoid the product inhibition, the cycloaddition must be either followed by a cheleotropic reaction or the haptene must be bulkier than the corresponding transition state IS]. However, Janda et al. reported a completely different approach to this problem [6]. They used the conforma-

( m . C O N M e 2 &CONMe2 NHCO(CH2)&02H

-

NHCO(CH2)&02H

8

Scheme 2.

tional highly flexible ferrocene 9 as haptene instead of the conformational rigid bicyclo[2.2.2]octane system 8 (Scheme 3). Due to the low rotational barrier of 8 along the metallocene axis this haptene mimics both the ortho-endo transition state 1Oa as well as the ortho-exo transition state 10b of the

R'

1Oa ortho-endo

&-R' ,

I

9

10b ortho-ex0

antibody

11

12

Pf CoNMe2

antibody

1365

NHCO~CHZC~H~CO~H 14 ex0

157

Scheme 3.

158

C. Biological and BiomimeticMethods

cycloaddition of diene 11 and dienophile 12. Thus two different antibodies 4D5 and 13G5 respectively were generated from 9, which catalyze highly diastereo- and enantioselectively the formation of 13 and 14 respectively. In a more application-oriented approach an antibody was developed, which is able to deactivate cocaine 15 by conversion to (-)ecgonine 16, before the drug is delivered to the central nervous system (Scheme 4) [7]. The antibody, which was raised against haptene 17, indeed shows similar enzyme kinetics compared to butyrylcholinesterase, the natural metabolic enzyme for compounds like 15, although the catalytic activity of the antibody still needs to be improved in order to successfully fight drug abuse. Despite the progress, which has been achieved by using catalytic antibodies, there still remain severe problems to be solved especially concerning the production of antibodies. The immunization process is rather time- and material-consuming. However, the tools of molecular biology should allow to generate whole antibody libraries without the requirement of animals [8].

-

N

% 15 cocaine

6-

CO2CH3

antibody 3B9

H3C-N

'OZCH3

N

O

H

16 (j-ecgonine

However, pericyclic reactions in natural systems do not necessarily require the presence of an enzyme. Several examples proceed spontaneously, e. g. the above mentioned

1,7-H shift in the biosynthesis of vitamin D3. Recently Boland et al. reported, that the ectocarpenes 19 and related substances, which were isolated from the brown algae Ectocarpus siliculosus, are not the sexual pheromones of the algae, but that these cycloheptadienes 19 are formed from the actual pheromones, namely the thermolabile cis-divinylcyclopropanes 18, by a spontaneous Cope rearrangement (Scheme 5) [9]. Thus the Cope rearrangement of 18 resembles a deactivation pathway of the pheromones.

16

R = H, Et, CH=CH2

19

Scheme 5.

Diels-Alder reactions have been postulated as key steps in a number of biosynthetic conversions. The biosynthesis of the endiandric acids 26 and 27 is discussed below as an example for a spontaneous [4+2]-cycloaddition. This class of compounds which is produced by the Australian plant Endiandra introsu (Lauruceae) is remarkable, because different constitutional isomers were formed simultaneously and in all cases racemic mixtures were synthesized by the plant. It was first postulated by Black et al. [lo] and later confirmed via biomimetic total syntheses by Nicolaou et al. [ll] that the endiandric acids A, B and C (26a, 26b and 27) are formed by a cascade of electrocyclic reactions (Scheme 6). The cascade is initiated by a conrotatory 8n-electron ring closure of the polyene carboxylic acids 20, 21 to the isomeric cyclooctatrienes 22 and 23, respectively, which subsequently undergo a disrotatory 6n-electron cyclization to 24 and 25, respectively. Termination of the cascade by an intramolecular Diels-Alder reaction yields either the tetracyclic endiandric acid 26a, b or the bridged derivative 27.

Discovering Biosynthetic Pathways - A Never Ending Story

23

22 6n disrot.

i

1

Ph

2Sa 26b

1

1

n = 0 endiandric acid A n = 1 endiandric acid B

6n disrot.

25

24

dS+ x2,

159

21

x4,

+ a2,

endiandric acid C

Besides those spontaneous processes a variety of [4+2]-cycloadditions exists for which it still remains unclear whether they are Diels-Alder reactions and if so, whether they proceed spontaneously or only in the presence of an enzyme. In this respect the stereospecific synthesis of the sesterpenoid heliocide H2 28, an insecticide isolated from cotton wool, from hemigossypolon 29 and myrcene 30 (Scheme 7) [12, 131 should be mentioned. Other examples of biomolecules which are probably formed by Diels-Alder reactions contain the chalcone kuwanon J 31 from the mulberry tree Morus alba L. [14], the mycotoxins chaetoglobosin A 33

Scheme 6.

[ 151 and brevianamide A 35 [ 161, the polyketide nargenicine 37 [I71 and mevinoline 39, a metabolite of the fungus Aspergillus terreus MF4845, which is used as a drug for decreasing the blood cholesterol level [181. However, until now there is no case known, where the corresponding enzyme system, that is the Diels-Alder-ase, could be detected. Even in the biosynthesis of the iboga and aspidosperma alkaloids the final proof for a DielsAlder reaction is still missing (Scheme 8) [19]. In 1970 Scott et al. were able to elaborate nearly the whole biosynthetic pathway by feeding experiments with plant seedlings

C. Biological and BiomimeticMethods

160

[20]. According to Scott isovincoside 41 is of 43 reacts as dienophile, the aspidosperma converted to stemmadenine 42 via several alkaloid tabersonine 44 is formed, whereas steps. Heterolytic ring opening and concomi- participation of the 2-dihydropyridine moiety tant dehydration leads to the postulated inter- as a diene leads to the iboga alkaloid catharanmediate dehydrosecodine 43. Starting from thine 45. The reversibility of the reactions lead the acrylic ester 43 two [4+2]-cycloadditions the authors to assume stepwise Michael addiare possible. If the 2-dehydropyridine system tions.

H HO

' o

r

n

"@

\-

HO

0

0

6''L' 20

HO

/

.

OH

OH

0

=

/ OH

OMe

30

29

OH

0

32

\

I

32

31

",,

eN?% 0

33

H

OH

a

N-

0

35

N

34

O

36

Scheme 7.

Discovering Biosynthetic Pathways - A Never Ending Story

Y O H

SR HO'"

37

38

39

40

Scheme 7 (Forts.).

41

L

I

44

COpMe

J

L

43

45

Scheme 8.

161

162

C. Biological and Biomitnetic Methods

With rcgard to such difficulties in detecting and isolating Diels-Alder-ases, one might assume, that there are no enzyme-catalyzed [4+2]-cycloadditions involved in natural systems. However, this assumption seems to be incorrect. Recently Oikawa, Ishihara et al. published experimental evidence, that the solanapyrones 48 and 49, two phytotoxines produced by the pathogenic fungus Alternaritr soluni, are probably formed by enzyme-catalyzed [4+2]-cycloadditions (Scheme 9 ) [2 1 1. Treatment of prosolanapyrone 111 47 with a cell-free extract of A. soluni at 30 "C for 10 min yielded a mixture of 48 and 49 (25 c/o conversion) with an exo/endo ratio of 53 : 47. In the absence of the cell-free extract under the same conditions the aldehyde 47 undergoes an uncatalyzed Diels-Alder reaction to 48 and 49 (15 % conversion) with an exdendo ratio of 3 : 97 [22]. Treatment of 47 with the denatured cell-free extract yielded likewise an exo/etido ratio of 3 : 97 (1 0 % conversion). Thus, the enzyme-related conversion is about 15 5% and the exdendo ratio 87 : 13 (> 92 % re for 48). The high exo selectivity is remarkable, because it can not be achieved by chemical methods. It should be emphasized, that i n the above mentioned investigations no isolated enzymes were used but a cell-free extract. Thus the postulated Diels-Alder mechanism needs to be further confirmed by characterization of the enzyme or enzyme complex. The biosynthesis of the solanapyrones 48, 49 shows an additional feature worthy of mention. Whereas the alcohol prosolanapyrone I I 46 does not form any cycloaddition products in aqueous medium without any catalyst, the presence of the cell-free extract induces the production of 1 9 % of the solanapyrones 48 and 49 (exdendo 85 : 15) and 6 c/o of the aldehyde 47. Apparently, the Diels-Alder-ase is accompanied by a dehydrogenase, which catalyzes the oxidation of 46 to 47. Further studies with isolated enzymes are required in order to investigate, whether these are separated enzymes or coupled in an enzyme complex.

OMe

47

rQH1 ex0

R=CHO

I :& endo

Dtels-Alder-ase

-

-

40

49

H

Scheme 9.

The conversion of oxidosqualene 50 to lanosterol 52, the so-called squalene folding in the biosynthesis of steroids has initiated much research efforts (Scheme 10) [23]. This process is catalyzed by the enzyme lanosterol synthase, which controls precisely the formation of four rings and six new stereocenters. According to the pioneering work by Eschenmoser and Stork the cyclization proceeds in a concerted fashion due to favorable orbital overlap [24, 251. In contrast Nishizawa et al. were able to trap several cationic intermediates 55-57 from a related model system 54 [26]. The most recent mechanistic studies of lanosterol biosynthesis, which have been conducted with purified enzyme from recombinant sources, have revealed that the cyclization involves discrete carbocations during Cring formation and specifically that a fivemembered C-ring cationic structure 58 is first

Discovering Biosynthetic Pathways - A Never Ending Story

50

51

52

Eschenrnoser-Storkhypothesis 53

@OAC ' 5

55a 55b

(C-1O)a-OH (C-1O)P-OH

56b

(C-8)p-OH

4.9%

0.8%

2) H20, KBr 4

9.0% 2.9 %

B W 57

-

50

HO

HO

58

Scheme 10.

8.8%

51

59

NHR' 0 ' R~~

0

?

proposed active site

H.

60

Scheme 11.

163

164

C. Biological and Biomimetic Methods

formed and then enlarged by expansion to a six-membered structure 59 (Scheme 11) [27]. Corey et al. overexpressed lanosterol synthase from Saccharomyces cerevisiae in baculovirus-infected cells [27]. With the purified enzyme the kinetics of the cyclization were determined using Michaelis-Menten analysis for 50 and two analogs, in which the methyl group at C6 was replaced by H or C1. The measured Vmax/K~ ratios indicated that oxirane cleavage and cyclization to form the A-ring are concerted, since the nucleophilicity of the proximate double bond influences the rate of oxirane cleavage. In addition, atomic absorption analysis revealed that activation of the oxirane 60 is effected by an acidic group of the enzyme (presumably aspartic acid D456) rather than a Lewis acidic metal ion. Complex polyketides like erythromycin A 61 not only have stimulated many synthetic organic chemists due to the complexity of their molecular backbone [28], there is also a

growing interest in their biosynthesis, because they exhibit prominent antibiotic activity (Scheme 12) [29]. Despite the structural diversity of these polyketides, it is proposed that their biological origin is related to the biosynthesis of fatty acids. Experiments with mutant strains of Saccharopolyspora erythaea yielded 6-desoxyethronolide B 63 as the first intermediate, which is not bound to an enzyme. Thus it was concluded that the biosynthesis of 61 occurs in two different sequences. First the carbon skeleton is built up in a chain reaction involving several acyl transfer, reduction and dehydration steps by the enzyme polyketide synthase (PKS) and then cyclized to 6 -desoxyerythronolide B 63, which is further modified and glycosylated to finally yield 61. The following mode of action of PKS was established via isotope labeling experiments and feeding studies with larger fragments of 63 [30]. As shown in Scheme 13 the methyl groups in the backbone of 63

0

OH

OH

I

precursors

61

elythrornycinA

"'OH

0

"OH

63 6-desoxyelythronolid B

Scheme 12.

Discovering Biosynthetic Pathways - A Never Ending Story

165

.oAsycoH 0

0

chain-elongating unit in all cycles

\

n

0

; '<

't

/

i

t

initiating acylgroup in cycle 1

short-circuit short-ctrcult at the end of cycles 1,2,5

\ R

\

shod-circuit at the end of cycle 3

0

II

0

II

'R

63

can be introduced, if the chain initiator acetate in the fatty acid synthesis is replaced by propionate and if 2-methyl-malonate is used instead of malonate for the chain elongating steps. Hydroxy- and keto groups can be obtained by a short-circuit of the usual fatty acid synthase cycle, that is the final dehydration and hydrogenation (enol reduction) steps are skipped out. In 1991 Katz et al. reported the complete sequence of the PKS gene, which encodes a large multifunctional protein [31]. From these findings it was proposed that PKS is organized as an array of homologous enzymes, each of them catalyzing a certain chain elongation step in the synthesis of 63. However, the exact mode of coordination and cooperation between these enzymes as well as the three-dimensional folding of the protein are not known until now. In conclusion, although our knowledge about many biosynthetic pathways has im-

Scheme 13. Proposed mode of action of erythromycin-PKS. KS = ketoacyl synthase; KR = keto reductase; DH = deydratase; ER = enol reductase; ACP = acyl carrier protein; CoA= coenzyme A.

proved much during the last few years, there still remains a lot of work to be done, especially concerning a detailed investigation of structural and functional aspects of the corresponding enzymes.

References [l] U. Pindur, G. H. Schneider Chem. Soc. Rev. 1994, 409-415; S . Laschat Angew. Chem. 1996, 108, 313-315; Angew. Chem. lnt. Ed. Engl. 1996,35, 289-291. [2] Despite various mechanistic investigations, it is still a matter of debate whether the enzymatic Claisen rearrangement proceeds through a concerted mechanism. See: Y. Asano, J. J. Lee, T. L. Shieh, F. Spreafico, C. Kowal, H. G. Floss J. Am. Chem. Soc. 1985, 107, 4314-4320. J. J. Delany, R. E. Padykula, G. A. Berchtold J. Am. Chem. Soc. 1992, 114, 1394-1397 and refs. cited therein.

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[3] Reviews: Acc. Chem. Res. 1994,26, 391-411. P. G. Schultz Angew. Chem. 1989,101, 13361348; Angew. Chem. Int. Ed. Engl. 1989, 28, 1283-1295. R. A. Lerner, S. J. Benkovic, P. G . Schultz Science 1991, 252, 659-667. C. Leumann Angew. Chem. 1993,105, 13521354; Angew. Chem. Int. Ed. Engl. 1993, 32, 1291-1293. [4] L. C. Hsieh, S. Yonkovich, L. Kochersperger, P. G. Schultz Science 1993, 259, 490-493. [5] D. Hilvert, K. W. Hill, K. D. Nared, M. T. M. Auditor J. Am. Chem. SOC. 1989, 111, 92619262. A. C. Braisted, P. G. Schultz J. Am. Chem. SOC. 1990, 112, 7430-7431. [6] J. T. Yli-Kauhaluoma, J. A. Ashley, C.-H. Lo, L. Tucker, M. M. Wolfe, K. D. Janda J. Am. Chem. SOC. 1995,117,7041-7047. [7] D. W. Landry, K. Zhao, G. X.-Q. Yang, M. Glickman and T. M. Georgiadis Science 1993,259, 1899-1901. [8] C. F. Barbas 111, J. D. Bain, D. M. Hoekstra, R. A. Lerner Proc. Natl. Acad. Sci. USA 1992,89,4457-4461. [9] W. Boland, G. Pohnert, I. Maier Angew. Chem. 1995,117, 1717-1719; Angew. Chem. Int. Ed. Engl. 1995,34, 1602-1604. [lo] W. M. Bandaranayake, J. E. Banfield, D. S. C. Black J. Chem. SOC. Chem. Commun. 1980, 902-903. [I 11 K. C. Nicolaou, N. A. Petasis, R. E. Zipkin, J. Uenishi J. Am. Chem. SOC. 1982,104, 55555564. [12] R. D. Stipanovic, A. A. Bell, D. H. O’Brien, M. J. Lukefahr Tetrahedron Lett. 1977, 18, 567-570. [13] In addition an enzymatic prenylation of the sesquiterpene hydroquinone 29 to the corresponding sesterpene 28 might be a possible alternative to the Diels-Alder mechanism. [14] Y. Hano, A. Ayukawa, T. Nomura Naturwissenschaften 1992, 79, 180-182. [ 151 H. Oikawa, Y. Murakami, A. Ichihara J. Chem. SOC.Perkin Trans. I1992, 2955-2959.

[16] J. F. Sanz-Cervera, T. Glinka, R. M. Williams J. Am. Chem. SOC. 1993,115, 347-348. [17] D. E. Cane, W. Tan, W. R. Ott J. Am. Chem. SOC.1993,115,527-535. [18] Y. Yoshizawa, D. J. Witter, Y. Liu, J. C. Vederas J. Am. Chem. SOC. 1994,116,2693-2694. [19] W. A. Carrol, P. A. Grieco J. Am. Chem. SOC. 1993, 115, 1164-1165. W. G. Bornmann, M. E. Kuehne J. Org. Chem. 1992,57, 17521760. [20] A. I. Scott Acc. Chem. Res. 1970,3, 151-157. E. Wenkert J. Am. Chem. Soc. 1962, 84, 98-102. [21] H. Oikawa, K. Katayama, Y. Suzuki, A. Ichihara J. Chem. SOC. Chem. Commun. 1995, 1321-1 322. [22] This ratio is comparable to the endo ratio of other Diels-Alder reactions in aqueous media. [23] R. Bohlmann, Angew. Chem. 1992, 104,596598; Angew. Chem. Int. Ed. Engl. 1992, 31, 582-584. [24] A. Eschenmoser, L. Ruzicka, 0. Jeger, D. Arigoni Helv. Chim. Acta 1955, 38, 1890-1904. [25] G. Stork, A. W. Burgstahler J. Am. Chem. SOC. 1955, 77,5068-5077. [26] M. Nishizawa, H. Takenaka, Y. Hayashi J. Am. Chem. SOC.1985,107,522-523. [27] E. J. Corey, H. Cheng, C . H. Baker, S. P. T. Matsuda, D. Li, X. Song J. Am. Chem. SOC. 1997, 119, 1277-1288, 1289-1296, and references cited therein. [28] J. Mulzer Angew. Chem. 1991, 103, 14841486; Angew. Chem. Int. Ed. Engl. 1991, 30, 1452-1454. [29] J. Staunton Angew. Chem. 1991, 103, 13311335; Angew. Chem. Int. Ed. Engl. 1991, 30, 1302-1 307. [30] D. E. Cane, C. Yang J. Am. Chem. SOC. 1987, 109, 1255-1257. [31] S. Donadio, M. J. Staber, J. B. McAlpine, J. B. Swanson and L. Katz Science 1991, 252,675-678.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Peptide Ligases Tools for Peptide Synthesis Hans-Dieter Jakubke

Introduction Following the first chemical formation of a peptide bond by Theodor Curtius in 1881 in the laboratory of Hermann Kolbe in Leipzig, chemical peptide synthesis [ 11 developed over the next ninety years culminating in the first total synthesis of an enzyme. Ribonuclease A (RNase A), composed of 124 amino acid residues, was constructed by condensation of fragments in solution [2] as well as by solid-phase synthesis [3]. Roughly ten years later Yajima and Fuji [4]synthesized RNase A according to an improved conventional synthetic strategy and obtained the first crystalline synthetic enzyme having full enzymatic activity. But an ideal, universally applicable method for chemical formation of the peptide bond has still not been found. Since chemosynthetic reactions are typically conducted with residues having chiral centers, racemization is a constant concern. Even stepwise chain extension using urethane type protecting groups, which are supposed to prevent racemization, may be affected [5]. Recently, the rate of racemization during solid-phase peptide synthesis was studied using capillary electrophoresis [6]. Using this separation method with a limit of detection of 0.05 % the formation of stereoisomers could be verified and was around 0.4% per synthesis

cycle. There is no doubt, that chemical linkage of peptide fragments is yet unreliable.

Principles of Enzyme-Catalyzed Synthesis Owing to the stereo- and regiospecificity of enzymes, their applicaton for the formation of peptide bonds certainly offers a list of advantages over chemical procedures, for example mild reaction conditions, no need for permanent protection of functional groups in side chains, racemization-free course of reaction, and simple scale-up after optimization of the process. To make full use of these advantages, however, a close to universally applicable peptide ligase is needed which in principle would display high catalytic efficiency for all theoretically possible combinations of amino acids. In deviation from EC nomenclature, the term peptide ligase here refers to a biocatalyst for the formation of the peptide bond. In other words, such a peptide ligase should be nonspecific and not affected by the side chain functions of the amino acids to be coupled. Since an ideal biocatalyst like the ribosomal peptidyl transferase is not available, and multienzyme complexes in bacterial peptide synthesis are limited to

C. Biological and BiomimeticMethods

168

Y-NH-H

1

0

5

KO 0

Y-NH-R

-

B

Y

-

Hydrolysis

0

mT C E O y m e

1

HOR

1

2

w-r 3 Y-NH-NH-R’

Scheme 1.

W

b

i

S

0 4

specific purposes, only proteases can be used for formation of the peptide bond. The idea of using enzymes to make peptide bonds is about as old as chemical peptide synthesis itself. In 1898, evoking the reversibility of chemical reactions, van’t Hoff predicted that enzymes could be used to catalyze the formation of peptide bonds. This idea was first taken up in 1938 by Max Bergmann and confirmed experimentally. In principle, two different mechanistic strategies for protease-catalyzed peptide synthesis are distinguished [7]. In kinetically controlled enzymatic peptide synthesis [8], the protease acts as a transferase using a weakly activated acyl donor to rapidly acylate a serine or cysteine protease, whereas the equilibrium-controlled approach represents the direct reversal of the proteolysis and ends with a true equilibrium. The kinetic approach can be more efficiently manipulated than the equilibrium approach. However, proteases are not perfect acyl transferases; owing to their limited specificity, other undesired reactions may take place parallel to acyl transfer, e.g. hydrolysis of the acyl enzyme 2, secondary hydrolysis of the peptide

product 4, and other undesired cleavages of possible protease-labile bonds in 1, 3 and 4 (Scheme 1). To eliminate or minimize these disadvantages, the enzyme can be engineered and/or the reaction medium and the mechanistic features of the process can be adjusted as shown schematically in Figure 1 [9]. Undesired hydrolytic side reactions may be eliminated by adapting the medium. Protease-catalyzed syntheses in monophasic organic solvents or in biphasic aqueous-organic systems proceed with minimal proteolytic side reactions. Since the reactants are better soluble in organic media, the chemical and enzymatic steps can be accomodated. Another option in modifying a kinetically controlled reaction is manipulating the leaving group so that the enzyme reacts exclusively with the acyl donor 1 and not with the peptide product 4 or the amino component 3. The even protease-labile products can be obtained in good yields. Two recent reviews give an overview of the current possibilities for manipulation [9,10].

Enzyme engineering The term enzyme engineering [ l l ] (see Fig. 1) describes a range of techniques from deliberate chemical modification to remodeling a wild-type enzyme by gene technology. “Subtiligase”, a mutant of subtilisin BNP’, was prepared by Jackson et al. [ 121 by protein design and used in a further total synthesis of RNase A. This work, which combines solid-phase synthesis of oligopeptides and enzymatic coupling of these fragments, demonstrates the state of the art in peptide synthesis and proves impressively the potential of enzymes for the formation of peptide bonds. Average yields of roughly 75% were obtained in the fragment condensations. The excellent leaving group of the Phe-NH2-modified carboxamido methyl ester, which even in unmodified

Peptide Ligases - Tools for Peptide Synthesis Catalytic antibody approach Design of new biocatalysts

169

Non-conventional Enzymatic Synthesis Strategies

Some new approaches to suppress competitive reactions in protease-catalyzed peptide synthesis have been developed in our group [ 141, namely leaving group manipulations at the acyl donor in kinetically controlled reactions, enzymatic synthesis in organic solvent-free ENGINEERING microaqueous systems, cryoenzymatic peptide synthesis, and biotransformations in frozen aqueous systems using the “reverse hydrolysis potential” of proteases and other hydrolases [ 151. Limitations for general application of the enzymatic approach result from the restricModulation of Avoidance tive specificity of proteases and the permanent substrate specificity of protcolysis danger of undesired proteolytic side reactions. While investigating irreversible strategies in protease-catalyzed peptide synthesis, we have focussed our interest in using ‘substrate Figure 1. Possibilities for engineering enzymatic mimetics’ as acyl donors in the kinetic peptide synthesis at different levels. approach. We have introduced the term substrate mimetics for acyl donor esters in which a cationic center is included in the leavform was found to be a very good acyl donor ing group instead of being in the acyl moiety, in other syntheses [13], and the use of a consi- i. e. the appropriate protease should be predoderable excess of acyl donor ensured that most minantly specific for the leaving group. The of the side reactions were suppressed. The term “inverse esters” was firstly used by Wagtotal yield after the five fragment condensati- ner and Horn [ 161 for p-amidinophenyl esters ons was 15%, and after the folding of the of aromatic carboxylic acids instead of p-amifinal product, 8 %. Thus starting with 100 mg dinobenzoic acid aryl esters in inhibition studof the initial peptide (residues 98-124), ies of trypsin and other serine proteases. In RNase A can be obtained on a 10-mg scale. 1991 we described the first application of The fragments (77-97, 64-76, 52-63, 21- inverse substrates in trypsin-catalyzed peptide 51, 1-20) were chosen such that the C-termi- synthesis [17]. Using acyl amino acid p-guanal residues, Tyr97, Tyr76, Val63, and Ala20, nidinophenyl ester the leaving group acts as were the closest to matching the substrate spe- a mimetic for the basic side chain function of cificity of the subtilisin mutant. A similar stra- arginine or lysine and this type of inverse subtegy was also used in the synthesis of three strate interacts readily with trypsin forming variants of RNase A, in which the two histi- the acyl enzyme. The latter reacts with the dine residues His12 and His119 at the active amino component yielding the desired pepcenter were exchanged individually and tide. Since the formed peptide bond does not simultaneously for L- 4 -fluorohistidine; the correspond to trypsin specificity the enzyme affect of these substitutions in the three analo- cannot split it. This irreversible synthesis approach allows even the synthesis of Progues of Rnase A was studied in detail. Site-directed mutagenesis

170

C. Biological and Biomimetic Methods

Xaa bonds catalyzed by trypsin. The improvements in the syntheses of acyl amino acid pguanidino as well as p-amidinophenyl esters [ 181 promote the application of this new irreversible strategy. Furthermore, the potential of substrate mimetics mediated synthesis could be extended to other suitable proteases [19].

ment of mutants based on proteolytically inactive zymogens with higher efficiency combined with the application of acyl donor esters with an improved acylation potential.

Abzyme-catalyzed Synthesis

Substrate binding at the active site [8] plays a crucial role in protease-catalyzed peptide bond formation. Unfortunately, a simple C-N In 1994, for the first time we were able to ligase is not capable of developing different show that zymogens, which are known as substrate binding regions, for example by catalytically inactive precursors of proteases, induced fit, for the structurally diverse amino can be used as biocatalysts for practically acid side chain functionalities. According to irreversible peptide bond formation [20]. In Linus Pauling the action of an enzyme order to confirm that the results obtained with depends on the complementarity of the active zymogens can be actually attributed to proen- site to the transition state structure of a reaczyme catalysis, it was essential to establish tion, as shown in Scheme 2 for peptide bond active enzyme-free zymogen preparations formation. Given the fact that the enzyme should not [14]. Firstly, we made use of the significantly different affinity of both enzyme and zymogen bind the substrate very strongly but must stato the basic pancreatic trypsin inhibitor bilize the transition state considerably, it is (BPTI). Doing so it was possible to analyze unlikely that a relatively simple enzyme can the esterase activity of the zymogen which is act as a universal peptide ligase. This premise an efficiency parameter in estimating their was recently confirmed by reports by Hirschpeptide bond forming potential. Due to the mann et al. [21] and by Jacobsen and Schultz fact that differences in the specificity constant [23] on peptide bond formation with catalytic k c , J K ~cover a range of about 5 orders of antibodies (abzymes). Analogues of the tranmagnitude, for a general use of zymogen cata- sition state were used as haptens to induce lysis it is essential to improve the acylation antibodies with the correct arrangement of rate ( k z ) . Using the carboxamido methyl ester catalytic groups. The idea behind both strateleaving group [ 131 the acylation efficiency gies is illustrated in Scheme 2 by the transition can be improved. Furthermore, guanidiated state analogue 6 synthesized by Hirschmann trypsinogen (which cannot be activated by et al. [21]. When these haptens are injected trypsin) could be used for successful acyl in animals, their immune systems generate transfer experiments. In addition, no second- antibodies against them. Since the structure ary hydrolysis of the formed peptide bond of the tetrahedral intermediate 5 is also greatly was observed in long-time experiments. Our affected by the amino acid side chains R' and studies show that zymogen catalysis can be R2, it is doubtful whether a universally appliregarded as an unexpected synthesis tool cable catalytic antibody can be generated for which allows practically irreversible peptide peptide bond formation. The structures of the bond formation. Starting with first sucessful transition state analogues 7,8a, and 8b were experiments, the improvement of this new changed deliberately, in particular by incorpostrategy necessitates simultaneous develop- ration of a cyclohexyl group, such that the

Zymogen-catalyzed Synthesis

Peptide Ligases - Toolsfor Peptide Synthesis

Scheme 2.

6

of an Wacylalanine azide with a phenylalanine derivative relative to the uncatalyzed reaction. The application of catalytic antibodies exploits the fundamental property of the immune system, generating binding sites in the folds of the antibodies which are analogous to the active sites in enzymes. However, extensive development is needed before this approach is applied as routinely as enzymatic peptide synthesis currently is, and this perspective emphasizes the importance of irreversible strategies in protease-catalyzed peptide synthesis.

abzyme that catalyzed the reaction of 9 and 10 would have broad substrate specificity (Scheme 3 ) . The abzyme-catalyzed dipeptide syntheses gave all possible stereoisomers in yields of 44 to 94 %. The abzymes did not catalyze the hydrolysis of either the dipeptide products or the activated esters employed. Further studies have revealed that the monoclonal antibody not only couples activated amino acids to form dipeptides with high turnover rates but also couples an activated amino acid with a dipeptide to form a tripeptide, as well as an activated dipeptide with another dipeptide to give a tetrapeptide [22]. Jacobsen and Schultz [23] elicited antibodies against a neutral phosphonate diester transition state analogue, which significantly accelerated the coupling

7 X= NH,R= -(CH,),COOH 8a X= 0, R= -(CH&OOH 8b X=O, R=Me

Abzyme

Ac-Xaa-ONp + H-Tv-NH, . 7 & A c - X a a - T v - N H , 9

(Xaa = Val, Leu, Phe)

10

17 1

HONp

11

Scheme 3.

References [I] H.-D. Jakubke, Peptide: Chemie und Biologie, Spektrum Akademischer Verlag, Heidelberg, 1996; B. Gutte (Ed.), Peptides: synthesis, structure, and applications, 1995, Academic Press, San Diego. [2] R. Hirschmann, R. F. Nutt, D. F. Veber, R. A. Vitali, S. L.Varga, T. A. Jacob, F. W. Holly, R. G. Denkewalter, J. Am. Chem. SOC. 1969, 91,507-508. [3] B. Gutte, R. B. Merrifield, J. Am. Chem. SOC. 1969, 91, 501-502. [4] H. Yajima, N. Fujii, J. Am. Chem. SOC.1981, 103,5867-5871. [5] N. L. Benoiton, Int. J. Peptide Protein Res. 1994,44, 399-400. [6] D. Riester, K.-H. Wiesmiiller, D. Scholl, R. Kuhn, Anal. Chem. 1996, 68,2361-2365. [7] Selected reviews: a) H.-D. Jakubke, P. Kuhl, A. Konnecke, Angew. Chem. 1985, 97, 79-87; Angew. Chem. Int. Ed. Engl. 1985, 24, 85-93; b) W. Kullmann, Enzymatic Peptide Synthesis, 1987, CRC, Boca Raton, 1987; c) H.-D. Jakubke in The Peptides: Analysis, Biology, (Eds.: S. Udenfriend, J. Meienhofer), Vol. 9, pp. 103-165, Academic Press, New York, 1987; d) P. Sears, C. H. Wong, Biotechnol. Prog., 1996, 12, 423-433. [8] V. Schellenberger, H.-D. Jakubke, Angew. Chem. 1991, 103, 1440-1452; Angew. Chem. Int. Ed. Engl. 1991,30, 1437-1449. [9] H.-D. Jakubke, J. Chin. Chem. SOC.1994, 41, 355-370. [lo] J. Bongers, E. P. Heimer, Peptides 1994, 15, 183-193. [ l l ] C.-H. Wong, Chimia 1993, 47, 127-132. [ 121 D. Y. Jackson, J. Vurnier, C. Quan, M. Stanley, J. Tom, J. A. Wells, Science 1994, 266, 243247. [13] P. Kuhl, U. Zacharias, H. Burckhardt, H.-D. Jakubke, Monatsh. Chem. 1986, 117, 11951204.

[14] H.-D. Jakubke, U. Eichhorn, M. Hansler, D. Ullmann, Biol. Chem. 1996,377,455-464. [15] M. Hansler, H.-D. Jakubke, J. Pept. Sci. 1996, 2,219-289; Amino acids, 1996, 11, 379-395. [16] G. Wagner, H. Horn, Pharmazie 1973, 28, 428-431; K. Tanizawa, A. Kasaba, Y. Kanaoka, J. Am. Chem. SOC. 1977, 99, 44854488 [17] V. Schellenberger, H.-D. Jakubke, N. P. Zapevalova, Y. V. Mitin, Biotechnol. Bioeng. 1991, 38, 104-108; 38, 319-321; K. Itoh, H. Sekizaki, E. Toyota, K. Tanizawa, Chem. Pharm. Bull. 1995,43, 2082-2087 [18] H. Sekizaki, K. Itoh, E. Toyota, K. Tanizawa, Chem. Pharm. Bull. 1996, 44, 1577-1579; 1585-1587; D. R. Kent, W. L. Cody, A. M. Doherty, Tetrahedron Lett. 1996, 37, 87 1 18714. [19] F. Bordusa, D. Ullmann, C. Elmer, H.-D. Jakubke, Angew. Chem. lnt. Ed. Engl. 1997, 36, 2473-2475. [20] D. Ullmann, K. Salchert, F. Bordusa, R. Schaaf, H.-D. Jakubke in Proc. 5th AkuboriConference, Max-Planck-Gesellschaft, (Ed. E. Wiinsch), pp. 70-75, R. & J. Blank, Miinchen, 1994. [21] R. Hirschmann, A. B. Smith, C. M. Taylor, P. A. Benkovic, S. D. Taylor, K. M. Yager, P. A. Sprengeler; S . J. Benkovic, Science 1994,265,234-237. [22] D. B. Smithrud, P. A. Benkovic, S. J. Benkovic, C. M. Taylor, K. M. Yager, J. Witherington, B. W. Philips, P. A. Sprengeler, A. B. Smith, R. Hirschmann, J. Am. Chem. SOC. 1997,119,278-282. [23] J. R. Jacobsen, P. G. Schulz, Proc. Natl. Acad. Sci. USA 1994,91,5888-5892.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Synthetic Ribozymes and Deoxyribozymes Petra Burgstaller and Michael Famulok

The principal aims of the early stages of protein engineering were limited to understanding how enzymes work. Today’s greatest challenge is the de novo design of synthetic enzymes with novel activities. Since the discovery of natural catalytic RNAs [l], however, progress in this field is no longer limited just to proteins. The development of methods for the screening of combinatorial nucleic acid libraries have made it possible to identify scarce functional molecules in pools of up to l O I 5 different sequences. [2,3] In a typical in vitro selection or in vitro evolution experiment, a pool of RNA or DNA molecules consisting of a randomized region flanked by defined primer binding sites is subjected to a selection step to isolate those molecules capable of performing the desired task. Active molecules are then amplified and applied to another round of selection and amplification. This iterative procedure allows the enrichment of functional molecules until they dominate the library even though they initially may have been represented in a very low proportion. Using the methods of in vitro selection and in vitro evolution not only the functionality and specificity of natural ribozymes could be altered or improved, but also nucleic acid based catalysts with new catalytic activities could be evolved. The latest results in this field demonstrate that ribozymes or deoxyri-

bozymes are able to catalyze a wide range of chemical reactions.

Aptamer-based Libraries The isolation of new ribozymes can be achieved by either direct selection of active sequences from completely randomized pools, or by first selecting for binding to a cofactor needed in the reaction and using the aptamer as a basis for the selection of functional molecules. The more challenging method of direct selection allows a more complete search of the available sequence space, while an aptamerbased selection strategy might facilitate the isolation of functional molecules. Lorsch and Szostak started [5] from a specific ATP-binding RNA, which had previously been selected by affinity chromatography on ATP agarose, [4] and used it to evolve an ATP-dependent oligonucleotide kinase. [5] An RNA pool in which the central sequence of the ATP binder had been partly randomized was synthesized and was surrounded by three completely randomized sequences of a total of 100 bases (Fig. 1). This pool was incubated with ATP-y-S. RNAs onto which the y-thiophosphate group of the ATP-y-S had been transferred could be separated from the rest

174

C. Biological and Biomimetic Methods

eluted by washing with an excess of 2-mercaptoethanol, amplified and reselected. After thirteen cycles of selection, seven classes of riboI AG~AA I zymes were characterized which catalyzed various reactions. Five of these RNA classes catalyzed the transfer of the y-thiophosphate onto their own 5'-hydroxyl group. The other two classes phosphorylated the 2'-hydroxyl groups of specific internal base positions. # Starting from one of these sequences, a ribo\completely randomized zyme was developed which can phosphorylate sequences the 5'-end of oligonucleotides in an intermoleFigure 1. Design of the RNA library for the ATPcular reaction (Fig. 2). In this way, multiple dependent kinase selection. The grey lines flanking turnover of ATP-dependent phosphorylation the 40 and 30 nt randomized region at the 3'- and 5'-end represent primer binding sites for PCR was demonstrated with enzyme kinetics according to the Michaelis-Menten equation. amplification. Comparison of the sequence region corresof the library on activated thiopropyl agarose, ponding to the original randomized ATP bindsince they specifically formed a disulfide bond ing site in the selected ribozymes with the between the thiophosphate group and the aga- sequence of the ATP aptamer revealed that rose. These covalently bound RNAs were then in the seven different ATP-dependent kinase partially randomized ATP binding site

Intramolecular thiophosphorylation

ATP-y-S

c" Intermolecular thiophosphorylation

substrate

enzvme

$ 3 HO

OH

ATP-Y-S

Figure 2. Schematic for the inter and intramolecular 5 '-thiophosphorylation reaction catalyzed by one class of ribozymes. Other ribozyme classes catalyzed the 2'-thiophosphorylation.

Synthetic Ribozymes and Deoxyribozymes

ribozymes only four retained the ATP motif to some extent. The other three classes had completely lost the aptamer motif. An analogous strategy was used by Wilson and Szostak [6] to isolate self-alkylating ribozymes using an iodoacetyl derivative of the cofactor biotin. After isolating biotin-binding RNA aptamers by repeated rounds of affinity chromatography and amplification, a second library was generated which consisted of the mutagenized aptamer sequence flanked on either side by 20 random nucleotides. Molecules from this library which were able to selfalkylate with the biotin derivative were separated from inactive sequences by binding to streptavidin. By the seventh round of selection, more than 50% of the RNA performed the self-biotinylation reaction. The sequencing of individual clones revealed that a majority of the ribozymes was derived from a single ancestral sequence. To optimize the activity, a third selection was carried out in which the incubation time as well as the concentration of the cofactor were progressively lowered. The resulting ribozyme alkylated itself at the N7 position of a specific guanosine residue within a conserved region (Fig. 3). It shows a rate acceleration of 2 x lo7 compared to the uncatalyzed reaction. This rate enhancement is comparable to that of highly active catalytic antibodies. The self-biotinylating ribozymes which originated from a biotin-binding aptamer show an astounding structural change compared to their ancestor. A highly conserved nucleotide stretch of the biotin binder which seems to directly mediate the interaction between biotin and the aptamers as well as the catalytically active molecules is retained in the self alkylating ribozymes with only a single point mutation. Yet, the secondary structural context of this consensus sequence is highly unrelated in the two classes of molecules. While the biotin aptamer contains a pseudoknot motif, the ribozyme forms a cloverleaf which resembles the structure of tRNAs.

115

K 0

HN

NH

Figure 3. Mode of alkylation of the N7 position of an internal guanosine residue catalyzed by the alkylation ribozyme.

Random Libraries Bartel and Szostak [7] succeeded in isolating ribozymes from a synthetic RNA library which were capable of ligating an oligonucleotide to their 5'-end with cleavage of the 5'-terminal pyrophosphate. The mechanism of this reaction corresponds to the mode of action of RNA-dependent RNA polymerases. The selection started with a pool containing a very long randomized synthetic sequence of 220 nucleotides. This length was chosen to increase the probability of isolating catatytically active sequences. To bring the 3'-hydroxyl group of the oligonucleotide in proximity to the triphosphate at the 5'-end of the RNA pool, a sequence in the constant region of the 5'-primer was constructed such that the substrate oligonucleotide could hybridize to the 5'-end of the pool. Catalytically active molecules were enriched in two steps. Following incubation with the oligonucleotide, the pool was purified by passage through an oligonucleotide affinity column, to which only successfully ligated sequences could bind. These were then eluted, reverse transcribed, and amplified in a PCR reaction with a primer that was com-

176

C. Biological and Biomimetic Methods

plementary to the sequence of the ligated oligonucleotide. In a second PCR reaction the original, unligated structure was then regenerated, from which an enriched RNA pool was transcribed for the next round of selection. Three of the ten selection rounds contained a mutagenic PCR step, so that “worse” catalysts had the chance to develop into “better” ones. This strategy led to an increase in the ligation rate from 3 x h-l, for the uncatalyzed rate, to 8 h-l. The characterization of individual sequences from this selection experiment revealed three different structural classes of ligases from which only one, the class I ligase, generates a 3’- 5’ phosphodiester bond at the ligation site. [8] An optimized version of this complex ribozyme [9] that differs at 10 positions from the original sequence has a k,,, of 100 min-’, a value comparable to that of the protein enzyme ligase (Fig. 4). [9] Ekland and Bartel [lo] took one step further in creating a plausible scenario for an “RNA world” in which ribozymes catalyzing the replication of RNA are postulated. They demonstrated that the class I ribozyme is capable of extending a separate RNA primer by one nucleotide in the presence of a template oligonucleotide and nucleoside triphos-

phates. The polymerization reaction exhibits a remarkable template directed fidelity. Mismatched nucleotides are added 1000-fold less efficiently. By linking the primer covalently to the ribozyme, the reaction could be expanded to the addition of three nucleotides. By designing the primer in a way that it was able to slip onto the template, even six nucleotides could be added to the primer in a template directed way (Fig. 5). In another attempt to provide a starting point for the evolution of self-replicating ribozymes, Chapman and Szostak [ 1I] designed a selection experiment for the generation of RNA molecules that ligate their 3’-end to a hexanucleotide with a 5’-phosphate activated as phosphorimidazolide. However, the isolated ribozyme catalyzed the attack of the 5‘-terminal y-phosphate group on the 5’-phosphorimidazolide of the substrate oligonucleotide forming a 5’-5’ tetraphosphate linkage. Depending on whether a 5’- mono-, di-, or tri-

5’

C

A

ACACACACAC

3’

XTPs

Drimer

Figure 4. Secondary structure of the class I ligase.

Figure 5. RNA polymerization of up to six nucleotides catalyzed by the class I ligase (Ribozyme).

Synthetic Ribozymes and Deoxyribozymes II II ~0-P-0-P-0-P-0 I I I -0 -0 -0

5’-PBS

3‘

177

3‘-PBS

Biotin

I

-0

Biotin

II

II

II

7

I

I

I

I

0-P-0-P-0-P-0-P-0

5’-PBS

3‘-PBS

Figure 6. Reaction catalyzed by the RNA to generate a 5’-5’-tetraphosphatelinkage.

phosphate was present, the 54 nucleotide long pseudoknot motif was also capable of generating di- or triphosphate linkages (Fig. 6). To make the existence of an “RNA world” as a step in prebiotic evolution feasible, not only self-replicating ribozymes are essential, but also a second type of catalytically active molecules. The transition from a world based on RNA catalysis to a world of protein enzymes demands ribozymes which are able to synthezise peptides from activated amino acids. A prerequisite for peptide and protein synthesis in all modem-day life forms is the formation of aminoacyl-tRNA carried out by aminoacyl-tRNA synthetases. These enzymes first activate the carbonyl group of the amino acid by forming an aminoacyl-adenylate containing a highly activated mixed anhydride group which is then used to transfer the amino acid to the 3’(2’)-hydroxy terminus of the cognate tRNA. Illangasekare et al. [12] used an in vitro selection strategy to obtain an RNA that catalyzes the esterification of an activated phenylalanine to its own 3’(2’)-end.

-

An RNA library consisting of l O I 4 different molecules was incubated with synthetic phenylalanyl-5’-adenylate. Those RNA molecules which had catalyzed their own aminoacylation contained a free a-NH3+-group from the amino acid. This nucleophilic a-NH3+group was selectively reacted with the Nhydroxysuccinimide of naphthoxyacetic acid. Thus, only those RNAs with the amino acid covalently attached to themselves contained the naphthoxy residue and therefore differed significantly in their hydrophobicity from inactive molecules. Consequently, separation from inactive sequences could be achieved by reversed phase HPLC (Fig. 7). Eleven cycles of selection resulted in a variety of selfaminoacylating ribozymes of which the most active showed a rate enhancement of lo5fold compared to the background rate. Lohse and Szostak [13] used a selection scheme that mimicks the transfer of formylmethionine from a fragment of Net-tRNA onto the hydroxy group of hydroxypuromycin, a simplified version of the ribosomal peptidyltransferase reaction. An RNA library

178

C. Biological und Biomimetic Methods

Base

Figure 7. 2'- and 2',3'-aminoacylation of catalytic RNAs. Catalytic RNAs that can self-aminoacylate are made more hydrophobic with a naphthoxyacetyl labcl. ,

comprising a 90 nucleotide random region G . U wobble base pairs at the donor/acceptor was treated with alkaline phosphatase to junction are important for the reaction. When expose the 5'-hydroxyl group and was incubat- replaced by G : C pairs, the value of k,;,, ed with a hexanucleotide charged at its 3'-end decreased 14-fold, while the template-only with biotinylated methionine acting as an directed reaction is optimal with a completely amino acid donor. Functionally active RNA Watson-Crick base paired duplex. The descrimolecules were separated from the inactive bed ribozyme is also capable of forming part of the library on streptavidin agarose via amide bonds which was demonstrated by the biotin tag. After eleven cycles of selection, replacing the attacking 5'-hydroxyl group by including two rounds of mutagenic PCR, the an amino group. enriched library showed a 1O4 -fold increase in acyl transferase activity. Cloning and sequencing revealed that the pool was dominated by one class of sequences with a highly TSA-based Selections conserved internal region. The 3'-end of this consensus sequence is complementary to the All ribozymes described so far were isolated hexa-oligonucleotide substrate, the 5'-part is by the method of direct selection, whereby able to basepair with the 5'-end of the RNA, the partly or completely randomized pool of thus bringing the 3'-end of the donor and the nucleic acids is subjected to a competitive 5'-end of the acceptor into close proximity. situation in which only those molecules surThe ribozyme, however, does not act merely vive that can catalyze a particular reaction. A as a template, since it shows a rate enhance- different strategy by which catalysis can be ment of lo3 compared to the rate of tem- achieved is the indirect selection for binding plate-directed acyl transfer. Interestingly, two to transition state analogs (TSAs), a tech-

gT :

Synthetic Ribozymesand Deoxyribozymes

179

\

3

2

1

4

Figure 8. Isomerization of the bridged biphenyl derivative 1 to its diastereomer 3 catalyzed by the rotamase ribozyme. The reaction proceeds through the transition state 2, mimicked by the transition state analog 4.

nique used for the isolation of catalytic antibodies. Following this strategy, Prudent et al. [14] have isolated RNA aptamers that could bind specifically to the TSA of the isomerization of an asymmetrically substituted biphenyl derivative (Fig. 8). The selection was performed by affinity chromatography of a randomized pool on the TSA immobilized on agarose.

After seven rounds of selection, the RNA pool was able to accelerate the reaction by a factor of 100 over the uncatalyzed reaction. A kinetic study showed that a Michaelis-Menten complex is formed initially, followed by the isomerization reaction and release of the reaction product. The reaction was completely inhibited by the planar TSA.

C"?+

COOH

i

COOH

COOH

i

COOH

TSA 1: X = CONH(Ct-!&NHCO(CH2)5NH-biotin TSA 2 X = COOH

Figure 9. Metalation of Mesopotphyrin and transition state analog N-methyl mesoporphyrin TSAl and TSAZ. TSAl was used for the selection by streptavidin immobilization.

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C. Biological and Biomimetic Methods

The second example of a catalytic RNA obtained by isolating an RNA aptamer for TSA binding was reported from the same laboratory [15]. Conn et al. recently reported the isolation of a 35 nucleotide RNA molecule which binds mesoporphyrin IX and catalyzes the insertion of Cuz+ into the porphyrin with a value of k,,,/K,,, of 2100 M-' s-l. The k,,,/K,,, value achieved by the RNA was close to that of the Fez+-metalation of mesoporphyrin catalyzed by the protein enzyme ferrochelatase (Fig. 9). The isolation of ribozymes by selection of TSA-binding nucleic acids may consitute an efficient method for investigating the diveristy of available chemical reactions that can be catalyzed by nucleic acids.

metal ion. All ribozymes whose reaction mechanisms have been studied are metalloenzymes. Metal ions such as Mgz+, or even Pbz+ in the case of the self-cleaving yeast tRNAPhe, were always involved in the catalytic mechanism and also served to maintain the correct folding of the RNA. Pan and Uhlenbeck [17] have shown that new ribozymes with Pbz+dependent phosphodiesterase activity could be isolated from a randomized pool of tRNAPhe molecules. The specificity of the reaction depends on the coordination of a Pb2+ ion to a defined position within the RNA. Breaker and Joyce also used Pb2+ as the cofactor in their selection. They generated a pool of about 1014 double-stranded DNAs with a randomized region of 50 nucleotides. One of the strands contained a biotin group at the 5'-end, followed by a defined 43-mer base sequence containing a single ribose adeDeoxyribozymes nosine unit. The double-stranded DNA was A new departure in the development of immobilized on streptavidin agarose, and the nucleic acid based catalysts was made three non-biotinylated strand was removed by years ago by Breaker and Joyce, who reported increasing the pH. The immobilized singlethe isolation of the first deoxyribozyme. The stranded DNA was then incubated in Pbz+proof that DNA can also catalyze chemical containing buffer. In active sequences this reactions is not completely unexpected, espe- led to cleavage of the phosphodiester bond at cially since it was shown shortly after the the ribose phosphate group, and hence to loss development of the in vitro selection tech- of the covalent attachment to the biotin-bearnique that single-stranded DNA molecules ing 5'-end. The catalytically active sequences can also be selected to bind to a variety of were thereby specifically eluted from the ligands. Meanwhile, several catalytically column, and were subsequently amplified active DNAs have been described, expanding and selected once more (Fig. 10). Five rounds the range of nucleic acid catalyzed reactions of selection afforded a population of singlestranded DNAs that could catalyze the Pbz+even further. Breaker and Joyce [16] accomplished the dependent cleavage of the ribose residue. selection of a DNA enzyme that could speci- These DNAs also show similarities in their fically cleave the phosphodiester bond of a sequences. Like the hammerhead and hairpin ribonucleotide. The DNA pool synthesized ribozymes, they contain two conserved, for this purpose contained a single ribonucleo- unpaired regions between two sequences tide at a specific position within a primer which can pair with bases upstream and binding site, in order to avoid the possible downstream of the splice site. This structural effect of RNA on the catalysis. In addition, motif served as the basis for the construction they assumed that a DNA-dependent cleavage of a shortened version of the catalytic and subat pH 7 would require a cofactor, possibly a strate domains. In this way, it was shown that

Synthetic Ribozymes and Deoxyribozymes

the 38 nucleotide long catalytic domain could cleave the 2 1-mer substrate specifically and with high turnover rates. The deoxyribozyme is, however, not capable of cleaving a pure RNA substrate, although the substrate binding to the enzyme is ensured with two longer base-paired regions. Using the same selection strategy, other experiments have been carried out to isolate DNA molecules with either RNA or DNA phosphoesterase activity. Since Mg2+-dependent rather than Pb2+-dependent cleavage is compatible with intracellular conditions and thus, more suitable for possible medical applications, Breaker and Joyce [18] also developed deoxyribozymes that used Mg2+ as a cofactor instead of Pb2+. The deoxyribozyme showed a cleavage rate of 0.01 min-' and was also capable of intermolecular cleavage.

-

primer 1 primer3 primer 2b

9biotinanchor D

ribo-A

I

18 1

Faulhammer and Famulok [ 191 attempted to develop deoxyribozymes that use a non-metal cofactor rather than divalent metal ions for the cleavage of a ribonucleotide residue. They performed a selection experiment under conditions of low magnesium concentration, or even without any divalent metal ions, by incubating the immobilized single-stranded DNA library in a large excess of histidine. Surprisingly, non of the resulting eight classes of deoxyribozymes utilized the histidine as a cofactor for the strand scission. Instead, some of them were dependent on the presence of divalent metal ions while others were able to accelerate the cleavage reaction even in the absence of divalent metal ions. Remarkably, one of the catalysts, showed higher cleavage activity in the presence of Ca2+than of Mg2+, even though magnesium was part of the selection buffer. A possible explanation

streptavidin matrix

Figure 10. Selection scheme for deoxyribozymes which cleave RNA/DNA chimeric oligonucleotides. In a first PCR (a), the starting pool was amplified using primer 1and primer 3. (b) In a second PCR, the 5'-end of the pool was biotinylated and the ribonucleotide serving as cleavage site was introduced using primer 2b and primer 3. The double-stranded pool was then loaded on a streptavidin column (c). The antisense strand is removed by raising the pH of the solution (d) and the remaining pool of single-stranded DNA allowed to fold (e) by rinsing the column with equilibration buffer. The equilibration was followed by addition of cleavage buffer (f). Cleavage products were eluted from the column (g) and amplified by PCR using the same primers as above.

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C. Biological and Biomimetic Methods

might be that in this special case Ca2+can be more suitably positioned at the cleavage site. This suggestion is supported by the observation that two Ca2+-ions are bound in a cooperative fashion by the deoxyribozyme. [20] Thus, the cleavage mechanism performed by the seelected deoxyribozyme might be highly similar to the “Two-metal ion“-cleavage mechanism recently suggested by Pontius et al. [21] for the hammerhead ribozyme (Fig. 11). From the unexpected result of this selection, one might conclude that in nucleic acids the number of potential binding sites for metal-ions is by far larger than for nonmetal cofactors. To further examine the catalytic potential of DNA, Carmi et al. [22] employed the in v i m selection protocol described above to generate deoxyribozymes that facilitate self-cleavage by a redox-dependent mechanism. The design of this selection was based on the fact that DNA is more sensitive to cleavage via depurination followed by D-elimination or via oxidative mechanisms than by hydrolysis. Therefore, single-stranded DNA (ssDNA) bound to streptavidin by its biotin-tag was incubated with CuC12 and ascorbate. The pool isolated after seven rounds of selection consisted of

two distinct classes of self-cleaving ssDNA molecules. While “class I” deoxyribozymes performed strand scission in the presence of both Cu2+ and ascorbate, “class II” molecules only required the copper ion as a cofactor. An optimized version of the “class 11” deoxyribozyme shows a rate enhancement of more than 106-fold compared to the background reaction. However, the catalytic potential of DNA is not only limited to phosphoresterase activity. Cuenoud and Szostak [23] designed a selection scheme to isolate DNA molecules that catalyze the ligation of their free 5’-hydroxyl group to the 3’-phosphate group of a substrate oligonucleotide activated by imidazolide. The resulting deoxyribozyme is dependent on the presence of Zn2+or Cu2+.It contains two conserved domains which position the 5’-hydroxyl group and the 3’-phosphorimidazolide of the substrate oligonucleotide in close proximity. However, the consensus sequences are flanked by highly variable regions, suggesting that several independent ways of arranging the consensus sequences resulted in active deoxyribozymes. Based on the selected sequences, a truncated version of the DNA ligase was designed that is able to ligate two DNA sub-

Figure 11. Proposed cleavage mechanisms for the hammerhead ribozyme. (a) One metal ion mechanism. (b) Two metal ion mechanism. This mechanism is also proposed for the calcium-dependent deoxyribozyme which binds at least two Ca2+ions in a cooperative manner.

Synthetic Ribozymes and Deoxyribozymes

strates in a multiple turnover reaction with a 3400-fold rate enhancement compared to the template-only directed ligation. Recently, in a similar approach as reported for an RNA selection [17], a DNA molecule able to catalyze porphyrin metallation was isolated [24]. An oligomer consisting of the 33 nucleotide long guanine-rich binding site of a randomly chosen aptamer that binds to the TSA N-methylmesoporphyrin IX showed a k,,, of 13 h-’ for the insertion of Cu2+ into mesoporphyrin IX. This corresponds to a rate enhancement of 1400 compared to the uncatalyzed reaction. A catalytic antibody for the same reaction shows a rate acceleration in the same range. [25] The deoxyribozyme is strongly dependent on the presence of potassium in the reaction buffer, which suggests the formation of guanine quartets. Despite the general acceptance that the 2’hydroxyl group of RNA is essential for its capability to form complex secondary and tertiary structures and therefore for its catalytic activity, the results of these in vitro selection experiments make clear that DNA also can adopt a variety of complex structures enabling it to catalyze a wide range of chemical reactions. [26] The man-made ribo- and deoxyribozymes will certainly be applicable in some diagnostic, technical or medical purposes, where it is advantagous that they are based not on proteins but on nucleic acids. We expect that we will soon see examples of ribo- and deoxyribozymes evolved for the catalysis of complex chemical transformations. There is enough reason to assume that such synthetic enzymes will be used as catalysts in organic syntheses. The novel catalysts not only support theories of an “RNA world”, [27] in which the metabolism and replication of primitive organisms were controlled by RNA enzymes. [28] There is also the potential for biotechnological, synthetical and diagnostical applications. One of the most obvious applications of synthetic nucleic acid-based enzymes is their use in vivo, for example as

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reporter systems in eucaryotic transcription assays which would greatly facilitate the development of highly sensitive screening assays.

References [l] Kruger, K., Grabowski, P. J., Zaug, A. J., Sands, J., Gottschling, D. E., Cech, T. R., Cell 1982, 31, 147-157; Guemer-Takada, C., Gardiner, K., Marsh, T., Pace, N., Altman, S., ibid. 1983, 35, 849-857. [2] Ellington, A. D., Szostak, J. W., Nature 1990, 346, 818-822; Tuerk, C., Gold, L., Science 1990,149, 505-510; Robertson, D. L., Joyce, G. F., Nature 1990, 344, 467-468. [3] Gold, L., Polisky, B., Uhlenbeck, 0. C., Yarus, M. Annu. Rev. Biochem. 1995, 64, 763-797; Joyce, G. F. Curi: Opin. Struct. Biol. 1994, 4, 331-336; Ellington, A. D. Curi: B i d . 1994, 4, 427-429; Klug, S. J. Famulok, M. Mol. Biol. Reports 1994, 20, 97-107; Famulok, M. Szostak, J. W. Angew. Chem. Int. Ed. Engl. 1992,31, 979-988. [4] Sassanfar, M., Szostak, J. W., Nature 1993, 364,550-553. [5] Lorsch, J. R., Szostak, J.W., Nature 1994,371, 31-36. [6] Wilson, C., Szostak, J. W., Nature 1995, 374, 777-782. [7] Bartel, D., Szostak, J. W., Science 1993, 261, 1411-1418. [8] Ekland, E., Szostak, J. W., Bartel, D., Science 1995,269,364-370. [9] Ekland, E., Szostak, J. W., Nucl. Acids Res. 1995,23, 3231-3238. [lo] Ekland, E., Bartel, D., Nature 1996,382, 373376. [ l l ] Chapman, K. B., Szostak, J. W., Chem. Biol. 1995,2,325-333. [ 121 Illangasekare, M., Sanchez, G., Nickles, T., Yarus, M., Science 1995,267,643-647. [ 131 Lohse, P. A., Szostak, J. W., Nature 1996,381, 442-444. [14] Prudent, J. R., Uno, T., Schultz, P. G., Science 1994,264, 1924-1927. [15] Conn, M. M., Prudent, J. R., Schultz, P. G. J. Am. Chem. SOC. 1996,118,7012-7013.

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[16] Breaker, R. R., Joyce, ti. F. , Chem. B i d . 1994, I, 223-229. [17] Pan, T. Uhlenbeck, 0. C., Nature 1992, 358, 560-563. [18] Breaker, R.R., Joyce, G. F., Chem. Biol. 1995. 2,655-660. [19] Faulhammer, D., FamuIok, M., Angew. Chem. Int. Ed. Engl. 1996,35, 2837-2841. [20] Faulhammer, D., Famulok, M., J. Mol. Biol. 1997, in press. [21] Pontius, B. W., Lott, W. B., von Hippel, P. H., Proc. Natl. Acad. Sci. USA 1997, 94, 22902294. [22] Carmi, N., Shultz, L. A., Breaker, R. R., Chem. Biol. 1996,3, 1039-1046.

[23] Cuenoud, B., Szostak, J. W., Nature 1995, 375,611-615. [24] Li, Y., Sen, D., Nature Struct. Biol. 1996, 3, 743-747. [25] Cochran, A. G., Schultz, P. G., Science 1990, 249,781-783. [26] Berger, I., Egli, M. Chem. Europ. J. 1997, in press. [27] Gilbert, W., Nature 1986, 319, 618. [28] Benner, S. A., Ellington, A. D., Tauer, A., Proc. Natl. Acad. Sci. USA 1989, 86, 70547058; Joyce, G. F., Orgel, L. E., in The RNA World (Eds.: Gesteland, R. F., Atkins, J. F.), Cold Spring Harbor Laboratory Pess, New York, 1993, 1-25.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Enzyme Mimics Anthony J. Kirby

Introduction

of chromophore intensity wiht aggregation state. [6] The pepzymes debacle has never been satisThis Highlight is part of an extraordinary story (also a cautionary tale) in the area of bio- factorily explained, though the published catalysis. The point of particular interest was results point unmistakeably to enzyme contathe incredible catalytic activity claimed for mination. The surfactant story on the other so-called ‘pepzymes’ - small synthetic pep- hand has been properly sorted out, to the satistides modelled to mimic the active site struc- faction of the original authors. Yet the lessons tures of trypsin and chymotrypsin. One was to be learned from these two case histories are claimed to hydrolyse a simple peptide (a tryp- basically the same - and by no means new. sin substrate) with efficiency comparable to Mechanisms generally cannot be proved, that of the native enzyme. This extraordinary only ruled out. So the design of control experesult provoked at least as much scepticism riments to test alternative explanations is at as excitement, and in the following months least as important as the key experiment several groups tried to reproduce the results. which appears to confirm a favourite or new They failed, comprehensively. [ 1,2] Some and exciting theory. It is an inconvenient but reasons why this failure came as no surprise inescapable fact of life that the more remarkwere subsequently summarised by Matthews, able the result, the more important are those Craik and Neurath, [3] and by Corey and control experiments. One of the great intellectual challenges Corey [4]. The background has been discussed in an Angewandte Review on Enzyme presented to Science by Nature is a proper understanding of how enzymes work. At Mechanisms, Models and Mimics. [5] The Highlight noted a second example of one level we can ,explain’ enzyme catalysis remarkably effective catalysis of amide hydro- - what an enzyme does is bind, and thus lysis, this time in a surfactant system. This stabilise, selectively the transition state for a work involved activated amides, and accelera- particular reaction. [7] But our current tions - though exceptional - less spectacular level of understanding fails the more severe, than those claimed for the pepzymes. Never- practical test - that of designing and making theless, this result too was not what it seemed: artificial enzyme systems with catalytic the apparent release of p-nitroaniline turned efficiencies which rival those of natural out to be an unusually slow physical change, enzymes.

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C. Biological and Biomimetic Methods

Enzyme mimics have long been high-profile targets for bioorganic chemists. The picture to date has been the familiar one of steady progress, with occasional flashes of inspiration; and a heightening awareness of just how complex the problem is. But two recent reports [8,9] - approaching the problem from completely different directions, claim catalytic efficiencies in artificial systems which are extraordinary in terms of conventional wisdom. First we should set the scene. The ‘conventional wisdom’ is based on the one hand on mechanistic work on enzymes, and on the other hand on (mostly separate) studies of binding and catalysis in simpler, artificial systems. Enzymes are of course more than just highly evolved catalysts: they also recognise and respond to molecules other than their specific substrate and product, as part of the control mechanisms of the cell. But the evolution of enzyme mimics is at a stage where the efficient combination of binding and catalysis is the main objective. A starting point may be a system which shows efficient binding; or the mechanism of the reaction concerned, since it is the ratedetermining transition state which is the most important target for the binding process. Eventually the two approaches must converge if a genuine enzyme mimic is to emerge. This sort of work holds out the promise of artificial catalysts, which may be more robust than proteins, for unnatural reactions of interest. On the other hand, the most natural basis for an enzyme mimic is inevitably a real enzyme. All these approaches are currently producing interesting results.

Enzyme-based Mimics It is possible to modify a natural enzyme, chemically or more commonly by the methods of protein engineering, in such a way that its specificity is altered, even to the point that the

modified system will catalyse a new reaction. Such systems are modified enzymes rather than enzyme mimics, which to qualify in this context should have been constructed artificially. When it became possible to identify the functional groups in enzyme active sites it was natural to look at small peptides containing active-site sequences of amino-acids as possible catalysts. The results of this sort of work were uniformly negative. We know now that a working enzyme active site has its functional groups disposed in a specific, dynamic three-dimensional array, with significant interactions with the rest of the protein, and this cannot successfully be modelled in two dimensions. A true enzyme-based mimic might try to reproduce the three-dimensional arrangement of the functional groups of the active site in a synthetic framework. The reasoning is simple; turning the idea into real molecules less so. However, what appears to be a major success for this approach is the report of Atassi and Manshouri [8] of the preparation of two so-called ‘pepzymes’, modelled from the active site structures of trypsin and chymotrypsin by ‘surface-simulation’. This involved the design and synthesis of a series of relatively small (29 residue) peptides containing the key catalytic and binding amino-acid sequences of the enzymes. These were connected by glycine spacers so as to model the 3D arrangement known from the X-ray structures of the enzyme and its complexes with substrate analogues. An early version which showed some trypsin-like binding activity was modified systematically to the point where the peptide shown (native active-site residues indicated in bold) shows extraordinary catalytic activity, specifically in the cyclic (disulphide) form. Not only does this molecule hydrolyse the simple trypsin ‘substrate’ N-tosyl-L-arginine methyl ester with kcat and K , comparable to those of the native enzyme, but it also hydro-

Enzyme Mimics

187

Cys-Gly-Tyr-His-Phe-Gly~-Ser-Asp-Gly-GIn-Gly-Ser-Ser-Gly~-Val-Ser-Trp-Gly-Leu-Gly~-Asp-Gly-Ala-Ala-His-Cys

lyses test proteins to give similar peptide pro- relevant: the Effective Molarity (EM: the files. A closely related peptide based on the effective concentration of the catalytic group, chymotrypsin active site had similar activity that would needed to make an intermolecular reaction go at the rate of the intramolecular and the expected, different specificity. It must be said that this level of activity is one). [lo] And - of course - the absolute rate surprising, especially against amide bonds, of the reaction. Because reactions in enzyme and intensive efforts to repeat the results are active sites are very fast: fast enough for under way. If confirmed this work will be many enzymes to have reached evolutionary seen as an important advance: the design perfection, defined by Albery and Knowles stage may be complex, but with modem syn- [ l l ] as catalytic efficiency so high that the thetic methods peptides of this sort of size rate determining step of the reaction concerned are quite reasonable synthetic targets. A prac- is diffusion away of the products. tical limitation, as always with enzyme-based EM’S as high as 1013-14 - meaning halfmimics, is that - at this stage of development lives of the order of a second - can be attained at least - complete success simply means in systems where an ordinary aliphatic amide doing a reaction as well as an available natural is forced into close proximity with a COOH group, [ l l , 121 or a phosphate diester with a catalyst. neighbouring OH, [13] and it is possible to define detailed mechanisms for such model reactions. These serve as an essential basis for the discussion of the mechanisms of the Mechanism based Mimics same reactions in enzyme active sites, or for At the other extreme, it is possible to achieve the design of enzyme mimics. Because it is enormous rate accelerations in quite simple not possible - so far at least - to attain ratesystems by by-passing the binding process enhancements of anything like this magnitude and making reactions intramolecular - that when the reacting groups are brought together is, by bringing the functional groups con- by non-covalent binding. cerned together on the same molecule. [lo] Typically, making the reaction of interest part of a thermodynamically favourable cyclisation can produce systems in which the extraordi- Binding-step Based Mimics narily stable groups of structural biology (amides, glycosides and phosphate esters have A minimum requirement for a true enzyme half-lives of many years under physiological mimic is a binding interaction between two conditions near pH 7) can be cleaved in a frac- molecules preliminary to the catalytic reaction of a second. Detailed chemical mecha- tion, indicated by Michaelis-Menten kinetics. nisms of catalysis can then be worked out for Intramolecular systems can support very specific reactions, studied under the same rapid reactions because we can use synthesis conditions and going at similar rates as the to bring groups together into close and same reactions between the same two (or unavoidable proximity. But an enzyme must more) functional groups in enzyme active select and bind its substrate non-covalently sites. Two measures of catalytic efficiency are in a dynamic equilibrium. The chemistry of

-

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C. Biological and Biomimetic Methods

P-

HP_ 0

R'--P-m

\0-

0

2

1

3

4

5

6

the Molecular Recognition processes involved is one of the most active areas of current research, and a popular topic for meetings [14,15] highlights [16] and reviews. [17] As with chemical catalysis, much of our understanding of non-covalent interactions comes from studies of simple systems designed to answer specific questions about the basic process. More directly relevant to the development of enzyme mimics are systems designed to achieve catalysis by binding, i. e. without specific catalytic groups built in. These fall into two important classes: synthetic hosts designed to bring two reactants into close and productive proximity, and most catalytic antibodies. The majority of catalytic antibodies [18,19] so far known have been designed to catalyse the hydrolysis of carboxylic acid derivatives, and have been raised against phosphonate haptens 2, which models the structure of the tetrahedral transition states involved (1). Catalysis of ester hydrolysis is rather reliably obtained with suitable haptens (and substrates), with the nucleophile coming from the solvent. More ambitious systems with catalytic groups built-in can in principle be

obtained by careful hapten design (coupled with a large slice of luck); or from an existing catalytic antibody by protein engineering. This is an area of definite promise, and much current activity. Careful hapten design also allowed the preparation of an antibody that catalysed the Diels-Alder reaction of tetrachlorothiophene dioxide 3 and N-ethylmaleimide. [20] Again, catalysis results simply from productive binding (an EM of > 110 M is estimated): turnover depends on the instability of the initial adduct 4, which loses SO:! very rapidly to give the aromatic product 5. This avoids product inhibition, which is a common problem with such potential catalytic systems: the hapten 6 is a reasonable transition state analogue, but geometrically very different from the final product. The Diels-Alder reaction can also be catalysed by simple artificial systems. A recent example is the reversible reaction between 7 and 8, which is accelerated by (stoicheiometric amounts of) a cyclic zinc-porphyrin trimer host which binds pyridine derivatives inside the cavity. [22] The product is the exo-adduct, produced up to 1000 times faster than the cor-

Enzyme Mimics

responding endo-isomer (which is obtained as the kinetic product in the absence of the macrocycle). This corresponds to an EM of about 20 M. The system is not catalytic because of product inhibition (as was an early example using the cavity of a cyclodextrin as host [23]).

Enzyme Mimics Showing Binding and Catalysis Many of the most successful enzyme mimics have involved functionalised cyclodextrins, and the work of Breslow in particular is familiar to anyone who has followed the field. [24] These hosts bind aromatic rings within a hydrophobic cavity. In another seminal contribution Lehn [25,26] has used polyammonium macrocycles to catalyse phosphate transfer reactions of ATP, demonstrating that multiple hydrogen-bonds can also be an effective source of binding between flexible systems in aqueous solution. A different approach has been reported by Benner and his group, [26] who based the design of a synthetic decarboxylase on the known properties of proteins and the mechanism of amine-catalysed decarboxylation of B-ketoacids. Their enzyme mimics are 14-

189

residue peptides (called oxaldie 1 and 2) based on leucine and lysine, in a sequence known to favour a-helix formation, and thus expected to adopt protein-like conformations, with a hydrophobic core and a hydrophilic exterior. They catalyse the decarboxylation of oxaloacetate by the expected mechanism shown, with the cationic lysine side-chains presumably involved in binding the two carboxylates of both substrate and transition state (acetoacetate, with a single C o y , is not a substrate). Michaelis-Menten kinetics are observed and imine formation is 103-4 times faster than with simple amine catalysts. And activity does indeed seem to depend on the degree of a-helix formation. The simplest, and one of the most remarkable, new enzyme mimics has emerged from a piece of ‘lateral thinking’ by Menger and Fei. [9] No synthesis is involved. These authors simply mixed long-chain carboxylic acids, amines, alcohols and alkylimidazoles, of the sort known to form aggregates, and eventually micelles, in aqueous solution: then screened large numbers of such mixtures for catalytic activity. The test reaction was the hydrolysis of the reactive ester 9 (X = 0), which is easily followed above pH 7 by the release of the p-nitrophenolate chromophore. Some of the mixtures used effected the hydrolysis of 9 (X = 0) at rates too fast to measure manually. Remarkably this was also true in the presence of a single component when this was the hexadecanoate anion, and this system also effects the hydrolysis of the p-nitroanilide (9, X = NH). This is an activated amide, but one that is not hydrolysed detectably in the presence of 0.2 M acetate at pH 7 (25°C). But under similar conditions, in the presence of just

d

9

190

3

C. Biological and Biomimetic Methods

O

2x M hexadecanoate its half-life is only 3 minutes. Only nucleophilic catalysis could account for such an efficient process. [lo] No EM can be calculated as no data are available for a suitable comparison, but hexadecanoate is at least lo* times more effective than acetate. Interestingly the reaction is stoicheiometric: though a mixed anhydride is almost certainly an intermediate its hydrolysis must be rate determining in the overall hydrolysis of the anilide. The authors suggest that the reaction takes place in sub-micellar aggregates or 'clumps,' in which hydrophobic association of the long alkyl chains brings anilide C=O and hexadecanoate COY groups into close and remarkably productive proximity (see 10). (Simply adding three methylene groups to the substrate [9, X = (CH&NH] eliminates the observed reaction.) Two points are of special interest here: the high reactivity, which is much greater than previously observed for such apparently loosely-associated systems: and the principle, of screening large numbers of simple systems, rather than actually synthesising complex, carefully designed ones. The newer approach supplements existing ways of thinking, and practical applications could result.

0

-

10

References [l] D. R. Corey, M. A. Philips, Proc. Natl. Acad. Sci. U.S. 1994, 91, 4106-4109. [2] J. A. Wells, W. J. Fairbrother, J. Otlewski, M. Lagowski, J. Bumier, Proc. Natl. Acad. Sci. U.S. 1994, 91,4110-4114. [3] B. W. Matthews, C. S. Craik, H. Neurath, Proc. Natl. Acad. Sci. U.S. 1994, 91, 41034105. [4] M. J. Corey and E. Corey, Proc. Natl. Acad. S C ~ U.S. . 1996, 93, 11428-11434. [5] A. J. Kirby, Angew. Chem., Intl. Ed. Engl., 1996,35,707-724. [6] W. K. Fife and S. Liu, Angew. Chem., Intl. Ed. Engl., 1995,34,2718-20. [7] Fersht, A. R., Enzyme Structure and Mechanism, second edition, W. H. Freeman, New York, 1985. [8] M. Z. Atassi and T. Manshouri, Proc. Natl. Acad. Sci. U.S., 1993, 90, 8282-8286. [9] F. Menger and Z. X. Fei, Angew. Chem., Intl. Ed. Engl., 1994, 33, 346-348. 101 A. J. Kirby, Effective molarities for intramolecular reactions. Adv. Phys. Org. Chem., 1980, 17, 183-278. I11 W. J. Albery and J. R. Knowles, Biochemistry, 1976, 15,5631. 121 F. M. Menger and M. Ladika, J. Am. Chem. Soc., 1988, 110, 6794. [I31 K. N. Dalby, A. J. Kirby and F. Hollfelder, J. Chem. Soc., Perkin Trans. 2, 1993, 1269. [ 141 Host-Guest Interactions: from Chemistry to Biology, D. J. Chadwick and K. Widdows, eds., CIBA Foundation Symposium No. 158, Wiley, 1991.

'

Enzyme Mimics [15] The Chemistry of Biological Molecular Recognition, A. J. Kirby and D. H. Williams, eds., Phil Trans. Roy. SOC. Lond. A, 1993, 345, pp. 1-164. [16] H.-J. Schneider, Angew. Chem., Intl. Ed. Engl., 1993, 32, 848. [17] R. J. Pieters and J. Rebek, Rec. Trav. Chim., 1993, 112, 330. I. Chao and F. Diederich, Rec. Trav. Chim., 1993, 112, 335. [18] P. G. Schultz, Angewandte Chemie, 1989, 28, 1283. [19] U. K. Pandit, Rec. Trav. Chim., 1993, 112, 431. [20] D. Hilvert, K. W Hill, K. D. Narel & M.-T. M. Auditor, J. Am. Chem. Soc., 1989, 111, 9261. See also reference 15. [21] A. C. Braisted and P. G . Schultz, J. Am. Chem. SOC.,1992, 112, 7431.

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[22] C. J. Walter, H. L. Anderson and J. K. M. Sanders, J. Chem. Soc., Chem. Commun., 1993, 458. See this paper for references to recent related work involving reactions between two bound molecules. [23] D. Rideout and R. Breslow, J. Am. Chem. Soc., 1980, 102, 7816. [24] For recent references and a review see R. Breslow, P. J. Duggan and J. P. Light, J. Am. Chem. Soc., 1992, 114, 3982; and R. Breslow, reference 8, p. 115. [25] M. W. Hosseini, J.-M. Lehn, K. C. Jones, K. E. Plute, K. B. Mertes and M. P. Mertes, J. Am. Chem. Soc., 1989, 111, 6330-6335. M. P. Mertes and K. B. Mertes, Accts. Chem. Res., 1990,23,413-418. [26] K. Johnsson, R. K. Allemann, H. Widmer and S . Benner, Nature (London), 1993, 365, 530532.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Metal-Assisted Peptide Organization: From Coordination Chemistry to De Novo Metalloproteins Heinz-Bernhard Kraatz

Contemporary research in chemistry often crosses the lines that previously divided the classical disciplines of chemistry and biology. Coordination chemistry has certainly been one of the areas of chemistry that has spanned the old boundaries. An inclusive definition of what constitutes coordination chemistry is emerging which requires “only that distinct molecular species be formed by the binding interaction.” [ l ] The modeling of active sites of metalloenzymes has always been a great stimulus to coordination chemists. An excellent example for this is the “nitrogenase problem”, which has played a pivotal role in the rapid development of the coordination chemistry of molybdenum and sulfur-based ligands. [2] Recent advances in the de novo design of nonnatural proteins have allowed the combination of classical coordination chemistry and protein biochemistry. The main idea of the design is to reduce the complexity of naturally occurring proteins to a set of minimal structural features necessary for a certain function. The model protein is prepared by standard synthetic methodologies, and can be used to evaluate the structural assumptions that led to its design and thereby lead to an understanding of the intricate interplay between protein structure and function. Using this general approach, research in this area has led to the successful

design of a range of artificial proteins and protein mimics. [3] Two major routes to the structural design of a de novo protein can be distinguished: (a) the synthesis of a larger peptide with subdomains of known secondary structure, which will adopt a particular tertiary structure, and (b) the design of smaller peptide subunits of known secondary structure and their assembly on a template to yield the final protein of a particular tertiary structure, such as described by Mutter et al. [4]The construction of specific and topologically predetermined protein structures from smaller amphiphilic peptide precursors by simple self-assembly is hampered by the tendency of peptides to establish an equilibrium between monomers and aggregates in aqueous solution. This makes controlling the number of participating peptides and their relative stereochemistry a formidable task indeed. There are however examples in the literature where control over the number the participating peptide subunits can be obtained, such as in Ghadiri’s peptide nanotubes [5], which is are formed by a self-assembly process starting from cyclic peptide subunits. In an novel approach, a metal ion mediated self-assembly process [6] is used in the spirit of the new inclusive definition of coordination chemistry. Peptides or amino acids can be covalently linked to a metal-binding ligand.

Metal-Assisted Peptide Organization

193

The coordination of chemically modified pep- protein designs based on coordination chemtides to a metal center through the ligating istry have appeared in the literature. [7] The group leads to the formation of a metal-pep- general aim is to utilize metal coordination to tide complex, thereby allowing control of the a ligating part of the peptide to influence the stereochemistry of the complex and the num- overall structure of the peptide. Recent ber of peptide subunits participating in the examples by Kelly and Fairlie demonstrate final de novo protein. To a large extent, the this simple design strategy. Using a bipyridine-based template, Kelly and art of successfully applying this strategy lies in the choice of the metal center and the chem- coworkers were able to stabilize a #I-sheet like ical modification of a specific peptide. This structure by the coordination of the peptidesurprisingly simple approach has been applied modified bipyridine (bpy) to a Cu(I1) center. to the synthesis of several helical metallopro- [8] The 6,6'-bis-(acylamino)-2,2'-bipyridineteins with well-defined stereochemistry such based peptide 3 is designed to promote a /3-sheet structure upon Cu(I1) binding. This as 1 (py = pyridine) [6a] and 2. [6b] template was chosen because the distance between the chains in the cisoid conformation hans-[RuClz(py-peptide)~] 1 is ca. 5.2 A, which is similar to the distance between the two strands in p-sheet structures. In the uncoordinated state, the peptide-modiThe final coordination geometry and stereo- fied bpy adopts a transoid configuration to chemistry of the complex is determined by the minimize steric interactions. The cisoid conparticular electronic and steric requirements formation has to be adopted in order for efficiof the metal atom and its ligands. In addition, ent Cu(I1) binding (4) and hence the peptide interactions of the peptide subunits with each residues will be forced in a spacial arrangeother and with the metal atom are of para- ment favoring #I-sheet formation (Fig. 1). The coordination geometry around the copmount importance in determining the overall structure of the complex. This makes it pos- per atom in 4 is similar to simple Cu comsible to create small artificial metallopeptides plexes of 6,6'-bis-(acylamino)-2,2'-bipyridine and metalloproteins with well-defined and amino acids in that the Cu(I1) is coordinated stable structural peptide motifs, such as the by the two bpy nitrogen atoms and the amide #I-sheet structure and helical bundle proteins oxygens. Amide oxygen coordination to consisting of helical peptide subunits. Recent- Cu(I1) is observed also in Fairlie's complex. ly a number of de novo metallo-peptide and In their work, Fairlie and coworkers have

4

Figure 1. Conformational changes mediated by Cu(I1) coordination to the bipyridine group of the transoid 6,6'-bis-(acylamino)-2,2'-bipyridine-peptide 3 to complex 4 having a cisoid conformation; R = a-amino acid side chain (adapted from [8]).

194

C. Biological and Biomimetic Methods

used the tridentate macrocycle 1,4,7-triazacyclononane modified by phenyl alanine methylester (5) and prepared a Cu(I1) complex 6 (Fig. 2). [9] Like its unsubstituted analogue, 6 coordinates to the copper center through the three nitrogen atoms. The X-ray crystallographic study clearly shows that the additional coordination of the amide oxygens to the copper atom forces the amino acid residues to one face of the molecule. Attachment of helical amphiphilic peptide chains to this metallotemplate are very likely to form bundle-like structures, similar to 1 and 2. [6a, 6c] Ghadiri and coworkers have refined this idea to such an extent that it has been possible to synthesize a Ru" metalloprotein with a well-defined metal-binding site. [ 101 This was achieved with peptide 7, which had two potential metal-binding sites - an N-terminal bpy and an imidazole nitrogen atom of a histidine residue close to the C-terminus of 7 - and should favor a helical structure. Incorporation of the bpy functionality at the N-terminus of each peptide allowed direction of the selfassembly of three peptides with a Ru" ion as

7

5 0

a template to form a three-helix bundle protein. Kinetically inert 8 is produced exclusively (Fig. 3). The higher kinetic stability of Ru(bpy)32+ compared to Ru(imH)62+ is seen as the determining factor for the formation of 8. This leaves the three His 18 -residues unligated. Since three peptide subunits are in close proximity, short-range intramolecular hydrophobic interactions amongst the three metalbound peptides exceed intermolecular interactions which thereby facilitates the formation of the overall helical tertiary structure of 8 (circular dichroism (CD) spectrum: 0 2 2 2 = -23 000 O cm2dmol-'). UV/VIS spectroscopy (A, = 289 and 475 nm), electrospray mass specrometry (found: M = 6887 k 2; calcd.: M = 6887), and gel permeation chromatography all provide unequivocal evidence for the identity of 8. It is important to point out that because of this helical arrangement, the three His 18-residues close to the C-termini of each of the three peptide subunits are close together, thereby forming an effective metal binding site. Coordination of Cu2+to this binding site does not significantly alter the structure of the protein, which indicates the presence of this binding after the self-assembly of 8 (CD spectrum: 8222 = -24 000 O cm2dmol-'). Based on the marked decrease in the fluorescence emisson of the adjacent tryrosine chromophore and analysis of the EPR (g I I = 2.27 and A I I = 173 cm-I x lo4) and UV/VIS (Amax = 375 (charge transfer) and 495 nm) spectra,

6

Figure 2. Coordination of Cu(1I) to the amino acid N-functionalized 1,4,7-triazacyclononane 5 (adapted from [9]).

Metal-Assisted Peptide Organization

Ghaderi and Case [ 101 demonstrated that Cu" is able to bind to this metal-binding site and leads to the formation of the Ru"Cu" protein 9 (Fig. 3). CU" binding increases the overall stability of the protein towards denaturation by 1.5 Kcal mol-I. Relevant in this context are the recent reports of the design and syntheses of cytochrome (cyt) models by Diederich et al. [ l l ] based on polyether-amide dendrites encapsulating a central Zn porphyrin core, and the approach by DeGrado and Dutton's for the synthesis of artificial proteins. 1121 In DeGrado and Dutton's approach, several peptides have been synthesized consiting of two identical 31-residue subunits linked by a disulfide bridge. The peptides contain histidine residues which allow the coordination of Fe" heme through two trans imidazole groups. The peptides associate to dimeric four-helix bundle structures. Model protein 11 was designed from the two identical subunits 10 (by oxidation of the cystein sulfhydryl groups), which each possess two histidine units (His10 and His24), to mimic the cyt b subunit of cyt bcl.

7

8

195

Compound 11 has two possible heme binding sites per peptide (based on two histidine residues) and an estimated separation between the Fe atoms of about 20 A. Due to dimerization of the model protein 11, addition of Fel' heme leads to the incorporation of four redox centers at the four predetermined binding sites of the protein dimer. CD spectroscopy also confirms in tis case that well-defined binding sites are present prior to heme coordination (8222 = -26 000 O cm2dmol-'). As expected the heme-protein complex exhibits a rhombic EPR spectrum (g, = 2.89, g, = 2.24, g, = 1.54) confirming the coordination of low-spin Fe2+ through two trans imidazole groups. These are only a few examples indicating the scope of this emerging area of research at the interface of peptide and protein chemistry and coordination chemistry. The synthesis of metal-binding metalloproteins and the introduction of redox-active metal centers into artificial proteins by self-assembly processes is surely only the beginning. One can certainly think of extending this approach to the incorporation of substrate-binding enzymatic func-

9

Figure 3. Assembly of Ru(I1) metallopeptide 8 from bpy functionalized peptide 7 . 8 possess a well-formed His3 metal-binding site to which Cu(II) binds to form 9.

fS-

10

11

fS-

12

Figure 4. Formation of a Fe(I1) heme binding protein 11 by dimerization of helical peptide subunits 10.

tions, as already demonstrated by Sasaki and Kaiser, [13] and photosensitive metal centers in proteins which can then act as light-harvesting analogues of the photosystem of green plants. The rational synthesis of enzyme analogues allowing efficient catalytic transformations of industrial relevance is perhaps one of the key driving forces. In addition, de n o w design of metalloproteins allows for a systematic study of several key biological functions, such as electron transfer [14] and other biological transformations and allows to develope an understanding of the intricate interplay between protein structure and its function.

References [ I ] D. H. Busch Chem. Rev. 1993,93, 847-860. [2] a) D. Sellmann and J. Sutter in: Transition Metal Sulfur Chemistry (Eds.: E. I. Stiefel, and K. Matsumoto) pp. 101-116, ACS Symposia Series 653, Washington D.C. 1996; b) D. Coucouvanis, K. D. Demadis, S. M. Malinak, P. E. Mosier, M. A. Tyson, L. J. Laughlin,

ibid. pp. 117-134; c) Ian Dance, ibid, pp. 135-152. [3] a) W. F. DeGrado, Z . R. Wasserman, J. D. Lear Science (Washington D. C. 1883) 1989, 243, 622-628; b) K. T. O’Neil, R. H. Hoess, W. F. DeGrado ibid. 1989, 243, 622-628; c) K. T. O’Neil, W. F. DeGrado Trends Biochem. Sci. 1990, 15, 59-64; d) K. S. Akerfeldt, J. D. Lear, Z. R. Wasserman, L. A. Chung, W. F. DeGrado Acc. Chem. Rex 1993, 26, 191197; e) K. W. Hahn, W. A. Klis and J. M. Stewart Science (Washington D.C. 1883) 1990, 248, 1544-1547; f) A. Grove, M. Mutter, J. E. Rivier, M. Montal J. Am. Chern. Soc. 1993, 115, 5919-5924; g) M. R. Ghadiri, J. R. Granja, L. K. Buehler Nature (London) 1990, 369, 301-304; h) N. Voyer, M. Robitaille J. Am. Chem. SOC. 1995, 117,6599-6600. [4] a) M. Mutter, S. Vuilleumier Angew. Chem. 1989, 101, 551-571; b) M. Mutter, G. G. Tuchscherer, C. Miller, K.-H. Altman, R. I. Carey, D. F. Wyss, A. M. Labhardt, J. E. Rivier J. Am. Chem. Soc. 1992,14, 1463-1470. [5] a) M. R. Ghadiri, K. Kobayashi, J. R. Granja, R. K. Chadha, D. W. McRee Angew. Chem. 1995, 107, 76; Angew. Chem. Int. Ed. Engl. 1995, 34, 93-95; b) M. Engels, D. Bashford, M. R. Ghadiri J. Am. Chem. SOC. 1995, 117, 915 1-9158.

Metal-Assisted Peptide Organization [6] a) M. R. Ghadiri, A. M. Fernholz J. Am. Chem. Soc. 1990, 112, 9633-9635; b) M. R. Ghadiri, C. Soares, C. Choi ibid, 1992, 114, 825-831; C) ibid. 1992, 114, 4000-4002. [7] J. P. Schneider, J. W. Kelly Chem. Rev. 1995, 95,2169-2187. [8] J. P. Schneider, J. W. Kelly J. Am. Chem. SOC. 1995, 117, 2533-2546. [9] A. A. Watson, A. C. Willis, D. P. Fairlie Inorg. Chem. 1997,36,752-753. [lo] M. R. Ghadiri, M. A. Case Angew. Chem. 1993, 105, 1663-1667; Angew. Chem. Int. Ed. Engl. 1993,32, 1594-1597.

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[ l l ] P. J. Dandliker, F. Diederich, M. Gross, C. B. Knobler, A. Louati, E. M. Sandford Angew. Chem. 1994, 106, 1821-1824; Angew. Chem. Int. Ed. Engl. 1994, 33, 1739-1742. [121 D. E. Robertson, R. S. Farid, C. C. Moser, J. L. Urbauer, S. E. Mulholland, R. Pidikiti, J. D. Lear, W. F. DeGrado, P. L. Dutton Nature (London) 1994,368,425-432. [13] T. Sasaki, E. T. Kaiser J. Am. Chem. SOC. 1989, 111, 380-381. [14] H.-B. Kraatz, J. Lusztyk, G . D. Enright Inorg. Chem. 1997,36,2400-2405.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Artificial Replication Systems Siegfried H o f i a n n

Introduction “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material” - rarely has anything fascinated science as much as Watson and Crick’s “holy” structure of DNA [la, b], in which the prophecy of Schrodinger for an “aperiodic crystal” [ lc] to be the genetic material [Id, e] became reality. The discovery of the DNA-structure altered our view of life. The prototype of a matrix became the beacon that enlighted research into the fields of molecular biology and redirected organic chemistry back to its early native pretension. The reduplication of the holy structure rendered the key mechanisms for prebiotic systems, when passing the borderline from inanimated to animated world.

Molecular Matrices Todd sought to answer for the outruled cheniistry in a landmark appeal: “The use of one molecule as a template to guide and facilitate the synthesis of another ... has not hitherto been attempted in laboratory synthesis, although it seems probable that it is common

in living systems. It represents a challenge, which must, and surely can, be met by Organic Chemistry” [2a]. And the grand concept appeared to be portentous. Quite soon Schramm et al. [2b] aroused enthusiasm with the “nonenzymatic synthesis of nucleosides and nucleic acids, and the origin of self-replicating systems“: the polycondensation of uridylic acid onto the orientating (A),-matrix - and the first attempt at an artificial matrix reaction [2]. Was this the breakthrough that would lead chemistry not only into the wonderland of biology, but also rapidly to ordered and instructed macromolecular organizations in its own dominion [2c-fl? Schramm’s dramatic experiments had to push the native standards back into the high error phase of a prebiotic beginning. Purely artificial template experiments [2c-el, however, were devoid of even this possible relationship to evolutionary development [3]. The first great “chemical” departure into the temptations of such matrix reactions ran aground on innumerable difficulties. The dominant element in scientific progress came to be not the variety of chemical matrices and the distant aim of building systems capable of self-replication. Rather, fascination with the elegance of the natural prototypes stimulated the vanguards of chemistry and

Artificial Replication Systems

biology in their campaign of molecular penetration of biological systems. The golden age of molecular biology had begun [2f, 31. Oparin’s [3a] and Haldane’s [3b] heirs, Eigen [3d, el and Kuhn [3fl, gave these events a time perspective, and with their “information” also described the vector of the “Grand Process”. Self-replication, mutation, and metabolism (as prerequisites for selection) made up the list of criteria; through these, information and its origin, evaluation, processing, and optimization had governed the evolutionary history of prebiotic and biotic systems [2f, 31.

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now almost forgotten. A “Kuhn” period of divergent evolution of matrix systems between molecular biology and classical chemistry had begun. “Minimal Self-Replicating Systems”

A rapidly growing number of artificial selfreproduction [2, 31, 51 models (Fig. l), covering nucleic acids [5a-c] as well as their near and distant analogs [5a-d], but also followers of nearly forgotten Fox-microspheres [3c] in the field of peptide [5e] and membrane [5f, g] components, endeavor to gain insights into the transition stages between chemical and biological evolution. Self-Reproduction Models After innumerable attempts to elucidate the matrix relationships of mono- and oligoIn connection with Spiegelman’s [4a] initial nucleotides to orientating and catalytic oligoexperiments, Eigen and Schuster [3d, el, and polynucleotide templates, two self-repliJoyce [3g, 4b], and others attempted to cating nucleic acid models, a DNA-analogous “bring to life” the theoretical premises behind hexamer system by von Kiedrowski et al. the laboratory realities of enzyme-catalyzed [6a, b] and an RNA-analogous tetrameric RNA replication and evolution experiments, assembly from the Orgel group [6c], opened an approach later on forwarded into the new ways. Von Kiedrowski’s first successful rapidly broadening creative fields of arti- model-hexadeoxyribonucleotide duplex beficially directed evolution [4]. Orgel’s groups came a leitmotif in the detailed treatment of [3h, 4c], by contrast, exerted themselves to growth kinetics and anticipated later selftransform diverse matrix relationships into replicating “minimal systems” in many ways artificial, enzyme-free nucleic acid formation. [6]. The ligation of cooperative oligonucleotiWhen Altman [4d] and Cech [4e] raised RNA des increased the stability of the matrix duplex to the throne of an archaic informational and and the ternary formation complex. The functional omnipotence, it amounted to a late choice of palindromic systems reduced the justification of the toil and trouble of this complexity of biological replication experi“nucleic acids first” route. “A tRNA looks ments to a simplified kinetic measurement like a nucleic acid doing the job of a protein”, of its identical (since self-complementary) Crick once observed. Now, self-splicing RNA matrix components, demonstrating self-replicomplexes, polymerase activities, ribozymes cation by autocatalytic behavior. The surprisand hypothetical RNA-somes afforded ing square root law of matrix growth kinetics unusual insights into the genotypical and(!) [6a, b, d-h] (curiously even computer viruses phenotypical complex behavior of a single seem to be in love with it) with its ideal case nucleic acid species. And with the supposedly of a parabolic reaction course - derived from greater understanding of this “RNA-world”, the hexadeoxynucleotide duplex, confirmed fresh impetus was given even to the purely slightly later by the ZielinsWOrgel system chemical approaches, once so promising and [6c], and, finally, also verified in the Rebek-

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C. Biological and Bioinirnetic, Methods

Figure I . Artificial replicators and matrices (left to right and top to bottom): Rebek’s distant nuclcoside [ 6k-in] and v. Kicdrowski’s amidinium-carboxylate [7f] replicators; Lehn’s chiral organic [7g] and elementorganic [7h] helicatcs: v. Kiedrowski’s [ ha, b, d-g] and Orgel’s [hc] “minimal self-replication systems”; Hofrmann’s alienated nucleic acids [2f, Sc, 7b, lOe] and Luisi’s “minima-vita” approach [Sf,g, Xu-d]; Eachennioser’s hexosc-nucleic-acids [IS], compared with Olson-type R/DNAs and hypothetical nucleation dynamics of nucleoprotcin systems [2f, 3k, Sc].

dimer assembly [Sd, 6i-11 -- was recognized as autocatalytic system behavior of self-replicating oligonucleotide templates under the constraints of isothermal conditions, where stability relationships of matrix reaction partners might exclude the expected exponential

growth kinetics. A hexaineric system, constructed l i o m t w o triineric blocks by phosphoatnidate coupling, revealed sigmoidal growth behavior and extraordinary autocatalytic efficiency [6d-g]. Continuations in more complex matrix block offers enriched

Artificial Replication Systems

.

the informational content of the model systems and invited for the first time studies of selection behavior [5d, 61. The patterns of autocatalysis with respect to parabolic and exponential reaction courses, that closely affect the conclusions of Eigen’s evolution experiments concerning the decision criteria for mutant selection and coexistence [3d, 1,6h], can by now be derived from the thermodynamic and kinetic data of the matrix partners and offer quite new views with autocatalytic cooperation between competitive species [5b, 6g, h]. Separate from “enzyme-catalyzed’’ evolution experiments with RNA- and DNA-systems, basic questions of prebiotic behavior can for the first time become the object of detailed experimental research. While continuing their studies on complex autocatalysis patterns, von Kiedrowski et al. diagnosed modulation of molecular recognition as an operational deficit of earlier artificial self-replicational nucleic acid systems with regard to exponential reaction courses and identified it as an ideal aim for future models [6fl. On its way to the nucleoprotein system, evolution must have had a similar view of the problem, when it endowed nucleic acids with proteins, experienced in phase and domain regulation strategies, and thus achieved an ideal milieu for directing modulations of recognition. While, presumably, the both informational and functional RNAs allowed for first successful self-replications, they seem to have been outclassed in future developments by the cooperative efforts of nucleic acids and proteins. The urgent demands to establish suitable and reliable regimes of strand-recognition, annealing, separation and reannealing - so far having only been brought about by drastic variations of reaction temperature - seem to have been accounted for under stringent isothermal conditions only by the complexity patterns of nucleoprotein systems. It had been the impressive, both functional and informational potencies of proteins that could like some “dei ex

201

machina” provide, by a permanently renewing coherency continuation of transiently acting complex order-disorder patterns along desirable trajectory bundles, suitable system-inherent isothermal conditions. Only the integrative efforts of nucleic acids and proteins, that submerged their structural individualities into the biomesogenic unifications of functionally and informationally completely new characteristics of dynamic nucleoprotein systems, reached the evolutionary breakthrough in selforganizational, self-replicational, and general information-processing abilities [2f, 31,5c]. Matrix growth kinetics as known for oligonucleotides are followed even by a drastically abstracted artificial replication system developed by Rebek’s group [5d, 6i-11. The dimer assembly of a distant peptide-nucleic-acid analog developed from host-guest relationships combined the interactive and cognitive possibilities of native nucleic acid matrices with the more general biopolymer relationships of the amide bond formation involved in the matrix reaction. When Rebek et al., who have in the meantime sought to stimulate the competition and selection behavior of their self-replicating species by “chemical mutations,” stated that one of their main aims is artificial peptide synthesis on a nucleic acid matrix [5d, 6, i-11, it is slightly reminiscent of Todd’s template vision [2a] in the very beginning. The dualities of supramolecular chemistry [7a] and biomesogen systems [7b] generate a tremendous number of new matrix and replication variations [7]. 2-Pyridone versions, already foreseen in mesogenic mono- and polymeric nucleic acid analog approaches [7b-d], reoccur in new appearances [7e]. In the attempt to reduce generalizing principles as far as possible, desirable operation modes astoundingly become accessible. Dramatically abstracted amidinium-carboxylate systems, which, nevertheless, cover certain essentials of complex nucleic acid-protein interactions, prove to be susceptible to molecular recognition modulation and seem even to delight

202

C. Biological and Biomimetic Methods

their examiners with exponential growth kinetics [7fl. The beauties of some sort of chiral main-chain LC-polymers -built up as impressive supramolecular helical arrangements from bifunctional recognition units - convincingly confirm the selection and discrimination facilities of supramolecular organizations in transitions from hetero- to homochirality [7g]. Detailed aspects, such as the possibilities of coordination matrices in native nucleic acid assemblies, make themselves independent in helicates [7h-11, whose structures reflect also relationships between our life process and its basic matrices [2fl. Matrix studies of complex duplex-triplex systems model regulation strategies of nucleic acid organization and by this detect not only protein-like behavior of RNA-Hoogsteen strands in reading informational DNA-duplex patterns, but bridge also the gap to basic hysteretic mechanisms of information processings in highly condensed systems [2f, 5c, 7b, m-q].

Playing the Game of Artificial Evolution

And then there is, finally, the “evolution” of an individual scientific life’s work [3i, 91, which itself follows decisive stages of the Grand Process: the exploration of early chemical requirements, the development of prebiotic ligand systems, the fixation into the ordered structures of informational inorganic matrix patterns and, finally, the liberation of their inherent wealth of design and information into the order-disorder dialectics of today’s nucleoprotein system. Using basic hexoses - somewhat the successor molecules of evolution - a never attempted, or perhaps only forgotten, “evolutionary step” is now taking place, once again in the area of replicative (homo)nucleic acid systems [9a-d]. But this is another whole story - and is another great game. A game that is representative in all its loveful utilizations and impressive manifestations of today’s chemistry standards and facilities for our future ways of “Minima Vita Models” modelling of what has created us - without It is fully within this context when, in addition any chance, however, to renew artificially the to the nucleic acidhucleic acid analog whole on our own. It is, indeed, just this native complexity pioneering triad of self-replication systems, a fourth forwarding approach adds to the “mini- which for our today’s chemistry provides mal systems” of preferentially informational provocation and stimulation, intimidation and replicators the new view of a “minima vita” temptation, love and hate and fate together. challenge [31,5f,g]. It appears somehow as a The present artificial systems still remain reincarnation of Fox’s microspheres [5d], utterly outclassed by even the most primitive when micelles advance in the hands of Luisi life forms such as RNA-viruses. The possibiet al. [5f,g,8] as first examples of “minimal lities of describing natural selection behavior life” models, where the chemical autopoiesis according to quasi-species distributions in is taken as a minimum criterium for not only the extreme multidimensionalities of sequence self-reproductive, but, moreover, in some spaces [3d, el are, for artificial systems, at best way life-bearing systems. An intriguing a very distant utopia. With all its early primiapproach, forwarded to stages where core tivity, but also with its promising inherent [8e] and shell [8a-d] reproduction has been potential of “minimal models” of self-replicaachieved by spherically bounded micelle tion [6,7,9] and -just to follow - “minima systems that host inside replicative nucleic vita models” [8], chemistry, nevertheless, is acids - demonstrating by this “minimal-cell- gaining new qualities by retracing transitions to life. models” [31, 5f, g, 8eJ.

Artificial Replication Systems

203

References [ l ] Replicative double helix: a) J. D. Watson, F. H. C. Crick, Nature 1953, 171, 737; b) F. H. C. Crick, J. D. Watson, Proc. R. SOC. London [Sex A ] 1954, 223, 80; c) E. Schrodinger, What is life ?, Cambridge Univ. Press, New York, 1944; d) F. Miescher, “On the chemical composition of pyocytes”, Hoppe-Seyler ’s med. Untersuchungen, 1871; Die histochemischen und physiologischen Arbeiten (Ed.: F. C. W. Vogel), Leipzig, 1897; e) R. Altmann, Arch. Anat. Phys. Phys. Abt. 1889; Die Elementarorganismen, Veit, Leipzig, 1890. [2] Molecular matrices: a) A. Todd, in Perspectives in Organic Chemistry (Ed.: A. Todd), Interscience, New York, 1956, p. 245; b) G. Schramm, H. Grotsch, W, Pollmann, Angew. Chem. 1962, 74, 53; Angew. Chem. Int. Ed. Engl. 1962, I , 1 c) W. Kern, H. Kammerer, Chem. Ztg. 1967, 91, 73; d) H. Kammerer, ibid. 1972, 96, 7; e) J. H. Winter, Angew. Chem. 1966, 78, 887; Angew. Chem. Int. Ed. Engl. 1966, 5, 862; f) S. Hoffmann, Molekulare Matrizen (IEvolution, II Proteine, Ill Nucleinsauren, IV Membranen), Akademie-Verlag, Berlin, 1978. [31 Evolution views: a) A. I. Oparin, Origin of Life, Moscow, 1924; b) J. B. S. Haldane, The Course of Evolution, Longman, New York, 1932; c) S. W. Fox (Ed.), The Origin of Prebiological Systems and of Their Molecular Matrices, New York, Academic Press, 1965; Science 1960, 132, 200; d) M. Eigen, Naturwissenschaften 1971, 58, 465; Stufen zum Leben, Pieper, Miinchen, 1987; Cold Spring Harbor Symp. Quant. Biol. 1987, LII, 307; e) M. Eigen, P. Schuster, Naturwissenschaften 1977, 64, 541; ibid. 1978, 65, 7; 9 H. Kuhn, Angew. Chem. 1972, 84, 838; Angew. Chem. Int. Ed. Engl. 1972, 11, 798; g) G. F. Joyce, Nature 1989, 338, 217; Cold Spring Harbor Symp. Quant. Biol. 1987, LIl, 41; h) L. Miller, L. E. Orgel, The Origins of Life on Earth, Prentice Hall, Englewood Cliffs, New York, 1974; i) A. Eschenmoser, in Origins Life 1994,24,389;k) S. Hoffmann, in Chirality - from Weak Bosons to the a-Helix (Ed.: R.Janoschek), Springer, Berlin-

Heidelberg-New York, 1992, p. 205; 1) SevProduction of Supramolecular Structures (Eds.: R. Fleischaker, S. Colonna, P. L. Luisi), NATO AS1 Sex 446, Kluwer Acad. Publ., Dordrecht-Boston-London, 1994; cf. also [2fl. [4] Artificially directed evolution: a) S. Spiegelman, Quart. Rev. Biophys. 1971, 4, 213; b) G. F. Joyce, Curr. Biol. 1996, 6, 965, and preceding communications (a.p.c.); in [31], 127; Scientific American 1992, 269, 48; c) L. E. Orgel, ibid. 9, a.p.c.; d) S. Altmann, Angew. Chem. 1990, 102, 735; Angew. Chem. Int. Ed. Engl. 1990, 29, 707; e) T. R. Cech, ibid. 745 and 716; cf also [3d, g, h, 11. [ 5 ] Self-reproduction models: a) L. E. Orgel, Nature 1992,358,203;b) D. Sievers, T. Achilles, J. Burmeister, S. Jordan, A. Terfort, G. von Kiedrowski, in [31], 45; c) S. Hoffmann, Angew. Chem. 1992, 103, 1032; Angew. Chem. Int. Ed. Engl. 1992, 31, 1013; in [31], 3; d) J. Rebek, Acta. Chem. Scand. 1996, 50, 469, a.p.c.; Scientific American 1994, 271, 48; e) R. Ghadiri, K. Kobayashi, J. R. Granja, R. K. Chadha, D. E. McRee, Angew. Chem. 1995, 107, 76; Angew. Chem. Int. Ed. Engl. 1995, 34, 93; f) P. L. Luisi, in [31], 179; g) P. L. Luisi, P. Walde, T. Oberholzer, Ber. Bunsenges. Phys. Chem. 1994, 98, 1160; h) D. Philp, J. F. Stoddart, Angew. Chem. 1996, 108, 1242; Angew. Chem. Int. Ed. Engl. 1995,35, 1154. [6] “Minimal models” of self-replication: a) G. von Kiedrowski, Angew. Chem. 1986, 93, 932; Angew. Chem. Int. Ed. Engl. 1986, 25, 932; b) G . von Kiedrowski, B. Wlotzka, J. Helbing, Angew. Chem. 1989, 102, 1259; Angew. Chem. Int. Ed. Engl. 1989, 28, 1235; c) W. S. Zielinski, L. E. Orgel, Nature 1987, 327, 346; d) G. von Kiedrowski, B. Wlotzka, J. Helbing, M. Matzen, S. Jordan, Angew. Chem. 1991, 103, 456, 1066; Angew. Chem. Int. Ed. Engl. 1991, 30, 423, 892; e) G. von Kiedrowski, J. Helbing, B. Wlotzka, S. Jordan, M. Mathen, T. Achilles, D. Sievers, A. Terfort, B. C. Kahrs, Nachr. Chem. Tech. Lab. 1992, 40, 578; f) T. Achilles, G. von Kiedrowski, Angew. Chem. 1993, 105, 1225; Angew.

204

C. Biological and Biomimetic Methods

Chem. Int. Ed. Engl. 1993,32, 1189; g) D. Sievers, G. von Kiedrowski, Nature 1994, 369, 221; h) E. Szathmm, in [31], 65; i) T. Tjivikua, P. Ballester, J. Rebek jr., J. Am. Chem. Soc. 1990, 112, 1249; k) J. Rebek jr., Angew. Chem. 1990, 102, 261; Angew. Chem. Int. Ed. Engl. 1990, 29, 245; 1) T. K. Park, Q. Feng, J. Rebek jr., J. Am. Chem. Soc. 1992, 114, 4529, a.p.c.; cf. also [5a-c]. [7] Surrounding matrix and replicator patterns : a) J.-M. Lehn, Science 1985, 227, 849; b) S. Hoffmann, in: Polymeric Liquid Crystals (Ed.: A. Blumstein), New York, Plenum, 1985, p. 423; Z. Chem. 1987, 27, 395; c) R. Heinz, J. P. Rabe, W.-V. Meister, S. Hoffmann, Thin Solid Films 1995, 264, 246; a.p.c.; d) S. Hoffmann, Z. Chem. 1979, 19, 241; e) F. Persico, J. D. Wuest, J. Org. Chem. 1993, 58, 95; f) A. Terfort, G. von Kiedrowski, Angew. Chem. 1992, 104, 626; Angew. Chem. Int. Ed. Engl. 1992, 31, 654; g) T. Gulik-Krzywicki, C. Fouquey, J.-M. Lehn, Proc. Nat. Acad. Sci. USA 1993, 90, 163; h) B. Hasenknopf, J.-M. Lehn, B. 0. Kneisel, G. Baum, J. Femske, Angew. Chem. 1996, 108, 1987; Angew. Chem. Int. Ed. Engl. 1996, 35, 1838; a.p.c.; i) C. R. Woods, M. Benaglia, F. Cozzi, J. S. Siegel, ibid. 1977, 1830; a.p.c.; k) A. F. Williams, C. Piguet, G. Bernardinelli, Angew. Chem. 1991, 103, 1530; Angew. Chem. Int. Ed. Engl. 1991, 30, 1490; 1) E. C. Constable, ibid. 1991, 103, 1482 and 1991, 30, 1450; m) K. J. Luebke, P. B. Dervan, J. Am. Chem. SOC. 1989, 111, 8733; n) E. Neumann, A. Katchalsky, Proc. Natl. Acad. Sci. USA 1972, 69, 993; 0) E. Neumann, Angew. Chem. 1973, 85, 430; Angew. Chem. Int. Ed. Engl. 1973, 12, 356; p) W. Guschlbauer, Encycl. Polymer Sci. Eng. 1988, 12, 699; in Dynamic Aspects of Conformation Changes in Biological Macromolecules (Ed.: c. Sadron), Reidel, Dordrecht, 1973; q) S. Hoffmann, in 2nd Swedish-German Workshopon Modern Aspects of Chemistry and Biochemistry of Nucleic Acids (Ed.: H. Seliger), Nucleosides & Nucleotides 1988, 7, 555; cf. also [2f; 3k].

[8] “Minima-vita’’ models: a) P. A. Bachmann, P. Walde, P. L. Luisi, J. Lang, J. Am. Chem. SOC. 1990, 112, 8200; J. Am. Chem. Soc. 1991, 113, 8204; b) P. A. Bachmann, P. L. Luisi, J. Lang, Nature 1992, 357, 57; c) P. L. Luisi, F. J. Varela, Origins Life 1990, 19, 633; d) K. Morigaki, S. Dallavalle, P. Walde, S. Colonna, P. L. Luisi, J. Am. Chem. SOC. 1997, 119, 292, a.p.c.; e) T. Oberholzei, R. Wick, P. L. Luisi, C. K. Biebricher, Biochem. Biophys. Res. Commun. 1995, 207, 250, a.p.c.; cf. also [31, 5f,g]. [9] Evolutionary hexose nucleic acids: a) A. Eschenmoser, Angew. Chem. 1988, 100, 5; Angew. Chem. Int. Ed. Engl. 1988, 27, 5; Nachl: Chem. Tech. Lab. 1991, 39, 795; Nova Acta Leopold. 1992, NF 67/281, 201; b) A. Eschenmoser, M. Dobler, Helv. Chim. Acta 1992, 75, 218; c) A. Eschenmoser, M. V. Kisakurek, Helv. Chim. Acta 1996, 79, 1249; d) R. Krishnamurthy, S. Pitsch, M. Minto, C. Miculka, N. Windhab, A. Eschenmoser, Angew. Chem. 1996, 108, 1619; Angew. Chem. Int. Ed. Engl. 1996, 35, 1537, a.p.c.. [ 101 Supramolecular chemistry and biomesogen systems: a) J.-M. Lehn, Angew. Chem. 1988, 100, 91; Angew. Chem. Int. Ed. Engl. 1988, 27, 89; ibid. 1990, 102, 1347 and 1990, 29, 1304; b) J.-M. Lehn, Supramolecular Chemistry, VCH, Weinheim, 1995; c) H. Ringsdorf, B. Schlarb, J. Venzmer, Angew. Chem. 1988, 100, 117; Angew. Chem. Int. Ed. Engl. 1988, 27, 113; d) M. Ahlers, W. Muller, A. Reichert, H. Ringsdorf, H. Venzmer, ibid. 1990, 102, 1310 resp. 1990, 29, 1269; e) S. Hoffmann, W. Witkowski, in Mesomorphic Order in Polymers and Polymerization in Liquid Crystalline Media (Ed.: A. Blumstein), Am. Chem. Soc. Symp.-Sel: 1978, 74, 178; f) S. Hoffmann, Living systems, in Handbook of Liquid Crystals, VCH, Weinheim, in press.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

D. General Methods and Reagents LiC104 and Organic Solvents Unusual Reaction Media Uschi Schrnid and Herbert Waldrnann

Many reactions can be influenced in a variety of ways by the solvent employed. This is especially the case when polarized transition states or ionic intermediates are involved and when the solvent is nucleophilic or electrophilic. A case to the contrary is the Diels-Alder reaction, which remains largely unaffected by the surrounding organic medium. In the mid-eighties, however, Breslow et al. [l] and Grieco et al. [2] demonstrated that DielsAlder reactions proceed with increased reaction rate and with improved endolexo selectivity when they are carried out not in organic solvents but in aqueous solutions. The effect is further enhanced by salts such as LiCl (salting-in effect), whereas the addition of guanidinium chloride has the opposite influence (salting-out effect). The use of water as solvent for such cycloadditions had already been described earlier by Alder et al. [3a] and later by Koch et al. [3b] The accelerating effect of this reaction medium is also manifested in many other reactions, [4] e. g. asymmetric hetero-Diels-Alder reactions [4b] and asymmetric nonhetero-Diels-Alder reactions, [4c, d] nucleophilic additions to iminium ions [4e] and carbonyl compounds, [4fl Claisen rearrangements, [4g] the benzoin condensation, [lb] and aldol reactions. [4h] It is attributed to the fact that a suitable aggregation is generated by hydrophobic interactions be-

tween the reaction partners (hydrophobic effect), and so exercises an “internal pressure” on the reactants encapsulated in “solvent cavities” whose effects are, in turn, comparable with a high external pressure, at least in the case of the Diels-Alder reaction. A solvent system described by Grieco et al., [5] namely a 5 M solution of LiC104 in diethyl ether, has a comparable, if not greater accelerating effect on Diels-Alder reactions. Already in 1959 Winstein et al. [6] noted that dissolving LiC104 in an organic solvent greatly enhances the polarity of the solution, i.e. a solution of LiC104 in diethyl ether was found to be more polar than glacial acetic acid. This remarkable effect was used for the first time by Sauer et al. [7] to influence the steric course of a Diels-Alder reaction. Based on the finding that the cycloaddition of methacrylic acid and cyclopentadiene proceeds with 88% endo selectivity in a 4 M solution of LiC104 in ether, the authors proposed that this reaction medium might be an advantageous solvent for different organic reactions. Mainly through the pioneering investigations of Grieco et al. was this expectation brought to reality. [8] The reaction of cyclopentadiene with ethyl acrylate to give the diastereomeric bicycloheptenes proceeds more rapidly and with higher endo-selectivity in 5 M LiClOJdiethyl

D. General Methods and Reagents

206

ether (endo :exo = 8 : 1) than in water. [8] Particularly impressive is the reaction of furan 1, which, owing to its aromaticity does not react with the thiophene derivative 2 under normal conditions (Scheme 1). In LiC104/ ether, however, the cycloadducts 3 and 4 are formed in 70 % yield in the ratio 85 : 15 after 9.5 h at room temperature and under atmospheric pressure. These values must be compared with those reported by Dauben et al., [9] who required 6 h and 15 kbar in order to achieve the same product ratio in their synthesis of cantharidin by the same reaction in CHzC12. Already in the early eighties B. Fohlisch et al. [lo] exploited the advantageous effects of the medium presented here in their detailed investigations of the [4+3] cycloadditions of a-halogeno- or a-sulfonyloxy-substituted ketones to 1,3-dienes, in particular to furan. The 8-oxabicyclo[3.2.l]oct-6-en-3-ones formed thereby are of interest, inter alia, as starting materials for the synthesis of tropones and other natural products. For the cycloadditions with the a-halogeno- or the a-mesyloxyketones, room temperature suffices, and interand intramolecular reactions can be carried out in satisfactory to good yields. A possible use of this method for the synthesis of natural terpenes, e. g. of the guajanolide, azulene, and hydroazulene type, seems very promissing.

f

2

5 M LiC104/Et20

9.5h, 70%

The thermal reaction between a,@-unsaturated carbonyl compounds like 5 and phenyl vinyl sulfide 6 usually proceeds to give the hetero-Diels-Alder adducts 7. However, according to Hall et al., [ l l ] in 5 M LiC104/ ether exclusively the [2+2] cycloadducts 8 are formed (Scheme 2). Tandem [2+2] cycloaddition-cycloreversion processes to form substituted alkenes and dienes have been described separately with highly reactive ketenes and are usually conducted at relatively high temperatures. Cossio et al. [12] have reported that even non-activated ketenes such as dimethylketene 9, generated in situ from the acyl chloride 10, react at room-temperature in 5 M LiClOJ ether with the aromatic aldehyde 11 to form the alkene 12. In this case, the reaction does not take place in the absence of lithium perchlorate (Scheme 3). These unusual results raise the question how LiC104 influences the course of these and further reactions. The similarity to the accelerating effect of water as solvent for carbo- and hetero Diels-Alder reactions suggests that an “internal pressure” might be operative, [5,13] but also an electrostatic catalysis by ion pairs [14] might be involved if polar transition states are passed. Finally, the lithium cation may serve as Lewis acid in an essentially non-acidic medium, a notion

b

4

Scheme I .

Lie104 and Organic Solvents - Unusual Reaction Media R'

207

+ 4c02Me R2

5

-\SPh

/

\

5 M LiC104/Et20 25"C, 20h

thermal

\

7565% 50 - 80% cis

4R2 SPh

dSPh

Me0

7

6

R2

R' = CN, C02Me R2 = CN, C02Me, H

Scheme2.

Me

0 0 10 5M

LiCIO4/Et20

r.t., 6h

81Yo

12

which is supported by kinetic measurements, [ 151 NMR experiments and MNDO calculations. [16] Whereas Li+ in the gas phase is a very strong Lewis acid in solution its acidity is weakened by solvation and by interaction with the accompanying anion. Not only cycloadditions are accelerated in solutions of LiC104 in organic solvents, but, in particular, these reaction media activate

Scheme 3.

carbonyl compounds towards attack by Cnucleophiles like TMS-CN and silyl ketene acetals. For instance, Grieco et al. [17] showed that 14 adds to the sterically hindered enones 13 exclusively in a 1,4-fashion (Scheme 4). In the presence of titanium Lewis acids 15a was obtained in only 10% yield, and in the case of 13b strong Lewis acids can not be employed at all. Reetz et al.

D. General Methods and Reagents

208

0

OTBDMS C02Me 4zy:DM

14

S

*

IML~CIO in~DME

Me

Me 15a R = M e 15b R = TBDMS

13a R = M e 13b R=TBDMS

93% quant.

Scheme 4,

acids like BF3aOEt2 in these cases give antiproducts with similar selectivity. A chemo- and regioselective conversion of epoxides to carbonyl compounds in 5 M LiC104/ether was reported by Sankararaman et al. [20] The stereoselectivity in the case of limonene oxide 20 can be explained by invoking the rule of diaxial ring opening (Scheme 6). The small differences in the activation barriers of the two diastereomers is manifested in LiClOdether.

[ 181 described the use of LiC104 in CH2C12 as solvent. In this solvent the reaction mixture is heterogeneous but the additions of e.g. silyl ketene acetals to carbonyl groups proceed faster than in ether. Furthermore the addition of allyl tin and -silicon nucleophiles to aldehydes is accelerated in LiClOdether. Ipaktschi et al. [19] found that for instance allyl tributyl tin 17a adds to the a-epoxy aldehyde 16 with high syn-selectivity (Scheme 5 ) . Typically Lewis m S n B u 3 17a

TMS-CN or

*

B u . , , , K N U

17b

H

H

5u LiC104 in EtzO

H

OR

16

R 18a 18b

b

1:l

A 19

0%45%

r.t.

yield

G +c allyl CN

H

SiMe,

95%, 90%,

syn: anti

90 : 10

85: 15

Scheme 5.

0

5~ LiC104/Et20

cis: trans

Nu

20

19 cis

Scheme 6.

Lie104 and Organic Solvents - Unusual Reaction Media

Pearson et al. [21] described that ally1 alcohols and their acetic acid esters (21) are subject to a nucleophilic substitution by silyl ketene acetals and other C- and N-nucleophiles (Scheme 7). This process offers an advantageous alternative to transition metal catalysed processes. Recently solutions of LiC104 in organic solvents were employed as media for the activation of various glycosyl donors. [22] In these solvents, glycosyl phosphates, glycosyl trichloroacetimidates and even the usually very stable glycosyl fluorides like the fucosyl donor 23 could be converted to glycosides like the trisaccharide 25 under neutral conditions and without the use of any further promotor (Scheme 8). Finally, the use of LiCIOdether for the elimination of acetic acid from serine derivatives [23] and for the synthesis of aromatic amines [24] was reported.

Grieco et al. and Ghosez et al. [25] have recently reported that lithium trifluoromethanesulfonimide (LiNTf2) in acetone or diethyl ether is a safe alternative to lithium perchlorate solutions for effecting Diels-Alder and hetero-Diels-Alder reactions. In addition, the lithium salt of tetrakis(po1yfluoroalkoxy)aluminate (LiAI(OC(Ph)(CF3)2)4) was described, a new hydrocarbon-soluble catalyst, for carbon-carbon bond-forming reactions like the 1,4 conjugate addition of silyl ketene acetals to a,p-unsaturated carbonyl compounds by Grieco et al. and Strauss et al. [26] In conclusion, the use of solutions of LiC104 in organic solvents opens up new opportunities to direct the course of various reactions and to carry out transformations under exceptionally mild conditions.

Me3SiCN or Me3SiN3or

22

21

NU = CN, N3, CH,C02Et, CHZCH=CHz,

R', R2, R3 = H, Ar, alkyl, -(cH2)3X' = OTBS, CH2SiMe3

Scheme 7.

X2 = OEt, H

H 3 c ~ ~ B z l 0.07 M OBzl BzlO 23

+ +

+

99%, a:p= 2:1

z

HO PMBO AcHN OAll bAll 24

209

25

Scheme 8.

2 10

D. General Methods and Reagents

References [1] a) R. Breslow, U. Maitra, Tetrahedron Lett. 1984, 25, 1239-1240, and references cited therein; b) review: R. Breslow, Acc. Chem. Res. 1991, 24, 150-164. P. A. Grieco, P. Galatsis, R. F. Spohn, Tetrahedron 1986, 42, 2847-2853, and references cited therein. a) 0. Diels, K. Alder, Justus Liebigs Ann. Chem. 1931, 490, 243-257; b) H. Koch, J. Kotlan, H. Markert, Monatsh. Chem. 1965, 96, 1646-1657. [4] a) Review: H. U. Reissig, Nachr. Chem. Tech. Lab. 1986, 34, 1169-1171; b) H. Waldmann, Liebigs Ann. Chem. 1989, 231-238, and references cited therein; c) H. Waldmann, M. Drager, ibid. 1990, 681-685; d) A. Lubineau, Y. Queneau, Tetrahedron 1989, 45, 6697-6712; e) S. D. Larsen, P. A. Grieco, W. F. Fobare, J. Am. Chem. SOC. 1986, 108, 3512-3513; f) H. Waldmann, Synlett 1990, 627-628, and references cited therein; g) P. A. Grieco, E. B. Brandes, S. McCann, J. D. Clark, J. Org. Chem. 1989, 54, 58495851; h) A. Lubineau, ibid. 1986, 51, 21422144. [5] P. A. Grieco, J. J. Nunes, M. D. Gaul, J. Am. Chem. SOC.1990, 112,4595-4596. [6] S. Winstein, S. Smith, D. Darwish, J. Am. Chem. SOC. 1959, 81, 5511-5512. [7] R. Braun, J. Sauer, Chem. Ber. 1986, 119, 1269-1274. [8] Reviews: a) P. A. Grieco, Aldricimica Acta 1991, 24, 59-66; b) H. Waldmann, Angew. Chem. 1991, 103, 1335-1337; Angew. Chem. Int. Ed. Engl. 1991, 30, 1306-1308; c) A. Flohr, H. Waldmann, J. Prakt. Chem. 1995, 337,609-611. [9] a) W. G. Dauben, C. R. Kessal, K. H. Takemura, J. Am. Chem. SOC. 1980, 102, 6893- 6894; b) for further details see: W. G. Dauben, J. Y. L. Lam, Z. R. Guo, J. Org. Chem. 1996, 61,4816-4819. [lo] a) R. Herter, B. Fohlisch, Synthesis 1982, 976-979; b) B. Fohlisch, D. Krimmer, E. Gerlach, D. Kashammer, Chem. Ber. 1988, 121, 1585-1593, and references cited therein. [ 111 W. Srisiri, A. B. Padias, H. K. Hall, Jr., J. Org. Chem. 1993,58,4185-4186.

[12] I. Arrastia, F. P. Cossio, Tetrahedron Lett. 1996,37, 7143-7146. [13] P. A. Grieco, J. P. Beck, S. T. Handy, N. Saito, J. F. Daeuble, Tetrahedron Lett. 1994, 35, 6783-6786. [14] Y. Pocker, J. C. Ciula, J. Am. Chem. SOC.1989, 111, 4728-4735, and cited literature. [I51 a) M. A. Forman, W. P. Dailey, J. Am. Chem. SOC. 1991, 113, 2761-2762; b) G. Desimoni, G. Faita, P. P. Righetti, G. Tacconi, Tetrahedron 1991, 47, 8399-8406. [16] R. M. Pagni, G. W. Kabalka, S. Bains, M. Plesco, J. Wilson, J. Bartmess, J. Org. Chem. 1993,58, 3130-3133. [17] P. A. Grieco, R. J. Cooke, K. J. Henry, J. M. VanderRoest, Tetrahedron Lett. 1991, 32,4665-4668. [18] a) M. T. Reetz, D. N. A. Fox, Tetrahedron Lett. 1993, 34, 1119-1122; b) M. T. Reetz, A. Gansauer, Tetrahedron Lett. 1993, 34, 6025-6030. [19] J. Ipaktschi, A. Heydari, H.-0. Kalinowski, Chem. Ber. 1994, 127, 905-909. [20] R. Sudha, K. M. Narasimhan, V. G. Saraswathy, S . Sankararaman, J. Org. Chem. 1996, 61, 1877-1879. [21] W. H. Pearson, J. M. Schkeryantz, J. Org. Chem. 1992,57, 2986-2987. [22] a) H. Waldmann, G. Bohm, U. Schmid, H. Rattele, Angew. Chem. 1994, 106, 20242025; Angew. Chem. Int. Ed. Engl. 1994, 33, 1936-1938; b) G. Bohm, H. Waldmann, Tetrahedron Lett. 1995, 36, 3843-3847; C) G. Bohm, H. Waldmann, Liebigs Ann. Chem. 1996, 613-619 and 621-625; d) U. Schmid, H. Waldmann, Tetrahedron Lett. 1996, 37, 3837-3840; e) U. Schmid, H. Waldmann Chem. Fur. J. 1998,4,494-501. 1231 T. L. Sommerfeld, D. Seebach, Helv. Chim. Acta 1993, 76, 1702-1714. [24] I. Zaltsgendler, Y. Leblanc, M. A. Bernstein, Tetrahedron Lett. 1993, 34, 2441-2444. [25] a) S. T. Handy, P. A. Grieco, C. Mineur, L. Ghosez, Synlett 1995, 565-567; b) R. Tamion, C. Mineur, L. Ghosez, Tetrahedron Lett. 1995, 36, 8977-8980. [26] T. J. Barbarich, S. T. Handy, S. M. Miller, 0. P. Anderson, P. A. Grieco, S. H. Straws, Organometallics 1996, 15, 3776-3778.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Reactions in Supercritical Carbon Dioxide Gerd Kaupp

The increasing global stress on the environment due to atmospheric pollutants from anthropogenic sources, in addition to those stemming from natural emissions, necessitates certain restrictions, for example on the use of organic solvents. For instance, lacquering is more and more frequently performed in a solvent-free fashion, and a great deal of effort is being made to avoid organic solvents in chemical syntheses, through the use of crystal photolyses, [ l ] gadsolid reactions, [2] and solid/ solid reactions. [3] An additional environmentally friendly approach is the use of supercritical carbon dioxide sc-COz as solvent for chemical syntheses. It is nontoxic, cheap, and nonflammable. It has already proven useful in some large-scale extraction processes in the food industry (e. g., decaffeination of coffee or extraction of hops). [4] In these processes, pressure or density changes lead to solubility variations which can also be exploited for chemical reactions in sc-CO2. The favorable ecological properties of CO2, especially when it is used in a closed loop system, are counterbalanced by the effort and expense associated with the use of high-pressure installations. High-pressure operations are more readily realized in large-scale production processes than in university or research laboratories. These suffer not only from an increasing lack of funding, but also

from the continually changing safety directions and lack of clearly assigned responsibilities. This has deterred academic researchers from undertaking and teaching high-pressure experiments. This misdirected development must be halted because of the detrimental effects on the environment. Many syntheses that cannot be performed as solid-state reactions rely on the use of inert solvents of medium polarity, which are frequently delicate. Therefore sc-CO2, with the critical temperature, pressure, and density values of T, = 31.06 "C, p c = 73.83 bar, D, = 0.467 g mL-', ought to be utilized. [5] In terms of polarity, sc-CO2 [Dimroth-Reichardt E ~ ( 3 0 value ) of 32 [6]] is roughly comparable to carbon tetrachloride. However, differences remain when the Kamlet-Taft n* solvatochromicity parameter (n*= -0.2) [7] is taken into account. Thus, sc-CO2 could be used as a replacement for commonly used organic solvents. Until 1994 it appears that most experiments have been primarily governed by academic curiosity, however, interest has largely increased since. Diels-Alder reactions have shown no discontinuities in reaction rates when liquid CO2 is replaced by sc-CO2, as long as the density is kept constant. [8] The reaction rates were roughly equal to those in solvents at normal pressures. 19,101 The reactions of isoprene and methylacrylate 1111 or cyclopenta-

2 12

D. General Methods and Reagents

diene and methylacrylate [I21 have been studied in mechanistic detail. It appears that the more involved cycloadditions of acetylenedicarboxylate to azulene derivatives in SC-CO: are of some preparative value. One example is shown in Scheme 1 (yields are 30% and 22 %). [ 131 Also [2+2] photocycloadditions of N-acylindoles with alkenes have been investigated in sc-C02. [ 141 Additionlcondensation reactions have been performed in liquid and sc-C02 when phytol or isophytol and trimethylhydroquinone gave a-tocopherol (vitamine E; Scheme 1). [I51 Mechanistic laser-flash photolysis studies of' benzophenone with H donors in SC-CO;!have shown that the local substrate clusters, which are considered crucial for the reactivity, exchange rapidly (in picoseconds) with the

supercritical medium. [ 161 The photochemical a-cleavage of asymmetric benzyl ketones also indicated that there is no cage effect for radical recombinations in sc-CO2. [17] The products are formed in a statistical ratio (Scheme 2). The formation of diphenylcarbene by laser flash photolysis of diphenyldiazomethane was studied in sc-CO2 and other supercritical media. [ 181 A laser-flash induced ring-closure reaction of a bipyridyl complex (Scheme 2) revealed solvation properties. [ 191 Laserflash impact to metal carbonyl complexes activated hydrogen and simple alkanes like CH4, C2H4, C2H6, and further inorganic reactions in supercritical fluids have been reviewed. [20] The carboxy inversion of diacyl peroxides has been interpreted as being an ionic reac-

+ E - C M

%?

HO phytol

PhCH&OCl&-p-Tol

PWt+

++ CO sc-CQ

t

t

PhCH&l+-p-Tol

PhCH&l&-p-Tol

%-

__*

sc-CQ

tocopherol

t

p-Tol-Cl+Cl+p-Tol

Scheme I .

25%

50% 25%

k +P W :

-co

18sc-CQ

Scheme 2.

Reactions in Supercritical Carbon Dioxide

Scheme 3.

tion. In sc-C02 it proceeds with a 17 % yield (40"C, d = 0.93 g mL-'), but slower than in CC14 or CHC13 (Scheme 3). [7] However, ionic reactions in sc-CO2 can be facilitated by phase-transfer catalysis. This is clearly shown by the substitution reaction of benzyl chloride in Scheme 3. [21] Acetone as a cosolvent helps. Radical chain reactions like the well-known oxidation of cumene to cumene hydroperoxide led to lower yields in sc-CO2 (llO°C, 200-414 bar), probably because it was not possible to prevent chain termination reactions due to the metal container (Scheme 3). [22] Recently, however, a number of studies were published which demonstrated that radical brominations [23] and polymerizations, [24, 251 can proceed providing better (or roughly equal) results than the corresponding reactions in conventional solvents. Furthermore, hydroformylations, [26] C02 hydrogenations, [27] catalytic additions/cycloadditions on C02, [28, 291 and enzymic reactions [30, 311 in sc-CO2 were successful. In many cases both reaction and extraction of products can profit from the supercritical phase. Radical reactions are nicely performed in sc-CO2. Thus, the homolytic cleavage of bitropenyl to give cycloheptatrienyl radical and its trapping by oxygen have been used to evaluate activation, stabilization and bond energies. [32]

2 13

The bromination of toluene with bromine in sc-CO2, photochemically initiated through a sapphire window, led to benzyl bromide (74 %) and 4 -bromotoluene (1 1 %). Ethylbenzene afforded 1-bromo-1-phenylethane in 95 % yield (Scheme 4). [23] In order to demonstrate that uncomplexed bromine atoms act as chain propagators, toluene and ethylbenzene were photobrominated in a competition study at pressures of 75 to 423 bar and at 40 "C. Over the entire pressure range, the reactivity of the benzylic secondary C-H bond in ethylbenzene was found to be about 30 times greater than that of the corresponding primary C-H bond in toluene. The analogous value for the reactivity in C c 4 at 40°C is 36. The bromine atoms in sc-C02 are therefore particularly free. It would be important to determine quantum yields (chain lengths) at various pressures to learn more about mechanistic aspects and other details of the reaction. Local solvent structures on model free-radical reactions in sc-CO2 have been analyzed in some detail. [33] The heterogeneous N-bromosuccinimide (NBS) bromination (Ziegler bromination; Scheme 4) of toluene in sc-CO2 was initiated photochemically with azobis(isobutyronitri1e) (AIBN) (40°C, 170 bar, 4 h). [23] In CC4, this reaction proceeds without succinimidyl radicals, with the same selectivity as the direct bromination. The yield is quantitative on the 4 mmol scale; no 4-bromotoluene is observed. Homogeneous fluoroalkene polymerizations (and copolymerizations) also proceed in sc-CO2 after AIBN initiation. [24, 251 In this case it is advantageous that highly fluorinated polymers (> 250 000 g mol-') and copolymers are very soluble (up to 25 %) in sc-CO2 at high pressures. This means that no chlorofluorocarbons need to be employed as solvents. The homopolymer (270000 g mol-') shown in Scheme 5 can be obtained from FOA in scC02 (59.4 "C, 207 bar, 48 h, no Trommsdorff effect [24]) in 65 % yield. The product can be precipitated from the homogeneous solu-

214

D. General Methods and Reagents

Q

Br;!

sc-coz

0

2Br

AIBN

tion by pressure release. It would be useful, however, to develop a workup procedure that does not offset the use of sc-CO2 by the necessity to dissolve the raw product in 1,1,2trifluorotrichloroethane. Statistical copolymers of FOA are also surprisingly soluble in sc-CO2. The kinetic parameters of the thermal AIBN decomposition in sc-C02 have been determined accurately, and 1,l-difluoroethylene was telomerized correspondingly. [22] After these pioneering investigations a large number of radical and cationic polymerizations have been performed in sc-CO2. These

- 7 0

t

AIBN

\CY(CFo)sCFs FOA

Scheme 5.

59.4%

I

Scheme 4.

include polymethylmethacrylate, polystyrene, polyesters, polyvinylalcohols, poly(2 -hydroxypropylmethacrylate), polyisobutylene, and polyacrylamide. [34] Spherical latex particles are usually formed and modified in (inverse) emulsion polymerizations. Organic aerogels with large inner surfaces (600-1000 m2 g-') and ultrafine pores were prepared by condensation polymerization of resorcinol and formaldehyde in water with subsequent supercritical drying. [35] Finally, crosslinked and natural rubber could be controllably depolymerized to obtain useful feedstocks in supercritical H20 and C02. [36] The inertness of sc-C02 is also useful for metal-catalyzed hydroformylations and hydrogenations of alkenes to the corresponding aldehydes. Selective hydroformylations were obtained with Co catalysts. [26] They profit from the good miscibility in sc-CO2 (Scheme 6). The reaction mixture is less viscous,

Reactions in Supercritical Carbon Dioxide

which leads to sharp 59C0 NMR signals (quadrupole nucleus), which in turn allows the identification of the catalytically active species by high-pressure NMR spectroscopy. The hydrogenation of double bonds does compete if MnH(C0)5 is the reagent (Scheme 6). [371 The solubility of Rh(1)phosphane complexes has been increased by substitution with four n-tridecafluorooctane and two trifluoromethyl side groups and the selectivity of the hydroformylation of 1-octene in SC-COZwas n h o 3.7 at 100 % conversion. The same catalyst was used to hydrogenate isoprene. [38] Asymmetric hydrogenations in sc-CO2 have been obtained heterogeneously and homogeneously. Thus, ethyl pyruvate gave @)-ethyl lactate enantioselectively on a Pt/A1203 catalyst with cinchonidine. However, COz deactivates the catalyst due to its reduction. [39] More general are soluble chiral Rh catalysts [ Rh(I)(cod)(R,R)-Et-DuPHOS trifluoromethane-sulfonate] or { -tetrakis-(3,5 -bis(trifluoromethy1)phenyl) borate} that hydrogenate the prochiral enamides (Scheme 6). Four /3monosubstituted compounds gave similar, two D,P-disubstituted ones considerably better ee values as those found in liquid organic media (methanol or hexane). [40]

A \

t c o t y

Co2( Cole sc-cq

/\/CHO

t

215

Hydrogenations of carbon dioxide to give formic acid (derivatives) are of particular concern. Noyori summarized his contributions, patents and improvements in that field in two full papers. [27] Simple soluble catalysts like RuC12[P(CH3)3]4, RuH2[P(CH3)314 or others are active in homogeneous hydrogenation of CO2 to formic acid as long as this reaction is coupled to salt formation. The reaction in scCOZ (50°C, 86 bar H2, 207 bar COZ, dissolved NEt3) proceeds with the highest rate of the numerous variants of this reaction, namely 1400 mole of formic acid per mole of catalyst per hour. This turnover frequency (TOF) is reduced to 1.3 h-' for the same composition when liquid CO2 (at 15OC) is employed. If cosolvents are added (water, or DMSO) a TOF of 4000 h-' is achieved. If methanol is added, the product is methyl formate, the presence of NEt3 still being necessary. Turnover numbers (TON) up to 3500 have been reached. All other high-pressure variants of this reaction in liquid solvents yield much lower TOF values. [27] The formic acid synthesis can also be coupled with subsequent reactions of formic acid with secondary amines, to even higher TON values up to 420 000 for the synthesis of DMF (TOF 8000 h-I), when in contact with a liquid phase starting with solid

/A

Scheme 6.

216

D. General Methods and Reagents

dimethyl-ammonium dimethylcarbamate as the dimethylamine source at 50 "C (Scheme 6). [27] This behavior indicates the favorable effect of the high solubility of H2 in sc-COZ as well as the high mass transport rate and recommends the system for continuous operation in industrial plants. It should be pointed out that the concentration of H2 in a supercritical mixture of H2 (85 bar) and C02 (120 bar) at 50°C is 3.2 M, while the concentration of H2 in THF under the same pressure is merely 0.4 M. [27] Importantly, the nonpolar catalyst could be recycled by extraction with sc-CO2. Oxidations with 0 2 in sc-CO2 (Scheme 7) also profit from miscibility of gases and high diffusivity. Oxirane and acetaldehyde were obtained by KrF excimer laser irradiation of ethylene and 0 2 in C02 under sub- and supercritical conditions. Also ethane and cyclohexane oxidized. [41] The cyclohexane oxidation giving cyclohexanone and cyclohexanol may be greatly manipulated in sc-C02. [42] Total oxidations in sc-C02 (to give C02 and H20) have been obtained with ethanol,

toluene and tetraline at >3OO"C. [43] Such reactions might have a bearing for waste treatment similar to related use of sc-HzO. Finally, it is also possible to perform Rh(1) catalyzed oxidation of THF in supercritical C02/02 to give butyrolactone (TON 100) (Scheme 7). [381 Polycarbonates and cyclic carbonates are obtained by the well-known and well-studied reactions of C02 and oxiranes (Scheme 7). These reactions have also been successfully performed in supercritical mixtures. [ 2 8 ] It turned out, however, that the industrial production of ethylene carbonate (similar to propylene carbonate) in a liquid (product) phase (190-200 "C, total pressure 80 bar) is more economical for capacities of 4000 t per year and installation when it is run nearly stoichiometrically. [44] In the cases of substituted or polycyclic oxiranes, solvents are usually added and 1 to 40 bar of C02 are introduced, depending on the catalyst employed. [28] However, the development of a CO2-soluble Zn catalyst formed the polycarbonate from

Scheme 7.

Reactions in Supercritical Carbon Dioxide

cyclohexene oxide in the absence of any additional organic solvent. [45] Homologous cyclic ethers (oxetanes, tetrahydrofurans, etc.) are also expected to undergo cycloaddition to COz and should be tried in sc-COz. A [2+2+2] cycloaddition of two moles of 3 -hexyne to one mole of COZ in the presence of the catalyst [ { Ni(cod)~}Ph~P(CH2)4PPh2] and of benzene (25 "C, 50 bar, 20 h at 120 "C), led to tetraethylpyranone (57 %) (Scheme 7). [46] A preliminary attempt to improve this yield by using the same catalyst in sc-COZ failed (102"C, 93 g COz in 200 mL, 69 h, 35%). [29] It appears however, that attempts to improve this yield are still in progress in spite of a number of experiments that have reproduced it. [29] Enzymic reactions in sc-CO2 cover oxidations and solvolyses. Good yields (75% at a residence time of only 13 s) were reported for the enzymic oxidation (immobilized cholesterol oxidase from G. chrysocreas) of cholesterol in supercritical C02/02 (9 : 1) (Scheme 8). Cosolvents, like tert-butyl alcohol, that increase the solubility and, to an even larger extent, those that assist aggregate formation, increase the rate of the reaction (fourfold in this case). [31] However, it appears that this line has not been pursued any further. Horseradish peroxidase was used in the oxidative polymerization of p-cresol by H202 in sc-CO2. Cosolvents were useful. The method was evaluated for manufacture of phenolic resins without incorporating formaldehyde. [47] I

h

One of the first enzymic esterifications (immobilized lipase MY) of rac-citronellol with oleic acid in sc-COZ close to the critical point led stereoselectively to 1.2-5.8 % of citronellol oleate (Scheme 9). Only at the critical temperature (31 "C, 84 bar) does the (S)-(-)-citronello1 oleate form with 99 % optical purity. Even small temperature increases (4-9 "C) led to a drastic reduction of the optical purity; pressure increases (up to 190 bar) had the same effect. This result was explained by the formation of clusters near the critical point, where pressure and temperature changes have particularly strong effects. No esterification took place in water-saturated cyclohexane. [30] Similarly, rac-ibuprofen was enantioselectively esterified in sc-COZ with 70 % ee, by immobilized Mucor miehei lipase. [48] After these pioneering results much work has been put into enzymic hydrolyses, esterifications, transesterifications in sc-CO2 (Scheme 9), due to high demands of the food industry. Numerous groups in Austria, Canada, Finland, France, Germany, Italy, Japan, Slovenia, Sweden, and USA have published on such research and several reviews are available. [49] Major topics are continuous processes, technology of fats, fatty acids and alcohols. Frequently, sc-COZ is used both for reaction and extraction. Also demands of fuel industry are covered (e.g. bio-Diesel). However, for the latter applications of S C - C O non-catalyzed ~ processes at higher temperatures may be more important, even though methanolysis of seed oils or soy

L

HO

OH t

sc-WQ?

oxidase

2 17

phenolic r e s i n

Scheme 8.

2 18

D. General Methods and Reagents

raccitronellol

(S)-(-)-oleate

racibuprofen

lipase

-

70% ee

(R)-(+)-cit.

wr

clnocww R C w t R’OH

c1

sc-CB

RCCH’+tW

c1

flakes have enzymicly succeeded. [50] A non-enzymic simultaneous extraction and methylation of herbicides like 2,4,5-T with CH31 and the phase transfer catalyst (C6H13)4N+HS04-was complete from 1 ppm solutions (Scheme 9). [51] Apparently, unnoticed by the recent studies, the photolysis of hops extracts in sc-C02 has been developed into an established industrial process. [52] The sc-COZextract contains the so-called “a-acids” (vinylogous carboxylic acids), for instance humulone, which are primary bittering agents with limited stability. These are isomerized into a-isoacids, such as trans-isohumulone (Scheme lo), stable and more soluble bittering agents, which give beer its characteristic taste. The conventional brewing method achieved this transformation in low yields by boiling the hops in the wort. It is more efficient to add the ingredients stemming from hops to the cold finished beer. This, however, requires the isomerization of the air-sensitive a-acids to be performed pho-

tochemically in the sc-CO2 extract before the addition to the beer. The quantum yield 4 is 0.03. The mechanism of this [1,2,3,4]-rearrangement [53] is unknown. Formally, the reaction can be considered an H migration from the OH group to the end of a four-membered chain with a concomitant acyl group migration from position 2 to 3 within that chain. According to the current canon of photochemistry, an oxa-di-nmethane rearrangement with subsequent [ 1,3]-H-migration and ring opening was formulated. [52] It is said that this procedure affords special protection to the flavors of the hops ingredients. The current state of knowledge [54] indicates the versatility of sc-C02 as a reaction medium. The last three years saw a tremendous increase in material giving reason to be optimistic that in the future even more reactions will be carried out in the ecologically sound sc-CO2 (closed loop systems) rather than in organic solvents. The theoretical and

Reactions in Supercritical Carbon Dioxide

2 19

sc-C&

hunulone

r

trans-isohunulone

oxa-di-lt-methane-product

mechanistic basics have been complemented by a great deal of practical and technical knowledge now exceeding the widespread knowledge from extraction processes utilizing sc-CO2. Industrial applications have become reality. However, teaching deficiencies persist. Textbooks on experimental techniques are still not covering unusual reaction media. Academia seems to be largely caught in thermodynamic measurements, although reactions are at work and thus, the more exciting creative aspects of the issue with new techniques including AFM and SNOM [2,55] should find due public support for the sake of an environmentally benign future.

References [ l ] V. Ramamurthy, Tetrahedron 1986, 42, 5753; G. Kaupp, Adv. Photochem. 1994, 19, 119; G. Kaupp in Handbook of Organic Photochemistry and Photobiology, (Ed.: W. Horspool), CRC, Cleveland OH, 1995, p. 50-63. [2] G. Kaupp, D. Matthies, Chem. Ber. 1986, 119, 2387; Mol. Cryst. Liq. Cryst. 1988, 161, 119;

Scheme 10.

G. Kaupp, D. Lubben, 0. Sauerland, Phosphorus Sulfur Silicon Relat. Elem. 1990, 53, 109; G . Kaupp, Mol. Cryst. Liq. Cryst. 1992, 211, 1; G . Kaupp, J. Schmeyers, Angew. Chem. 1993, 105, 1656; Angew. Chem. Int. Ed. Engl. 1993, 32, 1587, and references therein; G. Kaupp in Comprehensive Supramolecular Chemistry, Vol. 8, Chap. 9 (Eds.: J. E. D. Davies, J. A. Ripmeester) p. 381-423 + 21 color plates, Elsevier, Oxford, 1996. [3] F. Toda, K. Kiyoshige, M. Yagi, Angew. Chem. 1989, 101, 329; Angew. Chem. Int. Ed. Engl. 1989, 28, 320; Review: F. Toda in Reactivity in Molecular Crystals (Ed.: Y. Ohashi), VCHIKodansha WeinheidTokyo, 1993, p. 177; G. Kaupp, M. Haak, F. Toda, J. Phys. Org. Chem. 1995, 8, 545; G. Kaupp, J. Schmeyers, F. Toda, H. Takumi, H. Koshima, ibid. 1996, 9, 795. [4] R. Eggers, Angew. Chem. 1978, 90, 799; Angew. Chem. Int. Ed. Engl. 1978, 17, 751; K. Zosel, ibid. 1978, 90, 748 and 1978, 17, 702; P. Hubert, 0. G. Vitzthum, ibid. 1978, 90,756 and 1978,17,710; E. Stahl, W. Schilz, E. Schiitz, E. Willing, ibid. 1978, 90, 778 and 1978, 17, 731; K. Zosel (Studiengesellschaft Kohle), US-A 4260639, 1981; A. B. Caragay, Perfum Flavor 1981, 6, 43; H. Brogle, Chem.

220

D. General Methods and Reagents

Ind. (London) 1982, 385; R. Vollbrecht, ibid. 1982, 397; liquid: D. S. Gardner, ibid. 1982, 402. [5] According to its phase diagram, COn can only be liquefied by compression between the triple point at -57 W5.2 bar and the critical point. Above both Tc and pc, C02 is in the supercritical state. [6] Y. Ikushima, N. Saito, M. Arai, J. Phys. Chem. 1992, 96, 2293; Y. Ikushima, N. Saito, M. Arai, K. Arai, Bull. Chem. SOC. Jpn. 1991, 64, 2224; J. A. Hyatt, J. Org. Chem. 1984, 49, 5097. [7] M. E. Sigman, J. T. Barbas, J. E. Leffler, J. Org. Chem. 1987, 52, 1754. [8] For example, reaction of 1 .5 g cyclopentadiene with 0.5 g p-benzoquinone in 20 g COz: 25-40°C, 60-240 bar, k’ = 0.597 X 10.’ to 1.147 x 10-3 s-1. [9] N. S. Isaacs, N. Keating, J. Chem. SOC.Chem. Commun. 1992, 876. [lo] M. E. Paulaitis, G. C. Alexander, Pure Appl. Chem. 1987,59,61. [ 1 I] Y. Ikushima, N. Saito, 0. Sato, M. Arai, Bull. Chem. Soc. Jpn. 1994,67, 1734. [12] R. D. Weinstein, A. R. Renslo, R. L. Danheiser, J. G. Harris, J. W. Tester, J. Phys. Chem. 1996, 100, 12337. [13] R. Hunziker, D. Sperandio, H.-J. Hansen, Helv. Chim. Acta 1995, 78, 772. 1141 B. T. Des Islet, Univ. of Western Ontario, Diss. Abstr. Int., B 1996, 57, 334. Avail.: Univ. Microfilms Int. Order No. DANN03447. [151 R. Lowack, J. Meyer, M. Eggersdorfer, P. Grafen (BASF A.G.) US 5523420, 1995; DE 4243464 A l , 1992. [16] C. D. Roberts, J. E. Chateauneuf, J. F. Brennecke, J. Am. Chem. SOC. 1992, 114, 8455. [17] K. E. O’Shea, J. R. Combes, M. A. Fox, K. P. Johnston, Photochem. Photobiol. 1991, 54, 571; C. B. Roberts, J. Zhang, J. F. Brennecke, J. E. Chateauneuf, J. Phys. Chem. 1993, 97. 56 18; for high-resolution reference spectra see G. Kaupp, E. Teufel, H. Hopf, Angew. Chem. 1979, 91, 232; Angew. Chem. Int. Ed. Engl. 1979,18,215. [ 181 J. E. Chateauneuf, Res. Chem. Internzed. 1994, 20, 159.

[ 191 Q. Ji, C. R. Lloyd, E. M. Eyring, R. van Eldik,

J. Phys. Chem. A 1997, 101,243. [20] J. A. Banister, A. I. Cooper, S. M. Howdle, M. Jobling, M. Poliakoff, Organometullics 1996, 15, 1804; M. Poliakoff, M. W. George, S. M. Howdle, Chem. Extreme Non-Classical Cond. p. 189-218 (Ed.: R. Van Eldick, C. D. Hubbard), Wiley, New York, 1997. [21] A. K. Dillow, S. L. J. Yun, D. Suleiman, D. L. Boatright, C. L. Liotta, C. A. Eckert, Ind. Eng. Chem. Res. 1996, 35, 1801. [22] G. J. Suppes, R. N. Occhiogrosso, M. A. McHugh, lnd. Eng. Chem. Res. 1989, 28, 1152. [23] J. M. Tanko, J. F. Blackert, ACS Symp. Sex 1994, 577(Benign by Design), 98. [24] J. R. Combes, Z. Guan, J. M. DeSimone, Macromolecules 1994, 27, 865. [25] Z. Guan, J. R. Combes, Y. Z. Menceloglu, J. M. DeSimone, Macromolecules, 1993, 26, 2663. [26] J. W. Rathke, R. J. Klingler, T. R. Krause, Organometallics 1991, 10, 1350. 1271 P. G. Jessop, Y. Hsiao, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 8277; 1994, 116, 8851. [28] U. Petersen, Methoden Org. Chem. (Houben Weyl) 4th. ed. 1952, Chap. E4, 1983, p. 95. [29] M. T. Reetz, W. Konen, T. Strack, Chimia 1993, 47, 493. [30] Y. Ikushima, N. Saito, T. Yokoyama, K. Hatakeda, S. Ito, M. Arai, H. M. Blanch, Chem. Lett. 1993, 109; Y. Ikushima, N. Saito, M. Arai, J. Chem. Eng. Jpn. 1996,29, 551. [31] H. W. Blanch, T. Randolph, C. R. Wilke (University of California, Berkeley) US 4925790 A, 1985; T. Randolph, D. S. Clark, H. W. Blanch, J. M. Prausnitz, Science 1988, 239, 387. [32] W. R. Roth, F. Hunold, M. Neumann, F. Bauer, Liebigs Ann. 1996, 1679. [33] S. Ganapathy, C. Carlier, T. W. Randolph, J. A. O’Brien, lnd. Eng. Chem. Res. 1996, 35, 19. [34] Review of the contributions of J. M. DeSimone: K. A. Schaffer, J. M. DeSimone, Trends Polym. Sci. 1995, 3, 146; J. L. Kerschner, S. H. Jureller, R. Harris, Polym. Mate% Sci. Eng. 1996, 74, 246; G. Deak, T. Pernecker, J. P. Kennedy, Macromol. Rep. 1995, A32, 979; F. A. Adamsky, E. J. Beckman,

Reactions in Supercritical Carbon Dioxide Macromolecules 1994, 27, 5238; 312; T. Pernecker, J. P. Kennedy, Polym. Bull. (Berlin) 1994, 33, 13. [35] J.-H. Song, H.-J. Lee, J.-H. Kim, Han’guk Chaelyo Hakhoechi 1996, 6, 1082; Chem. Abstl: 1996,126, 104500. [36] D. T. Chen, C. A. Perman, M. E. Riechert, J. Hoven, J. Hazard. Muter. 1995, 44, 53. [37] P. G. Jessop, T. Ikariya, R. Noyori, Organometallics 1995, 14, 1510. [38] W. Leitner, S. Kainz, D. Koch, C. Six, K. Wittmann, Lecture at the Chemiedozententagung, March 16-19, 1997, Berlin; S. Kainz, D. Koch, W. Baumann, W. Leitner, Angew. Chem. 1997, 109, 1699; Angew. Chem. Int. Ed. Engl. 1997, 36, 1628. [39] B. Minder, T. Mallat, K. H. Pickel, K. Steiner, A. Baiker, Catal. Lett. 1995, 34, 1 . [40] M. J. Burk, S. Feng, M. F. Gross, W. Tumas, J. Am. Chem. SOC. 1995,117, 8277. [41] S. Koda, Y. Oshima, J. Otomo, T. Ebukuro, Process Technol. Proc. 1996,12, 97. [42] P. Srinivas, M. Mukhopadhyay, Ind. Eng. Chem. Res. 1994,33, 3118. [43] L. Zhou, A. Akgerman, lnd. Eng. Chem. Res. 1995,34, 1588; AlChE J. 1995,41,2122. [44] G. Hechler, Chem. lng. Tech. 1971, 43, 903. [45] C. A. Costello, E. Berluche, S. J. Han, D. A. Sysyn, M. S. Super, E. J. Beckman, Polym. Matel: Sci. Eng. 1996, 74, 430. [46] Y. Inoue, Y. Itoh, H. Kazama, H. Hashimoto, Bull. Chem. Soc. Jpn. 1980, 53, 3329. [47] K. Ryu, S. Kim, Korean J. Chem. Eng. 1996, 36, 415.

22 1

[48] M. Rantakylae, 0. Aaltonen, Biotechnol. Lett. 1994, 16, 825; enantioselective acetylations: E. Cemia, C. Palocci, F. Gasparrini, D. Misiti, N. Fagnano, J. Mol. Catal. 1994,89,Lll-L18. [49] 0. Aaltonen, M. Rantakyla, CHEMTECH 1991, 240; S . V. Kamat, E. J. Beckman, A. J. Russell, Crit. Rev. Biotechnol. 1995, 15, 41-71; K. Nakamura, Supercrit. Fluid Technol. Oil Lipid Chem. (Ed.: J. W. King, G. R. List), AOCS Press, Champaign, 111, 1996, 306-320. [50] M. A. Jackson, J. W. King, J. Am. Oil Chem. Soc. 1996, 73, 353. [51] M. Y. Croft, E. J. Murby, R. J. Wells, Anal. Chem. 1994,66,4459. [52] J. C. Andre, A. Said, M. L. Viriot (Centre National de la Recherche Scientifique), FRA1 2590589, 1987; J. Photochem. Photobiol. A 1988, 42, 383; M. L. Viriot, J. C. Andre, M. Niclause, D. Bazard, R. Flayeux, M. Moll, J. Inst. Brew. 1980, 86, 21; J. Am. SOC. Brew. Chem. 1980, 38, 61; J. C. Andre, M. L. Viriot, J. Villermaux, Pure Appl. Chem. 1986,58,907. [53] G. Kaupp, Top. Curl: Chem. 1988,146, 57. [54] Recently, interesting high-yield olefin metathesis cyclizations have been performed in sc-COz under the influence of Ru and Mo catalysts: A. Furstner, D. Koch, K. Langemann, W. Leitner, Angew. Chem. 1997, 109, 2562; Angew. Chem. Int. Ed. Engl. 1997, 36, 2466 [55] G. Kaupp, Chemie in unserer Zeit 1977, 31, 129; English translation is available in WWW under http://Kaupp.chemie.uni-oldenburg.de.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

The Selective Blocking of transDiequatorial, Vicinal Diols ;Applications in the Synthesis of Chiral Building Blocks and Complex Sugars Thomas Ziegler

For efficient chemical synthesis of complex blocking two hydroxyl functions in a monooligosaccharides, protecting group strategies saccharide simultaneously and selectively. As and blocking techniques are of overriding the example of methyl a-D-galactopyranoside significance. It is usually unavoidable first to in Scheme I illustrates, benzylidene acetals prepare protected smaller saccharide units can be the major product from 1,3-diols, so that enable a directed selective formation of that in the protected galactose derivative 1 the glycosidic bond and the sequential con- the hydroxyl functions of positions 2 and 3 struction of larger saccharides. To this end all are available for further reaction. In contrast, functional groups with the exception of the isopropylidene acetals can be selectively preprojected reaction center in the saccharide pared from vicinal cis-diols, with the result building block to be glycosylated (the gly- that in the example 2 chosen here the hydroxyl cosyl acceptor) must, as a rule, be protected, functions of positions 2 and 6 remain free. [ 13 and only in particularly favorable cases can Although isopropylidene acetals can also be partially protected glycosyl acceptors be used synthesized from monosaccharides with vicifor regioselective glycosylation. In the gly- nal trans-diequatorial diols, these acetals are cosyl donor, the saccharide building block usually so acid-labile that they are difficult to that must be linked to the glycosyl acceptor, handle and are therefore less suitable for glythe protecting groups must be very precisely cosylation reactions. In the search for acetal protecting groups tuned to the planned glycosylation method. Both the reactivity of glycosyl donor and gly- for vicinal trans-diequatorial diols that can cosyl acceptor and the anomeric selectivity of be selectively introduced, the research group the glycosylation step is dominated by the of S. V. Ley in Cambridge, England, recently protecting groups. The search for novel pro- developed the dispiroketal (Dispoke) [2] and tecting group strategies is therefore as urgent cyclohexane-1,2-diacetal (CDA) protecting for the carbohydrate chemist as the need for groups. 131 The former can be introducted by acetalization of a diol with the readily acuseful glycosylation methods. Of the classical protecting groups of esters, cessible 3,3 ‘,4,4‘-tetrahydro-6,6’-bis-2H-pyran ethers, and acetals that are favored in saccha- [4,5] (bis-DHP, 3a), the latter by acetalization ride synthesis, the benzylidene and isopropy- with the just as easily obtainable 1,1,2,2,lidene protecting groups have particular signi- tetramethoxycyclohexane 4. [3] In the case ficance, because both open the possibility of of the methyl a-D-galactopyranoside (Scheme

The Selective Blocking of trans-Diequatorial, Vicinal Diols

223

2 % 0

HO

2 PhCHO, ZnClp (95%)

HoOMe

(93%) HO

(76%)

(46%)

5a

6a

3bR=Ue 3CR=Ph

4

OMe

Scheme 1.

l), the trans-diequatorial hydroxyl functions The exceptionally high selectivity of the of positions 2 and 3 can be highly selectively Dispoke and CDA groups can be explained blocked as the Dispoke-protected galactoside by a steric interaction of the neighboring 5a (76%) [ 5 ] or the CDA-protected galacto- spiro centers and the equatorial arrangement side 6a (46%) [3]in this way. Dispoke and of the alkyl residue as well as a strong anomeCDA derivatives of monosaccharides are ric effect of the two acetal functions. [2,3] therefore useful complements to benzylidene This high selectivity is particularly impresand isopropylidene derivatives and to the sively reflected in the reaction of (S)-1,2,41,1,3,3-tetraisopropyl-l,3-disiloxane-1,3-diylbutanetriol with bis-DHP (3a) and a catalytic group which can be used as well for the pro- amount of camphorsulphonic acid (CSA), in tection of trans-diequatorial, vivinal diols in which the dispiroketal 7 (96%) is obtained monosaccharides. [6]Like the classical acetal as exclusive stereoisomer [2](Scheme 2). In protecting groups, the Dispoke group can be the case of the symmetric glycerol, a “desymremoved hydrolytically under acidic condi- metrization” of glycerol can even be achieved tions, preferably by transacetalization with during the Dispoke formation by the use of chiral Cz-symmetric bis-DHP derivative 3b. ethylene glycol. [5]

224

D. General Methods and Reagents

/\/\/OH HO

QH

OH

3a, (H')

(96%)

HO

8

R

I

\

1) TsCI, Py 2) tBuOK

(6 190)

3) 0 3

(70%)

9bR=Mei 9a

I

Scheme 2.

Here the only product is the enantiomerically pure compound 8 (96%). The compounds 7 and 8 can be transformed into the corresponding Dispoke-protected glyceraldehydes 9, which not only are thermally more stable than the isopropylidene glycerinaldehyde, [2,7] but also have a distinctly higher antiselectivity in the 1,2-addition of carbon nucleophiles to the aldehyde function [2] (Table 1). In the same way, glycolic acid can be stereoselectively transformed into the Dispoke derivative 10 (61 %) with enantiomerically pure 3b. [S] Formation of the ester enolate, alkylation with methyl iodide, renewed enolate formation and treatment with benzyl bro-

mide then give highly diastereoselectively in 5 1 % yield the protected a-hydroxycarbonic acid derivative 11 (Scheme 3). [S] Similarly, other meso-diols like myo-inositols are easily desymmetrisized by Dispoke derivatives 3b and 3c, respectively. [9, lo] It can be predicted that the C:!-symmetric Dispoke group will rapidly become popular as auxilliary in the stereoselective synthesis of small building blocks. Besides the 2,3 -protected galactosides 5a and 6a (Scheme l), other monosaccharides from the gluco, manno, rhamno, fuco, xylo, lyxo, and arabino series can be converted into the corresponding Dispoke- and CDAblocked derivatives 5 and 6. [3,10,11] How-

The Selective Blocking of trans-Diequatorial, Vicinal Diols

225

Table 1. Reaction of 9a with various organometallics R-M [2]. R-M

Conditions

Yield 10

anti/syn 10

MeLi MeMgCl MezCuLiMezS EtMgBr HzC=CHMgBr (HzC=CH)zZn HC=CMgBr AllylMgBr

EtzO/THF, -78 "C, 22 h THF, -78 "C, 24 h EtzO, -78 "C, 20 h THF, -78 "C, 6 h THF, -78 "C, 4 h THF, 25 "C, 48 h THF, -78 "C, 5 h THF, -78 "C, 18 h

82 % 92 % 69 % 62 % 56 % 84 % 65 % 89 %

8 2 : 18 81 : 19 12 : 88 73 : 27 91 : 9 67 : 33 8 9 : 11 68 : 32

a)

antilsyn Lit.a)

60 : 40 -

18 : 82 -

60 : 40 -

4 4 : 56 60 : 40

Reaction of isopropyliden-glyceraldehydwith the corresponding organometallic.

I

Me

ever, the regioselectivity of the acetal formation of Dispoke derivatives can in some cases (for instance, methyl a-L-rhamnopyranoside) lead to mixtures of the 3,4- and 2,3derivatives 5b and 5b', respectively. [ l l ] For the CDA analogues 6, the ratio is most often shifted so far to the side of the trans-diequatorially blocked compounds 6b that a preparative application seems meaningful [3] (Scheme 4). On the other hand the Dispoke and CDA protection for D-glucopyranosides presents problems, because here all secondary OH groups are trans-diequatorially arranged. Both with bis-DHP 3a and with 1,1,2,2-tetramethoxycyclohexane 4, mixtures of the 2,3 and 3,4-protected glucosides 5c,6c and 5c',6c', respectively, are obtained. [3,11,12] If, however, analogous to the "desymmetrization" of glycerol, phenyl-substituted, chiral

I

Me

Scheme 3.

bis-DHP 3c is used, for glucose derivatives the two regioisomers 12 and 13 can be prepared in a highly selective synthesis through double diastereoselection [13] (Scheme 5 ) . [ 141 For strategies with the Dispoke or CDA protecting groups in oligosaccharide synthesis the concept of armed and disarmed glycosyl donors [ 151 is especially fruitful. According to this principle the reactivity of a glycosyl donor is diminished by deactivating protecting groups (e. g. acyl groups) or by restricting the flexibility of the pyranose ring by bridging two hydroxyl functions (e. g. acetal protecting groups). Such a disarmed donor can then function a glycosyl acceptor and participate in a selective reaction with a reactive armed (most often benzyl-protected) glycosyl donor. The conformation-stabilizing Dispoke and CDA groups are plainly predestined to disarm a glycosyl donor. For example, the

226

D. General Methods and Reagents OMe

OMe

I

OMe

I

'(79%)

I

5b

5b'

6 b (74%)

6b' (8%)

OTBDPS + 3a

+

Scheme 4.

OTBDPS

5c,5c1

/OTBDPS

5c R=Dispoke (42%) 6~ R= CDA (50°/o)

5c' R=Dispoke (26%) 6 ~R= ' CDA (30%)

+3c-12 + ent-3c -,13

OTBDPS

HO OMe

13 (75%)

12 (88%) Ph

ethyl 1-thio-P-D-galactoside 14, conformationally fixed by a Dispoke group and thus disarmed, undergoes a smooth reaction with thiogalactoside 15 - reactive as a result of benzyl protection - and the mild activator iodonium dicollidine perchlorate (IDCP) to form disaccharide 16 [16] (Scheme 6). Through the subsequent use of the more reac-

Ph

Scheme 5.

tive activator N-iodosuccinimide (NIS), disaccharide 16 is armed and reacts with the 2 - 0 benzoyl-protected and thus disarmed thiomannoside 17 as glycosyl acceptor in attractive yield to afford trisaccharide 18. The transformation of 18 as trisaccharide donor without further protecting group manipulation is achieved with the pseudo disaccha-

The Selective Blocking of trans-Diequatorial, Vicinal Diols

BnO SEt

Bn?

)-

227

(OBn

o I Jy&

BnO

h

Bn\O

16

BnO

BnO

ZJ

15

17

SEt

NIS, TfOH, 0°C 5 rnin

*

(63%)

0 BnO

18

4Et O , Bn

. O W

Scheme 6.

ride acceptor 19 and NIS after prolonged reaction times. The pentasaccharide 20, a fragment of the GPI anchor of Trypanosoma brucei, is thus obtained in 41 % yield. [16]

Based on the concept of armed and disarmed glycosyl donors, the trisaccharide 23 can be constructed very elegantly from the two CDA-protected rhamnosides 6b and 6d

D. General Methods and Reagents

228

in a one-pot reaction similar to the ciclamycin trisaccharide synthesis [17] in two steps as follows: [18] The IDCP-catalyzed condensation of armed thiorhamnoside 21 and disarmed glycosyl acceptor 6d yields as intermediate a disaccharide that reacts immediately without further purification with the CDA derivative 6b under NIS activation to form 23 (62%). The disaccharide 22 is also found as by-product (10 %), which arises in the second glycosylation step from unconverted 21 and added 6b. The final deblocking of saccharide 23 furnishes the Streptococcus antigen trisaccharide 24 (Scheme 7). In particular, the examples given in Schemes 6 and 7 for the application of Dispoke and CDA groups in oligosaccharide synthesis demonstrate magnificently that with these novel protecting groups complex sugars can

&H Me0

R

SEt

B

OH

6b R=OMe

6d R=SEt

n

O

d OBn

21

Y

&+ 0

Me0

BnO

0

Me0

I

I

OBn

22 (10%)

J

23 (62%)

a-L-Rhap(l - + P ) - a - ~ - R h a p (-Z)-a-L-Rhap(l l -0Me)

24 (53%)

Scheme 7.

References [I] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Chemistry, 2nd Ed., J. Wiley, New York, 1991; P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994. [2] S. V. Ley, M. Woods, A. Zanotti-Gerosa, Synthesis 1992, 52-54. [3] S. V. Ley, H. W. M. Priepke, S. L. Warriner, Angew. Chemie 1994, 106, 2410-2412. [4] S. Gohsal, G. P. Luke, K. S. Kyler, J. Org. Chem. 1987,52,4296-4298. [5] S. V. Ley, R. Leslie, P. D. Tiffin, M. Woods, Tetrahedron Lett. 1992, 33, 476774770, [6] J. J. Oltvoort, M. Klosterman, J. H. van Boom, R e d . Trav. Chim. Pays-Bas 1983, 102, 501505. [7] G.-J. Boons, D. A. Entwistle, S. V. Ley, M. Woods, Tetrahedron Lett. 1993, 34, 56495652. [8] R. Downham, K. S. Kim, S. V. Ley, M. Woods, Tetrahedron Lett. 1994, 35, 769-772. [9] P. J. Edwards, D. A. Entwistle, S. V. Ley, D. Owen, G. Visentin, Tetrahedron Lett. 1994,35, 777-780. [lo] S. V. Ley, R. Downham, P. J. Edwards, J. E. Innes, M. Woods, Contemp. Org. Synth. 1995, 2, 365-392; and references cited therein. [ l l ] S. V. Ley, G.-J- Boons, R. Leslie, M. Woods, D. M. Hollinshead, Synthesis 1993, 689-692. [ 121 A. B. Hughes, S. V. Ley, H. W. M. Priepke, M. Woods, Tetrahedron Lett. 1994, 35, 773-776. [13] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 1985, 97, 1-3 1. [14] C. Genicot, S. V. Ley, Synthesis 1994, 1275. [I51 B. Fraser-Reid, U. E. Udodong, Z. Wu, H. Ottoson, R. Merritt, C. S. Rao, C. Roberts, Synlett 1992, 927-942; G. H. Veeneman, J. H. van Boom, Tetrahedron Lett., 1990, 31, 275 -278.

I ddoMe 24

1) 6d + 21, IDCP 2) + 6b, NIS,TfOH OMe

be synthesized very efficiently. This was also recently demonstrated for the elegant synthesis of nonasaccharide fragments related to glycoproteins. [19] The Dispoke and CDA acetals should therefore rapidly become standard practice in carbohydrate chemistry.

The Selective Blocking of trans-Diequatorial, Vicinal Diols [16] G.-J. Boons, P. Grice, R. Leslie, S. V. Ley, L. L. Yeung, Tetraheron Lett. 1993, 34, 8523-8526. [17] S. Raghavan, D. Kahne, J. Am. Chem. Soc. 1993,115, 1580-1581.

229

[18] S. V. Ley, H. W. M. Priepke, Angew. Chem. 1994,106,2412-2414. [19] P. Grice, S. V. Ley, J. Pietruszka, H. M. I. Osborn, H. W. M. Priepke, S. L. Warriner, Chem. E m J. 1997, 3, 431-440; and references cited therein.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Oxidative Polycyclization Versus the “Polyepoxide cascade”: New Pathways in Polyether (Bio)synthesis? Ulrich Koert

In 1983, Cane et al. postulated that polyether biosynthesis takes place as a two step process. The first of these steps was proposed to be the enzymatically polyepoxidation of an acyclic hydroxypolyene precursor, and the second comprised a cascade of intramolecular epoxide ring openings with formation of the polyether frame work. [l] For monensin A (3), for example, this is shown in Scheme 1: the (E,E,E)-triene 1 is transformed biosynthetically into the tris-epoxide 2, which reacts further in a cascade of epoxide ring openings to yield the natural product 3. [2] This biosynthetic scheme gained rapid acceptance, above all because of the elegance of the second step, the “polyepoxide cascade”. Polyepoxide cascades of the type 2 -+ 3 were reproduced in the laboratory [3] and used as key steps in the synthesis of polyethers. [4] The first step in the Cane-Celmer-Westley hypothesis, the stereoselective epoxidation, was subject to far less attention, even though it may be regarded as a weak point in the hypothesis. In feeding studies with Streptomyces cinnamonensis, no conversion of the (E,E,Ep)-triene 1 to monensin A (3) could be detected. [5] Earlier labeling studies had shown merely that the oxygen atoms in two tetrahydrofuran rings (0-7,8) and in the tetrahydropyran hemiacetal (0-9) were derived from molecular oxygen, and it was unclear

whether these were incorporated by epoxidation or by another oxidation process. [2] Although the second step of the the Cane-Celmer-Westley hypothesis, the polyepoxide cascade, is compelling, the initial, polyepoxidation step is still not sufficiently proven experimentally, and hence the entire hypothesis is uncertain. McDonald and Towne [6] extended studies of Townsend and Basak, [7] and presented an alternative model to the Cane-Celmer-Westley hypothesis: syn-oxidative polycyclization. The Townsend-Basak-McDonald hypothesis for the biosynthesis of monensin A (3) is depicted in Scheme 2. The starting point is the alkoxy-bound 0x0 metal derivative of a (Z,Z,Z)-triene 4. Intramolecular [2+2] cycloaddition affords a metallaoxetane 5, [8] and the first tetrahydrofuran ring is then closed by reductive elimination of the metal to form compound 6. An oxidation step from 6 to 7 activates the alkoxy bound metal for the next [2+2] cycloaddition (7 -+ 8). Reductive elimination of the metal with closure of the second tetrahydrofuran ring leads to the compound 9. The third tetrahydrofuran ring of monensin A is closed in a further, analogous oxidative cyclization sequence (9 -+ 10 + 11 -+ 12). From compound 12 the natural product can be obtained via the intermediate 13. The stereochemical

Oxidative Polycyclization Versus the “Polyepoxide cascade ”:New Pathways in Polyether

HO

1. Ib

HO

monensin A

Scheme 1. The Cane-Celmer-Westley hypothesis for the biosynthesis of monensin A (3); (a) stereoselective epoxidation; (b) polyepoxide cascade; it is assumed that the OH group at C(26) is also introduced during the epoxidation step.

course of the oxidative cyclization should be emphasized: because a [2+2] cycloaddition is involved, the two oxygen atoms are added to the double bond in a syn configuration. In order to construct the correct stereochemistry for the polyether framework of monensin A (3), the Townsend-Basak-McDonald hypothesis therefore postulates a (Z,Z,Z)-triene 4 as a biosynthetic precursor.

23 1

Using more simple systems, McDonald and Towne were able to demonstrate that pyridinium chlorochromate (PCC) is a suitable reagent for carrying out syn-oxidative polycyclizations (Scheme 3). [6] Thus, transformation of the (a-hydroxydiene 14 yielded the bis-tetrahydrofurans 15 and 16. Starting with the (E)-hydroxydiene 17, the bis-tetrahydrofurans 18 and 19 were obtained. The formation of 15 and 16 from the (Z)diene and of 18 and 19 from the (E)-diene support the assumption of a syn-oxidative mechanism. The authors present conformationalanalysis arguments to explain the preferred formation of the trans-tetrahydrofurans 15 and 18. [6] The low yields attained for the reactions shown in Scheme 3 call into doubt the usefulness of the syn-oxidative polycyclization under the published PCC-conditions for preparative purposes. However, the palette of possible oxidation reagents is by no means exhausted by PCC. Valuable ideas for a solution of the problem come from the work of Kennedy et al. with Re207 as an oxidizing agent for oxidative olefin cyclization. [6] As shown in Scheme 4 Keinan et al. [lo] applied Re207 successfully in an iterative oxidativeolefin-cyclization sequence leading to oligotetrahydrofurans (20 + 21 + 22). A fully satisfying answer to the question of the biosynthesis of polyether compounds such as monensin A (3) cannot be given from the results described here. However, it is clear that the new the Townsend-Bas&-McDonald hypothesis has gained ground on the older Cane-Celmer-Westley hypothesis. A key experiment to test the Townsend-Basak-McDonald hypothesis will be the use of labeled (Z,Z,Z)-triens of type 4 in feeding experiments with Streptomyces cinnamonensis.

HO

7

a

HO

0

M*'.

'%.

I....

C

0

0-yo

-)-(+$-

C

b

Hd

.

I

9

I 3

a

P

N

w

p3

Oxidative Polycyclization Versus the “Polyepoxide cascade”: New Pathways in Polyether

14

15

11 : 1

16

18

3.7 : 1

19

233

PCC HOAc 19 Yo

17

Scheme 3. Model reactions of the Townsend-Basak-McDonald hypothesis using PCC as the oxidizing agent.

H5106

53% 22

Scheme 4. Use of Re207 in an oxidative-olefin-cyclization sequence.

References [ I ] D. E. Cane, W. D. Celmer, J. W. Westley, J. Am. Chem. SOC.1983, 105,3594-3600. [2] J. A. Robinson, Prog. Chem. Org. Nat. Prod. 1991,58, 1-81. [ 3 ] a) W. C. Still, A. G. Romero, J. Am. Chem. SOC.1986, 108, 2105-2106; b) S. L. Schreiber, T. Sammakia, B. H u h , G. Schulte, ibid. 1986, 108, 2106-2108; c) S. A. Russell, J. A. Robinson, D. J. Williams, J. Chem. Soc. Chem. Commun. 1987, 351-352.

[4] For representative examples see: a) T. R. Hoye, J. C. Suhadolnik, J. Am. Chem. SOC. 1985, 107, 5312-5313; b) K. Nozaki, H. Shirama, Chem. Lett. 1988, 1847; c) I. Paterson, R. D. Tillyer, J. B. Smaill, Tetrahedron. Lett. 1993, 34, 7137-7140; d) U. Koert, H. Wagner, M. Stein, ibid. 1994, 35, 7629-7632. [S]D. S. Holmes, J. A. Sherringham, U. C. Dyer, S. T. Russell, J. A. Robinson, Helv. Chim. Acta 1990, 73, 239-259: the authors point

234

D. General Methods and Reagents

out that solubility problems may have played a role in the failure of the labeling experiment. [6] F. E. McDonald, T. B. Towne, J. Am. Chem. SOC. 1994, 116,7921-7922. [7] C. A. Townsend, A. Basak, Tetrahedron, 1991, 47,2591-2602. [8] Metallaoxetanes have not yet been directly identified. Their role as intermediates in oxida-

tive processes is however the subject of intensive discussion: K. A. Jorgensen, B. Schiott, Chem. Rev. 1990, 90, 1483-1506. [9] S. Tang, R. M. Kennedy, Tetrahedron Lett. 1992,33, 5303-5306. [lo] S . C. Sinha, A. Sinha-Bagchi, E. Keinan, J. Am. Chem. SOC.1995, 117, 1447-1448.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Radical Reactions as Key Steps in Natural Product Synthesis Ulrich Koert

Radical reactions have developed into indispensable methods in organic synthesis [ I] and are often used as key steps in the construction of complex natural products. Impressive demonstrations are found in the following examples taken from the current literature: the dactomelyne synthesis by Lee et al., [2] the camptothecin synthesis by Curran et al., [3] and of (7)-deoxypancratistatin by Keck et al., [4] and the approaches towards aspidospermidine by Murphy et al. [5] and pseudopterosine A by Schmalz et al. [6]. The total synthesis of the marine natural product (33-dactomelyne (1) requires the elaboration of the cis-linked pyranopyran skeleton and the stereoselective introduction of halogen atoms on the tetrahydropyran rings. Lee et al. [2] solved this problem by using of p-alkoxy-acrylates twice as radical acceptors (Scheme 1). A radical cyclization of the trichloro compound 2 afforded the bicyclic product 3. The selective monodehalogenation of the dichloro compound 3 giving 4 was accomplished with a radical reaction as well. Important for the desired stereoselectivity was the use of the silane (Me3Si)&H. Stannanes like nBu3SnH gave the other epimer 5 as the major product. The highlight of the synthesis was the construction of the second tetrahydropyran ring and simultaneous stereoselective

introduction of the bromo-substituted stereocenter: the radical reaction of P-alkoxy-acrylate 6 with n-Bu3SnH gave exclusively the desired bicyclic product 7. The authors propose a chairlike transition state 8 to explain the observed stereoselectivity. The bicyclic product 7 was converted in few steps into the target compound (3Z)-dactomelyne (1). The potent antitumor agents camptothecin (11) and its derivatives are targets of extensive synthetic activities. [7] A major contribution to this research area came from the laboratory of D. P. Curran [3] in Pittsburgh with a total synthesis of camptothecin relying on radical chemistry. In the key step of his synthesis (Scheme 2) the iodoalkyne 9 was allowed to react with phenyl isonitrile to provide the target compound 11. In this radical cascade reaction, an excellent example of a “sequential-reaction”, [8] the simultaneous construction of the B- and Crings of camptothecin was accomplished. The mechanism for this radical reaction is best explained by the transformation of the structurally less complex bromoalkyne 12 into the tetracyclic compound 17. First, a trimethylstannyl radical produced from hexamethyldistannane attacks the C-Br bond of compound 12. The resulting pyridone radical 13 reacts intermolecularly with the isonitrile 10 to yield the radical intermediate 14. An intra-

D, General Methods and Reagents

236

(32)-dactomelyne (1)

c-Hex3SnH AlBN

'!

67%

M e 0 2 C

?0 kc a

ph

T

3 Z

T H P

h

___)

Me02C

(Me,Si),SiH,

4

98%

Et3B

n-Bu3SnH, AlBN

i 5

13 : 1

1 : 1,6

83%

n-Bu3SnH

-*AlBN

eM? * TBDPSO

75'0

Br

TBDPSO

6

7 CI T

B

D

P

s

o

8

9.!fCOzMe s

B

r

Scheme 1.

molecular attack of the radical center in 14 on The alkaloid pancratistatin 18 isolated from the alkyne functionality leads to radical 15. Amaryllidaceous plants displays promising Finally, the A-ring is attacked by the radical antineoplastic and antiviral activity. [9a] The center in 15 leading to 16, which rearomatizes (7)-deoxy compound 19 exhibits both better therapeutic properties and decreased toxicity. to the desired compound 17.

Radical Reactions as Key Steps in Natural Product Synthesis

237

MeaSnSnMeB hv, 70 OC 63%

OH

OH

9

carnptothecin (11)

PhNC 10 Me3SnSnMe3 hv, 80 OC 40%

t

17

12

+ Me3Sn*

- MeaSnBr

phNcl 13

10

14

-H*

16

t 15

Scheme 2.

[9b] The group of G. E. Keck [4] successfully the conformational control dictated by the completed the total synthesis of (7)-deoxy- tert-butyldimethylsilyl (TBDMS) protected pancratistatin (19) using a radical reaction as six-membered lactol ring. Compound 22 was then transformed in few standard steps into a key step (Scheme 3). Here, the radical precursor 20 was treated the target compound 19. with nBu3SnH to yield the benzyl radical 21, J. A. Murphy et al. [5] were able to show which reacted further by a 6-exo-cyclization the synthetic potential of radical reactions in to the cyclohexylamine 22. Important for the a short and efficient synthesis of the ABCE excellent stereoselectivity of this step was ring system of aspidospermidine (23)

238

D. General Methods and Reagents

pancratistatin (18, R = OH)

7-deoxypancratistatin (19, R = H)

OMOM

9MOM TBDMSO

H“*OBn

0

0

20 0

f

n-Bu3SnH

N q

70%

OMOM TBDMSF:~

“OBn

0 L O

21

(Scheme 4). They used a tandem radical cyclization to directly convert the aryl iodide 24 into the tetracycle 25. The mechanism of this reaction sequence was rationalized as follows: A silyl radical produced from (MesSi)3SiH attacks first the aryl iodide bond in 24 forming the aryl radical 26. Intramolecular attack of the radical center in 26 on the double bond then affords the alkyl radical 27. Lastly, addition of this alkyl radical to the azide function followed by loss of N2 gives the observed product 25 via the N-radical intermediate 28. The high stereoselectivity and the excellent yield of this tandem radical cyclization is noteworthy.

Scheme 3.

New perspectives are opened by the combination of radical reactions with organometallic chemistry, as was demonstrated by the group of H.-G. Schmalz from the TU Berlin. [6] In the course of synthetic studies towards Pseudopterosin A (29) and related compounds they succeeded in the SmI2- induced cyclization of the arenetricarbonylchromium-complex 30 to the tricyclic pseudopterosin scaffold 31 (Scheme 5). The authors propose the following mechanism for this reaction: In the first step the ketyl radical 32 is produced, which adds to the arene ring to give 33. A second transfer of one electron by SmI2 affords the anionic

Radical Reactions as Key Steps in Natural Product Synthesis

239

aspidospermidine (23)

1. TTMS, AlBN CBH~, 80 OC, 5h 2.H20

H

Me0$

one stereoisomer only

U

Me02S

25

24

Q..% I H

Me02S

26

&) Y H

6 fN,

Me02S

28

0

Y H Me02S

27

r5 -complex 34. Subsequent protonation yileds r4-complex 35, from which the final product 31 is obtained after elimination of methanol and hydrolytic workup. It should be noted that the pendant trisubstituted double bond does not give rise to any side reactions. The present selection of natural product syntheses with radical reactions as key steps demonstrates the extraordinary potential applications of modern radical chemistry.

Scheme 4.

However, one limitation is evident: four out of the five reaction sequences presented involved an intramolecular cyclization reaction. [ 101 Intermolecular radical bond formations with companally high yields and stereoselectivities are still very rare in the total synthesis of bioactive compounds. One exception is Curran's camptothecin synthesis. However, progress in acyclic stereoselection of radical reactions [ll] should soon help to formulate new solutions for these synthetic challenges.

'9

D. General Methods and Reagents

240

-OH

OH

OH

pseudopterosin A (29)

2.5 equiv. Sml2

THF, HMPT t-BUOH 70 %

I

30

'

32

..0Sm12 '% & ' OMe

t

t

Yosm'2

'

31 H20

- MeOH

35

Sm12

Scheme 5.

Radical Reactions as Key Steps in Natural Product Synthesis

241

References [I] a) B. Giese, Radicals in Organic Synthesis: [7] a) D. P. Curran,J. Chin. Chem. SOC.1993,40, Formation of Carbon-Carbon-Bonds, Perga1; b) U. Koert, Nachr. Chem. Tech. Lab. 1995, mon, Oxford, 1986; b) D. P. Curran in Com43, 686. prehensive Organic Synthesis, Vol. 4 (Eds.: [8] L. F. Tietze, U. Beifuss, Angew. Chem. 1993, B. M. Trost, I. Fleming), Pergamon, Oxford, 105, 137; Angew. Chem. Int. Ed. Engl. 1993, 1991, p. 779; c) D. P. Curran, N. A. Porter, 32, 131. B. Giese, Stereochemistry of Radical Reac[9] a) G. R. Pettit, V. Gaddamidi, G. M. Cragg, tions, VCH, Weinheim, 1996. J. Nut. Prod. 1984, 47, 1018; b) S. Ghosal, S . Singh, Y. Kumar, R. S . Srivastava, [2] E. Lee, C. M. Park, J. S. Yun, J. Am. Chem. Phytochemistry 1989, 28, 61 1. SOC.1995,117, 8017. 131 a) D. P. Curran, S.-B. KO, H. Josien, Angew. [lo] D. P. Curran, J. Xu, E. Lazzarini, J. Am. Chem. Chem. 1995, 107, 2948; Angew. Chem. Int. SOC.1995,117,6603. Ed. Engl. 1995, 34, 2683; b) D. P. Curran, [ l l ] a) W. Smadja, Synlett 1994, 1; b) W. Damm, J. Dickhaut, F. Wetterich, B. Giese, TetraH. Liu, J. Am. Chem. SOC. 1992,114, 5863. hedron Lett. 1993, 34, 431; c) N. A. Porter, [4] G. E. Keck, S . F. McHardy, J. A. Murry, J. Am. B. Giese, D. P. Curran, Acc. Chem. Res. Chem. SOC.1995,lI 7,7289. 1991, 24, 296; d) P. Renaud, M. Gerster, [5] M. K i d , J. A. Murphy, J. Chern. Soc., Chem. J. Am. Chem. SOC.1995,117,6607. Commun. 1995, 1409. (61 a) H.-G. Schmalz, S. Siegel, J. W. Bats, Angew. Chem. 1995, 107, 2597; Angew. Chem. Int. Ed. Engl. 1995,34,2383.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Light-Directed Parallel Synthesis of Up to 250 000 Different Oligopeptides and Oligonucleotides Giinter von Kiedrowski

The development of enzyme inhibitors based the desired binding properties have already on oligopeptides makes it imperative to pre- been honored in a Highlight [ 3 ] . Recently Fodor et al. described a chemical pare a daunting number of oligopeptides with different sequences and to test their binding method for irrational drug design. [4] A comproperties in order to find an optimally bind- bination of three processes - solid-phase synthesis, photolithography, and affinity labeling ing ligand. Even if we restrict ourselves to the twenty - makes it possible to lay down next to each naturally occurring amino acids, 202 = 400 other up to 250 000 different oligopeptides or dipeptides, 203 = 800 tripeptides, and in gene- oligonucleotides per square centimeter on a ral 20”’ oligopeptides of length N are possible. glass slide and to test their binding to a given A systematic testing of all sequence alterna- receptor molecule. The principle of phototives with conventional techniques is already lithographic solid-phase synthesis is shown out of the question with tetrapeptides in Figure 1 for the example of the parallel con(160 000 compounds). Molecular modeling struction of two dipeptides from two amino and quantitative structure-activity relation- acids. The glass surface is first treated with 3 ships rule out many sequence alternatives based on a known guide sequence, but for a (aminopropy1)triethoxysilane and then the “rational drug design” [l] in the true sense, a free amino groups, now bound to the glass three-dimensional structure of the receptor surface by a C3 spacer, are protected with must be known. The prerequisite for “irratio- a nitroveratryloxycarbonyl (NVOC) group nal drug design” [2] (i. e., the filtering out of (Step I), which can be photochemically rebinding sequences from the pool of statistical moved. On illumination (Step 11) only those sequences) is the ability to isolate the best NVOC groups that are not covered by an ligand in pure form and in high enough quan- opaque mask are removed. The irradiated tities for a structure determination - or it must amino groups on the surface (field A) are now be possible to raise the concentration to the acylated with the first amino acid, which is required level. This last criterion restricts irra- protected by NVOC and is activitated as its tional drug design largely to biopolymers that 1-hydroxybenzotriazol (HOBt) ester (Step 111). can be cloned (e. g., antibodies) or replicated Field A is now masked, and field B exposed in vitro (nucleic acids). Such attempts to to light and thereafter acylated with the second select and amplify biomolecules possessing amino acid, thus completing the first phase

Light-Directed Parallel Synthesis of Up to 250 000 Different Oligopeptides

. . . 1. H x N - ( C H p ) ~ - S i O E ~ 2. Nvoc-CI I

- ,

.

NH-NVOC

HB-NVOC

(A)

(B)

243

1

Figure 1. Light-directed parallel synthesis of two dipeptides from two amino acids in two irradiation fields.

of the synthesis (Step IV). Further analogous irradiation and coupling steps construct the dipeptides in the second phase (Step V). In practice strips of the surface are exposed in each photolysis and coupling round of the synthesis. The strips irradiated in the next round lie perpendicular to those of the preceding round. This corresponds to oligopeptide construction in the rows and columns of a square matrix and enables a considerably shorter synthesis than were possible with successive illumination of each field. The shortest synthesis is achieved with the binary masking technique, in which the direction of the strip is changed in every cycle and its width is reduced to half every second cycle, while the number of strips in the mask is doubled. In this way, with n synthesis cycles 2” different oligomers can be constructed, whose lengths are described by a binomial distribution (combinatorial synthesis). Ten synthesis cycles, for example, yield 1024 (minus 1) different peptides with “1 of length 0”, and successively 10, 45, 120, 210, 252,

210, 120, 45, and 1 with lengths 1-10. Each peptide sequence is situated at one field of the (32 x 32) matrix. The last irradiation step removes the N-terminal NVOC groups of all peptides; other deprotecting steps may be necessary to free the funtional groups in side chains. For the affinity test the glass slide is simply held in a solution of the fluorescence-labeled receptor, rinsed, and scanned under the fluorescence microscope. The affinity of a peptide for a given receptor is determined from the fluorescence intensity of the corresponding field in the array. The authors demonstrated the whole process on a combinatorial synthesis of 1024 peptides, whose binding to the antibody 3E7 was to be tested. The 15 peptides with clearly recognizable affinity all begin with the sequence 5 ‘-H2N-Tyr-Gly.This result agrees with those by Cwirla et al., who claim an N-terminal tyrosine residue as the key determinant in the binding to 3E7. [5] As light source, the authors used a mercury arc lamp, that required an exposure of 20 min

244

D. General Methods and Reagents

at A = 365 nm and 12 mWcm-2. Shorter exposure times should be possible with an argon laser. To prevent excitation at aromatic side chains and, in particular, a photochemical decomposition of tryptophan, shorter wavelengths are not recommended. The total yield per synthesis cycle (irradiation and coupling) lies between 85 and 9 5 % , so that for oligopeptides with more than ten amino acids the process only makes sense in exceptional cases. With mask technology a resolution of > 20 pm2 per synthesis field can be achieved; thus with 50 pm2 elements, 250 000 syntheses can be addressed on a glass cover slide for microscopy. The authors show that their process is not only restricted to oligopeptides, but can also be applied to lightdirected oligonucleotide syntheses, in which case 5’-NVOC-protected nucleoside-3’-cyanoethylphosphoramidites are suitable monomeric building blocks. Three critical questions must, however, be answered experimentally before a general application to affinity studies is recommended:

1. Does the carrier-bound oligopeptide have the same conformation as in solution? 2. Which spacer can be used as alternative to a C3 chain, so that a large proportion of biological receptors can bind unhindered? 3. Can the yields of the synthesis cycles be improved, for instance, by the use of other protecting groups? We wait in suspense for a report in the near future that the authors can suggest a solution to these problems. If this is the case it is foreseeable that light-driven parallel synthesizer machines, similar to the present peptide and DNA synthesis machines with soon revolutionize many university and pharmacetical research laboratories. The site of the Affymax Research Institute of the authors in “Silicon Valley” will, of course, not hinder the development of the first prototype of the commercial machines.

References [I] H. Friihbeis, R. Klein, H. Wallmeier, Angew. Chem. 1987, 99, 413; Angew. Chem. Int. Ed. Engl. 1987,26, 403. [2] The term “irrational drug design” was recently proposed by S. Brenner at a symposium on natural and artificial selection processes (Max-Planck-Institut fur Biophysikalische Chemie, Gottingen, 17th-19th April 1991). In contrast to “rational drug design”, in which more or less detailed knowledge about the receptor, the ligands, and their interaction is available and does influence the development of better ligands, “irrational drug design” embodies attempts in the face of a void of knowledge in which a large repertoire of ligands are tested blindly. [3] A. Pliickthun, L. Ge, Angew. Chem.,1991 103, 301; Angew. Chem. Int. Ed. Engl,1991, 30, 296. [4] S . P. A. Fodor, J. L. Read, M. C. Pirrung, L. Stryer, A. T. Lu, D. Solas, Science 1991, 251, 767. [5] S. E. Cwirla, E. A. Peters, R. W. Barret, W. J. Dower, Proc. Natl. Acad. Sci. USA 1990, 87, 6378.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann CoovriahtO WILEY-VCH Verlaa GmbH.1998

Opportunities for New Chemical Libraries: Unnatural Biopolymers and Diversomers Rob M . J. Liskarnp

The solid-phase methodology for the synthesis of biopolymers is nowadays indispensable in chemistry, pharmacology, immunology, biology, physiology and biophysics. Using this fantastic tool, [l] it is not only possible to prepare (large) peptides in a (semi)automatic manner in which amino acids and other reagents are added, and excess of reagents and waste are removed (without the tedious purification of intermediates), but this methodology has also been successfully applied to the synthesis of nucleic acids and recently carbohydrates. [2,3] Once developed the next logical step was the adaptation of the efficient solid-phase methodology to the simultaneous synthesis of several peptides. This led to the development of several multiple peptide synthesis strategies with a large range of applications. [4] A significant step further were the peptide libraries, for example, aimed at the systematic synthesis of many - if not all possible peptides of a certain lenth. When each amino acid residue is one of the 20 proteinogenic L-amino acids, there are 400 possible dipeptides, 8000 possible tripeptides etc. in a library: with each amino acid increment the number of peptides increases 20 -fold. However, there will be intrinsic difficulties in preparing and handling such large libraries, [4] in addition to difficulties in identification, selection, and enrichment of promising com-

pounds from a library. In order to facilitate identification and enrichment, encoded libraries might be very interesting. In one type of these libraries a chemically synthesized entity, for example a peptide, is linked to a particular oligonucleotide sequence. It is proposed that the use of the encoding genetic tag should serve to identify and to enrich to promising compounds from the library. [5,6] Peptide libraries are undeniably useful in the discovery of chemical lead compounds. However, the chemical lead discoveries from these libraries still require extensive modifications before suitable drug candidates are produced. This is due to the disadvantages of peptides, such as their water solubility and in many cases their facile degradation by proteases, which limit their use in biological systems. Therefore the results described by Cho et al. and Hobbs DeWitt et al. were the next significant steps on the way to new libraries, [7,8] which first may - to a certain extent - circumvent these disadvantages, second provide lead compounds, possibly requiring less extensive modifications, and third may provide new frameworks for generating macromolecules with novel properties. Cho et al. described the principles of the solid-phase synthesis of an oligocarbamate as well as the generation of an oligocarbamate library. [7] This oligocarbamate was referred

D. General Methods and Reagents

246

to as “an unnatural biopolymer”, [9] “unnatural” because it is obviously not found in nature and “biopolymer” to hint at the origin of the monomers which were derived from proteinogenic amino acids. The term “biopolymer mimetic” is perhaps a better alternative, as “unnatural biopolymer” is a contradiction in itself. The monomeric, N-protected aminoalkylcarbonates were conveniently prepared from the corresponding N-protected amino acids or from amino alcohols derived from amino acids (Scheme 1). By using the baselabile Fmoc-protecting group, an oligocarbamate was synthesized by standard solidphase methods; the coupling yields were great-

LOH -Aminooralcohol PG-v R’

er than 99% per step. Even more interesting was the use of the photolabile nitroveratryloxycarbonyl (Nvoc) amino-protecting group (Scheme 1). This enabled the authors to prepare a library containing 256 oligocarbamates, by employing a binary masking strategy as was described by Fodor et al. in their lightdirected parallel synthesis of libraries of oligopeptides and oligonucleotides. [ 101 The library contains all of the compounds that can be formed by deleting one or more carbamate units from the parent sequence Ac-TyrCPhec-AhC-Sef-Lysc-IleC-PheC-Leu“ (the superscript “c” indicates the presence of a carbamate linkage). The library was attached to

Amino acid

ti

LJ

Me0 OMe

R’ = CH2CH(CH& RZ= Bn R3 = (CH&-NH2

Ac-LysC-PheC-LeuC-GIy-OH

one of 256

0 R

AT

-

R‘ = a.0. Ph, Chx R

N

R5=H.Me R6 = a.0. H. CI, NOp

R‘ array of 40

Scheme 1. Solid-phase synthesis of oligocarbamates and benzodiazepines starting with a resin-bound amino acid. The Fmoc-protected 4-nitrophenyl carbonate monomers derived from amino acids or amino alcohols were used in a normal solid-phase synthesis of an oligocarbamate, whereas the corresponding Nvoc-protected monomers were used in the generation of a library of 256 oligocarbamates of which is shown. An array of 40 diazepines was synthesized by one representative (Ac-Lysc-Phec-Leuc-Gly-OH) reacting the resin-bound amino acid with eight different 2-aminobenzophenone imines followed by cyclization. Ind = indolyl, Chx = cyclohexyl.

Opportunities for New Chemical Libraries: Unnatural Biopolymers and Diversomers

247

a glass surface of approximately 1.3 cm by compounds, which will be structurally more 1.3 cm and screened for its ability to bind a related to the ultimate drug, since lead commonoclonal antibody against Ac-TyrC-LysC- pounds discovered from peptide or nucleotide PheC-LeuC.It was found that the oligocarba- libraries still require extensive modifications mates Ac-Lysc-PheC-Leuc-Gly-OH(Gly is the (vide supra). Another equally important realinker in the keyhole limpet hemocyanin con- son is to rapidly obtain a large library of orjugate of this oligocarbamate), Ac-PheC-LysC- ganic compounds (comparable to an in-house Phec-Leu“-Gly-OH, Ac-Tyf-Lysc-Phec-Leuc- sample collection of a pharmaceutical company), which can be offered to the often Gly-OH, Ac-AlaC-Lysc-PheC-Leuc-Gly-OH, and Ac-Ilec-Phec-Leuc-Gly-OH were among automated, fast high throughput biological the ten highest affinity ligands based on fluo- screening assays. In contrast to the well-known procedure in rescence intensities. Competitive enzymelinked immunosorbent assay experiments in which polyethylene rods or pins were used as solution using the free oligocarbamates result- a solid support for multiple peptide synthesis ed in ICSOvalues between 60 and 180 nM. It in the “PEPSCAN’ method, [4, 121 hollow was therefore suggested that the dominant pins, ending in a glass frit were used, each epitope of the antibody was Phec-Leu“. Alt- containing approximately 100 mg resin to hough, Ac-Tyf-PheC-LeuC-Gly-OH contain- which a Fmoc amino acid was attached by a ing this epitope did bind in solution with an linker. The removal of the Fmoc-group from ICSOvalue of about 160 nM, the fluorescence eight amino acid resins and treatment of each signal associated with this oligocarbamate on resin with five different isocyanates followed the solid support, that is the glass surface in by cyclization led to 39 of the 40 desired the library, ranked in the bottom 30%. This hydantoins in 4-81 % yield. Similarly, by suggests that the conformation of the oligo- starting from Boc-protected amino acid Mercarbamate on the solid support may be dif- rifield resins (five), 40 different benzodiazepines were synthesized by reacting with ferent from that in solution. 1111 Although the oligocarbamate differs signi- eight different 2-aminobenzophenone imines ficantly from the corresponding polypeptide, followed by cyclization (Scheme 1). The 40 for example, it is more extended (that is there products were obtained in 9-63 % yield and are four atoms located between the side chains their purity was typically > 90 % (determined instead of two atoms as in a peptide), some by ‘H-NMR spectroscopy). These compounds inherent disadvantages of peptides seem to were then used in an assay for inhibition of be less pronounced in oligocarbamates: a) fluoronitrazepam. A report by Bunin and the oligocarbamates are significantly more Ellman had earlier described the solid-phase hydrophobic, as was determined from a com- synthesis of ten benzodiazepine derivatives parison of the water/octanol partitioning coef- using an alternative approach. [ 131 An important message from the reports is ficients ; b) the oligocarbamates are resistant that the authors were able - by carrying out to degradation by trypsin and pepsin. Contrary to the Berkeley and Affymax synthesis on a solid support - to prepare an report, the diversomer paper by Hobbs DeWitt array of unnatural compounds, which can be et al. placed no emphasis on the preparation of used for screening purposes to discover new an oligomer library but focussed entirely on lead compounds. These lead compounds may the generation of a library of diverse, albeit then be closer to ultimate drugs, because related, organic compounds called “diverso- they are obtained from an array of compounds mers”. [8] An important reason for the cre- further removed from natural systems such as ation of these libraries was to discover lead peptides and nucleotides.

248

D. General Methods and Reagents

Using the solid-phase strategy also libraries more accurately defined, for example, by of other biopolymer mimetics have become introducing rigid monomers at different loaccessible, for example, oligoureas, oligo- cations in an oligomer. This is noteworthy, sulfones, peptidosulfonamides, [ 141 peptido- since there is ample evidence in the literature phosphoramidates, and peptoids (Scheme 2). that in many cases merely the presence of [ 151 These compounds will undoubtedly functional groups delivered, for example, by provide new biologically active compounds an amino acid sequence is not sufficient for and also opportunities for the construction of an optimal biological activity, but that a proper orientation of functional groups is essentbiopolymers with novel properties. The diversomer library showed that an ial too. [16] In addition, the conformation on array of organic compounds can be synthe- the solid support of the library may be difsized, and, although the number was much ferent from that in solution (vide supra), smaller than that which can be achieved by wich may diminish the reliability of a library most of the current methods for generating for the selection process. This underlines the peptide and other libraries, a significant num- importance of creating library compounds ber of structural analogues was obtained in a with defined conformations that are similar if faster way than was the case when each of not identical in different environments. the compounds was synthesized separately. The scientist has an innate desire to be able Another challenge is still the development to rationally design a compound with a preof "conformationally restricted" libraries in dicted (biological) activity. Computer-assisted which the conformation of an oligomer is molecular modeling techniques, X-ray crys0 R I H

R'

H

0

R 3 H

0

1

2

R'

H

0

5

R3 4

H

0

R' 0.0

7

Scheme 2. A peptide (l),the comesponding oligocarbamate (2), oligoureas (3 and 4), peptoid (5),peptidosulfonamide (6), and oligosulfone (7).

Opportunities for New Chemical Libraries: Unnatural Biopolymers and Diversomers

tallographic analysis, and NMR methods have intensified this desire and belief that this should ultimately be possible for all drugs. Nevertheless, many of the current drugs or at least the lead compounds which initiated their development have been obtained by screening approaches, that is, by an “irrational” approach. Although it is expected that the rational design of drugs will remain important, screening approaches have gained momentum, since they contribute to a faster and more direct access to information. Therefore the rational design of irrational screening procedures holds promises for the future, and as a result there will be plenty of opportunities for the creation and applications of new libraries. [ 171

References [ l ] R. B. Memfield, J. Am. Chem. SOC. 1963, 85, 2149; Angew. Chem. 1985, 97, 801; Angew. Chem. Int. Ed. Engl. 1985,24, 799. [2] For a review: S. L. Beaucage, R. P. Iyer, Tetrahedron 1993,48,2223. [3] R. Verduyn, P. A. M. van der Klein, M. Douwes, G. A. van der Marel, J. H. van Boom, Recl. Trav. Chim. Pays-Bas 1993, 112, 464; S. J. Danishefsky, K. F. McClure, J. T. Randolph, R. B. Ruggeri, Science 1993, 260, 1307; S. P. Douglas, D. M. Whitfield, J. J. Krepinsky, J. Am. Chem. SOC.1991, 113, 5095; G. H. Veeneman, R. M. Liskamp, G. A. van der Marel, J. H. van Boom, Tetrahedron Lett. 1987, 28, 6695. [4] For a review on multiple peptide synthesis: G. Jung, A, G. Beck-Sickinger, Angew. Chem. 1992, 104, 375; Angew. Chem. Int. Ed. Engl. 1992, 31, 367. [5] S. Brenner, R. A. Lerner, Proc. Natl. Acad. Sci USA 1992, 89, 5381; I. Amato, Science 1992, 257, 330; J. Nielsen, S. Brenner, K. D. Janda, J. Am. Chem. SOC. 1993, 115,9812.

249

[6] For use of halogenated aromatic compounds as encoding tags, see: M. H. J. Ohlmeyer, R. N. Swanson, L. W. Dillard, J. C. Reader, G. Asouline, R. Kobayashi, M. Wigler, W. C. Still, Proc. Natl. Acad. Sci. USA 1993, 90, 1092210926. [7] C. Y. Cho, E. J. Moran, S . R. Cherry, J. C. Stephans, S. P. A. Fodor, C. L. Adams, A. Sundaram, J. W. Jacobs, P. G. Schultz, Science 1993,261, 1303. [8] S. Hobbs DeWitt, J. S. Kiely, C. J. Stankovic, M. C. Schroeder, D. M. Reynolds Cody, M. R Pavia, Proc. Natl. Acad. Sci. USA 1993,90,6909. [9] The antisense oligonucleotides are an earlier category of “unnatural biopolymers“: A. Peyman, Chem. Rev. 1990,90, 543. [ 101 S. P. A. Fodor, J. L. Leighton Read, M. C. Pirrung, L. Stryer, A. T. Lu, D. Solas, Science 1991, 251, 767; a highlight was devoted to this topic: G. von Kiederowski, Angew. Chem. 1991, 103, 839; Angew. Chem. Int. Ed. Engl. 1991, 30, 822. [ 111 This was one of the critical questions raised in the highlight by von Kiederowski [IOJ. [12] H. M. Geysen, R. H. Meloen, S. J. Barteling, Proc. Natl. Acad. Sci. USA 1984, 81, 3998. [13] B. A. Bunin, J. A. Ellman, J. Am. Chem. SOC. 1992, 114, 10997. [14] For example: W. J. Moree, G. A. van der Marel, R. M. J. Liskamp. J. Org. Chem. 1995, 6, 5157; D. B. A. de Bont, G. D. H. Bykstra, J. A. J. den Hartog, R. M. J. Liskamp, Bioorganic. Med. Chem. Lett. 1996, 6, 3035. [15] Peptoids were highlighted by H. Kessler, Angew. Chem. 1993,105,572; Angew. Chem. Int. Ed. Engl. 1993, 32, 543. [16] See for example the review on peptidomimetics: A. Giannis, T. Kolter, Angew. Chem. 1993, 105, 1303; Angew. Chem. Int. Ed. Engl. 1993,32, 1244. [17] A highlight was devoted to the “rationality of random screening”: A. Pluckthun, L. Ge, Angew. Chem. 1991,103, 301; Angew. Chem. Int. Ed. Engl. - 1991, 30, 296.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Reactive Intermediates Henning Hopf

The study of reactive intermediates will always be of prime importance in organic chemistry whether its synthetic, mechanistic or theoretical aspects are involved. And with organic chemistry being the chemistry of carbon compounds the prototype intermediates will always be carbon centered radicals, carbenes, carbanions, and carbocations as well as the numerous small acyclic and cyclic nsystems which form the very basis of the structural and reactive richness of this branch of chemistry. During the last decades the methods for studying reactive intermediates have changed: purely chemical approaches like the isolation or independent synthesis of reactive intermediates or their study by classical kinetic methods - although still of importance -have more and more been replaced by physical and theoreticalkomputational methods. Techniques reaching from the extremely “slow” ones encountered under e. g. matrix conditions at liquid helium temperatures to ultrafast femtosecond spectroscopic methods are having an enormous - and ever growing impact on the study and characterization of reactive intermediates. In fact, the latter techniques make the distinction between reactive intermediates and transition states so fundamental in the introductory teaching of chemistry - more and more meaningless.

Keeping with the title of this volume no attempt is made to present more than a small number of highlights which have appeared during the first half of the present decade. Highlights, though, which illustate some modern trends in “reactive intermediate chemistry” particularly well. Matrix isolation coupled with matrix spectroscopy has been used on numerous occasions to prepare and characterize highly reactive molecules which would be “non-existent” under normal laboratory conditions. A selection from the vast literature includes C402 1, the first dioxide of carbon with an even number of carbon atoms [ 11 and dicarbondisulfide C2S2 2 [2], the longsought diisocyan 3, [3] an isomer of cyanogen first prepared by GayLussac in 1815, and various halogen derivatives of cyclopropylidene 4. [4] When the parent system 4 is irradiated it isomerizes to the allenediradical 5 (“propargylene”), [ 5 ] which - incidentally - is one of the most abundant organic compounds in interstellar

3

4

Reactive Intermediates

space, itself a more and more important “laboratory” for highly reactive compounds. Among the structurally more complex reactive intermediates which have been prepared and spectroscopically characterized in matrix, 2-adamantylidene 6, a singlet carbene, [6] and 2,4-dehydrophenol 7, the first derivative of m-dehydrobenzene [7] should be mentioned. Unfortunately, matrix-isolated species normally cannot be studied by NMR spectroscopy, and hence the chemical shifts of the parent systems, which are of particular importance for comparison with the results obtained by theoretical calculations are unavailable. Substitution by bulky substituents or complexation by (transitions) metals, often used tricks to stabilize highly reactive species, lead to more or less pronounced disturbances of the parent molecules. An elegant esacpe from this dilemma has been accomplished by Cram and co-workers who were able to record the lH-NMR spectrum of 1,3-cyclobutadiene 8, [8] the epitomy of the unstable monocyclic, fully-conjugated n-electron systems, at room-temperature, the vibrational spectra having been recorded in a lowtemperature matrix already many years ago. When a-pyrone 9 is refluxed in chlorobenzene in the presence of the “hemicarcerand” 10 the lactone can slip into the hollow container molecule thus forming the encapsulated system 11. At room temperature, however, the “exits” of the latter are too narrow and do not allow 9 to leave the complex again. h a diation of ll with a xenon lamp first causes electrocyclization to 12 which then splits off carbon dioxide to provide cyclobutadiene in a “molecular prison” 13. According to the ‘H-NMR spectrum the cyclobutadiene in 13 exists as a stable singlet.

-

.

6

YH 7

8

25 1

oo +

11

9

hv

hv_ -coz 13 12

The so-called cryptophanes which are structurally related to 10 have shown to be capable of complexing stable molecules like methane or various fluorocarbons [9] and the number of “fullerenes with a content” - helium, neon, numerous metal ions [ 10,111 is rapidly increasing. Despite all the successes to prepare highly reactive intermediates in matrices, no “hard” structural information, i. e. X-ray structural data can be recorded under these conditions. The time-honored approach to stabilize highly reactive compounds by attaching sterically shielding or electronically stabilizing substituents to them has therefore not lost its attractiveness. This is borne out by the first stable and crystalline carbene 15 which has been prepared by Arduengo et al. by treating the precursor chloride 14 with sodium hydride in tetrahydrofuran in the presence of catalytic amounts of the DMSO-anion [12]. Carbene 15 melts at 240°C; the bonding angle at the carbene carbon center, determined by X-ray structural analysis to 102”, agrees well with the value calculated for z-donor substituted singlet carbenes. The extreme stability of 15 has several origins: the compound is stabilized thermodynamically by the

252

D. General Methods and Reagents

15

14

N-C=C-N fragment which serves as an electron donor and the g-electronegativity of the two heteroatoms. And it profits from the kinetic stabilization provided by the two bulky adamantanyl substituents. Still, these groups are not mandatory as illustrated by the perdeuterio derivative 16 which was shown to be a true carbene with negligible ylidic character by X-ray and neutron diffraction studies. [13] A quantitative study of the influence of sterically demanding substituents demonstrated that dimesitylcarbene 17 is ca. 160 times more stable than diphenylcarbene at room temperature; [ 141 and for didurylcarbene a still further increase of life-time has been observed because of the buttressing effect of the additional methyl substituents. In fact, 17 is so stable that it can be trapped by oxygen to yield the dioxirane 19 in 55 % yield, the first derivative of this three-membered heterocycle which is stable in condensed phase. The 17+ 19 oxidation process proceeds

19

by way of the carbonyl oxide 18, itself stable for several hours in solution at -78 "C. [ 151 Carbonyloxides have been discussed as intermediates in the ozonization of alkenes for a long time; apparently 18 is the first spectroscopically oberservable representative of these highly reactive intermediates. Whereas carbenes of type 17 are singlets the hexabromide 20 is a stable triplet both in solution and in the crystalline state as shown by ESR spectroscopy. Prepared by photolysis of a diazomethane precursor, crystalline 20 is stable for months at room temperature. [ 161 The question of singlet and triplet stability is not only of importance for carbenes but in many other diradicaloid systems as well. Especially triplet states are increasingly studied by material scientists because of the possible ferromagnetism of the appropriate compounds. In photobiology triplets may be involved in the primary steps of the lightinduced charge separation which takes place

20

Reactive Intermediates

253

in the reactions centers of the photosynthesis system. Two of the classical diradicals are 1,3-propanediyl 21 and trimethylenemethane 22 which have often been invoked as intermediates in photochemical and thermal processes. A recent surprising observation by Maier et al. makes these species available under the controlled conditions of a matrix experiment (at 10 K as compared to several hundreds of degrees in e.g. pyrolysis experiments [17,18]. Rather then using a pure noble gas 25 matrix these authors employed a halogendoped matrix. Working under these conditions Turning to carbene related reactive species, led to clean C-C bond cleavage and to the alkylidene carbenoids like 26 (X = halogen, generation of 21 and 22, allowing the registra- OR, NR2) are particularly valuable for pretion of the IR spectrum of the latter species for parative purposes since they can undergo the first time. [18] Diradical 22, the parent cycloaddition reactions with olefins (to system of the non-Kekul6 hydrocarbons, is a methylenecyclopropanes), isomerizations (to ground state triplet which is 110 kJ/mol more alkynes by the so-called Fritsch-Buttenbergstable than its singlet state [19]. Wiechell rearrangement), and dimerization Another classical non-KekulC molecule is (to [3]cumulenes). Although carbenoids have triangulene 23 (“Czar S hydrocabon”); which been studied extensively by NMR spectrosso far has escaped detection. With two half- copy [23], the first X-ray structural analysis filled degenerate molecular orbitals 23 should of a stable carbenoid, 27, as a TMEDA .2THF possess a triplet ground state and be para- complex has been reported only recently [24]. magnetic. As a first derivative of triangulene, the trianion 24 has recently been prepared. cl\ According to its ESR spectrum it is a triplet molecule with threefold symmetry [20]. Non-KekulC structures are of importance for the design of organic ferromagnets. Having prepared a hexacarbene with a tridecet ground state [21] Iwamura and co-workers 26 have now been able to obtain a branched CI nonacarbene, 25, which possesses the record 27 number of 18 unpaired electrons [22].

23

624

254

D. General Methods and Reagents

The carbenoid carbon atom shows interesting rehybridization phenomena which are caused by an increase in both the s-character of the C-Li- and the p-character of the C-X bond. Another class of reactive intermediates that in recent years has enormously profited from the symbiosis of theoretical chemistry and modern physical methods, is carbanion chemistry. A famous case in point is provided by CLi6 or hyperlithiated methane, calculated to possess considerable stability by Schleyer, Pople and co-workers in 1983 (251. Since these calculations are usually carried out for isolated molecules in the gas phase it is obvious to search for them by mass spectrometric measurements. In fact, when crystalline dilithioacetylene is subjected to radio frequency heating in a Knudsen cell and the gas mixture formed is analyzed by quadrupol mass spectrometry besides CLi3 and CLi4 CLi6 could be detected [26]. Whereas this approach clearly does not allow to prepare isolable amounts of poly- or perlithiated hydrocarbons, several preparative methods have been described for the prepartion of perlithiomethane (CLi4), (271 a grey extremely pyrophoric solid. As shown by extensive quantummechanical calculations hyperlithiation is not restricted to “saturated” systems. For example, several isomers of CzLi4 have been calculated whose most stable structure is not ethylenic but shows the typical bonding characteristics of hypermetalated species [28]. X-ray crystallography is by now one of the most important methods for the determination of carbanion structures. From the very large number of recently characterized carbanions only a few can be mentioned here. They include preparatively important species such as the first lithiated carbamide [29], the lithium and tetra-n-butyl ammonium salts of a a-sulfonyl substituted carbanion [30], and a protoype of the synthetically very useful Lochmann bases. [31] On the other hand structural work - both by X-ray crystallography and by various modern NMR spectros-

29

copic techniques - has also been carried out on the theoretically interesting dilithium salt of acepentalene 28 [32] and the tetralithium salt of corannulene 29. [33] That charged species form various types of ion-pairs in solution (solvent separated, solvent shared, and contact ion pairs) has been known for a long time in carbanion (and carbocation) chemistry. That cations and anions of sufficient structural complexity can even penetrate each other has, however, been established only recently. ‘H,’H- and llB,’HNOE measurements on tetra-n-butyl ammonium borohydride show for example that the BH4- anion and the quarternary nitrogen atom of the cation must be in very close contact, i.e. that the anion is positioned between the alkyl chains of the cation (“anion within the cation”). [34] Interpenetration of ions has also been established for 30. The (chiral) cation of this complex has been employed in phase transfer catalysis. It carries the BH4- anion into the organic phase where the former can cause optical induction in reduction reactions. L351 Whereas carbanion chemistry is of large current interest, carbocation chemistry is t

BK

30

Reactive Intermediates

255

nowadays associated largely with the sixties and seventies. Still, in this area of physical organic chemistry interesting results keep to be published. These concern classical carbo34 35 cations or those with novel structures on the one hand and carbocations as reactive intermediates in important organic reactions on chiometric amout of hydrogen is released. the other other. [39] This example is not only of interest in Among the long sought for carbocations, its own right but also sheds light on the the unsubstituted ally1 cation 31 should be mechanism of carbocation formation by promentioned, which has finally been prepared tonolysis of alkanes discovered independently in condensed phase by reaction of cyclopropyl in the late sixties by Olah and Hogeveen. bromide with SbF5 at 140 K in a matrix where How far carbocation chemistry has evolved from the old solvolysis days is demonstrated it also could be studied by IR spectroscopy. by two recent structure determinations: the IR spectrum of the nonclassical CH5+ cation has been measured by “solvating” this unusual species with molecular hydrogen in the gas phase. This slows down the ultrafast fluxional process which so far prevented the recording of vibrational spectra. The cluster I ions CH5+(H*), (n = 1, 2, 3), after mass selec32 tion by an ion trap, were then subjected to IR 33 laser spectroscopy/quadrupol mass spectroAll efforts to study 31 in solution by N M R metry which ultimately yielded the IR absorpspectroscopy have met with failure so far, tion. [40] And the benzene cation, formed by though [36]. The facile ring-opening of cyclo- removal of one electron from the parent propyl cations can be prevented, when a ferro- hydrocarbon was shown to possess D6h symcenyl substituent is introduced into the three- metry by rotation resolved ZEKE-photoelecmembered ring system: cation 32 is so stable tron spectroscopy (Zero Kinetic Energythat its N M R spectrum can be recorded at PES). [41] Turning to reaction mechanisms involving -60 “C. [37] The central eight-membered in the biscation 33 which should be planar accor- carbocations, important results have been ding to Hiickel’s rule, in fact prefers a tub-like published concerning one of the oldest organic conformation. It appears that the gain in delo- reactions: the electrophilic addition of halocalization energy for a planar structure is over- gens to olefins, which for a long time has balanced by an increase in angle strain and been formulated as a three step process: after growing non-bonding interactions between the initial 3t complex formation, a haloniumion complex (a complex) is formed which in the bicyclic substituents. [38] Among the novel carbocations discovered the last step is attacked in trans-fashion to recently the “internally H-bridged” bicyclic provide the 1,2-halogen adduct. In principle this process is reversible, and in fact for a species 35 is noteworthy. When the precursor in-out-hydrocarbon 34 sterically strongly shielded alkene such as is treated with trifluoromethanesulfonic acid adamantylidenadamantane 36 an equilibrium at room temperature in dichloromethane 35 is has been shown to exist between the free produced in quantitative yield while a stoi- olefin and bromine, the 3t complex, and

D.General Methods and Reagents

256

-0 36

The structural parameters of both the halogen and the hydrocarbon component are hardly influenced by the complex formation attesting to the weak interaction between the n bonds and the halogen molecule; and the latter is not polarized to any significant extent. All in all these experimental results beautifully confirm theoretical calculations and structural properties derived from matrix isolation studies. In a more complex case - which nevertheless demonstrates how new observations can be made for an old reaction - the highly hindered butadiene derivative 40 -which possesses an orthogonal structure - yields the substitution product 42 on reaction with bromine, not the a priori expected 1,2- and 1,4-dibromides. [50] In this case the sterically hindered cationic intermediate 41 prefers a-proton elimination over the usually observed interception by bromide ion. Propelled by recent developments in natural products chemistry (catchword: “enediyne antibiotics”) and material science (“novel carbon allotropes, carbon networks”) a veritable renaissance of acetylene chemistry has taken place during the last few years. [51] As far as reactive intermediates are concerned the emphasis has been on reducing the ring size of cyclic acetylenes to the ultimate limit: the three-membered ring. The small-ring acetylene project - originally initiated by Wittig - illustrates very nicely how an “isolable system” can be gradually transformed into a “reactive intermediate”. Or to put it another way: When discussing reactive intermediates vs. isolable

37

+

t-

36

31

the bromoniumion 37. NMR studies have furthermore revealed a fast degenerate equilibration between 36 and 37 by Br+ transfer. 142-451 Whereas crystal structures of bromonium and iodonium salts could be obtained, [43,46] experimental data on n complexes were scarce until recently when Legon and co-workers introduced a new method for studying the structures of labile molecular complexes. [47] This technique involves the rapid mixing of the components (halogen and olefin) while they expand into the evacuated resonator of a FT microwave spectrometer. Because of the collisonfree ultrafast expansion the molecular complexes formed cool down rapidly and hence possess only a very small internal energy. This prevents addition to the normally observed products and allows measurement of the rotational spectra of the n complexes and determination of their structures. The n complexes of ethylene and acetylene with chlorine were shown to have structures 38 [48] and 39, [49] respectively, i.e. arrangements in which the halogen molecule stands perpendicularly above the middle of the respective carbon-carbon multiple bond:

I

I

F‘ I 3.128(3.037) “.c~c..”

I,>

I

8)

/

\

F’

[ 3.165 (3.124)

-c-c-

(1.340)

(1.219)

38

39

40

42

Reactive Intermediates

molecules the question of reaction conditions and methods used - both chemical and physical - must always be asked and answered. Under “normal laboratory conditions” cyclooctyne is a stable molecule, although the deformation angle between the triple bond and the adjoining methylene group is ca. 22”, and the reactivity is increased as compared to a corresponding acyclic alkyne. In cycloheptyne this angle is 30-35”, and the laboratory conditions have changed to -76 “C and a half-life of one hour. And cyclohexyne is already so unstable that it can only be studied in a low-temperature matrix. [52] However, exploiting the trick of introducing heteroatoms (especially silicon has often been used) into the ring and shielding the reactive triple bond by voluminous groups, [53] Ando and co-workers have been able to prepare the cycloalkyne 43 - a compound with a halflife of 8 hours at 174 “C ! [54]

44

43

45

46

H

I

I

H 48

A -Me$iH

H 49

When subjecting the disilane 48 to a newly developed pyrolysis technique, trimethylsilane is split off and 1dacyclopropylidene 49 is formed as the most stable C2H2Si isomer. Photolysis of this “silylene” with monochromatic light yields 50 which was identified by comparing its IR spectrum with a calculated spectrum. Whether 50 is a “true” cycloalkyne or a diradical, a singlet or a triplet must await further investigation as must the study of its chemical behavior. Highly strained compounds also result when allenic or cumulenic units are introduced into a cyclic or bicyclic molecule. A particularly interesting example is provided by 1,2,4-hexatriene or isobenzene 52, an allenic isomer of benzene.

41

Cyclopentyne 44 could not be generated so far; during an attempted photochemical synthesis the allene 45 was obtained, indicating that 44 - if formed at all - is very likely photolabile. [55] Extensive recent abinitio calculations suggest that cyclobutyne 46 should be observable in a matrix, whereas for the “end point” of the series, cyclopropyne 47, no minimum could be found on the potential energy surface. [56] It is thus all the more surprising that Maier and co-workers have been able to produce the silicon-containing 50, as the first observable cyclopropyne derivative: [57] H-CGC-Si-SiMe,

257

50

54

This cycloallene was first prepared by Christ1 and co-workers from the bromofluorohydrocarbon 51 by treatment with methyl lithium. [58] The C6H6 isomer does not survive the conditions of its generation but can be trapped with e. g. styrene to yield the bicyclic adduct 54. In the meantime a further route to 52 has been found, consisting in the thermal cyclization of 1,3-hexdien-5 -yne 53. [59] Hydrocarbon 53 is a close relative of 3hexen-13 -diyne 55, the parent enediyne system for which Bergman first described the cyclization 55-46 which later should carry his name.

258

D. General Methods and Reagents

The remainder of this brief overview will be dedicated to some methods for the direct observation of transitions states, clearly a question of utmost importance for the deter55 55 mination of reaction mechanisms. One of classical and well studied examples Because this process forms the basis for the of a molecule undergoing dynamic changes biological action (DNA cleavage) of several is cyclooctatetraene 60, which, of course, is highly potent cancerostatica [51] a lot of also an important representative of a 4nn-elecmechanistic work has been carried out on it tron system; it avoids antiaromaticity by bond including the exact determination of its activa- fixation and molecular deformation in the tion parameters, [59] the measurement of the ground state (tub-like structure with D2d symheat of formation of the diradical involved, metry). Cyclooctatetraene participates in two 56 (p-dehydrobenzene), [60] and the incor- types of dynamic processes: ring inversion poration of the enediyne unit into a large num- via a planar eight-membered ring with alternating single and double bonds 61 (Dabsymber of more complex molecules. [51, 611 Another interesting diradical - also formed metry) and a double bond shift which takes by interaction between two triple bonds - is place via antiaromatic transition state 62 the bicyclic 1,4-didehydro-l,3 -butadiene 58. (D8h symmetry) in which all C-C bonds are When strained cyclic dialkynes, symbolized of the same length. The delocalized structure 62 has now been by the general formula 57 are heated to temperatures between 80 and 150 "C they cyclize to observed directly by, Borden and co-workers 58, a reactive intermediate which can be trap- [65] using photo electron spectroscopy. As ped by various hydrogen donors to provide starting material for 62 the authors used the radical anion of cyclooctatetraene 63 which the bicyclic dienes 59. [62] can be prepared by electron capture in an ion source, and which is known to be planar from experimental and theoretical studies. When this species is irradiated with monochromatic light the weakly bonded excess 57 58 59 As already shown by many of the above examples, physical methods, especially spectroscopic ones, are having a very strong impact on the development of physical organic chemistry, and it is only for lack of space that such important techniques as laser flash spectroscopy can only be mentioned here in passing. Having established itself as a highly efficient method for the study of carbenes and carbocations [631 laser flash spectroscopy has also been used to generate carbanions and promises liketothe become trityl aanion useful recently, method[64] for the determination of carbanion reactivity as well.

60

tl

04Q=O 6ip4,,)

\ -e

LpA

D4h

0-3 (Qja2(D8h)

-

60 P 2 d )

63 0 4 3

64 (Dsh)

Reactive Intermediates

electron is split off and neutral cyclooctatetraene is formed. Since this latter process is faster than the movement of the nuclei of cyclooctatetraene the neutral hydrocarbon produced retains the planar structur of the prescursor ion. The kinetic energy of the liberated electrons - which is measured by the PE-spectrum - contains the spectroscopic information of planar cyclooctatetraene (i. e. 62). As the analysis of the fine structure of the PE spectrum shows, both D4h- and Dgh cyclooctatetraene are generated in this experiment; even more: it could also be observed that D,, cyclooctatetraene occurs as a singlet (the transition sate 62) and as a triplet species 64, with the latter being a true, though very short-lived intermediate. Whether bond-alternation can be induced in 4n+2, i. e. aromatic n systems has been discussed in organic chemistry long before Hiickel formulated his famous rule. After many attempts, hydrocarbon 65 has now been shown to be the first mononuclear benzenoid hydrocarbon with a true cyclohexatriene structure. [66] Its internal ring is planar, all internal angles amount to 120°, yet the two nonequivalent C-C bonds in the benzene ring differ by 0.089 A, corresponding to Pauling bond orders of 1.86 and 1.39 for the shorter and the longer bond, respectively.

65

If there is an ultimate method for the direct observation of transition states femtosecond spectroscopy could well qualify for it. This method, largely developed by Zewail and co-workers, is now more and more used to study - even complex - uni- and bimolecular processes. It employs an extremely short pulse from a femtosecond laser to initiate a

259

reaction, for example the dissociation or an isomerization of a molecule. By a second laser pulse from the same pump laser, triggered a few femto (10-15) or picoseconds (lo-’* s) later, the products formed and their internal states are then registered. As a particularly important example for organic reaction mechanisms Zewail et al. recently reported a study of the real-time dynamics of the retroDiels-Alder reaction of norbornene and norbornadiene, [67] which, of course, also sheds light on the reverse process, the Diels-Alder addition. After starting the decomposition, which was carried out in a molecular beam to isolate the elementary process, the authors “watched” the excited species by studying the molecular beam with pulses at femtosecond intervals from the second laser. These pulses ionize the reactive intermediates thus making them amenable for mass spectral analysis. The mass spectra show peaks corresponding to the starting materials (mlz = 94 and 92, respectively), but also a peak at mfz = 66 corresponding to one of the cleavage products, cyclopentadiene. Interestingly, however, this signal builds up in the course of the decomposition and eventually it disappears. It can hence not be due to cyclopentadiene itself but must represent a reactive intermediate. For this signal a decay time of 220 fs is registered. The decay time of the mlz = 94 signal (for norbornene) amounts to 160 fs, i.e. it takes this time for two C-C bonds to rupture. A non-concerted and a concerted route are thus both available for the retroDiels-Alder reaction, and by implication for the forward (addition) process as well. The reaction times measured are also much shorter than the 1 to 10 picoseconds it takes for a C-C bond to rotate. There is hence no contradiction betwen the stereospecificity of the process which, of course, has been known for a long time from classical mechanistic studies - and the presence of an intermediate. The old problem of concertedness vs. nonconcertednew which has dominated the discussion on

260

D. General Methods and Reagents

cycloadditions for decades, may hence finally have been solved: both symmetric and nonsymmetric motions of the two C-C bonds in the above examples are possible, leading eventually to (competing) concerted and nonconcerted reaction paths! The route which a particular cycloaddition or its reverse process prefers will hence depend on the asymmetry of the structures involved, the different energy barriers, and the energy available. The impact which femtosecond spectroscopy is also having on the study of the reaction mechanisms of biological systems is finally illustrated by an investigation of the cisltrans isomerization of rhodopsin 66 + 67, [68] the primary step of the vision process. The reaction lasts 200 fs and is thus one of the fastest photochemical processes known so far. The formation of the photoproduct 67 occurs without an activation barrier.

I

I

opsm

hv

References [l]G. Maier, H. P. Reisenauer, H. Balli, W.

Brandt, R. Janoschek, Angew. Chem. 1990, 102, 920-923;Angew. Chem. Int. Ed. Engl. 1990, 29, 905; cf. D. Siilzle, H. Schwarz, Angew. Chem. 1990, 102, 923-925; Angew. Chem. Int. Ed. Engl. 1990,29,908. [2]G. Maier, H.P. Reisenauer, J. Schrot, R. Janoschek, Angew. Chem. 1990, 102, 14751477;Angew. Chem. Int. Ed. Engl. 1990, 29,

1464.

[3]G. Maier, H. P. Reisenauer, J. Eckwert, C. Sie-

rakowski, Th. Stumpf, Angew. Chem. 1992, 104, 1287-1289; Angew. Chem. Int. Ed. Engl. 1992, 31, 1218. 41 G.Maier, T. Preiss, H. P. Reisenauer, B. A. Hess, Jr., L. J. Schaad, J. Am. Chem. Soc. 1994,116,2014-2018;cf. G.Maier, T. Preiss, H. P. Reisenauer, Chem. Ber. 1994, 127,779-

782. 51 R. Herges, A. Mebel, J. Am. Chem. Soc. 1994, 116, 8229-8237; cf. R. A. Seburg, R. J. McMahon, Angew. Chem. 1995, 107, 21982201;Angew. Chem. Int. Ed. Engl. 1995, 34, 2009. [6]T. Bally, S. Matzinger, L. Truttmann, M. S.

Platz, S. Morgan, Angew. Chem. 1994, 106, 2048-2051; Angew. Chem. Int. Ed. Engl. 1994,33, 1964. [7]G.Bucher, W.Sander, E. Kraka, D. Cremer, Angew. Chem. 1992,104, 1225-1228;Angew. Chem. Int. Ed. Engl. 1992, 31, 1230. In the meantime the parent system of 7,1,3-didehydrobenzene (m-benzyne) has also been generated and spectroscopically characterized in matrix: R. Marquardt, W. Sander, E. Kraka, Angew. Chem. 1996, 108, 825-827; Angew. Chem. Int. Ed. Engl. 1996,35, 746-748. [8]D. J. Cram, M. E. Tanner, R. Thomas, Angew. Chem. 1991, 103, 1048-1051;Angew. Chem. Znt. Ed. Engl. 1991, 30, 1024; cf. H. Hopf, Angew. Chem. 1991, 103, 1137-1139;Angew. Chem. Int. Ed. Engl. 1991, 30, 1 1 17.For the activation energy of the valence isomerization of cyclobutadiene see G. Maier, R. Wolf, H.-0. Kalinowski, Angew. Chem. 1992, 104, 764-766;Angew. Chem. Int. Ed. Engl. 1992, 31, 738. Very recently dehydrobenzene has been prepared and studied by the scene approach: R. Warmuth, Angew. Chem. 1997, 109, 1406-1409; Angew. Chem. Int. Ed. 1997,36, 1347-1350. [9]L. Garel, J.-P. Dutasta, A. Collet, Angew. Chem. 1993, 105, 1249-125 1 ; Angew. Chem. Int. Ed. Engl. 1993, 32, 1169. 101 Review: H. Schwarz, Angew. Chem. 1992, 104, 301-305; Angew. Chem. Int. Ed. Engl. 1992, 31, 293. 111 Review: F. T.Edelmann, Angew. Chem. 1995, 107, 1071-1075;Angew. Chem. Int. Ed. Engl. 1995, 34, 981.

Reactive Intermediates [12] A. J. Arduengo 111, R. L. Halow, M. Kline, J. Am. Chem. SOC.1991,113,361-363. [ 131 A. J. Arduengo 111, H. V. Rasika Dias, D. A. Dixon, R. L. Harlow, W. T. Klooster, T. F. Koetzle, J. Am. Chem. Soc. 1994, 116, 68126822. [14] H. Tomioka, H. Okada, T. Watanabe, K. Hirai, Angew. Chem. 1994, 106, 944-946; Angew. Chem. Int. Ed. Engl. 1994,33,873. [15] A. Kirschfeld, S. Muthusamy, W. Sander, Angew. Chem. 1994, 106, 2261-2263; Angew. Chem. Int. Ed, Engl. 1994, 33, 2212. H. Tomioka, T. Watanabe, K. Hirai, K. Furukawa, T. Takui, K. Itoh, J. Am. Chem. Soc. 1995, 117,6376-6377. G. Maier, St. Senger, Angew. Chem. 1994, 106, 605-606; Angew. Chem. Int. Ed. Engl. 1994, 33, 558. [l8] G. Maier, H. P. Reisenauer, K. Lanz, R. TroB, D. Jiirgen, B. Andes Hess, Jr., L. J. Schaad, Angew. Chem. 1993, 105, 119-121; Angew. Chem. Int. Ed. Engl. 1993, 32, 74. [ 191 0. Claesson, A. Lund, T. Gillbro, T. Ichikawa, 0. Edlund, H. Yoshida, J. Chem. Phys. 1980, 72, 1463-1470. [20] G. Allinson, R. J. Bushby, J.-L. Paillaud, D. Oduwole, K. Sales, J. Am. Chem. Soc. 1993, 115,2062-2064. [21] N. Nakamura, K. Inoue, H. Iwamura, T. Fujioka, Y. Sawaki, J. Am. Chem. Soc. 1992, 114, 1484-1485. [22] N. Nakamura, K. Inoue, H. Iwamura, Angew. Chem. 1993, 105, 900-901; Angew. Chem. Int. Ed. Engl. 1993, 32, 872. [23] D. Seebach, R. Hassig, J. Gabriel, Helv. Chim. Acta. 1983, 66, 308-337. [24] G. Boche, M. Marsch, A. Miiller, K. Harms, Angew. Chem. 1993, 105, 1081-1082; Angew. Chem. Int. Ed. Engl. 1993,32, 1279. [25] P. v. R. Schleyer, E.-U. Wiirthwein, E. Kaufmann, T. Clark, J. A. Pople, J. Am. Chem. SOC.1983,105, 5930-5932. [26] H. Kudo, Nature 1992,355,432-434; see also A. E. Reed, P. v. R. Schleyer, R. Janoschek, J. Am. Chem. Soc. 1991, 113, 1885-1892. [27] Review: A. Maercker, M. Theis, Top. Curr. Chem. 1987,138, 1-61. [28] A. E. Dorigo, N. J. R. van Eikema Hommes, K. Krogh-Jespersen, P. v. R. Schleyer, Angew.

26 1

Chem. 1992, 104, 1678-1680; Angew. Chem. Int. Ed. Engl. 1992, 31, 1602. [29] Th. Maetzke, C. P. Hidber, D. Seebach, J. Am. Chem. Soc. 1990, 113, 8248-8250. [30] H.4. Gais, G. Hellmann, H. J. Lindner, Angew. Chem. 1990, 102, 96-99; Angew. Chem. Int. Ed. Engl. 1990, 29, 100; cf. H. J. Gais, G. Hellmann, J. Am. Chem. SOC. 1992, 114, 4439-4440. The increasing importance of heteroatom substituted organolithium compounds for enantioselective synthesis has been demonstrated by several authors e. g. T. Ruhland, R. Dress, R. W. Hoffmann, Angew. Chem. 1993, 105, 1487-1489; Angew. Chem. Int Ed. Engl. 1993, 32, 1467; H. J. Reich, R. R. Dykstra, Angew. Chem. 1993, 105, 1489-1491; Angew. Chem. Int. Ed. Engl. 1993, 32, 1469. [31] M. Marsch, K. Harms, L. Lochmann, G. Boche, Angew. Chem. 1990, 102, 334-336; Angew. Chem. Int. Ed. Engl. 1990, 29, 308. [32] R. Haag, R. Fleischer, D. Stalke, A. de Meijere, Angew. Chem. 1995, 107, 16421644; Angew. Chem. Int. Ed. Engl. 1995, 34, 1492. [33] M. Baumgarten, L. Gherghel, M. Wagner, A. Weitz, M. Rabinovitz, P.-C. Cheng, L. T. Scott, J. Am. Chem. SOC. 1995, 117, 6254-6257. [34] T. C. Pochapsky, P. M. Stone, J. Am. Chem. SOC. 1990,112,6714-6715. [35] T. C. Pochapsky, P. M. Stone, S. S. Pochapsky, J. Am. Chem. Soc. 1991,113, 1460-1462. [36] P. Buzek, P. v. R. Schleyer, H. Vancik, Z. Mihalic, J. Gauss, Angew. Chem. 1994, 106, 470-473; Angew. Chem. Int. Ed. Engl. 1994, 33, 448. [37] G. K. S. Prakash, H. Buchholz, V. P. Reddy, A. de Meijere, G. A. Olah, J. Am. Chem. SOC.1992,114, 1097-1098. [38] T. Nishinaga, K. Komatsu, N. Sugita, J. Chem. Soc. Chem. Commun. 1994,23 19-2320. [39] J. E. McMurry, T. Lectka, J. Am. Chem. SOC. 1990,112, 869-870. [40] D. W. Boo, Z. F. Liu, A. G. Suits, J. S. Tse, Y. T. Lee, Science 1995, 269, 57-59. [41] R. Lindner, H. Sekiya, B. Beyl, K. MiillerDethlefs, Angew. Chem. 1993, 105, 631-634; Angew. Chem. Int. Ed. Engl. 1993, 32, 603.

262

D. General Methods and Reagents

[42]R. S. Brown, R. W. Nagorski, A. J. Bennet,

[58]M. Christl, M. Braun, G. Miiller, Angew Chern. 1992, 104, 471-473;Angew. Chem. Int. Ed. R. E. D. McClung, G. H. M. Aarts, M. KloEngl. 1992, 31, 473; cf. R. Janoschek, bukowski, R. McDonald, B. D. Santasiero, Angew. Chem. 1992, 104, 473-475; Angew. J. Am. Chem. SOC.1994,116,2448-2456. Chem. Int. Ed. Engl. 1992, 31, 476.For the [43 G. Belluci, R. Bianchini, C. Chiappe, V. R. generation of two other benzene isomers, Gadgil, A. P. Marchand, J. Org. Chem. 1993, 1,2,3-cyclohexatriene and I-cyclohexen-3 58, 3575-3577. yne see W. C. Skakespeare, R. P. Johnson, [44 G. Bellucci, R. Bianchini, C. Chiappe, F. J. Am. Chem. SOC.1990,112,8578-8579. Marioni, R. Ambrosetti, R. S. Brown, H. Slebocka-Tilk, J. Am. Chem. SOC. 1989, I l l , [59]W. R. Roth, H. Hopf, C. Horn, Chem. Ber. 1994,127,1765-1779;cf. H. Hopf, H. Berger, 2640-2647. G. Zimmermann, U. Niichter, P. G. Jones, [45]R. S. Brown, R. Geyde, H. Slebocka-Tilk, I. Dix, Angew. Chem. 1997,109, 1236-1238; J. M. Buschek, K. R. Kopecky, J. Am. Chem. Angew. Chem. Int. Ed. 1997,36,1187-1190. SOC.1984,106,4515-4521. [46]H. Slebocka-Tilk, R. G. Ball, R. S. Brown, [60]P. G.Wenthold, R. R. Squires, J. Am. Chem. SOC.1994,116,6401-6412. J. Am. Chem. SOC.1985,107,4504-4508. [47]A.C. Legon, C. A. Rego, J. Chem. SOC.Fara- [61]Review: R. Gleiter, D. Kratz, Angew. Chem. 1993, 105, 884-887;Angew. Chem. Int. Ed. day Trans. 1990,86,1915-1921. Engl. 1993,32,842. [48]H. I. Bloemink, K. Hinds, A. C. Legon, J. C. Thorn, J. Chem. SOC.Chem. Commun. 1994, [62]R. Gleiter, J. Ritter, Angew. Chem. 1994,106, 2550-2552; Angew. Chem. Int. Ed. Engl. 1321-1322. 1994,33, 842. [49]H. I. Bloemink, K. Hinds, A. C. Legon, J. C. [63]See for example: F. Cozens, J. Li, R. A. Thorn, Chem. Phys. Letters 1994,223, 162. McClelland, S. Steenken, Angew. Chem. [50]H. Hopf, R. Hanel, P. G. Jones, P. Bubenit1992, 104,753-755;Angew. Chem. Int. Ed. schek, Angew. Chem. 1994,106, 1444-1445; Engl. 1992,31,743. Angew. Chem. Int. Ed. Engl. 1994,33, 1369. [51]P.J. Stang, F. Diederich (Eds.), Modem Acety- [64]M. Shi, Y. Okamoto, S. Takamuku, Bull. Chem. SOC.Jpn. 1990,63,453-460. lene Chemistry, VCH, Weinheim, 1995. [52]C. Wentrup, R. Blanch, H. Briehl, G. Gross, [65]P. G. Wenthold, D. A. Hrovat, W. T. Borden, W. C. Lineberger, Science, 1996,272, 1456J. Am. Chem. SOC.1989,110, 1874-1880;cf. 1459; cf. W. T. Borden, H. Iwamura, J. A. W. Sander, 0. L. Chapman, Angew. Chem. Berson, Acc. Chem. Res. 1994,27,109-1 16. 1988, 100, 402-403;Angew. Chem. Int. Ed. [66]H.-B. Biirgi, K. K. Baldrige, K. Hardcastle, Engl. 1988,27,398-399. N. L. Frank, P. Gantzel, J. S. Siegel, J. Ziller, [53 A. Krebs, J. Wilke, Top. Cur. Chem. 1983, Angew. Chem. 1995, 107, 1575-1577; 109, 189-233. Angew. Chem. Int. Ed. Engl. 1995,34, 1454. [54 W. Ando, F. Hojo, S. Sekigawa, N. Nakayama, Traditionally bond alternation is discussed in T. Shimizu, Organometallics 1992,11, 1009terms of the so-called Mills-Nixon effect, see 1011;cf. F. Hojo, S. Sekigawa, N. Nakayama, J. S. Siegel, Angew. Chem. 1994,106,1808T. Shimzu, W. Ando, Organometallics 1993, 1810;Angew. Chem. Int. Ed. Engl. 1994,33, 12, 803-810. 1721. [55]0.L. Chapman, J. Gato, P. R. West, M. Regitz, G. Maas, J. Am. Chem. SOC.1981,103,7033- [67]B. A. Horn, J. I. Herek, A. H. Zewail, J. Am. Chem. SOC.1996,118,8755-8756. 7036. [56]H. A. Carlson, G. E. Quelch, H. F. Schaefer [68]R. W. Schoenlein, L. A. Peteanu, R. A. Mathies, C. V. Shank, Science, 1991, 254, 111, J. Am. Chem. SOC.1992,114,5344-5348. 412-415. [57]G. Maier, H. P. Reisenauer, H. Pacl, Angew. Chem. 1994, 106,1347-1349;Angew. Chem. lnt. Ed. Engl. 1994,33,1248-1250.

Part 11. Applications in Total Synthesis Synthesis of Natural and Non-natural Products

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Pentazole and Other Nitrogen Rings Rudolf Janoschek

Dimroth and de Montmollin [2] also had no luck when they planned to prepare phenylpentazole from a chain of six nitrogen atoms (3). Then in 1915 success seemed to be at hand when Lifschitz [3] believed he had synthesized pentazolyl acetic amidrazone (5) from tetrazolecarbo-nitrile (4). But in the same year came a rebuttal from Curtius et al. [4] with the title “Die sogenannten Pentazol-Verbindungen von Lifschitz” (“The so-called pentazole compounds of Lifschitz”). They did not mince their words: “Ein derartiger Reaktionsverlauf w k e im hochsten Grade uberraschend ... Lifschitz glaubt die Richtigkeit seiner Auffassung ‘mit vollkommener Sicherheit’ folgern zu mussen ... ohne weitere Priifung in das Reich des Unmoglichen zu verweisen ... dass alle seine Beobachtungen und Folgerungen auf Irrtum beruhen ... von

Although the road of the pentazoles through chemistry has not only just begun, its end is not yet in sight; they have proved that they can stay the distance. Their history began in 1903 when Hantzsch [I] tried in vain to form phenylpentazole (2) by rearrangement of benzene-diazonium azide (1); (formerly the azide structure was assumed to be a three-membered ring. This is documented on the Curtius monument in Heidelberg).

1

2

+ 2 N2H4

+

I N\\N

4

/N-CH2-c 5

\NH-NH,

+ NH,

266

Applications in Total Synthesis

Pentazol keine Rede sein kann.” (“Such a course for the reaction would be extremely surprising ... Lifschitz believes he must conclude that his interpretation is correct ‘in perfect confidence’ ... without further proof it must be relegated to the realm of the impossible ... all his observations and conclusions are based on error ... there can be no question of pentazoles in this case”). Dispute, misunderstanding, and failure dogged the pentazoles from the beginning. Curtius’s verdict hit hard. Almost half a century passed before anyone again ventured a search for pentazole. Huisgen and Ugi [5] thus solved a classic problem in 1956 when they proved that they could link the benzenediazonium ion (6) with the azide ion to form benzene-diazoazide (7),which on ring-closure yielded phenylpentazole (2). The first structure determination by X-ray diffraction on a pentazole was performed in 1983 by Dunitz and Wallis. [6] The N-N bond lengths in the five-membered ring were all similar (1.31-1.35 A) and lie between the standard values for N-N (1.449 A) and N=N (1.252 A), which can be interpreted as a clear sign of an aromatic ring with six n electrons. Indeed, the recently performed natural bond orbital analysis (NBO) of the parent pentazole HN5 (8) has shown that formula 8 is not a good Lewis structure. The 2pn lone pair at N(H) donates 25 % of its charge into the antibonding NN n*-orbitals. This information does not, however, close the chapter on the pentazoles. In fact quite to the contrary, it is now all the more puzzling why the parent compound of the pentazoles, HN5 (8), is still unknown. After all, it would be the final member of a well-known series that begins with pyrrole and breaks off prematurely at tetrazole. Perhaps theory can help solve the enigma.

6

7

s-a \N/

I

H

8

The interest of the quantum chemists in pentazoles was aroused by Ferris and Bartlett. [7] They employed ab initio calculations such as the nth order many-body perturbation theory, abbreviated to MBPT(n), whose better known variant is the nth order Moller-Plesset perturbation theory, MPn. The MBPT(n) procedure takes account of all the terms to a predetermined final order n for the electron correlation. In the coupled cluster (CC) theory, on the other hand, certain contributions from the MBPT formalism are summated for all orders n. Use of the DZP basis set with these procedures yielded the anticipated structural parameters for cyclic HN5 (8) with CzVsymmetry and proof that it represents a minimum on the energy hypersurface. The energy barrier for potential decomposition into HN3 and NZ was given on the MBPT(2) level as 19.8 kcal mol-l. The question in the title of reference [7], “Does it exist?’, can, of course, not yet be answered on these grounds alone. Experience shows that the MBPT procedure yields energy barriers that are too high. This will be demonstrated later in this report for the Nq molecule. To estimate the kinetic stability of 8 more accurately, other calculation methods such as MP2, MP4, CC, or MCSCF-CI should also be employed. Meanwhile, density functional theory (DFT) has been developed and the available basis sets are extended to higher angular momentum quantum numbers. Therefore, the author of this report applied himself

2

Pentazole and Other Nitrogen Rings

to the problem of the uncertainty in this decomposition barrier, and in addition, also to other problems of nitrogen rings. The computational method is Becke's density functionals (B3LYP) using the correlation consistent polarized valence triple zeta (cc-pVTZ) basis sets which are in standard notation: N(4s,3p,2d,lf), H(3s,2p,ld). Table 1 collates some of the results for the decomposition barrier of 8. The height of the barrier varies between 13.7 and 20.9 kcal mol-*, which might cast doubt on the kinetic stability. Furthermore, it was stressed repeatedly in the past that the energy hypersurface for the triplet state may not be ignored, because it might cross energy barriers leading to spinforbidden processes (intersystem crossing) and thus to other decomposition pathways. However, recent B3LYPkc-pVTZ calculations could not confirm a low-lying triplet state at the transition structure. Moreover, the triplet energy is significantly above the ground state singlet energy at any point of the energy profile of the ring opening process. Only one issue is definite: theory has pointed the way; the next step must be left to experiment. Matrix isolation has provided many a surprise in the past. As dramatic as the tale of the pentazoles is the story of the unsuccessful attempt to detect a six-membered nitrogen ring. The first calculations were performed in the early seventies. In 1980 Vogler et al. [8] found indications that N6 is formed on UV irradiation from cis[Pt(N3)2(PPh3)2] embedded in a matrix, but it is only stable at low temperature. At that time hexaazabenzene (9) was considered the only feasible structure for Ng. This report unleashed an avalanche of quantum chemical calculations, in particular because 9 is isoelectronic with benzene and thus should likewise display aromatic stabilization. The calculations over the decade produced every conceivable answer: hexaazabenzene has D6h symmetry ... has D3h symmetry ... does not exist, because 9 is the transition structure for nitro-

267

Table 1. The activation barrier AE [kcal mol-'] incorporating the zero-point vibrational correction for the decomposition HN5 -+ HN3 + N2, calculated with several methods. Method")

AE

MBPT(2)/DZP [7] MP2/6- 3 1G * MP4/6-31G* CCSD/6-3 1G* B~LYP/cc-PVTZ

19.8 13.7 18.9 20.9 16.4

")The calculations with the 6-31G* basis set were performed with the program GAUSSIAN 92 [1993]; for the B3LYP calculations GAUSSIAN 94 was used [1997].

gen exchange for 3 N2. The latest MBPT calculations of Bartlett et al. [9] nullified all previous efforts. According to them, hexaazabenzene cannot exist because this arrangement of atoms (&h) gives two imaginary frequencies for the out-of-plane vibrations. Recently performed B3LYPkc-pVTZ calculations yielded three imaginary frequencies. The naive view and the conclusions from it that all cyclic compounds with six ?t electrons must be aromatic had already been convincingly disproved by Shaik et al. [lo] The idea that Vogler's N6 could be diazide (lo), which was shown by calculations [ l l ] to be 35 kcal mol-' more stable than 9, was supported repeatedly during the past ten years. Now that the birth of the five-membered nitrogen rings has been announced only after a long labor, and a six-membered nitrogen ring has even been disputed by theory, it is

9

10

Applications in Total Synthesis

268

the turn of three- and four-membered nitrogen rings. In 1977 triaziridine N3H3 was discovered in small amounts bound as a complex to a zeolite crystal. X-ray diffraction confirmed the ring structure. [12] More recent ab initio calculations suggest that this compound can also exist in uncomplexed form, since the three-membered nitrogen ring represents a minimum on the energy hypersurface. [13] The authors of this paper, however, are even self-critical and issue a warning that applies to all the theoretical investigations considered here: "... but we must do more work to understand the kinetic lability of these compounds".

11

12

The localization of an energy minimum is certainly not sufficient for the stability of a chemical structure. In addition, heights of activation barriers for ring opening processes are necessary for the discussion of kinetic lability. New computational results for three-, four-, and five-membered nitrogen rings are presented in Table 2. These cyclic systems exhibit low activation barriers to ring opening and high product stability. Curtius's cyclic azide structure 11 and pentazole 8 are seen to be in competition with respect to their instability. Triaziridine 13 is the most stable one among this series, according to its lowest product stability (triimide 14) and highest activation barrier of 33.0 kcal mol-'. No singlet transition structure could be localized for

H

15

the concerted decomposition of the hypothetic tetraaziridine 15 to diimide. For this case, a two-step mechanism is assumed for the decomposition where a low-lying triplet diradical indicates the instability of the fourmembered ring. In the form of 16, a structure isoelectronic with cyclobutadiene, Nq exhibits a similar stability than tetraazatetrahedrane (17). Because of the homology to the known tetrahedral P4, more attention has been paid to structure 17 than to 16. After the most thorough theoretical study yet undertaken, Lee and Rice [14] calculate a considerable energy barrier of 61 kcal mol-' for the decomposition N4 + N2. The authors exploited all possibilities both with the basis set (DZP, [4s, 3p, 2d, lfl) and Table 2. Calculated energy profiles for the decomposition of nitrogen rings. B3LYPIcc-pVTZ calculated relative energies [kcal mol-'1 including zeropoint energy correction. TS: transition structure; T: triplet minimum structure. 11 45.6

TS 65.4

12 0.0

13 28.1

TS 61.1

14 0.0

15 32.4

T(HN-(NH)*-NH) 33.2

2 NzH2 0.0

8 41.7

TS 58. I

12 + NZ 0.0

TS 71.1

Diazoazide 66.4

____

13

14

8 41.7

Pentazole and Other Nitrogen Rings

with the methods of calculation (CASSCF, MP2, CC) to separate the less appropriate methods from the better ones by comparing the different results. In the process, the energy barrier for the decomposition was lowered from 80 to 61 kcal mol-'. Bartlett et al. [9] report a quite high value of 79 kcal mol-l from only one MBPT calculation, which leads to the conclusion that energy barriers calculated with MBPT are too high as a result of a systematic error, and the kinetic stability of all the compounds covered here is therefore overemphasized. The lower, but nevertheless still substantial barrier for N4 decomposition must not lead to a premature euphoria, [9] because the triplet energy hypersurface intersects this barrier low down. [14] A fast spinforbidden process (double intersystem crossing) can therefore annihilate N4. Most importantly, the relative energy of N4 with respect to 2 N2 turned out to be as high as 186 kcal mol-'. N

16

17

This trail through the territory of the nitrogen rings should not end without mention of the latest candidates for experimental proof. Minima have been located on the energy hypersurface for bipentazole N5-N5 [7] and octaazacubane Ns, [9] and structural data have been reported. Have nitrogen rings or cages any interesting property that makes the effort to synthesize them worthwhile? A glance at the reaction energies on decomposition to N2 gives an answer. The energy released per N2 unit on decomposition of N4 is 93 kcal mol-I and of Ns, 112 kcal mol-I. Such high energy density makes these compounds promising rocket fuels. In fact, theory predicts a better effici-

269

ency for N8 than for the conventional fuel, which is based on H2 and 0 2 . The intention of this short report was to show the advance of theory through quantum chemical calculations in the field of nitrogen rings. Although the calculated molecular properties can still be extended and refined, already a quite clear picture emerges. Nitrogen rings, and in particular nitrogen cages, are extremely energy-rich and kinetically labile systems. In comparison with the results of theoretical studies, the yield of the experimental investigations is as yet small. N3H3 is an unintentional success. Well-targeted photochemical studies under matrix conditions will probably still expose several surprises.

References [l] A. Hantzsch, Be,: Dtsch. Chem. Ges. 1903,36, 2056. [2] 0. Dimroth, G. de Montmollin, Be,: Dtsch. Chem. Ges. 1910,43,2904. [3] J. Lifschitz, Be,: Dtsch. Chem. Ges. 1915, 48, 410. [4] T. Curtius, A. Darapsky, E. Miiller, Be,: Dtsch. Chem. Ges. 1915,48, 1614. [5] R. Huisgen, I. Ugi, Angew. Chem. 1956, 68, 705; Chem. Be,: 1957,90,2914. [6] J. D. Wallis, J. D. Dunitz, J. Chem. Soc. Chem. Commun. 1983,16,910. [7] K. F. Ferris, R. J. Bartlett, J. Am. Chem. Soc. 1992, 114, 8302. [8] A. Vogler, R. E. Wright, H. Kunkely, Angew. Chem. 1980, 92, 745;Angew. Chem. Int. Ed. Engl. 1980,19, 717. [9] W. J. Lauderdale, J. F. Stanton, R. J. Bartlett, J. Phys. Chem. 1992, 96, 1173. [lo] S. S. Shaik, P. C . Hiberty, J. M. Lefour, G. Ohanessian, J. Am. Chem. SOC. 1987, 109, 363. [ l l ] M. T. Nguyen, J. Phys. Chem. 1990,94,6923. [12] Y.Kim, J. W. Gilje, K. Seff, J. Am. Chem. SOC. 1977, 99,7057. [13] D. H. Magers, E. A. Salter, R. J. Bartlett, C. Salter, B. A. Hess, Jr., L. J. Schaad, J. Am. Chem. SOC. 1988, 110, 3435. [14] T. J. Lee, J. E. Rice, J. Chem. Phys. 1991, 94, 1215.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

New Total Syntheses of Strychnine Uwe Beifuss

Strychnine (l),the active component of a notorious arrow poison in Southeast Asia, has a mysterious history. [ l ] It is a convulsant blocking synaptic inhibition in the spinal cord by acting as an antagonist of the inhibitory neurotransmitter, glycine. [2] In therapeutic doses strychnine has a mildly analeptic effect; in toxic doses it leads to uncoordinated tonic convulsions induced by acoustic, tactile, or optical stimuli. Paralysis of the respiratory organ results in death; 100-300 mg is the lethal dose fur an adult human. [2c] In 1818 strychnine (l), which in larger amounts occurs in the poison nut (Strychnos nux vornica L.) and the St. Ignatius' bean (Strychnos ignatii Bergius), was isolated by Pelletier and Caventou [3] and was one of the first alkaloids obtained in pure form. The structure determination by chemical degradation of the natural product, a complex structure with seven rings and six stereogenic centres, proved to be difficult and tedious. Many

1

2

Strychnine

Wieland-Gumlich aldehyde

structural formulae were proposed and rejected before Robinson et al. (1946) and Woodward et al. (1947) presented the correct formula. [4] A few years later the relative and absolute configuration was determined by X-ray crystallography. [5] The structure determination culminated in the total synthesis of 1 by Woodward et al., which was the only total synthesis of this natural product for nearly forty years. [6] Even today it is still considered a highlight in the development of modem organic synthesis, for the deliberate design and execution of the synthesis of a such a complex molecule was unprecedented at that time. Despite the rapid development of organic chemistry since then, strychnine has remained an attractive and challenging synthetic target. A number of novel approaches to the strychnos alkaloids have been devised, [7,8] but the molecules prepared frequently lack the functionalities required for the construction of the sevenmembered allylic ether G ring of strychnine. Recently, almost forty years after Woodward, four research groups achieved the total synthesis of strychnine. In 1992 Magnus et al. reported on the successful conclusion of the second total synthesis of strychnine and, at the same time, the first total synthesis of the so-called Wieland-Gumlich aldehyde 2. [9] In 1993 Overman et al. published the first

New Total Syntheses of Strychnine

mNH2+

I

271

P

MeO2C

C02Me

H

q 3

Me02C

4

"

a,b,c,d

__._)

-6

Me02C

5

and so far only enantioselective route to strychnine (1). [lo] In an extension of this work Overman et al. recently reported on the first synthesis of unnatural strychnine (ent-1). [lob] In the meantime Kuehne et al. [ l l ] and Rawal et al. [I21 have also completed their total syntheses of ruc-1. This certainly provides ample grounds for discussing these new syntheses. Magnus' synthesis [9] follows the retrosynthetic analysis of the strychnos framework successfully employed by Harley-Mason in the syntheses of several natural products in the 1960s and 1970s. [13] The key step of this strategy is the transannular iminium ion cyclization of a nine-membered ring for the stereoselective construction of rings D and E of the strychnos alkaloids. Magnus follows the classical approach right from the start with the multistep conversion of the tetracyclic amine ruc-5, which is readily accessible from 3 and 4, into 6 (Scheme 1). A crucial step is the B,B,p-trichloroethyl chloroformate induced fragmentation of the tertiary amine ruc-5 to provide the expanded nine-membered ring system. One of the most remarkable steps in the remainder of the synthesis is the construction of the F ring by intramolecular conjugate addition. For this purpose amide 7a is prepared and treated with sodium hydride in THF, which results in the facile diastereoselective transformation into ruc-8. The stereo-

C02Me

6

Scheme 1. (a) ClCOzCH2CCI3,

CH2C12; (b) NaOMe, MeOH;

(c) 50 % aq NaOH, CH2C12,

ClCOzMe, benzyltriethylammonium chloride; (d) Zn, CH3COOH, THE

selectivity of this 1,4-addition is attributed to the protonation of the intermediate ester enolate from the top face. Oxidation of ruc-8 to give the corresponding mixture of sulfoxides is then followed by a Pummerer reaction and Hg2+-mediated hydrolysis to furnish ruc- 9 (Scheme 2). Magnus et al. obtained both enantiomers of 9 with considerable effort by acylation of 6 with (+)-(R)-p-toluenesulfinylacetic acid and cyclization of the resulting sulfoxide 7b, separation of the four diastereomers formed this way, combination of the pairs with the same absolute configurations at C6 and C7, and subsequent conversion into the two enantiomers 9 and ent-9. [9a] The cyclization of sulfoxide 7b yields the two products enantiomeric at C6 and C7 in a 55 :45 ratio. This is why this route is not only laborious but then only insignificantly more efficient than resolution. After transformation of ruc-9 into acetal ruc-10 (Scheme 2) rings D and E are constructed in the most critical step of the entire synthesis. A transannular iminium ion cyclization [7,13] provides predominantly ruc-12 in 65 % yield with remarkable regio- and stereoselectivity. [14] It is assumed that treatment of ruc-10 with mercury(I1) acetate in acetic acid leads primarily to the cyclic iminium ion ruc-11, which then gives ruc-12.

272

Applications in Total Synthesis

7a R=SPh

Scheme 2. (a) PHSCHzCOzH, bis(2-oxo-3-oxazolidinyl)phosphinic acid (BOPCI), Et3N, CHzC12; (b) NaH, THF; (c) rn-chloroperbenzoic acid (MCPBA), CHzC12,O "C; (d) trifluoroacetic anhydride (TFAA), 2,6-di-tert-butyl-4methylpyridine; (e) HgO, CdC03, THF, H20; (f) BrCHzCHzOH, 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU), C7Hs; (g) BH3 . THF; (h) NazC03, MeOH, 65 "C.

8

+

7b R = g S T o l 0-

9

10 7

11

12

-@ ab

\

H

=

12

03

c,d,e_

\ HO : @

16

R

C02Me

13a: a-C02Me 13b : P-C02Me

H i H

14 R = gS02C6H40Me

h-m

H*

R

OTIPS

15 R = pSO2CBH4OMe

OR'

R

CHO

16 R'=TBDMS 17 R ' = H R = gSO2C6H4OMe

Scheme 3. (a) Zn, HzS04, MeOH; (b) MeONa, MeOH; (C) p-MeoC6H4So~C1, EtNiPr2, 4-dimethylaminopyridine (DMAP), CHzCl,; (d) LiBH4, THF, HN(CHzCHz0H)z; (e) HC104; (f) triisopropylsilyltrifluoromethanesulfonate (TIPSOTO, DBU, CH2C12; (g) (Et0)zP(O)CHzCN, potassium hexamethyldisilazide (KHMDS), THF, 25 "C; (h) diisobutylaluminium hydride (DIBAL), CHzC12, H30+; (i) NaBH4, MeOH; (i) 2 N HCl, MeOH; (k) tertbutyldimethylsilyltrifluoromethanesulfonate (TBDMSOTf), DBU, CHzClZ, -20 "C; (1) so3 . C S H ~ NDMSO, , Et3N; (m) pyridine, HF.

New Total Syntheses of Strychnine

A number of steps are required for the conversion of rac-12 into the cyclic hemiacetal rac-14 (Scheme 3). This compound is important to the rest of the synthesis, since it cannot only be prepared from tryptamine (3) and dimethyl 2-ketoglutarate (4), but can also be obtained readily in substantial amounts and in enantiomerically pure form by degradation of strychnine. As soon as enough of this relay hemiacetal has been secured, assembly of the G ring can be tackled. Since just a compound with an (E)-configuration double bond as in 17 can be used for the synthesis of the G ring, the construction of the hydroxyethylidene double bond must be diastereoselective. This very problem had challenged Woodward et al., and like those pioneers Magnus et al. were also foiled: WittigHomer reaction furnishes the a$-unsaturated cyanide 15 as a 2:3 mixture of the (Z) and (E> isomers. Although the undesired (Z) isomer can be isolated and isomerized photochemically to give a mixture of both isomers, this step is far from being optimal. The next steps in the synthesis include the multistep conversion of (E)-15 into 16, subsequent cleavage of the silyl ether protecting group, and cyclization of 17, which cannot be isolated, to provide hexacyclic 18. With the reductive removal of the sulfonamide Magnus et al. arrived at their first goal, the total synthesis of the Wieland-Gumlich aldehyde (2). The conclusion of the total synthesis of strychnine is also within reach; the authors succeed in converting 2 into the natural prod-

18 R = pS02CBH,0Me 2 R=H Wieland-Gumlich aldehyde

213

uct in a one-step reaction with malonic acid, following the method of Robinson et al. [15] With 27 steps this synthesis is only negligibly shorter than Woodward’s 28-step synthesis from 1954. But Magnus et al. achieved an overall yield of roughly 0.03 %, which is more than 1000 times greater than Woodward’s overall yield of 0.00006 %. This result would have been impossible without powerful new synthetic methods. Magnus’ synthetic strategy has a classical form, and he prepared enantiomerically pure compounds very effectively by traditional means, namely via a relay compound obtained by degradation of the natural product itself. The third total synthesis of strychnine (l), so far the only enantioselective route to the natural product, was accomplished by Overman et al. [lo] The key to their approach to 1 is the sequential cationic aza-Cope rearrangementMannich cyclization, which is frequently employed with success in alkaloid synthesis. With the synthesis of akuammicine rac-19 the authors proved that this strategy offers an efficient route to the strychnos alkaloids. [8g] The crucial compound in this strychnine synthesis is azabicyclo[3.2. lloctane 31, which is the substrate for the aza-Cope-Mannich sequence (Scheme 4).In the preparation of 31, meso-diester 20 is subjected to acetylcholine esterase catalyzed hydrolysis to yield 21 with high enantiomeric purity. Eighteen ensuing steps then provide 31 in 14% yield. The allylic carbonate obtained from 21 is

19 Akuammicine

274

d 91%

Applications in Total Synthesis

ul:*

C02R

AcO Ot Bu

+

GI

Of Bu

0

MeNKNMe

2,5% Pd2dk, 22% Ph&, CO, LiCI, NMP, 700C

$ 8"

b

80%

Me3Sn

27

28

Ot Bu

R2N

X=NHCOCF,

/ \

29

NRZ

30

0

1,)

MeNKNMe NR2=

P4 62%

HO

o/"" 31

-I

CQEt

f BuO

0

22

Scheme 4. (a) ClCOZMe, pyridine, CHzClz, 23 "C; (b) tBuOCHzCOCHzCOzEt (22), NaH, 1 % [Pd2(dba)3], 15 % PPh3, THF, 23 "C; (c) NaCNBH3, TiC14, -78 "C; (d) dicyclohexylcarbodiimide (DCC), CuC1, C6H6, 80 "C; (e) DIBAL, CHzClz, -78 "C; (f) TIPSCI, tetramethylguanidine, N-methyl-2pyrrolidone (NMP), -10 "C; (g) Jones oxidation, -5 "C; (h) L-Selectride, PhNTfi, THF, -78 "C + 0 "C; (i) MesSnz, 10% [Pd(PPh3)4], LiCl, THF, 60°C; (i) tBuOzH, Triton-B, THF, -15°C; (k) Ph3P=CHz, THF, 0 + 23 "C; (1) tetrabutylammonium fluoride (TBAF), THF, -15 "C; (m) methanesulfonyl chloride (MsCl), iPrzNEt, CHZClz, -23 "C; (n) LiC1, DMF, 23 "C; ( 0 ) NHzCOCF3, NaH, DMF, 23 "C; (p) NaH, C6H6, 100 "C; (4) KOH, EtOH-H,O, 60 "C.

New Total Syntheses of Strychnine

used in a palladium-catalyzed allylic substitution with 22 to furnish the cis products 23, which are reduced with high diastereoselectivity (> 20 : 1) in accord with the Felkin-Anh model to provide a mixture of the trans$hydroxy esters 24. Subsequent syn elimination affords the ( E ) isomer 25 almost exclusively (97 : 3). In this way Overman et al. succeeded in solving the problem of the stereoselective construction of what will become the allylic ether double bond at C20 of the natural product early in the synthesis. The next important intermediate is the a,p-unsaturated ketone 29, which is accessible by the palladium-catalyzed, carbonylative cross-coupling of vinyl stannane 27 with the triazone-protected oiodoaniline 28. In turn, 27 is prepared by the palladium-catalyzed Stille coupling of the enol triflate obtained regioselectively from 26. The key step in the transformation of 29 into 31 is the stereoselective, intramolecular aminolysis of epoxide 30, which is the product of the substrate-controlled stereoselective epoxidation and subsequent Wittig methylenation of 29. Now the aza-Cope-Mannich cascade must be triggered, in other words, amine 31 must be converted into the corresponding formaldiminium ion 32 (Scheme 5). This is achieved by reaction with paraformaldehyde without added acid. Intermediate 32 undergoes cationic [3,3] sigmatropic rearrangement under these reaction conditions to give 33, which contains all the structural features that are required for the ensuing intramolecular Mannich cyclization. At the end of the sequence 34 is obtained stereoselectively and almost quantitatively (98 % yield) - an outstanding example of the efficiency and flexibility of this synthetic strategy. The cyclization product 34 is then acylated with methyl cyanoformate, and cleavage of the triazone protecting group affords pentacycle 35, which contains all of the C atoms required for the synthesis of the Wieland-Gumlich aldehyde 2. The conversion of 36 into strychnine (1) by conventio-

275

nal means is the concluding step in the first synthesis of this natural product proceeding without the resolution of racemates and without relay compounds. Overman et al. accomplish this in a total of 25 steps and with an overall yield of approximately 3 %. This first enantioselective total synthesis is achieved in excellent yield. But just as impressive is the underlying retrosynthetic analysis, which is then followed by combining several modern palladium-catalyzed reactions and the elegant aza-Cope-Mannich sequence, a distinctive feature of Overman’s work. In an extension of this work Overman and his group have achieved the total synthesis of unnatural strychnine (ent-1) as well. [lob] Their approach is based on the palladium catalyzed coupling of the hydroxy acetate 21 with the sodium salt of 22 followed by acetylation to yield the cyclopentenyl keto ester ent-23. This intermediate was readily converted to unnatural strychnine (ent-1) following the chemistry developed in the natural series. The beginning of Kuehne’s total synthesis of racemic strychnine rac-1 [ 111 is promising, since the highly diastereoselective construction of the tetracycle rac- 42 from tryptamine 38 and butenal 39 proceeds in just one synthetic operation (Scheme 6). The yield for this novel and efficient sequential reaction is 51 % after cleavage of the acetal to provide aldehyde ruc-43. Presumably the cyclizing Mannich reaction leading to ruc-40 is followed by a [3,3] sigmatropic rearrangement giving ruc-41, which in turn undergoes acid-catalyzed cyclization to afford rac- 42. This new method also provides access to the indolenine ruc-44, [8fl a compound containing all but two carbon atoms of ring C of the target molecule. However, it has not been possible so far to employ the furan ring in 44 to construct rings F and G in strychnine. This is why Kuehne et al. relied on ruc-42 in their approach to the natural product.

276

Applications in Total Synthesis

PtBu

1

ptBu

32

34

33

35

36 a - C 0 2 M e 37 B-co2Me Scheme 5. (a) Lithium diisopropylamide (LDA), NCCOZMe, THF, -78 "C; (b) 5 % HCl-MeOH, reflux; (c) Zn, 10 % HzS04-MeOH, reflux; (d) NaOMe, MeOH, 23 "C; (e) DIBAL, CHzCIz, -78 "C; (f) CHZ(CO~H)~. AczO, NaOAc, HOAc, 110"C.

This entailed the lengthy and difficult successive construction of the three missing rings F, G , and C. The synthesis of the F ring is the least troublesome, as it succeeds in only three steps and with 67 % yield (ruc-45 -+ ruc-47) (Scheme 7). The key step is the intramolecular nucleophilic ring-opening of the unisolated epoxide ruc-45; the thermodynamically controlled reaction yields ruc- 46 exclusively. In contrast to Magnus and Overman, who directed their syntheses towards the WielandGumlich aldehyde ruc-2 and its straightforward conversion into strychnine ruc-1,

Kuehne focussed on the synthesis of isostrychnine ruc-53 (Scheme 8) and had to rely on the isostrychnine - strychnine transformation, which Woodward had already recognized as being exceptionally difficult. First, ring C is assembled. The key step is the intramolecular Claisen reaction of the acetamido ester ruc48 to give ketolactam ruc-49. Although the overall yield for the construction of the C ring is good (ruc-47 + ruc-51), the eight steps are relatively laborious. In the next part of the synthesis Kuehne, like Magnus, learned by experience that the (@-selective construction of the allylic ether group at C20, which

New Total Syntheses of Strychnine

qkH CHzPh

+

H

BFaEt20

oHc$oMe

C0,Me

GHa, 110'C. 18h

L

OMe

38

39

1 .

40

41

10% HCIO,

THF, 2PC, 5h

9

51% H

C0,Me

42

RCH(OMe)Z

43

R=CHO

Me3S+I-, n BuLi THF

44

Scheme 6.

-

9

COzMe

H

43

& & H

'",O

C02Me

45

Scheme 7.

277

278

Applications in Total Synthesis LiN(SiMe,), THF. 66OC

47 a,b,c_ 83%

48

49

d,e

wH P

"OAc

(48-50)

OAc

51

50

\

N

87%

rl5\

H I

0

52

H

C02Me

N

\

H I

\ H

0

28% 85OC ,EDH

-

1

OH

53 lsostrychnine

Scheme 8. (a) NaBH&N, HOAc, 23 "C; (b) AczO, pyridine; (c) NaOMe, MeOH, 0 "C; (d) NaBH4, MeOH; (e) AczO, pyridine; (f) DBU, dioxane-Hz0, 100 "C; (8) Swern oxidation; (h) (EtO)ZP(O)CHzC02Me, KN(SiMe&, THF, 23 "C, 2 h; (i) hv; (i) DlBAL, BF3 . EtzO, -78 "C.

is critical for closure of the G ring, is not possible at such a late stage of the synthesis. Wittig olefination of ruc-51 provides a 1 : 1 mixture of the (0 and (Z) isomers of ruc-52, which can be enriched by irradiation in favour of the required (0-acrylic ester (8: 1). The reduction of (E)-ruc-52 to isostrychnine ruc53 is straightforward; as expected, however, the last step of the synthesis, the problematic conversion of isostrychnine ruc-53 into strychnine ruc-1, could not be solved in a satisfactory manner: strychnine ruc-1 was isolated in only 28 % yield in addition to 61 % unreacted starting material. One could argue that not every step in Kuehne's synthesis proceeds with the desired selectivity and yield and that the synthesis is not enantioselective. Yet it should be stressed that this synthesis, designed around a new and efficient key sequence, is one of the shortest routes to

strychnine ruc-1 with 17 steps and an overall yield of roughly 2%. The efficiency of the synthesis could also be improved by avoiding the isostrychnine - strychnine conversion and the consequent time-consuming assembly of the C ring. A strategy combining the advantages of both the intramolecular Diels-Alder reaction and the intramolecular Heck reaction was successfully tested in Rawal's synthesis of ruc-1. [12] Heating precursor ruc-59, which is prepared from 54 in eight steps, [8i] to 185 "C provides tetracycle ruc-60 in 99 % yield as the sole product of the Diels-Alder reaction (Scheme 9). The rapid construction of the C ring by intramolecular amide formation in only two steps is also remarkable. Allylation of ruc-61 with 62 furnishes ruc-63. Subsequent intramolecular Heck reaction leads to the diastereoselective ring closure providing

New Total Syntheses of Strychnine

279

ii MeO&

I

Me02C

59

60

@fjH +

B

rI

k

y CHZOTBS

___)

1-( 74%

0

61

H

0

63

62

-

67%

1

OH

53

Scheme 9. (a) BrCHZCHzBr, 50 % NaOH, CH3CN, nBu4NBr, 23 "C; (b) DIBAL, C7H8, -78 "C, H3O+; (c) BnNH2, EtzO; (d) MesSiCl, Nal, DMF, 60 "C; (e) ClCOZMe, acetone, 23 "C; (f) 10 % PdC, HCOzNH4, MeOH; (g) 23 "C; (h) ClCOZMe, PhNEtz; (i) MesSil, CHC13, 61 "C, 5 h; 0) MeOH, 65 "C, 6 h; (k) DMF, acetone, K2C03; (1) Pd(OAc)z, Bu4NC1, DMF, KzC03,70 "C, 3 h; (m) 2 N HCl, THE

280

Applications in Total Synthesis

the bridged piperidine system with retention efficient synthesis of strychnine and strychnos of stereochemistry at the double bond of the alkaloids will continue. vinyl iodide. Deprotection concludes this hitherto shortest synthesis of racemic isostrychnine ruc-53 which has 14 steps and a References 35% yield. But Rawal et al. are confronted with the problem of the inefficient final trans[I] L. Lewin, Die Pfeilgifte, J. A. Barth, Leipzig, formation to give ruc-1. If one assumes Kueh1923. ne’s reported yield of 28 % for this step, [16] [2] a) Betz, Angew. Chem. 1985, 97, 363; Angew. Chem. Int. Ed. Engl. 1985,24, 365; b) E. Teuthen Rawal formally achieves the synthesis scher, U. Lindequist, Biogene Gifte, Gustav of the natural product - in racemic form, Fischer, Stuttgart, 1987; c) Allgemeine und though - in only 15 steps and with almost spezielle Pharmakologie und Toxikologie 10 % yield, which is in the range of Kuehne’s (Ed.: W. Forth), 5th ed., Bibliographisches and Overman’s results. Institut & F. A. Brockhaus, Mannheim, 1987. Whether the four new total syntheses repre[3] P. J. Pelletier, J. B. Caventou, Ann. Chim. sent a fundamental improvement over WoodPhys. 1818, 8, 323. ward’s strychnine synthesis can certainly be [4] a) H. T. Openshaw, R. Robinson, Nature 1946, debated, as well as the extent of this improve157,438; b) R. B. Woodward, W. J. Brehm, A. L. Nelson, J. Am. Chem. SOC. 1947, 69,2250. ment. It cannot, however, be contested that [5] a) J. H. Robertson, C. A. Beevers, Acta Overman et al. accomplished the first and Ciystallogl: 1951, 4, 270; b) C. Bokhoven, only enantioselective synthesis of the natural J. C. Schoone, J. M. Bijvoet, Acta Crystalproduct, and that Kuehne and Rawal with logr. 1951, 4, 275; c) A. F. Peerdeman, Acta their respective 17- and 15-step syntheses Ciystallogl: 1956, 9, 824. devised approaches with markedly fewer reac161 a) R. B. Woodward, M. P. Cava, W. D. Ollis, tion steps than Woodward’s 28-, Magnus’ 27A. Hunger, H. U. Daeniker, K. Schenker, and Overman’s 25-step syntheses. The conJ. Am, Chem. SOC. 1954, 76, 4749; b) siderable improvement in the overall yields Tetrahedron 1963, 19, 247. relative to that of the first total synthesis is [7] Reviews: a) J. Bosch, J. Bonjoch in Studies in Natural Product Chemistry. Vol. 1. Stereosealso noteworthy. Whereas Magnus improved lective Synthesis (Part A) (Ed.: Atta-ur-Rahthe yield by a factor 1000, Overman, Kuehne man), Elsevier, Amsterdam, 1988, p. 31; b) and Rawal upped the overall yield by a factor G. Massiot, C. Delaude in The Alkaloids, of 100OOO! These impressive numbers cannot Vol. 34 (Ed.: A. Brossi), Academic Press, be attributed solely to improved synthetic New York, 1988, p. 211. methods and modern reagents, but emphasize [8] a) J. Bonjoch, D. SolC, J. Bosch, J. Am. Chem. the importance that sequential reactions [ 171 SOC. 1995,117, 11017; b) J. Bonjoch, D. SolC, have achieved in the construction of complex J. Bosch, J. Am. Chem. SOC. 1993, 115, 2064; natural products. c) M. Amat, J. Bosch, J. Org. Chem. 1992, The four new total syntheses demonstrate 57, 5792; d) G. A. Kraus, D. Bougie, Synlett 1992, 279; e) M. E. Kuehne, C. S. Brook, that some of the difficulties in the synthesis D. A. Frasier, F. Xu, J. Org. Chem. 1995, 60, of strychnine, such as the diastereoselective 1864; 0 R. L. Parsons, J. D. Berk, M. E. construction of the double bond at C20, can Kuehne, J. Org. Chem. 1993, 58, 7482; g ) now be solved elegantly, but that others like S. R. Angle, J. M. Fevig, S. D. Knight, R. W. the isostrychnine - strychnine conversion Marquis, Jr., L. E. Overman, J. Am. Chem. remain unsolved. Thus it can be expected SOC. 1993, 115, 3966; h) J. M. Fevig, R. W. that the search for improved solutions for the Marquis, Jr., L. E. Overman, J. Am. Chem.

New Total Syntheses of Strychnine SOC. 1991, 113, 5085; i) V. H. Rawal, C. Michoud, R. F. Monestel, J. Am. Chem. SOC. 1993, 115, 3030; j ) H.-J. Teuber, C. Tsaklakidis, J. W. Bats, Liebigs Ann. Chem. 1992, 461; k) J. Nkiliza, J. Vercauteren, J.-M. LCger, Tetrahedron Lett. 1991, 32, 1787; 1) D. B. Grotjahn, K. P. C. Vollhardt, J. Am. Chem. Soc. 1986, 108, 2091; m) D. B. Grotjahn, K. P. C. Vollhardt, J. Am. Chem. Soc. 1990, 112, 5653; n) S. F. Martin, C. W. Clark, M. Ito, M. Mortimore, J. Am. Chem. Soc. 1996,118, 9804. [9] a) P. Magnus, M. Giles, R. Bonnert, C. S. Kim, L. McQuire, A. Merritt, N. Vicker, J. Am. Chem. SOC.1992, 114, 4403; b) P. Magnus, M. Giles, R. Bonnert, G. Johnson, L. McQuire, M. Deluca, A. Merritt, C. S. Kim, N . Vicker, J. Am. Chem. Sac. 1993, 115, 8116. [lo] a) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. SOC. 1993, 115, 9293; b ) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1995, 117, 5776.

28 1

[ll] M. E. Kuehne, F. Xu, J. Org. Chem. 1993,58, 7490. [12] V. H. Rawal, S . Iwasa, J. Org. Chem. 1994,59, 2685. [13] J. Harley-Mason, Pure Appl. Chem. 1975,41, 167. [14] Typically rac-12 was obtained in 50% yield Pbl. [15] F. A. L. Anet, R. Robinson, Chem. Ind. (London) 1953, 245. [ 161 The authors do not give a yield for the conversion of isostrychnine rac-53 into strychnine rac-1. [17] a) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137; Angew. Chem. Int. Ed. Engl. 1993, 32, 131; b) L. F. Tietze, Chem. Rev. 1996, 96, 115.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Total Syntheses of Zaragozic Acid Ulrich Koert

Who is nowadays not aware of the negative effects on health of high cholesterol levels in blood? Atherosclerosis, hypertension, and myocardiac infarction can be the consequences

of this metabolic disturbance (Scheme 1). [l] On the one hand the diet influences the cholesterol level exogenously, on the other hand the body builds up cholesterol endogen-

Atherosclerosis, hypertension, myocardial infarction

t

Blood lipids

t I

endogenous

exogenous

Cholesterol

diet

Squalene +-+ Farnesyl diphosphate

t

Mevalonate

3-Hydroxy-3-methylglutary I-CoA

Squalene-synthaseinhibitors Zaragozic Acids

-

HMG CoA reductaseInhibitors Mevinic Acids Cornpactin, Lovastatin

Scheme 1. Cholesterol in the human body: endogeneous build up, exogeneous introduction, and pathological consequences.

Total Syntheses of Zaragozic Acid

283

ously. The biosynthetic pathway of cholesterol begins with a branching of the citric acid cycle. Starting from 3 -hydroxy-3 -methylglutaryl-(HMG)-CoA, farnesyl-diphosphate is formed via mevalonate. The coupling of two molecules of farnesyldiphosphate yields squalene, which is then converted into cholesterol. If this endogenous production of cholesZaragozic Acid C 1 terol could be reduced, it would be of signi~--- -.. ---~. ficant therapeutic use. With the discovery of -. 0 the mevinic acids almost 15 years ago, an enzyme inhibitor for an enzyme participating in cholesterol biosynthesis, namely HMGCoA reductase, was found for the first time. Ph Today lovastatin, simvastatin, and pravastatin are standard components of the battery of pharmaceuticals. Zaragozic Acid A 2 Now a group of recently discovered natural (Squalestatin S l ) products that inhibit another enzyme, squalene synthase, has become the focal point citric acid molecule (Fig. lb) in a frozen conof attention: the zaragozic acids. In 1992 re- formation. Thus, the binding site of squalene searchers at Merck, Sharp and Dohme, [2] synthase for zaragozic acids could be one for and Glaxo [3] independently reported the dis- citric acid. The biological activity of zaragozic acids covery of a new family of natural products with squalene synthase inhibiting properties. and the complexity of their structures have The Merck group gave the new compounds attracted the attention of numerous synthetic the name zaragozic acids after the Spanish city of Zaragoza in which they had been a) 0 OH found for the first time in fungal cultures. The Glaxo researchers named the new comHO2C &cl-sK pounds squalestatins after their squalene synHO2C 3O2 thase inhibiting effect. HO CO2H Representative compounds of this new group of natural products are zaragozic acid C (1) and zaragozic acid A (2) ( = squalestatin Sl). All zaragozic acids share a common 2,8dioxabicyclo[3.2.lloctane skeleton (Fig. la), which is extremely polar as a result of three carboxyl groups in positions 3, 4, and 5 as Ho2& well as three hydroxyl groups at C4, C6, and b) HO2C Ph C7. An alkyl side chain (CH2-C1-SK) is "0c02H found at C1 and a fatty acid side chain at C 6 - 0 (C6-0-SK-CO). The spatial arrange- Figure I . (a) Structure of the zaragozic acids with ment of the three COOH groups and the OH the 2,8-dioxabicyclo[3.2.l]-octane skeleton (red); group at C4 is remarkable. This arrangement (b) conformationally frozen citric acid partial strucof functionalities corresponds to that of a ture (blue) in zaragozic acid C.

C6-o-SKYo

284

Applications in Total Synthesis

precursor of the dioxabicyclo[3.2. lloctane 4. The retrosynthetic cut between C1 and the adjacent C atom of the C1 side chain yields the building blocks 9 and 10. These two syntheses have the common feature that the dioxabicyclo[3.2. lloctane is constructed inclusive of the carboxyl functions. A different route was followed by Carreira. In this the three carboxyl groups are introduced after the completion of the dioxabicyclo[3.2.1]octane. Thus, compound 4 is traced back to the tetraol 11, which should be accessible from the acyclic precursor 12. The cleavage of the Cl-C7 bond leads to the building blocks 13 and 14. Compared with the strategies of Nicolaou and Evans, Carreira thus has the chance to rapidly assemble the dioxabicyclo[3.2.l]octane. However, as it turned out the construction of the three carboxyl functions requires a considerable number of steps at the end of the synthesis. In all three

chemists within a very short space of time. [4] At the end of 1994, three total syntheses were published: one by Carreira et al. (zaragozic acid C), [5] one by Nicolaou et al. (zaragozic acid A), [6] and one by Evans et al., which was carried out in collaboration with researchers at Merck, Sharp and Dohme (zaragozic acid C). [7] These three syntheses are compared in this highlight. Scheme 2 shows the three retrosyntheses of zaragozic acids 3. All three research groups introduce the acyl side chain at C 6 - 0 as the last step. Thus, the alcohol 4 is obtained as the precursor of the complete molecular skeleton 3. Apart from that, the synthetic pathways differ. Nicolaou derives the dioxabicyclo[3.2.1]octane skeleton from the ketone 5, which can be split into the two building blocks 6 and 7 by cleavage of the Cl-C7 bond. The synthetic strategy of Evans regards the ketone 8 as the

HO dOzH

u

I 9

U

a

4

5

/r

11

lo

Carreira

12

Scheme 2. Comparison of the retrosyntheses by Nicolaou, Carreira und Evans.

13

14

Total Syntheses of Zaragozic Acid

syntheses, the dioxabicyclo[3.2. lloctane skeleton is obtained by acetal formation of a 4,6 -dihydroxyketone by using standard procedures. The efficiency with which the acyclic precursors 5 , 8, and 12 with their five stereogenic centers can be assembled will be important in the assessment of the syntheses.

285

The synthesis of zaragozic acid A [5] by Nicolaou is summarized in Schemes 3-7. Four of the five stereogenic centers are constructed by two stereo-selective Sharpless dihydroxylations (Scheme 3). In the first, the diene 20, which is synthesized in a few steps from the simple building blocks 15-18, is

OH
Me02C

17 1. PMBCI, NaH

n Bu~NI,DMF

2. Bu3SnH, Pd(PPh3)zCb THF, 25 OC, 17h

PMBOp2SnBu3

78%

i

C6H6

25 OC 24 h

Me02C

19

16

20

21

2-Methoxypropene PMBo PPTS, CHzCls PMBO 12h, O°C

-*

18

DDQ, CHCIfizO 20:1,12h, 25 OC

Me0 88%

86%

22 0 ~ 0 4NMO , THF/ t BLOWH20 l:l:l, 18h, O°C

OSEM 83%

23

24

Scheme 3. Total synthesis of zaragozic acid A (2) by Nicolaou, part 1.

Applications in Total Synthesis

286

'0

TBDPSO--,,, OSEM

1.3 imidazole, eq. TBDPSCI, DMAP,

0G

O

S

E

M

o0xo

89%

24

25

1. Dess-Martin

3. N,N'-Dayclohexyl-O benzylisourea

OSEM

1.2 eq. TBAF, 2 eq. HOAc THF, 2h, 0 OC

*

96%

*

96%

26 1. Dess-Martin reagent 2. NaC102, NaHzP04, 2-Methyl-2-butene, t BUOH/H~O 3. N,N'-Dicyclohexyi-O benzylisourea

HO-

d4-EM ooxo

65%

27

28

TFA, CHzCI$

1. CH3N(TMS)COCFs 2. cat. PPTS, CH2CIz,MeOH

5 min, 25 OC

3. Dess-Martin

80%

88%

29

converted enantioselectively to give the diol 21 (20% yield, 78% ee); in the second the olefin 23 is diastereoselectively dihydroxylated, and the product undergoes spontaneous lactonization to give 24 (83% yield, as a single diastereomer after crystallization). In the subsequent 12 steps (Scheme 4) the two primary alcohol functions in 24 are oxidized to carboxyl functions and protected as benzyl esters. After trimethylsilyl(TMS)-protection of the OH group at C4 Nicolaou then obtains the aldehyde 30. Addition of the lithium compound prepared from the dithiane 31 to the C1 side chain (Scheme 5 ) of 30 deli-

30

Scheme 4. Total synthesis of zaragozic acid A (2) by Nicolaou, part 2.

vers, with the formation of the alcohol 32, the missing fifth stereogenic center. This addition is however unselective: two epimeric alcohols are formed (total yield 75 % in a 1 : 1 ratio) and must be separated by chromatography. Removal of the thioacetal function in 33 leads to the hemiacetal34. Under carefully worked out acidic conditions the lactone hemiacetal 34 rearranges into the dioxabicyclo[3.2. lloctane 35 (Scheme 6). By changing the alcohol protecting group and exchanging the methyl ester for a benzyl ester the diol 38a is obtained, whose C6-OH function is esterified with the

Total Syntheses of Zaragozic Acid

287

ODTBMS

30

31, nBuLi, THF, - 30 OC, 1.5 h, then 30, -78 OC, 5 min

31

75%

32 2% HCI in MeOWCH2CI21:l

33 Hg(CI04)2,CaC03 THFIHpO 5:1,25 'C, 2h 83%

OH

ODTBMS

34

carboxylic acid 38b leading to the formation of the tetraester 39.The latter already contains the complete skeleton of zaragozic acid A. In this esterification the C6- and the C7-OH group can react. The selectivity of 3 : 2 in favor of the desired C 6-OH group established by Nicolaou is rather low. Starting from 39 protecting group manipulations (5 steps, Scheme 7) gave the target compound zaragozic acid A (2). The synthesis of zaragozic acid C (1) by Carreira [6] is given in Schemes 8-10. This

Scheme 5. Total synthesis of zaragozic acid A (2)

by Nicolaou, part 3.

synthesis starts from D-erythronic-y-lactone (42), a compound from' the chiral pool. An impressive feature of the synthesis is the conversion of the amide 43 into the alcohol 44 (Scheme 8): The reaction of ethoxyvinyllithium with the dimethylamide 43 can be stopped at the ketone intermediate. The subsequent reaction of the carbonyl function with the organomagnesium compound prepared from TMS-C=CH proceeds stereoselectively (20 : 1). The vinyl ether group in 44 is a latent ester function: the ozonolysis of 44 in ethanol

288

Applications in Total Synthesis

HO

OH Ph

Bn02C M HOC02Bn e O

2

1. LiOH, THF/HzO 2 3 , 25 OC, 1h 2. N,N'-DicyclohexylObenzylisourea THF, 55 OC, I.5h

W

CCI&(OPMB)=NH, CSA, CH&

Ph

____)

37

74%

21%

36

Scheme 6. Total synthesis of zaragozic acid A (2) by Nicolaou, part 4.

....

....

1. TESOTf, Py C H ~ C I22 ~ ,O C , 20 min

0 BnOzC B

0

... ..

-

.

.... 0

2O:l. 22 "C. 1 h

2

WPh

HOCOzBn

.. ...

. ..

2. DDQ, CH&/H2O

OH

n

. . .

39

OTES

B n 0 BnOZCHOC02Bn

77%

. ..

I . Ac20. Py, DMAP, CH2C12, 22 OC. 4h Z.TBAF, THF 2

w Ph

40

. ..

o OC,

-*

15 mln

84%

BnozM 0

10% PdIC,

1,4-cycIohexadiene dioxane. 110 C :' '

0 OH Bn02C HoCozBn

41

Ph

50%

HOzC

Ph

Zaragozic Acid A (2)

Scheme 7. Total synthesis of zaragozic acid A (2) by Nicolaou, part 5.

Total Syntheses of Zaragozic Acid

289

2. TMSCCMgBr, THF

42

43

45

46

44

1. TBDMSCI, EQN

47

‘

1. BuLi, LiBr

Ph

then 48, THF 2. Dess-Marlin

Ph

4a 86%

0 49

1. OsO,, NMO

(DHQD),PHAL

ph

2. HCI,MeOH

90%

50

OPiv

BnO H & o

Ph

OH

51

Scheme 8. Total synthesis of zaragozic acid C (1) by Carreira, part 1.

affords the ethyl ester 45. Subsequently the To construct the missing quaternary center terminal acetylene 47 is obtained via 46 by a C4 Carreira transforms the compound 51 into standard sequence. The C1 side chain is atta- the ketone 53 (Scheme 9). The addition of ched through the coupling of 47 with the alde- lithiated TMS-C=CH to the carbonyl funchyde 48 to give the ketone 49. The two stereo- tion of 53 to give the alcohol 54 is achieved genic centers still missing are produced by with a stereoselectivity of 86: 14. At this Sharpless dihydroxylation of the olefin 50 ob- stage the pivaloyl protecting groups are tained after the oxidation and removal of the replaced by acetyl protecting groups and silyl protecting groups. Without a chiral the triple bond is reduced to a double bond ligand stereoselectivity cannot be achieved to give compound 56 in this bishydroxylation step. With a chiral Carreira now oxidizes the two primary alcoligand, the diol is formed in a reagent-con- hol groups sequentially to give the carboxyl trolled reaction in the ratio 64 : 36 in favor of functions (56 -+ 57 -+ 58, Scheme 10). The the desired stereoisomer. In the subsequent third carboxyl function is formed by ozonolysynthetic step, the diol is cyclized under sis and subsequent oxidation of the aldehyde acidic conditions to give the dioxabicyclo- (58 + 59). This is followed by a remarkably selective hydrolysis of the triacetate 59 to [3.2.l]octane acetal (51).

Applications in Total Synthesis

290

1. TBDMSCI, Et3N

OPiv BnO

83%

OH

1. Hz, Pd(0H)z-C

DMAP, CHzClz 2. PivCI, DMAP, CICHzCH2Cl.50 'C

PivO

OPiv

BnO

TBDMso%

Pd-CaCO, 2. (COCI)2. DMSO Et3N. CH2CIz

OPiv Ph

OTBDMS

51

89%

52 1. AgN03, 2.6-iutidine

PivO

TBDMso*ph 0

2. DIBAH. toluene

OPiv OPiv

0 OTBDMS

TMSCCU,

3. Ac2O, Py.

OPiv

DMAP, CH& Ph

78%

53

76%

54

TBDMS(

55

56

Scheme 9. Total synthesis of zaragozic acid C (1) by Carreira, part 2.

give the monoacetate 60 in 92% yield (!). With regard to his final step, the introduction of the acyl side chain at C6-0, Carreira faces the same problem as Nicolaou: how can the C6-OH group be esterified selectively in the presence of the free C7-OH group? Carreira is unable to provide a satisfactory solution to the selectivity problem. From the reaction of the diol 60 with the acid chloride 61 he obtains the regioisomeric esters in the ratio 3 : 1 in favor of the undesired isomer. The desired isomer can be isolated by chromatography and after acidic hydrolysis of the tertbutyl esters the target compound zaragozic acid C (1) is obtained. The total synthesis of zaragozic acid C (1) by Evans [7] is shown in Schemes 11 and 12. Evans identified a tartaric acid unit in the C3-C4 partial structure of zaragozic acid. Accordingly, his synthesis commences from a tartaric acid derivative (Scheme 11). The

enantiomerically pure acetal 61 is readily accessible from di-tert-butyl D-tartrate. This is transformed into the silylketene acetal 62, which reacts in a Lewis acid catalyzed aldol addition with the aldehyde 66 to give the adduct 67. The aldehyde 66 was prepared stereoselectively with the oxazolidinone method developed by Evans (64 + 65+63+66). The Dess-Martin oxidation of 67 yields the ketone 68. Addition of vinylmagnesium bromide to the keto-carbonyl function in 68 leads to the stereo-controlled construction of the quaternary center C5 with the formation of 69. The stereochemical course of this addition can be explained with a chelate-controlled transition state controlled by the adjacent benzyl ether. Next, Evans transforms the styryl group in 69 oxidatively into a carboxyl function and closes the butyric lactone ring to give 70. By the sequence 70+71 the vinyl groups is transformed into the missing

Total Syntheses of Zaragozic Acid

29 1

1. Dess-Martin

2. NaC102,NaH2P04 O-isoarnylene. THFMPO then N,N-Diisopropyl0-t-butylisourea 3.HF-Py, THF

1. Dess-Martin 2. NaC102, NaH2P0, O-lsoarnylene, THFM20 then N,N-Diisopropyl0-t-butylisourea

Ph

76%

AcO

tB

’

57

-

OAc

O-lsoamylene, THFMZO MPh

U

80%

1. 03, CH,CIfleOH 78% 2. NaCIOp, NaH2P04

56

HoC02t Bu

AcO

then 0-t-butylisourea N,N-Diisopropyl- B t U02+ tBu02C

OAc

Ph

HOC02t BU

85%

bC03 MeOH

0

58

92%

59

61 OH

I

CI 1. 61,DMAP

HO

-

p

-

h

w

CHpClp

2. TFA

tBuO2C t Bu02-

0 HOCO~tBU

Ph

Ph

87%

60

Zaragozic Acid C 1

Scheme 10. Total synthesis of zaragozic acid C (1) by Carreira, part 3.

third carboxyl function of the zaragozic acid skeleton. In the further course of the synthesis (Scheme 12) Evans attaches the side chain to C1 by the reaction of the organolithium compound accessible from the iodide 72 with the lactone 71 under the formation of 73. The replacement of the puru-meth-oxybenzyl(PMB) protecting group with an acetyl group yields the hemiacetal74. Subsequently, the hemiacetal 74 is converted under acidic conditions into the dioxabicyclo[3.2. lloctane 75. With wise foresight the C7-OH group has been protected since the beginning of the synthesis as a silyl ether with the result that the problem of selectivity between C6-OH and C7-OH does not arise in the following acyla-

tion step. The acyl side chain can thus be attached to C6-0 without any problems: the reaction of the alcohol 75 with the carboxylic acid 76 affords the desired ester 77 in 82% yield. The deprotection of 77 to give the target compound zaragozic acid C (1) is almost quantitative. A discussion of the preparation of the C1 side chains and the C6-0 carboxylic acid, which was also effected by the three research groups by different methods, is not within the scope of this highlight. The interested reader should refer to the information in the original literature. [4-71 All three total syntheses of zaragozic acid are examples of modern, efficient syntheses of natural products. The comparison of the

292

Applications in Total Synthesis BUpBOTf,

I

61 LiHMDS TMSCI, THF -78°C->OoC lh

t BuO& M O S T*@ ;

65

64 97y0

-

0 - fBU

62

(i PO)TiCI, CH2Ct2, 78 C '

+ 66 OTBDMS

-

Ph

67 20 eq. CH2=CHMgBr

Dess-Martin

-CHpCI$THF, 78OC, 10h 6:l

PY, CHzCIz

____)

94%

OTBDMS

68

Hd

76%

Ph

1 . Os04, NMO, t BUOH, THF, H p 0

G

76%

69

91%

70

Scheme IZ. Total synthesis of zaragozic acid C (1) by Evans, part I .

number of steps and the overall yields of different synthetic routes is always difficult and of only limited value. The longest linear sequence as a measure for the number of steps for the presented syntheses is 33 (Nicolaou), 36 (Carreira), and 21 steps (Evans). The overall yields are calculated to be 1 (Nicolaou), 1 (Carreira), and 15 % (Evans). Noteworthy in the synthesis by Evans is the highly selective formation of each new stereogenic center. The stereo- and regioselectivities of some of the steps in the syntheses by Nicolaou and Carreira will surely be improved. The two research groups of Carreira and Nicolaou have been the first cross the finish line in the race for the total synthesis of zaragozic acids.

L p h

OTBDMS

k

1.03. CHpC12; Me$

v

.

2

71

OTBDMS

Ph

Total Syntheses of Zaragozic Acid 1.7 eq. 72,3.4 eq. t BuLi,

71

1. DDQ.

73

72

1. CHzCb, TFA, H20,

20:10:1 2 . 7 eq. N,N'-Diisopmpyi0-Cbutyl-isourea

Ph

OH

76 .HO

OTBDMS

t B~UB O ~~Co ~ *

82%

Ph

76, DCC, DMA?, CH2C12.36h 82%

HoCOzt BU

74

t

293

75

B

tBuOpC

0

u

OTBDHS O

0

2

1. TBAF, THF o C , 15min Ph 2. TFA, CH& 24h

w

Ph

98%

0

OH

H O0 HOZC HOC02H

HoC02t BU

z

W Ph

Zaragozic Acid C 1

77

Scheme 22. Total synthesis of zaragozic acid C (1) by Evans, part 2.

References [ 11 Goodman and Gilman's The Pharmacological

Basis of Therapeutics 8th ed. (Eds.: A. Goodman Gilman, T. W. Rall, A. S. Nies, P. Taylor) Mc Graw-Hill, New York, 1993, p. 874. [2] K. E. Wilson, R. M. Burk, T. Biftu, R. G. Ball, K. Hoogsteen, J. Org. Chem. 1992, 57, 7151-7158; J. D. Bergstrom, M. M. Kurtz, D. J. Rew, A. M. Amend, J. D. Karkas, R. G. Bostedor, V. S. Bansal, C. Dufresne, F. L. VanMiddlesworth, 0. D. Hensens, J. M. Liesch, D. L. Zink, K. E. Wilson, J. Onishi, J. A. Milligan, G. Bills, L. Kaplan, M. Nallin Omstead, R. G. Jenkins, L. Huang, M. S. Meinz, L. Quinn, R. W. Burg, Y. L. Kong, S. Mochales, M. Mojena, I. Martin, F. Pelaez, M. T. Diez, A. W. Alberts, Proc. Natl. Acad. Sci. USA 1993, 90, 80; C. Dufresne, K. E. Wilson,

S. B. Singh, D. L. Zink, J. D. Bergstrom, D. Rew, J. D. Polishook, M. Meinz, L. Huang, K. C. Silverman, R. B. Lingham, M. Mojena, C. Cascales, F. Pelaez, J. B. Gibbs, J. Nut. Prod. 1993, 56, 1923. [3] J. M. Dawson, J. E. Farthing, P. S. Marshall, R. F. Middleton, M. J. O'Neill, A. Shuttleworth, C. Stylli, R. M. Tait, P. M. Taylor, H. G. Wildman, A. D. Buss, D. Langley, M. V. Hayes, J. Antibiot. 1992, 45, 639-647; P. J. Sidebottom, R. M. Highcock, S. J. Lane, P. A. Procopiou, N. S. Watson, ibid. 1992, 45, 648; W. M. Blows, G. Foster, S. J. Lane, D. Noble, J. E. Piercey, P. J. Sidebottom, G. J. Webb, ibid. 1994, 47, 740. [4] a) V. K. Aggarwal, M. F. Wang, A. Zaparucha, J. Chem. SOC. Chem. Commun. 1994, 87;

294

Applications in Total Synthesis

b) R. W. Gable, L. M. McVinish, M. A. Rizzacasa, Aust. J. Chem. 1994, 47, 1537; c) H. Abdel-Rahman, J. P. Adams, A. L. Boyes, M. J. Kelly, D. J. Mansfield, P. A. Procopiou, S. M. Roberts, D. H. Slee, N. S. Watson, J. Chem. Soc. Chem. Commun. 1993, 1839; synthesis of the C l side chains: d) A. J. Robichaud, G. D. Berger, D. A. Evans, Tetrahedron Lett. 1993, 34, 8403; synthesis of the C6 acyl-side chain: e) C. Santini, R. G. Ball, G. D. Berger, J. Org. Chem. 1994, 59, 2261; for a recent synthesis of the core of zaragozic acids see: f) I. Paterson, K. Fessner, M. R. V. Finlay, M. F. Jacobs, Tetrahedron Left. 1996, 37, 8803; g) Y. Xu, C. R. Johnson, Tetrahedron Lett. 1997, 38, 1117. [5] E. M. Carreira, J. DuBois, J. Am. Chem. Soc. 1994, 116, 10825-10826 E. M. Carreira, J. DuBois, ibid. 1995, 117, 8106-8125. [6] a) K. C. Nicolaou, E. W. Yue, Y. Naniwa, F. De Riccardis, A. Nadin, J. E. Leresche, S. La

Greca, Z. Yang, Angew. Chem. 1994, 106, 2306; Angew. Chem. Int. Ed. Engl. 1994, 33, 2184; b) K. C. Nicolaou, A. Nadin, J. E. Leresche, S. La Greca, T. Tsuri, E. W. Yue, Z. Yang, Angew. Chem. 1994, 106, 2309; Angew. Chem. Int. Ed. Engl. 1994, 33, 2187; c) K. C. Nicolaou, A. Nadin, J. E. Leresche, E. W. Yue , S. La Greca Angew. Chem. 1994, 106, 2312; Angew. Chem. Int. Ed. Engl. 1994, 33, 2190; d) K. C. Nicolaou, E. W. Yue, S . La Greca, A. Nadin, Z. Yang, J. E. Leresche, T. Tsuri, Y. Naniwa, F. D. Riccardis, Chem. Eur. J. 1995, 1, 467; e) for a review of the chemistry and biology of the zaragozic acids by Nicolaou see: K. C. Nicolaou, A. Nadin, Angew. Chem. 1996, 108, 1732; Angew. Chem. Int. Ed. Engl. 1996, 35, 1622. [7] D. A. Evans, J. C. Barrow, J. L. Leighton, A. J. Robichaud, M. Sefkov, J. Am. Chem. SOC. 1994, 116, 12111-12112.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

The First Total Syntheses of Taxol Ludger A. Wessjohann

Introduction

of this unusual and extremely demanding molecule, a race which involved (and inIn modem chemistry it is a considerable rarity volves) over forty of the best known research for the total synthesis of a medicinally groups in the field of natural product synand commercially significant natural product thesis. Taxol and the efforts to complete its not to appear till 22 years after its complete synthesis gave rise - at least in the USA structural elucidation in 1971. Though taxol and amongst natural product chemists - to at (paclitaxel, 3a), [l] a terpenoid first isolated least as much excitement as did fullerenes in in 1962 from the pacific yew tree (Taxus physical organic chemistry, though with the brevifolia Nutt), is one of the most promising decided difference that taxol (paclitaxel) and agents against breast cancer and other types its derivative taxotere rapidly became real of cancer, it took some time before synthetic market products for the treatment of breast chemists became interested in it, for several and ovarian cancer and useful tools in cell reasons. Thus, nearly a decade elapsed before biology. Indeed, because of problems with taxol’s likely biological mode of action - an supply and limited possibilities to synthesize unusual stabilization of the microtubuli - and derivatives, its full medicinal potential has its significance for a novel cancer therapy still only been investigated to a limited extent. [ lg-i, 3, 41 were recognized (cf. [ 11). [2] Most studies of structure activity relationHowever, from the middle of the 1980s onwards, the number of synthetic attempts ships (SAR) rely on degradations of baccatin increased in an almost explosive manner. and semisynthesis. [l, 3, 41 First insights Initial milestones and still the most important into the SAR of taxol derivatives have been synthetic processes for the industrial produc- summerized in a recent article on C ring aryl tion of taxoids are semisynthetic methods in derivatives, [4] and more can be expected in which a suitable side chain is attached to bac- the near future as patented information becocatin 111 (1) to give either taxol (3a) or taxo- mes released. Total synthesis, especially in tere (3b). [la-d] Baccatin 111 is available preparing the way for the synthesis of derivafrom renewable parts of a variety of yews in tives, will be of great importance to elucidate the relationship between structure, microlarger amounts. [la-d, f, g] In the early 90’s an intense competition tubuli stabilization and anticancer activity developed to complete the first total synthesis more thoroughly. This impact of total syn-

296

Applications in Total Synthesis

thesis is exemplified by SAR-studies done on rearrangement products of intermediates of Wender’s taxol synthesis (v. i. and [3]), which could be developed into compounds with excellent microtubuli stabilization, partly exceeding that of taxol, but with a dramatically decreased cancerostatic effect, i. e. microtubuli and cytotoxic effect could be separated. [ 3 ] An initial peak of the taxol excitement was reached in 1994 when the first two total syntheses by R. A. Holton et al. [5] (Florida State University) and K. C. Nicolaou et al. [6] (University of California, San Diego and Scripps Research Institute) were published almost simultaneously. These highlights of organic synthesis will be discussed in more detail in the second part of this review, followed in a third part by a brief survey of the two other syntheses known to date, accomplished by S. J. Danishefsky et al. [7] (SloanKettering Cancer Center, New York) and by Paul A. Wender and coworkers [8] (Stanford University). What was it that made the synthesis of taxol so difficult? For a while, the assertion that every molecule that can exist can today be made, given enough manpower, [9] was almost called into question. To analyse the synthetic problem, it is useful to concentrate on the tricyclic A/B/C ring system of baccatin

I11 (l),which can be treated with 2, for example, by the method of Holton and Ojima [ Id] (Scheme 1) to give taxol (3a). [la-d] The oxetane ring (D) may be treated as a functional group. Apart from this group, the most remarkable feature is the unusual anti-Bredt double bond of the A ring. However, in contrast to normal doctrine, in this case it leads to a reduction in the total strain (ca. -1.5 kcal mol-I), whereas the very rigid, arched structure of the entire molecule is highly strained from the steric effect of the bridges dimethyl group at C15 (strain energy +I0 kcal mol-I), in cooperation with the transannular C8 -methyl group, which also projects outwards. The main problem in taxol synthesis is, then, the construction of the highly functionalized and strained eight-membered ring (B). Although the methyl groups (C16/C 19) projecting into this ring are not too close to each other in taxol (convex face), most reactions with prefabricated A/C rings bring them into too close a proximity during B ring closure reactions. In addition, the possibilities for subsequent stereoselective functionalization of the central eight-membered ring are limited, because of its rigidity and steric shielding, and because of the lability of the oxetane ring. Accordingly, in most early syntheses of the taxane skeleton (A/B/C

-

18

Baccatin 111 1. PG = H

Acq

.o

Taxol 3a, R = Bz Taxotere 3b. R = BOC

Scheme 1. Semisynthesis of taxol (paclitaxel) and taxotere from protected baccatin 111 according to Holton and Ojima (cf. [la-d]); strategic bond cleavages for the syntheses of Holton et al., [5] Nicolaou et al., [6] Danishefsky et al. [7], and Wender et al. [8] are indicated by the last names initials. PG = protecting group. [lo]

The First Total Syntheses of Taxol

rings) one of the two (or three) central methyl groups have been missing. If all of them were indeed present, it has not been possible to introduce the necessary functional groups afterwards. Alternative routes with the annulation and functionalization of a lateral ring after the B ring has been completed must be less convergent in principal. C ring annulations also will have to address the base sensitivity of the C7-C8 bond to retroaldollaldol reactions equilibrating the stereocenter at C7 in favor of the more stable unnatural epimer. The successful research groups have solved these problems very differently, but in part also with almost identical reactions. [lo]

(-)-Camphor 4

5

TESO

Dieckmann condensation

0

291

The Pioneer Syntheses of Holton and Nicolaou Holton et al. [5] first constructed the A and B rings, in a linear strategy using the elegant fragmentation of the [3.3.0] system 5 derived from P-patchoulene oxide (Scheme 2), which they had previously used for the synthesis of ent-taxusine. However, to obtain the correct enantiomeric series, they had to start extravagantly, using (-)-camphor (4). The resulting A/B fragment 6 contains the complete, homochiral A ring and all the methyl groups, as well as one oxygen functional group in both

..

6

-

TESO

ozonolysis

59 % c--

0 8

7

Chan rearrangement

31 %

TEsO

oxidation

TBSO,,,,,,,,

29 %

PhLi

7-BOMBaccatin 111

93 %

Taxol

3a

9

Scheme 2. Total synthesis of taxol according to Holton et al. [5] Taxol numbering (Scheme 1) is used. [lo]

298

Applications in Total Synthesis

the upper and lower region of the B ring for further modifications. The problematic stereocenter at C7 was constructed early, by using a diastereoselective aldol reaction with magnesium diisopropylamide and 4-pentenal. Since three of four missing C ring atoms could be introduced here in a simple manner, derivatizations will later presumably be easy at this step. C4 was provided by a carboxylic ester - initially introduced as a carbonate protecting group in intermediate 7 - through a Chan rearrangement. This was followed by a few less elegant steps for deoxygenation at C3 (SmI2) and oxidation at C1 (cf. Wender’s findings [8b]). The latter was only possible with the BIC-cis compound, by an unusual, selective enolate formation to the bridgehead C1 rather than to the doubly activated C3 - a further proof for the unusual steric and conformational characteristics of taxoids. After reduction and isomerization to the trans compound, the resulting C 1/C2 diol was quantitatively protected with phosgene (cf. 8) and, at the same time, prepared for the later formation of the benzoate at C2 by addition of phenyllithium and selective fragmentation [ 111 (cf. 9). First, however, the vinyl group had to be degraded oxidatively to give ester 8. The C ring was then closed by an effective Dieckmann condensation, and decarbalkoxylated. The remaining keto group at C4 enables the oxidation of C5, and the conversion to methylene compound 9. This last step is sterically problematic and was achieved in moderate yield by a methyl Grignard addition in dichloromethane (instead of ether) and elimination with Burgess’ reagent. Dihydroxylation afforded the precursor to the oxetane, which was obtained by nucleophilic substitution of a secondary mesyl or tosyl group (OR at CS), followed by acetylation of the remaining tertiary OH group. These steps, with substitution at the secondary carbon rather than at the primary one (as suggested by the textbooks), were similar to those used by the

other groups, [6-8a] albeit with considerable variation of the leaving groups and yields. In principle they correspond to the biosynthesis proposed by Halsall and Potier (see [l]), Finally, the upper bridge in the B ring had to be oxidized, for which benzeneseleninic anhydride was very cleverly employed. On the route to 7-BOM-Baccatin 111, the unusual release of the TBS-protected C 13-OH group with TASF [tris-(dimethy1amino)sulfur (difluorotrimethyl-silanide)] should be mentioned. Nicolaou et al., who only worked on the synthesis of taxol for about two years, [6] follow a much more convergent route (Scheme 3), which begins, however, with achiral precursors. The A-ring precursor was constructed by a Diels-Alder reaction (14 + 15) and refunctionalized to the sulfonylhydrazone 16. This reacted according to Shapiro to give the corresponding alkenyllithium nucleophile, a procedure which is reminiscent of Danishefsky’s [7] and of Funk’s synthetic routes (cf. [lb]). The C2 aldehyde group of 13 served as the electrophile and reacted diastereoselectively in excellent 82 %J yield to give the A-C coupled alcohol. Chelatedirected epoxidation of this alcohol then led to 18. Compound 13 was accessible from racemic 12, the product of the Diels-Alder reaction between 3-hydroxypyrone 11 (from muck acid) and the dienophile 10. The epoxide 18 was selectively hydrogenated at C14, and the resulting C1/C2 diol protected as the carbonate (see above). [ l l ] After oxidation of C9 and C10 to the aldehyde level, the key step followed. A wellestablished method for the construction of strained structures, the McMurry pinacol coupling, was chosen to form the top B ring bridge, which afforded the diol 17 in 23 % yield. The only other successful eight-membered ring closure starting from an “advanced” A/C system with all methyl groups in place, which was known at that time, was also based on a McMurry reaction at these positi-

The First Total Syntheses of Taxol OH

299

OBn

61 % 70 %

OH

HO

20%

"'0H 0

10

<40 &%

11

O

F

rac-I 3

rac-12

+ "kf"

37 %

N-NHS02Ar

14

15

16 oxidation + McMurry coupling (23 %)

Taxol 3a

3.4%'

/

TBSO

i'

7.2 % BHdH202 14

+ -

6H 2

oxidation

HQ

~017

!

iy

4

rac-18

Scheme 3. Total synthesis of taxol according to Nicolaou et al. [6] Taxol numbering (Scheme 1) is used. [ 101 * = yield obtained without enantiomer separation. The percentages below the retrosynthetic arrows for the compounds 10, 11 and 14 relate to their yields from readily available precursors according to the literature given in [6].

ons. It also gave yields in the lower 20% region (Kende, cf. also Pattenden). [lb] Nicolaou et al., however, stopped this reaction at the diol level, permitting further functionalization and enantiomer separation. With Kende's alkene, this was not possible. In order to construct the oxetane ring, the C5-C6 double bond was hydroborated and oxidized with moderate regioselectivity and yield. Oxetane ring closure and benzoate formation at C2 [ 111 followed as already discussed. The late, regioselective oxidation at C13,

the linkage point to the taxol side chain, is unusual and was accomplished with a very large excess of pyridinium chlorochromate (PCC, cf. also Danishefsky et al. [7]). The ketone formed was then reduced stereoselectively with borohydride. This introduction of the C13-hydroxy group into an otherwise fully functionalized baccatin derivative and the beforementioned transformation of the C 1 K 2 carbonate to the C2 benzoate probably were the most valuable contributions of this route with an impact on later approaches.

300

Applications in Total Synthesis

The Danishefsky and Wender Syntheses of Taxol

dione by the same strategy discussed for compound 16 (cf. Scheme 3). Similar to Nicolaou’s approach are the Cl-C2 coupling of the two building blocks, the oxidation at C1, Danishefsky’s synthesis (Scheme 4) [7] start- and the formation of the C 1-C2 carbonate ed from the readily available Wieland-Mie- (cf. 23). Finally formation of an enol triflate scher ketone (19) which, by a series of mainly at C11 and extension at C10 to form a vinyl protection and oxidation reactions, was trans- group set the stage for a Heck coupling reacformed to the fully functionalized C ring pre- tion of 23 to close ringB. The Heck reaction cursor 21. The oxetane moiety was introduced gave up to 49 % of tetracyclus 24, but required very early on in the synthesis, from a corre- more than equimolar amounts of palladium(0) sponding triol, again by nucleophilic substitu- and long reaction times. This is no surprise tion at C5. Noteworthy is the selective protec- considering the strain and steric impediment tion or modification of primary versus which has to be overcome during bond formasecondary versus tertiary hydroxy groups for tion and may inhibit not only the addition this purpose. The benzyl protected enolized reactions but also the subsequent elimination form 20 then could be oxidized, cleaved oxi- of palladium. At this stage it should be noted datively and processed to compound 21 that other attempts for ringclosure at this or which, apart from complete C/D rings, posses- other positions (e. g. Cl-C2 closures as final ses the necessary handles (C2 and C9/lO) to step) failed or were thwarted. Unfortunately it proved to be very difficult bind to the A ring precursor 22 and thus to functionalize and cleave the highly shielded form the B ring. Counterpart 22 was available from the em-methylene group at ClO in taxoid 24. corresponding 2,2,4 -trimethylcyclohexan-1,3 - Only after intermediate transformation of the OTBS

9.5 %

__I)

0

TMSO

oxidative

Weland-Miescher ketone

0

-

0 0

6Bn

bBn

cleavages

19

22

4

;*’

OTBS

20

21

-

Li

D

21%

23

24

Scheme 4. Total synthesis of taxol according to Danishefsky et al. [7] Taxol numbering (Scheme 1 ) is used. [lo]

The First Total Syntheses of Tax01

301

other (bridgehead) double bond to an epoxide sible six-membered rings can be used (or and reaction of the carbonate to form the C2- formed), instead of difficult eight-membered benzoate, it became accessible to oxidation ones; the strain energy hidden in the four, Pb(OAc)4]. Oxidation membered ring can inherently accomodate [equimolar 0 ~ 0 4 then at C9 and C13 were performed as discussed for the strain energy of the B ring, thus elimifor the Holton and Nicolaou syntheses, nating thermodynamic problems of linear ring respectively, and completion of the molecule closures; and the steric interaction and preorganisation in the intermediates is better. followed accordingly. It is noticable that the strategy which has Finally the Wender group succeeded with probably been chosen most often in successful such an approach, [8a] which also not only constructions of basic taxane tricycles, the proved to be the most efficient to date, but fragmentation of bicyclo[4.2.0] systems (cf. also undoubtly is the most elegant one, at e. g. 28) to yield the B ring, [la-c] was not least regarding the construction of the AJB involved in one of the first successes for fragment (Scheme 5). Wender's construction of the A/B ring a complete synthesis. The advantage of the 61416 to 618 strategy in A/B ring or BIC ring system [8a] in principle resembles the Holton construction are evident: usually easily acces- synthesis, but makes use of the 416 precursor

-

I

-

I

67 %

-

hv. MeOH

___c

76 %

25

26

28

u t

CO2Et

27

Oflkdation of enolate

29

Scheme 5. Total synthesis of taxol according to Wender et al. [Sa] Tax01 numbering (Scheme 1) used. [lo]

302

Applications in Total Synthesis

28 of the B ring instead of Holtons 5/5 precursor (5). This allows the use of readily available verbenone 25 (an oxidation product from a-pinene) to produce enantiomerically pure aryltaxanes in only six steps. [8b, d] In order to set the stage for the 4/6ringopening, verbenone 25 was premodified at C11 to give 26. It then was rearranged to the corresponding chrysanthenone derivative by a photochemically induced allylshift (cf. arrows in verbenone derivative 26), [8b-d] and further functionalized at C9 to yield Michael acceptor 27. In order to prepare the 6/4/6 system 28, the 6-membered ring B2 has to be formed by addition of a suitably tethered C3 nucleophile to the chrysanthenone carbonyl group (C2) in 27. This is a very difficult task. Not only is the hindered chrysanthenone keto group difficult to attack in general without initiating an uncontrolled cleavage of the cyclobutanone moiety, it also does not allow free access from the /?-face which is shielded by the CIS-methyl group, definately not along a Biirgi-Dunitz trajectory (dashed arrow in 27). [8c, d] A four atom tethered nucleophile certainly has an entropic advantage but can access C2 exclusively from the /?-face and under a disfavored angle. Wender et al. achieved such attacks with sp2-nucleophiles, which do not have steric bulk orthogonal to the attacking electron pair and thus can pass by the C15-methyl group (for attempts with larger groups like sp3-C ring precursors see ref. [8d]). The small alkinyl precursor 27 is extremely suitable, and a domino 1,4/1,2 addition reaction with methyl cuprate gave the ring B2 together with the introduction of C19 in fantastic 97 % yield (cf. arrows in 27). After some standard transformations the base induced double ringopening of 28 to A/B ring compound 29 was achieved in 85 % yield, including protection at C13. For the oxidation at C1 in 29 the proton was abstracted with potassium t-butoxide at the tertiary carbon and not at C9 to give once again the unusual bridgehead enolate, which was oxi-

dized with oxygen or air as previously reported by the same group. [8b] The introduction of a side chain at C3 and its functionalization to prepare for the construction of the C- and D ring followed, as well as oxidation at the upper rim and benzoylation at 0 2 via the cyclic carbonate as described previously. The resulting ketoaldehyde 30 could be closed by an aldol reaction with DMAP or 4-pyrrolidinopyridine and immediate protection of the kinetic aldolate with trichloroethoxycarbonyl chloride (TrocC1) to give 31 with the desired stereochemistry at C7 (11 : 1 ratio), thus providing a solution to the epimerization problem encountered with other bases, without selectively scavanging the desired aldolate (see introduction). Interestingly the aldol reaction did not proceed with a Cl-C2 carbonate. Further transformations were achieved analogously to previously described methods to yield deacetylbaccatin 111, baccatin I11 (1) and finally taxol (3a).

The more convergent routes of Nicolaou et al. and Danishefsky et al. with B ring closure from a tethered A-C precursor are clearly the least efficient with respect to total yield (about 0.01 % starting from commercially available materials) if directly compared to the other two routes. Additionally the Nicolaou route needs enantiomer separation or a presumably less favorable - asymmetric synthesis, whereas the Danishefsky route addresses absolute stereochemistry but involves more steps. Holton’s synthesis shows quite good yields throughout with a total one of approximately 0.1 %, but has less room for improvements and is based on a not readily available starting material. The best synthesis in all respects to date is the one of Wender and coworkers, which is about 1-2 orders of magnitudes better in total yield (ca. 0.8%),

The First Total Syntheses of Taxol

utilizes cheap chiral pool material, and offers possibilities for derivatization which are at least equal to those of the other approaches. In the end, however, a comparison of number of steps and yields in this case should not be overestimated. More important factors are practicability and versatility of the syntheses, their usefulness to prepare derivatives for SAR studies and their impact on the solution of other synthetic problems. Since none of the total syntheses yet can compete with the semisynthesis from baccatin 111, the potential for the preparation of derivatives is crucial. Convergent syntheses are principally better if varied building blocks shall be combined. This requirement is met by Nicolaou’s and Danishefsky’s routes. They also permit easy mutations in the A ring building blocks. With Nicolaou’s procedure, however, increased steric hindrance with more complex derivatives may lead to problematic yields for the ring closure. B ring and especially C ring derivatives can, in principle, be provided by all procedures., Ideally derivatizations should take place as late as possible in the reaction sequence, in order to minimize the additional labor required to produce them. With respect to C ring versatility the Wender and Holton routes provide probably the best basis. However, for any alteration desired it must be kept in mind that experience with taxanes has taught that even the tiniest change in the substituents or the skeleton can cause great problems with the synthesis. Most published fully synthetic analogues have been C ring aromatics, [4]but also spin-offs of the total synthesis have been reported (see introduction [3]). In spite of the fantastic successes from the groups of Holton, Nicolaou, Danishefsky and Wender much excitement remains in the total syntheses of taxoids [12]. Compounds and procedures, superior to the known ones with respect to variability, yield, and commercial feasibility are more than ever a challenge for the inventive chemist. Apart from the more

303

practical viewpoint, all approaches demonstrate state of the art organic synthesis and the high intellectual standard reached in this area, be it through earlier efforts of the developers of selective synthetic methods and tools (cf. e. g. the McMuny reaction or the interplay of protective groups), the proper combination and selection of such tools (e.g. leaving an oxetane ring untouched through multiple transformations), or the beauty of the concept as found in the Holton and especially the Wender synthesis with their multiple rearrangements not immediately obvious from standard retrosynthetic considerations.

References [ l ] Several excellent review articles on the chemistry and biology of taxol have been published, as well as its history and even politics related to the compound. For this reason the preliminary work and synthetic routes of other authors are not quoted individually in the text; they can be found in the following reviews on chemistry and related subjects: a) G. I. Georg, T. T. Chen, I. Ojima, D. M. Vyas (Eds.), Taxane Anticancer Agents Basic Science and Current Status, Vol. 583, American Chemical Society, Washington, 1995; b) K. C. Nicolaou, W.-M. Dai, R. K. Guy, Angew. Chem. 1994, 106, 38-69; Angew. Chem. Int. Ed. Engl. 1994, 33, 45; c) D. Guenard, F. Gueritte-Voegelein, P. Potieg Acc. Chem. Res. 1993, 26, 160167; d) I. Ojima, Acc. Chem. Res. 1995, 28, 383-389. On biochemistry, biology, medicine & related subjects: e) P. E. Fleming, H. G. Floss, M. Haertel, A. R. Knaggs, A. Lansing, U. Mocek, K. D. Walkez Pure Appl. Chem. 1994, 66, 2045-2048; f ) G. Appendino, Nut. Prod. Rep. 1995, 12, 349-360; g) G. M. Gragg, S. A. Schepartz, M. Suffness, M. R. Grevez J. Nut. Prod. 1993, 56, 1657-1668; h) F. Lavelle, Exp. Opin. Invest. Drugs 1995, 4, 771-775; i) K. J. Bohm, K. W. Wolf, Biol. unserer Zt. 1997, 27, 87-95.

304

Applications in Total Synthesis

[2] The influence of taxol on microtubuli is so extraordinary that only recently and after an immense screening effort other compounds of similar properties have been found. However, at the time of this writing it is still open, if they will have an impact on cancer therapy cf. [lh] and L. Wessjohann, Angew. Chem. 1997, 109, 739-742; Angew. Chem. Int. Ed. Engl. 1997, 36, 715-718; cf. also [3]. [3] U. Klar (Schering AG, Berlin, Germany), Symposium “Aktuelle Entwicklungen in der Naturstofforschung” - 9. Irseer Naturstofftage der DECHEMA e. b! (Irsee, Germany) 26.-28. Feb. 1997, Lecture 6: “Inhibitoren der Tubulindepolymerisation - von Taxol zu einer neuen, nicht-taxoiden Leitstruktur”. [4] Simple aromatic taxoids have been synthesized e. g. by K. C. Nicolaou, C. F. Claibome, K. Paulvannan, M. H. D. Postema, R. K. Guy, Chem. EUK J. 1997, 3, 399-409; ref. cited therein; and Wender et al. [8b] [5] R. A. Holton, C. Somoza, H.-B. Kim, F. Liang, R. J. Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile, J. H. Liu, J. Am. Chem. Soc. 1994, 116, 1597-1598; R. A. Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P. D. Boatman, M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P. Vu, S . Tang, P. Zhang, K. K. Murthi, L. N. Gentile, J. H. Liu, J. Am. Chem. Soc. 1994, 116, 1599-1600. [6] K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F. Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, Nature (London) 1994, 367, 630-634; K. C. Nicolaou, P. G. Nantermet, H. Ueno, R. K. Guy, E. A. Couladouros, K. Paulvannan, E. J. Sorensen, J. Am. Chem. SOC. 1995, 117, 624-633; K. C. Nicolaou, J.-J. Liu, Z. Yang, H. Ueno, E. J. Sorensen, C. F. Claiborne, R. K. Guy, C.-K. Hwang, M. Nakada, P. G. Nantermet, J. Am. Chem. SOC. 1995, 117, 634-644; K. C. Nicolaou, Z. Yang, J.-J. Liu, P. G. Nantermet, C. F. Claiborne, J. Renaud, R. K. Guy, K. Shibayama, J. Am. Chem. SOC.1995, 117, 645-652. [7] S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K.

Jung, R. C. A. Isaacs, W. G. Bommann, C. A. Alaimo, C. A. Coburn, M. J. Di Grandi, J. Am. Chem. Soc. 1996, 118, 2843-2859; and references cited. [8]a) P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, M. G. Natchus, A, J. Shuker, J. C. Sutton, R. E. TayloI; J. Am. Chem. Soc. 1997, 119, 2757-2758; P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, C. Granicher, J. B. Houze, J. Janichen, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, T. P. Mucciaro, M. Miihlebach, M. G. Natchus, H. Paulsen, D. B. Rawlins, J. Satkofsky, A. J. Shuker, J. C. Sutton, R. E. Taylor, K. Tomooka, J. Am. Chern. SOC. 1997, 119, 2755-2756; b) P. A. Wender, T. P. Mucciaro, J. Am. Chem. Soc. 1992, 114, 5878-5879; c) P. A. Wender, L. A. Wessjohann, B. Peschke, D. B. Rawlins, Tetrahedron Lett. 1995, 36, 7181-7184; d) P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, T. P. Mucciaro, M. Miihlebach, M. G. Natchus, T. Ohkuma, B. Peschke, D. B. Rawlins, A. J. Shuker, J. C. Sutton, R. E. Taylor, K. Tomooka, L. A. Wessjohann in Taxane Anticancer Agents - Basic Science and Current Status, Vol. 583 (Eds.: G. I. Georg, T. T. Chen, I. Ojima, D. M. Vyas), American Chemical Society, Washington, 1995, pp. 326-339. [9] The man years contributed by all the research groups presumably well exceed those required for the synthesis of, for example, vitamin B 12 or any other single substance. [lo] The addition, alteration, or removal of protecting groups will not be discussed here: Ac = Acetyl, Ar = 2,4,6-triisopropylphenyl,Bn = benzyl, Bz = benzoyl, BOC = tert-butoxycarbonyl, BOM = benzyloxymethyl, TBPS = tert-butyldiphenylsilyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl, TIPS = triisopropylsilyl, TMS = trimethylsilyl. Actual yields of the first published procedures are given, conversions and loss to formation of isomers were included in the calculations where necessary. For precursors the yields were taken from the references given by the authors and used to

The First Total Syntheses of Taxol calculate back to commercially available starting materials. This leads to lower values than those presented in the references. [ 111 This important partial reaction has been registered as a patent by Nicolaou et al., and has been published in detail: K. C. Nicolaou, P. G. Nantermet, H. Ueno, R. K. Guy, J. Chem. Soc., Chem. Commun. 1994, 295296; K. C. Nicolaou, E. A. Couladouros, P. G. Nantermet, J. Renaud, R. K. Guy, W. Wrasidlo, Angew. Chem. 1994, 106, 1669-

305

1671; Angew. Chem. Int. Ed. Engl. 1994, 33, 1581-1583. [ 121 Note added in proofi A new total synthesis of Baccatin I11 and Taxol including a new method for the introduction of the phenylisoserine side chain was published after the typesetting for this book: I. Shiina, H. Iwadare, H. Sakoh, M. Hasegawa, Y.4. Tani, T. Mukaiyama, Chem Lett. 1998, 1-2; I. Shiina, K. Saitoh, I. Frkchard-Ortuno, T. Mukaiyama, Chem. Lett. 1998, 3-4.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Erythromycin Synthesis A Never-ending Story? Johann Mulzer

The synthesis of the macrolide antibiotics, erythromycin A (1) and B (2), which are highly effective against gram-positive pathogens, has been one of the most extensive project in the history of synthetic organic chemistry. [l] This phenomenon is not rational as 1 and 2 are available in large quantities from fermentation of the microorganism Streptomyces erythreus. It is the complexity of the molecular structure, the plethora of stereocenters and functional groups, and the magic of the medium ring that has kept about 15 large research groups busy worldwide for more than a decade. All total syntheses follow the same pattern. They first aim at the aglycons (erythronolides A and B, 3 and 4 respectively) in protected form, which are synthesized from the corresponding seco acids by lactonization; for example, 3 is prepared from 5-7, and 4 from 8-11. The seco acids are assembled from smaller chiral fragments which are obtained from the chiral carbon pool, by optical resolution, or by enantioselective synthesis. The final glycosidation, and with it the synthesis of 1 and 2, has been achieved three times only. [2,16,18] Over the years the priorities have been shifted several times. Initially the attention focused on the seco acid fragments and therefore on the stereocontrolled construction of the often recurring P-hydroxycarbonyl and

1,3-diol units of 314. In this connection the development of methods for enantio- and diastereomeric control (acyclic stereoselection [9]) proved to be unbelievably fruitful. The first syntheses of seco acids [2,6] required cyclic intermediates and optical resolution, and often resorted to “relay compounds” recovered from the degradation of the natural 0

3,R’ =OH, R2 =R3 = H 4, R‘ = R2 =R3 = H

Scheme 1.

Erythromycin Synthesis - A Never-ending Story?

product. Nowadays derivatives such as 10 and 11 can be prepared stereoisomerically pure in ca. 15 steps and in gram amounts. [7,8] In all these synthesis it has been a tacit dogma, that the carbon framework of the seco acids be assembled in a convergent manner from two major fragments (“eastern” and “western” zones). R. W. Hoffmann et al. were among the first to show that even a highly functionalized seco acid such as 21 can be constructed in a linear fashion. [15a] Starting from the C13-Cll fragment 20 the chain was elongated successively by aldehyde borocrotylation using the chiral reagents 23 and 24 respectively. This process was combined with other stereoselective reactions such

as Wittig olefination and Sharpless epoxidation to generate the protected seco acid 21, and after lactonization and deprotection (9s)dihydroerythronolide A (22) was formed. In a related fashion, Evans has made use of his iterative polypropionate methodology to prepare 6 -deoxyerythronolide B . [ 15b] In view of the growing number of easily accessible seco acids the attention was directed more and more toward the lactonization step, which is routinely carried out via an activated ester intermediate (12, Table 1). However, the formation of a 14-membered ring proved to be not straightforward; dimerization and polymerization are significant side reactions. Corey’s thiopyridyl activation (via the U

20 Ar = p-MeOC& Cy = cyclohexyl

22

Scheme 2.

307

308

Applications in Total Synthesis

J

9 161

\ Scheme 3.

Erythromycin Synthesis - A Never-ending Story?

309

qCH3

HN

55%

Scheme 4.

intermediates 12a,b) [lo] was the standard macrolactonization procedure for ten years, but has now been replaced by the Yamaguchi lactonization which uses the mixed anhydride 12c. Next to carboxyl group activation the X hydroxyl protecting groups play a central role. 0-protective groups not only suppress the formation of rings of unwanted size, they may also be used to stabilize conformations which are particularly favorable for cyclization. For instance, the 33-acetal or ketal unit in 5-11 freezes the C2-C6 fragment of the 13 molecule in a rigid, extended conformation, due to the diequatorial arrangement around the 1,3- dioxan chair. This allows the 6-OH 0 c. 0 0 function to remain unprotected, because it Figure 1. Conformational Change of the Activated could only be lactonized after flipping the Seco Acid 10 to an Optimum Conformation 13 for acetonide to the highly unstable 3,5 -diaxial conformation. The 9- and 11-hydroxyl groups Macrolactonization.

- -

3 10

Applications in Total Synthesis

Table 1. Macrolactonization to form the 14-mem- rigid Cl-C6 fragment around the C5/6 and bered ring in the erythromycin synthesis. C6/7 axes lead to an optimal conformation for cyclization (13). The 11-OH group is out of reach of the carboxyl function and can remain unprotected. [7] In view of the high macrolactonization yields for 10/11 (Table 1) the ultimate problem 12 Activating group X Product yield in [%I of the erythromycin synthesis are the 3-1 and 4-2 glycosylations, which are indispensible for the physiological activity. As shown early by the Woodward group [2] the monosaccharide blocks desosamine (15) and cladinose (16), both in suitably protected and activated form, can be coupled with an almost “naked” aglycon (14). Only the 5 - and the 3-OH groups are reactive towards the glycosyl donors, the 5-OH group showing a clear kinetic advantage over the 3-OH function c [I11 C d z - 0 7 (27)[4], 10 (89)[7], (scheme 4).

Po--- no

A

Cl

11 (>95)[8]

N-C6H1I

-/ are often protected by a cyclic acetal (such as in 5-S), in which the 9’-substituent induces considerable transanndar strain. In fact, 9‘disubstituted derivatives such as 7 are substantially more difficult to cyclize than the corresponding 9’-monosubstituted seco acids 6 and 8 (Table 1). [3,4] Moreover, the configuration at C9 is important: (9s) seco acids cyclize much more readily than the (9R) isomers do. [2] Many of these hitches may be avoided by the introduction of a C,C-double bond in the critical region between C7 and C11 (see 9-11). At least one OH function and its protecting group is then missing; in addition the two sp2 centers on the ring periphery decrease the transannular ring strain. Trisubstituted olefins display the phenomenon of allylic 1,3 strain. [12] In seco acid 10 this leads to a sickle-like conformation of the C7-10-carbon chain. Simple rotations of the

\

CH3

\

CH3

Scheme 5.

CH3

\

OH CH3

17

19

3 11

Erythromycin Synthesis - A Never-ending Story ?

In a remarkable experiment (scheme 5 ) S. F: Martin and M . Yamashitu [13] have parted with the accepted philosophy of erythromycin synthesis, namely to perform first the lactonization and then the glycosidation. They

prepared diglycosidated seco acid 17 from 2 via partial synthesis in ten steps and subjected it to Yamaguchi's macrolactonization conditions. However, this protocol afforded only minor amounts of the desired macrolide 18,

-

p-anisaldehyde dimethylacetal, CSA, CH2CIz. -3O"C, 72h 87%

''I%,,

25

22

28,NIS, TfOH. MS 4A, CH2CI2,

mCPBA, CH2Clz 2 5 T . 10 min

-35°C. 10 min c90%

c -

IW%

"'OH

27

29

-

-

Hi. Raney-Ni (W4), EtOH, 40°C. 1,5h

mCPBA, CHzCIz, 2 5 T , 10 min

99%

54%

H2.

1

Scheme 6.

Raney-Ni (W4). EtOH, 25"C, Ih t -

84%

3 12

Applications in Total Synthesis

the major products being the two C 2 epimers of the seven-membered lactone 19. This is not surprising because the formation of seven-membered rings is a favorable process and can readily occur, since the 6-OH function is not protected and it is not conformationally deactivated by the presence of a 3,5ketal. As predicted, the Yamaguchi lactonization of the 6-OMe derivative of 17 (14 steps from 2) exclusively affords the 6-OMe derivative of 18, but in only 53 % yield. After a longer hiatus, the Martin group has, quite recently, reported the first synthesis of erythromycin B (2). Remarkably, in their communication [161 the authors did not comment on their previous strategy, but, quite matter-of-factly, they used the conventional procedure developed by the Woodward group for erythromycin A, instead. [2] Thus, O-protected 9(S)-dihydro-erythronolide B was prepared by total synthesis, deprotected at the 3 - and 5-positions and successively submitted to 5 - and 3-glycosylation to give after the usual manipulations, erythromycin B (2). Similarly, in the synthesis of 1 by Toshima et al. [17] the aglycon 22 was converted into the 9,l I-acetonide 25, which was than selectively glycosylated at the 5-position with the protected desosamine thioglycoside 26 to give the monoglycoside 27. After N-oxidation the cladinose anhydrothioglycosyl donor 28 was used to convert 29 into 30. Further mani pulation eventually gave 1. The crucial problem of stereoselective 0 - 3 -a-glycosylation was thus successfully solved. In the light of these recent results it appears advisable to concentrate on further optimization of the glycosilation of 314 derivatives, perhaps by enzyme catalysis. After all, the biosynthesis follows this pathway: first aglycon 4 is generated, and from there 2 is formed. ~141 In this connection it is remarkable that the cladinose residue is not essential for the antibiotic activity of erythromycin A. Apparently the cladinose can be replaced by a 3-keto

function to give “ketolides” which are highly potent antibiotics. Additionally, two additional rings are fused to the “north western” hemisphere of the ketolide to enhance stability, bioavailability and antimicrobial activity (“tricyclic ketolides”). [ 181

H~cH*c(~~ -*H3

0

“Tricyclic Ketolide”

Scheme 7.

References [l] Review: I. Paterson, M. M. Mansuri, Tetrahedron 1985,41, 3569. [2] R. B. Woodward et al. J. Am. Chem. SOC. 1981, 103, 3210, 3213,3215. [3] G. Stork, S. D. Rychnovsky, J. Am. Chem. SOC. 1987,109, 1564, 1565. [4] H. Tone, T. Nishi, Y. Oikawa, M. Hikota, 0. Yonemitsu, Tetrahedron Lett. 1987, 28, 4569; M. Hikota, H. Tone, K. Horita, 0. Yonemitsu, Tetrahedron 1990, 46, 4613. [5] N. K. Kochetkov, A. Sviridov, M. S. Ermolenko, D. V. Yashunsky, V. S. Borodkin, Tetrahedron 1989, 45, 5 109. [6] E. J. Corey et al., J. Am. Chem. SOC. 1978, 100,4618. [7] J. Mulzer, H. M. Kirstein, J. Buschmann, C. Lehmann, P. Luger, J. Am. Chem. SOC. 1991, 113, 910. [8] J. Mulzer, P. A. Mareski, J. Buschmann, P. Luger, Synthesis 1992, 215. [9] P. A. Bartkett, Tetrahedron 1980, 36, 1. [lo] E. J. Corey, K. C. Nicolaou, J. Am. Chem. SOC. 1974, 96, 5614; E. J. Corey, D. J. Brunelle, Tetrahedron Lett. 1976, 3409.

Erythromycin Synthesis - A Never-ending Story ? [ll] J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. SOC. Jpn. 1979, 52, 1989. [12] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841. [13] S. F. Martin, M. Yamashita, J. Am. Chem. SOC. 1991, 113, 5478. [14] J. Staunton, Angew. Chem. 1991, 103, 1331; Angew. Chem. Int. Ed. Engl. 1991, 30, 1302; R. Pieper, C. Kao, C. Khosla, G. Luo, D. E. Cane, Chem. SOC. Rev. 1996, 297.

3 13

[15] a) R. Stunner, K. Ritter, R. W. Hoffmann, Angew. Chem. 1993,105, 112; Angew. Chem. Int. Ed. Engl. 32, 101; b) D. A. Evans, A. S. Kim, Tetrahedron Lett. 1997, 38, 53. [16] S. F. Martin, T. Hida, P. R. Kym, M. Loft, A. Hodgson, J. Am. Chem. Soc. 1997,119,3193. [17] K. Toshima, J. Nozaki, S. Mukaiyama, T. Tamai, M. Nakata, K. Tatsuta, M. Kiroshita, . I Am. . Chem. SOC. 1995, 117, 3717. [18] S. C. Stinson, Chem. Eng. News, 1996, 75.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Great Expectations for a Total Synthesis of Vancomycin Kevin Burgess, Dongyeol Lim, and Carlos I. Martinez

1 and 3 in a total synthesis, presumably for the following reasons. Vancomycin has only one chlorine atom on rings C and E, whereas both ortho positions on the corresponding aryl rings of synthon 3 are chlorinated. These extra chlorines were critical in the synthesis of that material. Synthon 3 was prepared by two thallium trinitrate-mediated couplings, which absolutely require both ortho positions .sugar relative to the phenolic-OH to be blocked. F‘ Furthermore, the formation of 1, an oxidative coupling of the carbons marked a and b in structure 2, required harsh conditions (VOF3, BFyOEt2, TFA, TFAA, CH2C12, 0 “ C , then Zn) that may not be suitable in the absence of chlorine blocking groups at both ortho positions of ring C. vancomycin Reduction of a single C-C1 bond to a C-H on a dichlorinated aromatic ring is a chalIn 1993 there were two reasons to suppose lenging transformation. When two such monothat a total synthesis of vancomycin might be substitutions must be made in a molecule conachieved soon. [l] First, the cyclic molecule taining two dichlorinated aryl rings, it is more 1 had been prepared. [2] This closely resemb- difficult; if the chlorines on each ring are les the “southwestern fragment” of vancomy- inequivalent due to atropisomerism, [4] then cin which includes the AB biaryl linkage. Sec- the task is formidable. Little activity was ond, the bicyclic molecule 3 also had been then reported in this area, implying that a synmade; [3] this is closely related to the central thetic stalemate has been reached. Very reregion of vancomycin which incorporates the cently, however, the oxidative route has been improved by using 2 -bromo- 6 -chlorophenols C, D, and E rings. Despite this optimism, it has not been con- allowing selective reduction of the C-Br venient to exploit the syntheses of fragments bond after cyclization in a synthesis of the Vancomycin has a complicated molecular architecture and clinical significance as an antibiotic for treatment of infections caused by gram positive bacteria. These two attributes have inticed several groups of organic chemists into attempting to prepare this molecule, but no total synthesis has been reported to date.

Great Expectations for a Total Synthesis of Vancomycin

MeHN

MeHNCO

HO 2

1

(P= 3,4-dichlorobenzyl) OH

F‘

I OBn

related reactions to prepare compound 5, which has a 14-membered ring, then the 14,16 ring fused system 6 similar to that in teicoplanin (a natural product structurally related to vancomycin). [8-101 Model studies in the vancomycin series showed that 16-membered peptidic biaryl ethers also could be prepared, [4, 91 an observation which Rao and coworkers confirmed shortly after. [ l l ] These important studies proved that the closure would work even for 16-membered rings of the type found in vancomycin, which had been shown to be difficult to form via other conditions (vide supra). Moreover, Zhu’s research demonstrated the cyclization could be performed with minimal racemization at an arylglycine residue within the incipient ring. Indeed, the conditions are sufficiently

3

C-0-D ring derivative 4. [5] Nevertheless, alternatives to these oxidative routes are highly desirable. Since 1993, relatively new competitors in the vancomycin synthesis arena have provided an impetus which may have sufficient momentum to bring about a total synthesis of vancomycin. Notably, a series of papers from Zhu and co-workers have focused on intramolecular nucleophilic aromatic substitution (SNAr) reactions as a means to cyclize peptide-based systems containing biaryl ether linkages. This approach is a notable improvement on Ullmann coupling procedures using aromatic compounds which are not activated to nucleophilic attack. The latter approach had been explored by Boger and co-workers, [6] but the extreme temperatures and prolonged reaction times preclude application of such “classical” Ullmann couplings in vancomycin syntheses. Zhu’s first efforts in this area included a synthesis of the 17-membered ring compound K-13 via biaryl ether formation as the ring closure step. [7] Since then, his group has used

3 15

5

I

OzN 6

71 YO

3 16

Applications in Total Synthesis

mild (e.g. KzC03, DMF, 25°C) that they should be suitable for more complicated substrates. A recent publication from Zhu’s group proved that this methodology could be applied to prepare a close analog of the vancomycin C-0-D ring. [12] Shortly after these studies were published, Boger and co-workers reported the same type of cyclization method to prepare synthons for the C-0-D and D-0-E rings of vancomycin, compounds 7 and 8 respectively. [ 131 Boger’s intermediate 7 is notable as it has functionality appropriate for attempted formation of the vancomycin AB biaryl fragment. Later, Evans and Watson also used the SNAr to generate functionalized C-0-D and D-0-E ring analogs with protecting groups presumably chosen for elaboration into more complex intermediates in the vancomycin series. 1141 The Rao Group have also expanded their studies; in recent work they prepared a teicoplanin fragment via a similar SNAr route. [ 151 The next landmark in the evolution of this story was to produce molecules with both the C-0-D and D-0-E rings, i. e. C-0-D-0-E vancomycin fragments. The Zhu group were the first to report this, and they demonstrated two logical approaches. [16, 171 In the first, they prepared an acyclic precursor and attempted to form the C-0-D-0-E ring system via two cyclizations in one reaction vessel. All four atropisomers formed when the reaction was run at room temperature, but compound 9 was isolated in 60% yield after a reaction at -5 “C. This is an encouraging result even though this atropisomer does not correspond to that in vancomycin. Zhu’s stepwise couplings were less stereoselective. Cyclization of the appropriate aryl fluoride gave compounds 10 in a 2 : 3 ratio favoring the unnatural atropisomer series. These were separated, elaborated to other aryl fluorides, and cyclized to give l l d l l b (3 : 1) and l l d l l d (1 : 2). Thus, all four stereoisomers of the C-0-D-0-E ring system could be obtained.

Y

OMe 9

.,

OMe

OM€! 10a X = NOz, Y = H 10bX= H, Y = NO;!

Currently, it is the Evan’s group, however, who can claim to have produced the most advanced compound in a vancomycin synthesis. They used an oxidative coupling to produce the C-0-D ring in compound 12, [ 181 and a SNAr cyclization to produce the complete AB-C-0-D-0-E system 13. [19] The latter transformation favors the atropisomer corresponding to the vancomycin D-0-E atropisomer by a 7 : 1 factor, in a reaction that was surprisingly efficient (90% yield of combined cyclization products). Based on the current literature, a total synthesis of vancomycin is imminent. The AB-C-0-D-0-E core has been produced, and coupling of the carbohydrate residues to one of the phenolic oxygen atoms of vancomycin is a known transformation. [20] Other

Great Expectations for a Total Synthesis of Vancomycin

methods for the production of biaryl ethers are emerging, [21, 221 but it seems that SNAr couplings of nitroaryl fluorides will be featured in the first vancomycin synthesis.

Y

OMe

lla llb llc lld

X = 'f = N02, Y = x'= H X = x'= NOz, Y = Y = H X = X = H , Y = Y ' = NO2 X=Y'=H,Y=X=NOn

BnO%BiBn 12

BnO"OBtBn

13

References [l] A. V. R. Rao, M. K. Gurjar, K. L. Reddy, A. S . Rao, Chem. Rev. 1995,95,2135-67. [2] D. A. Evans, C. J. Dinsmore, D. A. Evrard, K. M. DeVries, J. Am. Chem. SOC. 1993, 115, 6426-7. [3] D. A. Evans, J. A. Ellman, K. M. DeVries, J. Am. Chem. SOC. 1989,111, 8912-4.

3 17

[4] R. Beugelmans, G. P. Singh, M. Bois-Choussy, J. Chastanet, J. Zhu, J. Org. Chem. 1994, 59, 5535-42. [5] H. Konishi, T. Okuno, S. Nishiyama, S. Yamamura, K. Koyasu, Y. Terada, Tetrahedron Lett. 1996,37, 8791-4. [6] D. L. Boger, Y. Nomoto, B. R. Teegarden, J. Org. Chem. 1993,58, 1425-33. [7] R. Beugelmans, A. Bigot, J. Zhu, Tetrahedron Lett. 1994, 35, 7391-4. [8] J. Zhu, R. Beugelmans, S. Bourdet, J. Chastanet, G. Roussi, J. Org. Chem. 1995, 60, 6389-96. [9] R. Beugelmans, L. Neuville, M. BoisChoussy, J. Zhu, Tetrahedron Lett. 1995, 36, 8787-90. [lo] R. Beugelmans, S. Bourdet, J. Zhu, Tetrahedron Lett. 1995,36, 1279-82. [ l l ] A. V. R. Rao, K. L. Reddy, A. S . Rao, Tetrahedron Lett. 1994, 35, 8465-8. [12] J. Zhu, J.-P. Bouillon, G. P. Singh, J. Chastanet, R. Beugelmans, Tetrahedron Lett. 1995, 36,7081-4. [13] D. L. Boger, R. M. Borzilleri, S . Nukui, Biorg. Med. Chem. Lett. 1995,5, 3091-6. [14] D. A. Evans, P. S. Watson, Tetrahedron Lett. 1996,19, 3251-4. [15] A.V. R.Rao, K.L. Reddy, A. S . Rao,T. V. S. K. Vittal, M. M. Reddy, P. L. Pathi, Tetrahedron Lett. 1996, 37, 3023-6. [16] R. Beugelmans, M. Bois-Choussy, C. Vergne, J.-P. Bouillon, J. Zhu, . I . Chem. SOC., Chem. Commun. 1996, 1029-30. [17] C. Vergne, M. Bois-Choussy, R. Beugelmans, J. Zhu, Tetrahedron Lett. 1997, 38, 1403-6. [18] D. A. Evans, C. J. Dinsmore, A. M. Ratz, D. A. Evrard, J. C. Barrow, J. Am. Chem. SOC. 1997,119, 3417-8. [19] D. A. Evans, J. C . Barrow, P. S. Watson, A. M. Ratz, C. J. Dinsmore, D. A. Evrard, K. M. DeVries, J. A. Ellman, S. D. Rychnovsky, J. Lacour, J. Am. Chem. SOC. 1997, 119, 3419-20. [20] R. G. Dushin, S. J. Danishefsky, J. Am. Chem. SOC. 1992, 114, 3471-5. [21] A. J. Pearson, G. Bignan, P. Zhang, M. Chelliah, J. Org. Chem. 1996, 61, 3940-1. [22] K. C. Nicolaou, C. N. C. Boddy, S. Natarajan, T.-Y. Yue, H. Li, S. BrSSse, J. M. Ramanjulu, J. Am. Chem. SOC. 1997,119,3421-2.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

The Dimeric Steroid-Pyrazine Marine Alkaloids : Challenges for Isolation, Synthesis, and Biology Arasu Ganesan

Isolation of Cephalostatins and Ritterazines

tain the novel structural framework of two steroids linked by a pyrazine at the A ring (Fig. 1). The “right half’ is identical in fifteen of the alkaloids, including the Cz-symmetric homodimer cephalostatin 12.

Since 1955, the American National Cancer Institute (NCI) has conducted a massive search for compounds with antitumor activity, with successes including the Wnca alkaloids from the Madagascar periwinkle and taxol from the Pacific yew tree. This highlight [ l ] covers a family of steroids also discovered by the NCI efforts. In 1974, extracts of the tiny ( - 5 mm) cephalostatin 1 marine tube worm Cephalodiscus gilchristi collected off South Africa were found to be ’“OH active in the NCI’s primary assay, the murine lymphocytic leukemia P388. Fifteen years of “relentless research” by Pettit’s group culminated in the isolation of 139 mg of the major bioactive component, cephalostatin 1, from 166 kg wet weight of the tube worm, and its structural elucidation. [2] This phase was summarized [3] as follows: “Interest in such a powerfully antileukemic agent as cephalostatin 1 ... has prompted Americans to dive extensively at a depth of 20 meters to collect C. gilchristi in open seawaters controlled by the white shark.” Cephalostatin 1 is extremely potent against P388, with an ED50 of 10-7-10-9 pg mL-’. Over the years, the Pettit group has characterized [4] sixteen other cephalostatins. All con- Figure I. Three of the cephalostatins. ,Ma..

\..,+-OH

The Dimeric Steroid-Pyrazine Marine Alkaloids

# \

1

,."

=-

ritterazine G

LlY-J

3 19

'o

\-'

o"' rinerazine D

Scheme 1. Possible mechanism of the ritterazine CD-ring rearrangement.

In 1994, a steroid-pyrazine dimer was nism for the rearranged "right half' in some reported [5] from an unexpected source. Fuse- of the ritterazines may involve (Scheme 1) tani's group isolated ritterazine A, with an protonation of the D-ring alkene followed by ED50 of pg mL-' against P388, from either a 1,2-Wagner-Meerwein shift or retrothe tunicate Ritterella tokioka collected off Prins and alternative Prins ring closure. The compounds from C. gilchristi and Japan. Twelve other ritterazines have since been described [6] (Fig. 2), including one R. tokioka are clearly related (ritterazine K, homodimer, ritterazine K. A possible mecha- for example, contains the "left half' of cephalostatin 7), although the same alkaloid has yet to be identified from both. Meanwhile, their presence in two phyla suggests they may be produced by a symbiotic microorganism.

Synthetic Studies

1 1y . % ^.. %

ritterazine K

Figure 2. Three of the ritterazines.

Initial synthetic attention focused on preparation [7] of symmetrical steroid-pyrazine dimers by the classical condensation of a-amino ketones (Scheme 2). Interestingly, dimer 1 is itself weakly cytotoxic, with an ED50 around 10 pg mI-' against tumor cell lines. Most of the natural products are unsymmetrical dimers. Novel methods have had to be developed for the synthesis of such compounds. At Berkeley, Smith and Heathcock [7b] used the combination of an a-amino oxime ether and an a-acetoxy ketone (Scheme 3). At 90 "C, 2 and 3 preferentially react with

320

Applications in Total Synthesis

version, yields are significantly improved. Pyrazine 4, for example, was formed in 78 % yield. The proposed mechanism (Scheme 4) involves imine formation followed by a series of prototropic shifts and the irreversible loss of nitrogen and rnethoxylamine.

-0 androstanolone

- H*N‘dl

H,, Pd-C or Ph3SnH(Fuchs)

or Ph3P. H20 (Heathcock)

0

1

Scheme 2. Synthesis of symmetrical steroid-pyrazine dimers.

each other to give intermediates which aromatize to pyrazine 4 at higher temperature. The two-stage protocol is necessary as the a-amino oxime ether condenses with itself at 140 “C. Recently, the Fuchs group at Purdue has introduced [8] a modification of the Heathcock protocol, whereby an a-azido ketone is substituted for the a-acetoxy ketone. In this

0 3

Scheme 3. Smith and Heathcock‘s unsymmetrical

dimer synthesis.

Scheme 4. Proposed mechanism for the Fuchs

dimerization.

Introduction of asymmetry into a homodimer was demonstrated [9] by Winterfeldt and coworkers at Hannover (Scheme 5 ) . Commercially available hecogenin acetate was transformed [ 101 to 5 and dimerized to symmetrical diketone 6. The two carbonyls could be statistically differentiated by controlled reduction or trapping of the dienolate to yield hydroxy ketone 7. Compounds 6 and 7 were evaluated at the NCI. The symmetrical 6 affects 32 of the 58 cell lines tested, while a saturated version lacking the D ring alkene shows weak activity. Meanwhile, unsymmetrical 7 is significantly cytotoxic against all 58 cell lines, being approximately 4,000 times weaker than cephalostatin 1. The Winterfeldt group has also developed [ 111 an unsymmetrical dimerization procedure (Scheme 6). The two reacting partners are vinyl azide 8 and enamino ketone 9. Thermolysis of 8 generates an azirine in situ, which

The Dimeric Steroid-Pyrazine Marine Alkaloids

-7 steps

36 %

Ad)

hecogenin acetate

32 1

Br,,,.,

5

1

dirnerization 51 %

1

NaBH,. -76 "C (47 %) or i. KHMDS. fBuC0CI; ii. NaBH4; iii. aq. KOH (31 O h )

Scheme 5. Desymmetrization of a homodimer by Winterfeldt et al. [9].

Scheme 6.

Winterfeldt et al.'s unsymmetrical dimerization.

322

Applications in Total Synthesis

reacts by the likely mechanism shown to give fine balance, as there are four pairs of ritteradimer 10. The enamino ketone is itself stable zines differing only in configuration at the spiroketal carbon. In this case, the desired and not prone to self-dimerization. So far, all the publications related to total product 13 was obtained by the sequence of synthesis have been from Fuchs’ group, who electrophilic bromoetherification and halogen first reported [12] a symmetrical dimer cor- removal. Dimerization afforded the cepharesponding to the “right half’ of cephalostatin lostatin 12 analog, whose biological activity 1 but lacking the D ring alkene and C17 alco- was not revealed. hol. The dimer can be considered an analog of A series of communications from the Fuchs cephalostatin 12, whose existence had yet to group climaxed [13] in the total synthesis of be disclosed then. three of the alkaloids. The presence of the D The synthesis began with a derivative of ring alkene and C17 alcohol in the natural hecogenin acetate, which already contains all products necessitated a different route from the carbons needed. Classical Marker sa- the above. First, Marker sidechain degrapogenin spiroketal ring-opening gave 11 dation of hecogenin gave enone 14 (Scheme (Scheme 7) which was carried forward to 12. 8). The D ring functionality was introduced, Acid-catalyzed cyclization of 12 yielded a and ring E constructed by intramolecular mixture of 515 and 615 spiroketals epimeric Wadsworth-Emmons reaction of 15. The rest to the natural product. In general, the ratio of of the sidechain was reintroduced by methalspiroketal products with these intermediates lyl stannane addition to 16, yielding 17. The two epimers of 17 were separated, and is highly sensitive to the specific substitution pattern. The natural products also reflect this individually processed to eventually yield

Py.HCI, (C12CHC0)20 70 %

-

12

11 I

Scheme 7. Synthesis of a cephalostatin 12 analog by Fuchs et al. [12].

The Dimeric Steroid-Pyrazine Marine Alkaloids

monomers 18 and 19. In the grand finale, a 1 : 1 mixture of the a-azido ketones was reduced to give roughly the expected 1 : 2: 1 mixture of three dimers, with the heterodimer predominating. Separation and deprotection afforded the natural products. Fuchs et al. suggest that similar statistical coupling occurs in nature, which implies that ritterazine K is also produced by C. gilchristi. Indeed, examination of residual material in the Pettit group identified a compound in microgram quantities with the same chromatographic profile.

--

TMS,

1. NaH 2. oxidation state adjustment

10 steps

54 %

15

methaliyi stannane, 5 M LiClOl >95%

16

323

This work represents a milestone in the synthesis of complex marine natural products. At the same time, it reflects on the state of organic synthesis, which some consider to be a fully mature science. While total synthesis is effective, in the sense that any stable compound can probably be made, it is seldom efficient. [14] The preparation of the two halves from hecogenin acetate required over 20 steps, the majority of which involve functional group interchange and protecting groups. This is typical of targets containing a multiplicity of functional groups at various oxidation levels. Clearly, there are worthy challenges left for the organic chemist of the next century! The Fuchs group has also prepared [ 151 “dihydrocephalostatin 1”. In this synthesis (Scheme 9), the angular methyl group of keto alcohol 20 (obtained from hecogenin acetate) was functionalized by Meystre’s hypoiodite method and oxidized to yield 21. Further reactions via intermediates 22 and 23 afforded 24, which was coupled with a-amino oxime ether 25 (prepared from 18) to give dihydrocephalostatin 1 after deprotection. This dihydro derivative had biological activity comparable to cephalostatin 1.

17

These alkaloids do not contain functional groups such as alkylation sites, Michael acceptors, intercalators, or redox-active qui+ nones commonly associated with cytotoxicity, while their scarcity has hindered investigation of the mechanism of action. An early proposal, [16] taking into account the steroidal and dimeric nature of the alkaloids, was that 19 these compounds span the lipid bilayer 1. NaHTe 2. silica, air oxidation (cephalostatin 1 is 30 long) and perturb the 3. Bu4N+Fcephalostatin 12 + cephalostatin 7 + ritterazine K eukaryotic cell membrane. 11 % 28 % 184~ Fuchs has considered [7a] that the alkaloids Scheme 8. Synthesis of three natural steroid-pyra- are enzyme inhibitors forming hydrogen bonds with a specific target. More recently, zine dimers by Fuchs et al. [13]. separation, lulther steps

F

A

18

324

Applications in Total Synthesis ,CHO

1. Pb(OAc),. l2 2. H~CrO,

-%"

-%" 21

20

--

%,

7 steps

7 steps _)-

45 96

51 %

"-,23

24

+

Y

OMe

42 %

25

dihydrocephalostatin1

Scheme 9. Preparation of dihydrocephalostatin 1 by Fuchs et al. [S].

he has suggested [15a] that a process similar to Scheme 1 (vide infra) may occur in vivu, in which protonation or epoxidation of the D-ring alkene generates reactive electrophilic intermediates. This seems consistent with the fact that the natural products and biologically active synthetic analogs contain at least one alkene, while the tetrahydro-derivatives appear inactive. The advantage for the alkaloids to be dimeric is also unclear. An analogy may be drawn with the potent immunosuppressive agent FK506, where a synthetic dimer has unique properties. [17] Steroids have important roles in providing membrane rigidity, as components of lipoproteins, and as ligands which dimerize the nuclear hormone receptor superfamily, result-

ing in gene transcription or repression. The effects of steroids can also be indirect, for example, in triggering apoptosis (programmed cell death), while the antiinflammatory glucocorticoids have recently been shown to interfere with NF-KB signaling besides binding their hormone response element. [ 181 The determination of the precise biological target of these alkaloids requires larger amounts of material. Thus, it is particularly exciting that Winterfeldt's synthetic dimer 7, prepared in 10 steps from hecogenin acetate, displays high activity. According to Pettit, [19] cephalostatins 1 and 7 are undergoing preclinical development. Random screening continues to be an important source of leads for drug discovery.

The Dimeric Steroid-Pyrazine Marine Alkaloids

The cephalostatins and ritterazines highlight the power of screening natural product extracts over currently fashionable synthetic combinatorial libraries in terms of structural novelty and complexity. Today, libraries are constructed by short sequences of synthetic transformations, whereas many natural products are the result of much longer and more creative pathways. Finally, these alkaloids illustrate the ability of nature to assemble unusual arrays of functional groups that are beyond our imagination. Before the isolation of the natural products, methodology for the preparation of unsymmetrical pyrazines was unknown. The synthetic chemists have risen to the occasion, and three separate protocols are now available.

Note added in proof The Fusetani group has reported [ 13 the structures of 13 new ritterazines. Some chemical transformations of ritterazine B and their effect on antitumor activity are also described. The Fuchs group has published [2] a full paper on the total synthesis of cephalostatin 1. They have also prepared two ‘hybrid’ dimers. The dimer containing the ritterazine G “right half’ coupled to the cephalostatin 1 “right half’ has similar activity to cephalostatin 1. A review has appeared [3] on steroid dimers and oligomers. [l] S. Fukuzawa, S. Matsunaga, N. Fusetani, J. Org. Chem. 1997,62,4484-4491. [2] T. G. LaCour, C. Guo, S. Bhandaru, M. R. Boyd, P. L. Fuchs, J. Am. Chem. Soc. 1998, 120,692-707. [3] Y. Li, J. R. Dias, Chem. Rev. 1997, 97, 283304.

325

References [I] For a more comprehensive review covering the work up to 1995, see: A Ganesan in Studies in Natural Products Chemistry, Vol. 18, Stereoselective Synthesis (Part K) (Ed.: Atta-ur-Rahman), Elsevier, Amsterdam, 1996, p. 875-906. [2] G. R. Pettit, M. Inoue, Y. Kamano, D. L. Herald, C. Arm, C. Dufresne, N. D. Christie, J. M. Schmidt, D. L. Doubek, T. S . Krupa, J. Am. Chem. Soc. 1988,110, 2006-2007. [3] F. Pietra, A Secret World: Natural Products of Marine Life, Birkhauser, Basel, 1990, p. 149. [4] For the most recent reference, see: G. R. Pettit, J.-P. Xu, J. M. Schmidt, Bioorg. Med. Chem. Lett. 1995,5, 2027-2032. [5] S. Fukuzawa, S. Matsunaga, N. Fusetani, J. Org. Chem. 1994,59,6164-6166. [6] For the most recent reference, see: S. Fukuzawa, S. Matsunaga, N. Fusetani, Tetrahedron 1995,51, 6707-6716. [7] a) Y. Pan, R. L. Merriman, L. R. Tanzer, P. L. Fuchs, Bioorg. Med. Chem. Lett. 1992, 2, 967-972; b) C. H. Heathcock, S. C. Smith, J. Org. Chem. 1994,59,6828-6839. [8] C. Guo, S. Bhandaru, P. L. Fuchs, M. R. Boyd, J. Am. Chem. SOC. 1996,118, 10672-10673. [9] A. Kramer, U. Ullmann, E. Winterfeldt, J. Chem. Soc. Perkin Trans. I 1993, 28652867. [lo] R. Jautelat, E. Winterfeldt, A. Miillerfahrnow, J. Praktische Chem. 1996, 338, 695-701. [ l l ] M. Drogemiiller, R. Jautelat, E. Winterfeldt, Angew. Chem. Int. Ed. Engl. 1996,35, 15721574. [12] J. U. Jeong, P. L. Fuchs, J. Am. Chem. SOC. 1994,116,773-774. [13] J. U. Jeong, S. C. Sutton, S. Kim, P. L. Fuchs, J. Am. Chem. Soc. 1995,117, 10157-10158. [14] This distinction has been elegantly stated by C. H. Heathcock: Angew. Chem. Znt. Ed. Engl. 1992, 31, 665-681; Proc. Natl. Acad. Sci. USA 1996,93, 14323-14327. [15] a) S. Bhandaru, P. L. Fuchs, Tetrahedron Lett. 1995,36,8347-8350; b) ibid. 1995,36,83518354; c) reference 8. [16] A. Ganesan, C. H. Heathcock, ChemtractsOrg. Chem. 1988, I , 311-312.

326

Applications in Total Synthesis

[17] D. J. Austin, G. R. Crabtree, S. L. Schreiber, Chern. Biol. 1994, I , 131-136. [18] B. van der Burg, J. Liden, S. Okret, F. Delaunay, S. Wissink, P. van der Saag, J.-A. Gustafsson, Trends Endocrinol. Metabol. 1997, 8, 152-157. [19] G. R. Pettit, J. Nut. Prod. 1996, 59, 812-821.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

New, efficient routes to cyclic enediynes B. Konig

The special fascination of strained cyclic ene- too. 171 Their method is based on a sequence diynes lies in their intrinsic tendency to of tandem carbenoid coupling-elimination of undergo thermal cyclisation. This aspect has two propynylic bromide units, a strategy pubbeen stimulating the research activities on enediynes since their beginnings more than 20 years ago, [I] and it is this reactivity of CsF. CH,CN. electrophile R' the enediyne structure that brings about the ___) pharmacological effectiveness of natural 40 - 85 % products, like Dynemicin A. [2] The synthesis of an enediyne parent system calls for mild conditions with, at the same CrCI,, cat. Nicl, time, strong driving forces of the ring closure reaction. Various approaches have been taken b) 44 % 0 to generate strained cyclic enediynes. Scheme / I 1 summarizes the major ones: Most often, an acetylide carbonyl addition is used as the ring closure reaction (Scheme 1, routes a and b). [3] Danishefsky, however, efficiently ob- C) OAc tained highly substituted, 10-membered enediyne cycles by two-fold palladium-catalyzed A coupling of iodoacetylene with cis- 1,2-bis(trimethyltinethylene) (route c). [4] Substitution 1) Tf,O reactions can yield 10-membered enediyne 2) CAN cycles as well, though only after the ring 53 % strain has been reduced (route d). [ 5 ] In difference to a ring closure, Nicolaou employed a ring contraction of cyclic sulfones to synthesize strained cyclic enediynes (route e). [6] Jones, Huber and Mathews were now able to demonstrate that strained cyclic enediynes are accessible via carbenoid intermediates, Scheme 1. I '

328

Applications in Total Synthesis

lished by the same group [S]: Here, the syn- diynes linked to DNA intercalators, like 9, thesis of the acyclic enediyne bis(trimethy1- have been synthesized already. [ 121 si1yl)hexadiyne (3) was achieved by reaction of trimethylsilylpropynylic bromide (1) with LiHMDS lithium hexamethyldisilazide (LiHMDS) in R 69-95% THF/HMPT (HMPT = hexamethylphosphoric Br triamide) at -85 "C. A &/trans-selectivity of 6 7 about 2 : 1 was attained in good yields. Probably, a propynylic carbenoid is formed which can insert intermolecularly into the C-H bond of another propargyl bromide. The E2-elimination of HBr from the intermediate bromide (2) then leads to the product. As this method proved to be broadly applicable for substituted propynylic substrates, Jones et al. even had it patented. [9] Recently, still higher sub9 stituted acyclic enediynes like 4 and 5 could Scheme 3. be obtained with this approach. [lo] While most attention has been directed towards the preparation of carbocyclic enediynes, ten-membered heterocyclic enediynes cisArans2.1:l

2

1

TMS 1. CBr,, PPh, 2. arnberlyst-15

3

sBTo : - (

82%

-

~

*

-

10 TMS

TMS 4

TMS 5

11

1. TBSCI 2. cisdichioroethene Pd(PPh,),, Cul

NaOH

alcohol, Pd(PPh,),.

Scheme 2.

The intramolecular variant of this synthesis HO- renders cyclic enediynes. Ten-membered 12 functionalized enediyne cycles (7) were generated in yields of up to 95 % using slightly NaOH. altered reaction conditions. Since the starting 990/0 materials are easily accessible, a synthesis of enediynes in multigramm scale can be achiev= ed. Thus, it should be possible to use those functionalized enediyne components to build libraries of enediyne diversomers, by the 14 approach of Nicolaou and others. [11] Enediyne-steroide conjugates, like 8, and ene- Scheme 4.

~

i

71%

13

HA

I. BuLi, (cH,o), 2 . PPh,, Br,

Br

64 %

15

OH

New, eficient routes to cyclic enediynes

(13) have been prepared, too. [13] Two independent syntheses were investigated, either involving a Williamson type ring closure or the intramolecular carbenoid route. Overall, the carbenoid route proved far superior. Starting from the propynylic bromide 16 Hopf, Werner, et al. successfully synthesized an only 8-membered cyclic aryl- 1,2-diyne 17. [14] The remarkably stable molecule was obtained by cyclisation with BusSnSiMe3/ CsF [15] in 60 % yield. Bu,SnSiMe,, CsF, DMF

60 YO 16

17

Scheme 5.

With the mechanistically interesting new approaches described here the spectrum of methods for the synthesis of strained cyclic enediynes could be enlarged markedly. It is to be expected that the search for simple pharmacologically active enediyne derivatives will benefit accordingly.

References [l] a) R. R. Jones, R. G. Bergman, J. Am. Chem. SOC.1972, 94, 660-661; b) R. G. Bergman, Acc. Chem. Res. 1973,6,25-31. [2] Recent reviews on the synthesis and properties of enediyne-prodrugs: a) M. E. Maier, Synlett, 1995, 13-26; b) K. C. Nicolaou, W.-M. Dai Angew. Chem. 1991, 103, 14531481; Angew. Chem. Int. Ed. Engl. 1991, 30, 1387-1415; c) enediynes as building blocks for new carbon allotropes: F. Diederich, Nature 1994, 369, 199-207; d) R. Gleiter, D. Katz, Angew. Chem. 1993, 105, 884-887; Angew. Chem. Int. Ed. Engl. 1993, 32, 842845. [3] a) P. A. Wender, S. Beckham, D. L. Mohler, Tetrahedron Lett. 1995, 36, 209-212; b) T.

329

Brandstetter, M. E. Maier, Tetrahedron 1994, 50, 1435-1448; further examples using this ring-closure method: H. Mastalerz, T. W. Doyle, J. F. Kadow, D. M. Vyas, Tetrahedron Lett. 1996, 37, 8683-8686; H. Mastalerz, T. Doyle, J. Kadow, K. Leung, D. Vyas, Tetrahedron Lett. 1995, 36,4927-4930; A. G. Myers, M. Hammond, Y. Wu, J.-N. Xiang, P. M. Harrington, E. Y. Kuo, J. Am. Chem. SOC.1996, 118, 10006-10007; M. F. Brana, M. Morin, M. J. P. de Vega, I. Pita-Romero, J. Org. Chem. 1996, 61, 1369-1374; Y.-F. Lu, C. W. Hanvig, A. G. Fallis, Can. J. Chem. 1995, 73, 2253-2262; L. Banfi, G. Guanti, Angew. Chem. 1995, 107, 2613-2615; Angew. Chem. Int. Ed. Engl. 1995, 34, 2393-2395. [4] M. D. Shair, T. Yoon, S. J. Danishefsky, J. Org. Chem. 1994, 59, 3755-3757; synthesis of acyclic enediynes from alkenylbis(pheny1iodonium)triflates: J. H. Ryan, P. J. Stang, J. Org. Chem. 1996,61,6162-6165. [5] P. Magnus, Tetrahedron, 1994, 50, 13971418; T. Takahashi, H. Tanaka, A. Matsuda, H. Yamada, T. Matsumoto, Y. Sugiura, Tetrahedron Lett. 1996, 37, 2433-2436; synthesis of an eleven-membered cyclic enediyne via SN-ring-closure: A. Basak, U. K. Khamrai, U. Mallik, Chem. Commun. 1996, 749-750; synthesis of macrocyclic enediynes: B. Konig, W. Pitsch, I. Thondorf, J. Org. Chem. 1996, 61, 4258-4261; B. Konig, W. Pitsch, I. Dix, P. G. Jones, Synthesis, 1996, 446-448. [6] K. C. Nicolaou, G. Zuccarello, Y. Ogawa, E. J. Schweiger, T. Kumazawa, J. Am. Chem. SOC. 1988, 110, 4866-4868; synthesis of cyclic dihydroxy enediynes via Sm- or Ti-mediated pinacol coupling: K. C. Nicolaou, E. J. Sorensen, R. Discordia, C.-K. Hwang, R. E. Minto, K. N. Baharucha, R. G. Bergman, Angew. Chem. 1992, 104, 1094-1096; Angew. Chem. Int. Ed. Engl. 1992,31, 1044-1046. [7] G. B. Jones, R. S. Huber, J. E. Mathews, J. Chem. SOC., Chem. Commun. 1995, 1791-1792. [8] a) G. B. Jones, R. S. Huber, Tetrahedron Len. 1994, 35, 2655-2658; b) the synthesis of 3 from 1 was reproduced in our laboratory without difficulties. However, the yield and stereoselectivity were slightly lower than reported.

330

Applications in Total Synthesis

[9] A New Route to Enediynes G. B. Jones, R. S. Huber, US-A 5436361,1995. [lo] G. B. Jones, Clemson University, Clemson, SC (USA), personal communication; for an alternative route to compound 4, see: R. R. Tykwinski, F. Diederich, V. Gramlich, P. Seiler, Helv. Chim. Acta 1996, 79, 634-645. [ll] a) K. C. Nicolaou, A. L. Smith, E. W. Yue, Proc. Natl. Acad. Sci. USA 1993, 90, 58815892; b) K. Toshima, K. Otha, A. Ohahsi, T. Nakamura, M. Nakata, S. Matsumura, J. Chem. SOC., Chem. Commun. 1993, 15251527; c) M. Tokuda, K. Fujiwara, T. Gomibuchi, M. Hirama, M. Uesugi, Y. Sugiura, Tetrahedron Lett. 1993, 34, 669-672; d) M. F. Semmelhack, J. J. Gallagher, W. Ding, G. Krishnamurthy, R. Babine, G. A. Ellestad, J. Org. Chem. 1994, 59, 4357-4359; e) D. L. Boger, J. Zhou, J. Org. Chem. 1993, 58,3018-3024.

[12] G. B. Jones, R. S. Huber, J. E. Mathews, A. Li, Tetrahedron Lett. 1996, 37, 3643-3646; G. B. Jones, J. E. Mathews, Tetrahedron 1997, 53, 14599-14614. [13] G. B. Jones, M. W. Kilgore, R. S. Pollenz, A. Li, J. E. Mathews, J. M. Wright, R. S. Huber, P. L. Tate, T. L. Price, R. P. Sticca, Bio. Med. Chem. Lett. 1996,6, 1971-1976. [14] a) H. Hopf, C. Werner, P. Bubenitschek, P. G. Jones, Angew. Chem. 1995, 107, 2592-2594; Angew. Chem. Int. Ed. Engl. 1995, 34, 23672368; for the first synthesis of a cyclooctaenediyne, stabilized as the alkynecobaltcarbonyl complex, see: b) G. G. Melikyan, M. A. Khan, K. M. Nicholas, Organometallics 1995,14,2170-2172. [15] H. Sato, N. Isono, K. Okamura, T. Date, M. Mori, Tetrahedron Lett. 1994,35, 2035-2038.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Conocurvone - Prototype of a New Class of Anti-HIV Active Compounds? Hartmut Laatsch

Workers at the National Cancer Institute recently achieved a remarkable success in their search for active plant metabolites. During routine screening, extracts of a shrub indigenous to Australia were noted for their exceptionally high, and, more importantly, selective anti-HIV activity in a variety of cellular in vitro tests. The substance responsible for this effect was the naphthoquinone conocurvone la, which was isolated after an elaborate purification procedure in a yield of 22 mg per kg plant material (Conospermum sp., Proteaceae). [ 1,2]

la

tb: hydrogen instead of ring A

As fluorescence tests with BCECF (2’,7’bis-2(2 -carboxyethyl)- 4(5)-carboxyfluorescein), the XTT tetrazolium test, and a test with the intercalating dye DAPI (4’,6 -diamidino-2-phenylindole dihydrochloride) showed, the presence of conocurvone l a at a concentration of ECso s 0.02 ,UM completely averted the death of HIV 1-infected human lymphoblastoid cells (CEM-SS). Measurements of viral reverse transcriptase, the viral P24 antigen, and the syncytium forming units (SFU) revealed that virus replication came to a standstill at the same time. Since

28: R1= H, R2 =OH

2b:R’= R z = H 2c: R1= H,

R* = pOCOC&Br t d : Rl = R2 = SC6H5

332

Applications in Total Synthesis

conocurvone l a is cytotoxic and inhibits growth only at or above a concentration of 50 ,VM, the therapeutic index has the unusually high value for a virostatic of 2500. Whether this value also holds for other viruses, or is limited to HIV-1 viruses, was not reported. [3] Conocurvone l a is a deoxy-trimer of teretifolion B (2a), a compound that has been known for longer and was first isolated from Conospermum teretifolium. The fast atom bombardment (FAB) mass spectrum of the trimeric quinone revealed a molecular ion corresponding to the formula C60H56011,but the structure of l a was in the end only fully elucidated by synthesis. The reason for this was that atropoisomeric equilibria were formed and led to more or less complex IH-NMR spectra that varied with solvent and with temperature. The compound therefore appeared to be a complex mixture. However, the synthetic product was identical to the natural material, even in its chiroptical parameters, thus confirming the structure and also the low rotation barrier around the quinone-quinone axis, a property which has also been found for other quinonoid-quinonoid-coupled oligomers. Quinones constitute an extremely important group of natural products. They are one of the oldest known classes of compounds, have achieved importance as dyestuffs, and in addition possess many different biological activities: many quinones are active as anti0

OH

R2 0

3

4a: Rl =Me, RZ = OH

4b R'

= H,

RZ =OH

4c. R l = OH, R2 = H

biotics, are cytotoxic [like daunomycin (3)], or are (weakly) antiviral. Even simple compounds such as plumbagin (4a) prove to be highly effective and selective as enzyme inhibitors. For other quinones the activity derives from interaction with physiological redox systems, or - at least for unsubstituted quinonoid double bonds - from the reaction with nucleophiles. [4] In the case of conocurvone (la) a physiological effect has once again been found for an oligomeric quinone, which is completely absent for the monomer 2a or related compounds. [5] This must therefore be a new property that arises from the oligomerization, and should thus stimulate renewed interest in oligonaphthoquinone synthesis. A brief outline of the current state of knowledge about this class of substances is hence justified. In all but a few cases (one of which is la), the over seventy naturally occurring dimeric, trimeric, cyclo-trimeric, and higher oligomers are all constructed of identical units derived from juglone (4b, 5 -hydroxynaphthoquinone). These units are linked together in various ways, symmetrically or asymmetrically with respect to the c-C framework. With the exception of crisamicin A, all these compounds have an oxygen atom in the ortho position to the linkage site. The reason for this variety lies in the mechanism of formation of dimeric quinones, which may be regarded as a phenol oxidation. The synthesis starts from substituted naphthols, such as 5b, and leads, depending on the initial substrate and the enzymes of the organism concerned, not only to the monomeric quinone but via binaphthols [e. g. vioxanthin (Sc)] also to dimeric [e. g. xanthomegnin (?id)] or oligomeric quinones. It also yields the polymeric, black allomelanin, which gives ebony, for instance, its characteristic color. This pathway is confirmed by the presence - often in the same organism - of dimers with lower oxidation states, which are formal intermediates in diquinone biosynthesis:

Conocurvone - Prototype of a New Class ofAnti-HNActive Compounds?

/ A I F - - B I

8 5a = A-B

5b:only component B

333

OMe

I

OMe 6

5c: B instead of A in 521

5d A instead of B in 5a

examples are the monoquinone viomellein 5a and the binaphthylidenedione 6 (diosindigo A). In nature, the oxidative dimerization of phenols is controlled by enzymes, as is demonstrated by the axial chirality of the 6,8’coupled juglone derivative isodiospyrin. In synthesis, however, phenol oxidation only proceeds in high yields when the enzymatic reaction control is replaced by substituent control, that is, if all but one of the positions with high spin density in the radical (orthoand para positions) are blocked. The synthetic usefulness of this principle is well documented by numerous examples, even under biomimetic conditions. [6] In this way, using a similar synthetic sequence by co-oxidation of 7a and 7b, we have obtained not only the dimers, but also quinones 8a and 8b. [7] These are related to conocurvone la, but their antiviral properties have not yet been studied. Unlike in the case of phenols, direct oxidative dimerization of quinones only takes place under drastic conditions and requires a hydroxy or amino group on the quinonoid double bond, as in Lawson 4c, the dye in Arabian henna. Since the work of Pummerer (1937), however, it has been known that monomeric 1,4-quinones can be oligomerized much more easily under acidic or basic conditions. [8] In pyridine/ethanol, or by warming in glacial acetic acid, we have converted naphthoquinone, 1,4-anthraquinone, and nu-

merous derivatives - though not benzoquinones - smoothly into dimers and cyclo-trimers. In this highly regioselective so-called phenol/ quinone addition, juglone (4b) and several of its derivatives afford exclusively the symmetrical 3,3’-linked dimers, several of which were already known as natural products. [9] It was only recently discovered that o-quinones may also be dimerized by this principle. [ 101 According to Brockmann, this process is an autocatalytic one, in which traces of hydroquinone, which are always present, undergo a Michael addition to the excess of quinone to form a biaryltetrol (12), [ 111 an intermediate which also occurs during phenol oxidation. Dehydrogenation of this intermediate by the monomeric quinone yields the biaryldiquinone and further hydroquinone, until all the monomeric quinone has been transformed (3 9 + 1Oc -+ 12c + lob). When air is excluded, conversions of naphthoquinone reach

H

0 7a 7 b only component A

8a 8 b himer instead of tetrami

334

Applications in Total Synthesis

90%; when air is present, or when nitroben- two equivalents of teretifolion B (2a) with zene is used as solvent, the yield of dimer naphthoquinone in glacial acetic acid afforded can be increased even more through reoxida- the predicted l b in 9 96 yield. For the synthesis of conocurvone (la), 2-deoxyteretifolione tion of the hydroquinone. Under suitable reaction conditions, the (2b) was warmed with two equivalents of 2a dimer that is initially formed can react further in pyridine, analogously to the synthesis of to yield trimers of type 8b. It has not yet been 2,2’-binaphthyldiquinone. All the spectrospossible to isolate these compounds, since copic and pharmacological properties of the they are always converted into the trimeric synthetic material agreed with those of the cyclic quinones 13a. Indeed, 8b is also con- natural product. The main difficulty in the synthesis of la lay verted into 13a by phenol oxidation under weakly basic conditions. The stability of in the deoxygenation of 2a to 2b. This was conocurvone l a is therefore due to the pres- eventually carried out by transforming the ence of hydroxy groups at position 2 of the p-bromobenzoate 2c to 2d with thiophenol, monomer, which prevent cyclization. This with subsequent catalytic reduction with cyclization via a symmetrical dimer of type Raney nickel. Nothing is yet known about the site of 12b explains why none of the known hydroxylated cyclo-trimers (e. g. cyclo-trijuglone action or structure-activity relationship for 13b) display Cs-symmetry with respect to derivatives of la (as, for example, lb), and any discussion is therefore very speculative. the peri-hydroxy groups. The synthesis of conocurvone (la) also However, it is conceivable that la assumes a makes use of the well established principle helical conformation which winds into the of phenol/quinone addition, even though the groove of the DNA strand. Similar conformaterm was inspired by the reaction of quinones tions are also expected for 8a, and in particwith hydroxy-2H-1-benzopyran-%-ones, a ular for 8b and higher oligomers. As we have reaction that was discovered later but pro- shown, partial reduction of these compounds ceeds in a similar manner. Brief warming of leads to deep blue, intramolecular quinhydro-

& f @I

I-

\

--

d

x

0\

/

09

10a

10b OH mstead of 0-

11

OH 12a:R = H 12b:R=OH 12c: R = H, quinone instead of hydroquinone

13a: R = H 13b:R = OH

Conocurvone - Prototype of a New Class of Anti-HIVActive Compounds?

nes, which are also stable in solution and can be shown by molecular modelling to be stabilized in a helical conformation. For la, additional interactions may be expected between the quinonoid hydroxy groups and peptides, like those that play a role in coloring hair and skin with henna (4c). It will be fascinating to see whether these hypotheses are confirmed.

References [ l ] L. A. Decosterd, I. C. Parsons, K. R. Gustafson, J. H. Cardellina 11, J. B. McMahon, G. M. Cragg, Y. Murata, L. K. Pannell, J. R. Steiner, J. Clardy, M. R. Boyd, J. Am. Chem. SOC. 1993,115,6673-6679. 121 Y. Kurimura, Bio Ind. 1996, 13, 71-7. [3] M. R. Boyd, J. H. Cardelina 11, K. R. Gustafson, L. A. Decosterd, I. Parsons, L. Pannel, J. B. Mcmahon, G. M. Cragg, PCT Int. Appl., WO 9417055 A1 940804 (1994).

335

[4] R. H. Thomson, Naturally Occurring Quinones, Vol. 2, Academic Press, London, 1971; Naturally Occurring Quinones, Vol. 3, Chapman and Hall, London, 1987. [5] J.-R. Dai, L. A. Decosterd, K. R. Gustafson, J. H. Cardellina 11, G. N. Gray, M. R. Boyd, J. Nat. Prod. 1994,57, 1511-1516. [6] H. Laatsch, Liebigs Ann. Chem. 1987, 297304, and preceeding publications on the same theme. [7] H. Laatsch, Liebigs Ann. Chem. 1990, 433440. [8] E. Rosenhauer, F. Braun, R. Pummerer, G. Riegelbauer, Ber. Dtsch. Chem. Ges. 1937, 70,228 1-2295. [9] H. Brockmann, H. Laatsch, Liebigs Ann. Chem. 1983,433-447. [lo] K. Krohn, K. Khanbabaee, Liebigs Ann. Chem. 1993,905-909. [ l l ] H. Brockman, Liebigs Ann. Chem. 1988, 1-7. After proofreading of this contribution, J. Y. Yin and L. S. Liebeskind submitted a paper on a novel access to trisquinones (Angew. Chem. 1998, in press).

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Progress in Oligosaccharide Synthesis through a New Orthogonal Glycosylation Strategy Hans Paulsen

Glycoconjugates have numerous important biological functions. [ 1, 21 For a better understanding of these functions, defined natural and modified glycoconjugates are needed. To this end, intensive efforts in the last few years have aimed at the synthesis of glycoconjugates, resulting in remarkable progress in oligosaccharide synthesis. New glycosyktion methods have been developed with efficient leaving groups, which lead to good yields and high steroselectivity under mild conditions. The halide, thioglycoside, and trichloroacetimidate methods, [3-51 in modified forms, have proved to be especially effective. Chemical and enzymatic reactions can also be combined, as long as the glycosyl transferases and the activated nucleotide sugar are available. [6] The most effective methods for the construction of larger oligosaccharides is block synthesis, in which blocks of di- or trisaccharides are coupled. The configuration of the anomeric centers is already fixed in the nonreducing block sequences. [7] One drawback here is that the anomeric center at the reducing unit of a block must be reactivated for subsequent coupling. Activation of the anomeric center should not require many steps or, better yet, should be direct. Thus 2-(trimethylsily1)ethylglycosides, for example, have been prepared from blocks, [8] which are readily

deprotected and converted into activated trichloroacetimidates. [5, 91 Glycal-type structures can also be activated by expoxidation, making renewed coupling possible. [ 101 However, use of stable thioglycosides at the anomeric center of the block is best, since a wide variety of structures and promoters is possible. For the construction of an oligosaccharide building block a glycosylation reaction is also necessary. The synthesis of a thioglycoside-containing unit, for example, requires a different glycosylation procedure with a different leaving group for the donor, since the potentially activatable thioglycoside would be destroyed otherwise. Numerous strategies are available, which involve several or more additional reaction steps, depending on the blocking pattern. The coupling of donors activated by benzyl substituents with acceptors deactivated by acetyl groups has also been suggested. [11,12] Ogawa et al. recently described an interesting and provocative strategy that starts with a set of two donors, which can be extended in an orthogonal glycosylation reaction. [ 131 The approach was demonstrated with a model reaction sequence leadind to longchain B( 1 -+4)-glycosidically linked 2-acetamido-2-deoxy-~-glycoseunits (Scheme 1). Thioglycoside 1 and glycosyl fluoride 4 serve

Progress in Oligosaccharide Synthesis through a New Orthogonal Glycosylation Strategy R En0

a SPh +

O

0nO R O

a

NPhth

F

i

R 0nO O & : e F

NPMh

1 R-Ac

0~"

NPhlh

3R-H

2R-H

5R-Ac

6R-H

4R-Ac

+

5 + 2 -

,j

A Brio c c

J

a

:

@

NPhlh

:

337

ii

RO0no &$@SPh NPhth

0 0 ~

7R-Ac

a

8R-H

NPhlhSPh

0011

9

9 + 3 -

Bno NPhth

OBn

NPhlh

O0n

NPhth

OBn

10R-Ac 11 R - H

9

+

11

'

J-

AcO OEn

NPMh

OBn

NPhlh

OEn

12

Scheme 1. i) NIS-TfOH (AgOTf); ii) CpzHfClZ-AgC104.

as the two building blocks. Thioglycoside 1 can be coupled with the deactylated glycosyl fluoride 3 without affecting fluorine at the anomeric center, and the resulting disaccharide 5 with the activated anomeric center can be used directly for further glycoside synthesis. Inversely, the reaction of glycosyl fluoride 4 with the deacetylated thioglycoside 2 yields disaccharide 7 in which the thioglycoside is unchanged. This disaccharide can also be employed directly in further glycosidation without any additional steps. This flexible method thus enables glycosidation without destruction of the active anomeric center at the acceptor. This promising strategy can be applied to other systems. The phenylthioglycosides employed are activated with N-iodosuccinimide trifluoromethanesulfonic acid (NIS-TfOH) (or NISAgOTf), and the phenythiogroup acts as a leaving group. In reactions with the glycosyl fluorides the promotor is the reagent Cp2HfC12-AgC104. Thus larger oligosaccharide blocks can be constructed from the two monosaccharides 1 and 4 with these two rea-

gents. Compounds l and 4 contain an Nphthaloyl group at C2, which induces uniform @-glycosidiclinkage. The approach was demonstrated with the following synthesis. Coupling of 1 and 3 affords disaccharide 5 (85 %), whereas the reaction of donor 4 with 2 gives the disaccharide 7 (81 %). Disaccharide 5 is treated with 2 to furnish trisaccharide 9 (72%). The subsequent coupling of 9 with 3 yields tetrasaccharide 10 (65 %). Deacetylation of 10 to 11 can be followed by block condensation of trisaccharide 9 with 11, which yields heptasaccharide 12 (67 %). Phenylthioglycosides and glycosy1 fluorides are used both as donors and as acceptors, and additional steps for activation of the anomeric center are not required in either case. Kahne et al. [ 141 used a similar strategy in a very elegant synthesis of a trisaccharide in partically one step. The building blocks they used, the S-glycosides 13, 14, and 16, have considerably different reactivities at the anomeric center (Scheme 2). Phenylthioglycoside 14 is definitely the least reactive,

338

Applications in Total Synthesis

0

H3c@s

0

HO OEn

13

14

H3cP OBn

J

15

H

16 I1

I

,

C

d

H 3 C H o OBn OBn

17

Scheme 2. i) TfOH, HC=CCOzCH3, -78 "C.

BnO

0

18

19 i

OBn

23 +22-

ii BnO BnO

24

Scheme 3. i) (PhP3)RhCl; ii) TMSOTfKH3CN.

while phenyl sulfoxide 16 is considerably more reactive. The reactivity of 16 can be increased yet further by introduction of a methoxy substituent on the phenyl group, thus giving the highly reactive p-methoxyphenylsulfoxide 13. A solution of building blocks 13, 14, and 16 in Et20KH~C12is simply mixed in the presence of TfOH and HC=CCOzCH3 at -78 to -7O"C, and trisacchride 17 is isolated in 25% after 45 min. It is assumed that the modestly reactive 14 react first with the highly reactive 13 to give disaccharide 15; the silyl ether is cleaved simultaneously, and 15 reacts with the moderately reactive 16 to provide 17. An interesting, new strategy which can also be used for an orthogonal oligosaccharide synthesis has been developed by Boons. [15,16] It calls for the use of substituted type 18 allylglycosides with latent active group at the anomeric centre. Using (PhP3)RhCl as the catalyst, compound 18 can be rearranged to the 2-isobutenyl glycoside 19. Since the vinyl ether moiety is a good leaving group, compound 19 can serve as a glycosyl donor.

Progress in Oligosaccharide Synthesis through a New Orthogonal Glycosylation Strategy

339

The building block 19 can therefore be con- hydroxyl group can also be set free so that a verted to the disaccharide 21 in the presence glycosyl acceptor can be obtained from the of TMSOTf by reaction with the acceptor 20, same molecule as well. An example from the which can also be obtained from compound area of trichloracetimidate methodology is 18 by deacetylation. This reaction sequence shown in Scheme 4. Compound 25 could be could be repeated analogously. Rearrange- obtained by trichoracetimidate coupling ment of compound 21 in the presence of Wil- according to Schmidt. [ 15,17,18] From comkinson catalyst furnished the corresponding pound 25, the glycosyl donor 26 could be activated disaccharide donor 23. This could obtained after cleavage of the TBDMS group then be coupled in like manner with acceptor and treatment with trichloracetonitrile. Hy22, which can be obtained by deacetylation drolysis of the isopropyiidene .group of comof compound 21, to give the tetrasaccharide pound 25 gave the glycosyl acceptor 27. 24. The yields were over 80 % in all cases. In Coupling of 26 with 27 furnished the hexasaccompound 24, a rearrangement of the allylgly- charide 28, which could then be activated at coside to the vinyl ether and hence to the gly- the anomeric centre or just as easily deblocked cosy1 donor would be possible. However, selectively at the non-reducing end. Further compound 24 could also be converted at the coupling steps would then be possible. The nonreducing end into a glycosyl acceptor by compounds are intermediates of a LewisX cleavage of the acetyl group. Consequently, synthesis. [ 171 all the oligosaccharides could be prepared It was also possible to reactivate the anofrom one starting product 18. meric centre through a differentiation of activity In principle, this strategy can also be ex- at the anomeric centre during the synthesis tended to other glycosylation reactions. How- of di- and oligosaccharides. A corresponding ever, it must be assured that the anomeric example is shown in the reaction sequence of centre can be readily activated, if possible in Scheme 5. Pinto [19,20] observed that selenoone step, to the glycosyl donor and that a glycosides are more reactive and could thereBnO

26

+

27

,OBn

IV

OTBDMS

BnO

28

Scheme 4. i) Bu4NF; ii) CC13CNDBU; iii) TFNCH2C12; iv) BF3.OEt2.

-

TBDMS ' tBuMqSi

340

Applications in Total Synthesis

B Bn0n

29

O

aSEt

NH

A

%

p h T )

NPMh SePh& * * : A AcO

:

a

S

h

AcO

PhthN

PhthN

PhthN

PhthN

33

SePh

Bno& BnO

SEi BnO

32

30

Scheme 5. i) Et3SiOTf/-78 "C; ii) AgOTf/KZC03.

fore be more readily activated than thioglycosides. In the presence of Et3SiOTf at -78 "C, the imidate 29 could be coupled with the selenoglycoside 30 to give the disaccharide 32. The selenodisaccharide 32 could then be coupled with the thioglycoside 31 in the presence of AgOTf to give the trisaccharide 33 without the thio group of compound 31 being attacked during the reaction. With compound 33, another coupling at the anomeric centre with thiophilic reagents would be possible. It would also be possible to elongate both compounds 32 and 33 at the OH groups after cleavage of the benzylidene group.

The long known influence of the substituent pattern on the reactivity at the anomeric centre [21] can also be used to advantage for a differentiation during synthesis of an oligosaccharide. Ether substituents on the hydroxyl groups of the pyranose residue always lead to a higher reactivity at the anomeric centre, whereas acyl groups on the hydroxyl groups lower the reactivity. Fraser-Reid [ 111 has used the terms armed and disarmed to describe this effect. A combination of this effect with the seleno effect is shown in the reaction sequence in Scheme 6 performed by Ley. [22] The highly reactive (armed) seleno-

+3

* / ** BnO

34

SePh

OMe

*-#+ OMe

36

SePh

35

SePh

Y-

OMe

OMe

OMe

37

SEt

TPS

Scheme 6. i) N-IodsuccinimidelTfOH (10 min); ii) N-IodsuccinimidelTfOH.

-

SEt

38

t BuPbSi

Progress in Oligosaccharide Synthesis through a New Orthogonal Glycosylation Strategy

glycoside 34 was treated for a very short reaction time with the acceptor 36 to give the disaccharide 35. Coupling of the selenoglycoside 35 with the thioglycoside 37 resulted in the corresponding trisaccharide 38. In 38, an activation and coupling at the anomeric centre is possible with thiophilic reagents. Cleavage of the TPS groups would give free OH groups for an acceptor reaction. In view of the available arsenal of glycosidation reactions, these examples should point the way for the development of similar strategies.

References [ l ] A. Varki, Glycobiology 1993, 3, 97. [2] R. A. Dwek, Biochem. SOC.Trans. 1995,23, 1. [3] 0. Lockhoff, Houben-Weyl: Methoden der Organischen Chemie, Vol. E14d3, Thieme, Stuttgart, 1992, 621. [4] K. Toshima, K. Tatsuda, Chem. Rev. 1993,93, 1503. [5] R. R. Schmidt, W. Kinzy, Adv. Carbohydl: Chem, Biochem. 1994,50,21. [6] C.-H. Wong, R. L. Halcomb, Y. Ichikawa, T. Kajimoto, Angew. Chem. 1995, 107, 569; Angew. Chem. Int. Ed. Engl. 1995, 34, 521. [7] H. Paulsen, Angew. Chem. 1990, 102, 851; Angew. Chem. Int. Ed. Engl. 1990,29,823. [8] J. Jansson, G. Naori, G. Magnusson, J. Org. Chem. 1990,55, 3 18 1. [9] H. Paulsen, M. Pries, J. P. Lorentzen, Liebigs Ann. Chem. 1994,389.

34 1

[lo] S. J. Danishefsky, K. F. McClure, J. T. Randolph, R. B. Ruggeri, Science 1993, 260, 1307; J. T. Randolph, S. J. Danishefsky, Angew. Chem. 1994, 106, 1538; Angew. Chem. Int. Ed. Engl. 1994, 33, 1470. [ l l ] D. R. Mootoo, P. Konradsson, U. Udodong, B. Fraser-Reid, J. Am. Chem. SOC. 1988, 110, 5583. [12] L. A. J. M. Sliedregt, K. Zegelaar-Jaarsveld, G. A. van der Marel, J. H. van Boom, Synlett 1993, 335. [I31 0. Kanie, Y. Ito, T. Ogawa, J. Am. Chem. SOC. 1994, 116, 12073. [I41 S. Raghavan, D. Kahne, J. Am. Chem. SOC. 1993,115, 1580. [I51 H.-J. Boons, Tetrahedron 1996, 52, 1095. [16] G.-J. Boons, B. Heskamp, F. Hout, Angew. Chem. 1996, 108, 3053; Angew. Chem. Int. Ed. Engl. 1996,35, 2845. [I71 A. Toepfer, W. Kinzy, R. R. Schmidt, Liebigs Ann. Chem. 1994,449. [I81 R. R. Schmidt in Methods in Carbohydrate Chemistry (Eds.: S. E. Khan, R. A. O'Neill), p. 20, Hamood Academic Publisher, Amsterdam, 1996. [ 191 S. Mehta, B. M. Pinto, J. Org. Chem. 1993,58, 3269. [20] S. Mehta, B. M. Pinto in Methods in Carbohydrate Chemistry (Eds.: S. E. Khan, R. A. O'Neill), p. 107, Harwood Academic Publisher, Amsterdam, 1996. [21] H. Paulsen, A. Richter, V. Sinnwell, W. Stenzel, Carbohydx Res. 1978, 64, 339. [22] P. Grice, S. V. Ley, J. Pietruszka, H. W. M. Priepke, Angew. Chem. 1996, 108, 206; Angew. Int. Ed. Engl. 1996, 35, 206.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Analogues of the Sialyl LewisXGroup and of the N-Acetylneuraminic Acid in the Antiadhesion Therapy Athanassios Giannis

In the past years our understanding of carbo- ria, while B and T lymphocytes are responhydrate-protein interactions inreased dramati- sible for the specific immune response. As cally [ 13. Do to significant advances in molec- part of the immune response leukocytes ular biology and carbohydrate chemistry the leave the blood vessels and migrate to the implication and importance of cell surface zone of infection and the secondary lymphatic glycoconjugates in cell-cell interaction and in organs. The cells leave the blood vessels cell adhesion phenomena was elucidated. A through the endothelium of the postcapillary great amount of literature on carbohydrate- venules in the area of the target tissue. The complex multistage event leading to binding proteins (lectins) and their ligands and carbohydrate-metabolizing enzymes was migration of leukocytes into the zone of infecpublished. For these reasons carbohydrates tion occurs during normal chronic inflammaare attractive starting points for drug develop- tion as well during acute inflammation and is ment [2]. In order to demostrate this fact I will mediated by a specific and regulated cell-cell discuss below examples of carbohydrate- recognition process between leukocytes and based antiinflammatory and antiviral com- endothelial cells. This cell-cell recognition takes place by means of the interaction of a pounds. number of membrane-bound adhesion receptors with the corresponding membrane-bound ligands. The following receptors are known The Sialyl LewisX Group to be involved [3]: a) selectins, b) integrins, and c) members of the immunoglobulin superand its Analogues as Ligands family. for Selectins: Chemoenzymatic The selectin family consists of three memSynthesis and Biological bers, which are all glycoproteins and which Functions mediate the initial stage of leukocyte adhesion (Fig. l), namely, L-, E-, and P-selectin. LWhite blood cells or leukocytes are compo- selectin is constitutively expressed on the surnents of blood that play a vital role in the face of leukocytes. It is involved in the recirimmune response. Neutrophils, for example, culation of lymphocytes in peripheral lymph are responsible for rapid and unspecific nodes as well as in the recruitment of leukoimmune defense by digesting invading bacte- cytes at the zone of inflammation. E-selectin

Analogues of the Sialyl L e w i s Group and of the N-Acetylneurarninic Acid basement membran leucocyte

------@I ,

endothelial cell layer

I

1 -

1 -

rolling activation

343

1

1 -

firm adhesion

~

c extravasation

I

-

t -

v

4

selectin

carbohydrate ligand integrin (non-activated)

\) integm (aktivated) y ICAM 0 PAF

’-*Extravasation

/I, PAF-Receptor

Figure I . Interaction between leukocytes and endothelial cells of blood vessels (modified from [3e]). Top: overview; bottom: single steps with explanation of the symbols. Stimulation of endothelial cells by various mediators and factors leads to the expression of selectins and platelet-activating factor (PAF). The extravasation of leukocytes from the postcapillary venules starts with a weak, low-affinity, selectin-mediated adhesion of the leukocytes to endothelial cells, which leads to a slowing down of the leukocyte velocity (rolling). In the second phase a PAF-mediated activation of the leukocyte integrins occurs, In the third phase the activated integrins bind with high affinity to their ligands which are located on the endothelial cell surface. These ligands are called intercellular cell adhesion molecules (ICAM) and are members of the immunoglobulin superfamily. The firm adhesion of the leukocyte cells to the endothelium and finally their departure from the blood vessel (extravasation) results.

344

Applications in Total Synthesis

is expressed on the surface of endothelial cells a few hours after stimulation with interleukin 1 or tumor necrosis factor a. P-selectin is kept in intercellular stores in blood platelets (thrombocytes) and endothelial cells. Within a few minutes of exposure to thrombin, histamin, substance P, peroxide radicals, or complement factors, P-selectin is mobilized from these stores and transported to the cell surface. The exact structure of the membrane-associated carbohydrate ligand for L-selectin is not known. However, it is known that the L-selectin ligand is located at the postcapillary endothelium of the high endothelial venules (HEV) of the peripheral lymph nodes. According to the available data it is a sialic acid containing, sulfated, and fucosylated oligosaccharide [4]. The sialyl LewisX group (SLeX) (1 without R in Fig. 1) serves as a common ligand for all three selectins and is a component of cell surface glycosphingolipids and particularly glycoproteins. The physiological SLeX-containing glycoproteins ligands for L-, P- and E-selectin are GlyCAM-1, PSGL-1 and ESL-1 respectively. In the case of PSGL-1, recent data indicate that high affinity binding is mediated at least in part by the comined recognition of sialylated oligosaccharides and tyrosine sulfate residues [5]. The importance of this oligosaccharide group for leukocyte adhesion was recently underlined by investigations into a hereditary disease, namely, leukocyte adhesion defiency type 2 [6]. Owing to a defect in the biosynthesis of the SLeX group, the neutrophils are not able to adhere to stimulated endothelium and thus to migrate into the zone of inflammation. Patients with this condition suffer from recurrent severe bacterial infections. On the other hand, there is also a series of acute and chronic diseases whose course is negatively influenced when too many leukocytes migrate to the area of the infection or in the area of the pathological process itself. These include cardiogenic shock, stroke, thrombosis, rheumatism, psoriasis, dermatitis, adult respiratory

distress syndrome, bacterial meningitis, and encephalitis. In addition, metastasis in a number of tumors seems to be linked to expression of SLeXand other closely related oligosaccharides on the membrane surface of the tumor cells and the interaction of these groups with endothelial selections. Efforts have thus been directed towards the development of adhesion blockers as new antiphlogistics, antithrombotics, immunosuppressants, and as drugs to prevent the formation of metastases. A topic of high priority in the last years was the synthesis of the SLeXgroup and analogues thereof, which could act as alternative selectin ligands and thus block the interaction between endothelium and leukocytes. Oligosaccharide synthesis must meet a number of criteria; it must be efficient, highly regio- and stereoselective, and suitable for large-scale production. In addition, the synthesis of a potential pharmaceutical must fulfill economic and ecological requirements (e. g. reagents containing heavy metals should be avoided). The groups of J. C. Paulson and C.-H. Wong have gone a long way towards solving these problems through the development of a clever (though not uncomplicated) enzyme-catalyzed synthesis of SLeX (Fig. 2) [7]. They employ the glycosy1 transferases involved in the biosynthesis of SLeX. A number of difficulties had to be overcome before the synthesis became viable: a) although galactosyl transferase was available, neither the NeuSAc transferase (Neu5AcT) nor the Fuc transferase (FucT) were; b) the pertinent glycosyl donors (sugar nucleotides) are too expensive to be used in stoichiometric amounts in large-scale synthesis ; c) the glycosyl transferases are inhibited by final products and/or intermediates. The first problem was overcome by cloning and expressing the genes for NeuSAc transferase and Fuc transferase [8] in Sf9 cells. In this way both transferases could be produced

Analogues of the Sialyl LewisX Group and of the N-Acetylneuraminic Acid

345

OH

coo-

7

4. ;

,

CMP-Neu5AcSynthetase

Neu5Ac

Y

HO

0-R

ct2,3NeuSAcT (24%)

I GDP-Fuc -------;

I, Ho

HN'

L o

H3C

Figure 2. Chemoenzymatic synthesis of SLeX according to Paulson, Wong et al. (R = CH2-CH=CH3).

346

Applications in Total Synthesis

in large amounts. A new method for cofactor regeneration in situ allowed the sugar nucleotides (UDP Gal, CMP NeuSAc, GDP Fuc) to be easily generated and also largely suppressed the inhibition of the enzymes by products. To enable easy isolation, the SLeX group was synthesized as the 0-allylglycoside 1 (R=CHzCHCH2, Fig. 2). I3C-labeled SLeX derivatives were also synthesized for NMR spectroscopic studies. These studies showed that the SleX group has a folded, low-energy conformation, in which the L-fucose residue lies above the D-galactose unit. Therefore it appears that the tetrasaccharide forms a well-defined hydrophilic surface along the NeuSAc-Gal-Fuc structural unit, while a hydrophobic region exists below the NeuSAc-Gal-GlcNAc structural unit. The fact that the transferases show some flexibility with regard to the glycosyl residues they will accept allowed the synthesis of several SLeX analogues such as the glucal derivative 2 [9] (Scheme l), which were used for investigations into structure-activity relationships [lo]. The affinity of 2 for E-selectin was found to be similar to that of SLeX. Based on these investigations and the fact that the sulfatides 3 and 4 (Scheme 1) isolated from biological material [ 111 demonstrated a higher affinity for E-selectin DeFrees, Gaeta et al. postulated a model of the E-selectin-

SLeX interaction: the structural elements of the SLex unit essential for the recognition by E-selectin include the carboxyl function of N-acetylneuraminic acid, part of the galactose residue (possibly only the 4 - and 6-hydroxyl functions), and the three hydroxyl groups of the L-fucose residue. The CH3 group of this L-sugar seems to be not essential. These structure-activity relationships are largely in accordance with those found by Tyrrell et al. [I21 The pharmacophore are highlighted in the chemical formula of SLeX-R 1 (Fig. 2). It is important to note here that according to mutagenesis studies and crystallographic data the selectins have only one [13] binding site for the SLeX group. However multivalency of both oligosaccharide and selectins on the surface of cells (cf. Fig. 1) generate high affinity binding. Recently the conformations of the NeuAca2(I) -+ 3Gal~l(II)+4[Fucal(III)-+ 31GlcNAc-0-CH3 tetrasaccharide (SLeX-OCH3),in aqueous solution and bound to recombinant, soluble E-, P-, and L-selectin have been determined using high resolution NMR spectroscopy [14]. In the free ligand, the conformation of glycosidic linkage I is disordered with {@I, YI} sampling values close to (-60, 0}, {-loo, - S O } , and { 180,O). The trisaccharide portion is rigid and characterized by {@II, YII; QIII, !&} = {46", 18"; 48", 24'1. The

HO

HS03-3Galpl,3GlcNAc Pl,3Gal 2

4

Schemel.

Analogues of the Sialyl LewisXGroup and of the N-Acetylneuraminic Acid

bound conformations (bioactive conformation) of the ligand were calculated from the full relaxation matrix analysis of transferredNOE spectra for E- and P-selectin or by using a two-spin approximation for the L-selectin complex. Both E- and P-selectin recognize the (-60", W} conformation of SLeX while the {-loo", -50") conformer is probably recognized by L-selectin. The conformation of the branched trisaccharide portion in the bound state remains close to the conformation of the free ligand. In the E-, P-, and L-selectin complexes the GalH4 proton is in the vicinity of protein aromatic protons, most likely Tyr94 and/or Tyr48. The measured equilibrium binding constants ( K D )of SLeX, were 0.4 mM, 1.0 mM, and 0.6 mM for E-, P-, and L-selectin, respectively. On the other hand, the physiological ligands seem to have much higher affinities for the selectins. For example, a KDvalue of 70 nM for monomeric, soluble P-selectin interacting with its native ligand on HL-60 cells was measured [15]. The final confirmation of the efficacy of 1 (R = H) as an antiinflammatory drug was provided by Mulligan et al. [16] with animal models. Rats were injected with a poison isolated from cobras (cobra venom factor, CVF), which led to a P-selectin induced adhesion of neutrophils to the endothelium of blood vessels of the lungs. This in turn resulted in a massive accumulation of neutrophils in the tissues of the lungs as neutrophils left the blood vessels and invaded the surrounding tissues. The accompanying increase in the permeability of the blood vessels led to lung edemas, bleeding in the alveoli, and severe damage to the lungs. An intravenous injection of SLeX 1 (R = H) was given shortly before application of the snake venom, a 50 % reduction in the amount of bleeding in the lungs and accumulation of neutrophils in lung tissues was observed compared to that in untreated animals. In contrast, the same dose given after the application of snake venom was less effective in reducing the damage. Other, non-

347

fucosylated oligosaccharides such as Neu5 Aca2,3Gal/31,4GlcNAc proved to be inactive. The fact that such a low dose induces this protective effect is quite surprising: a single dose of 200 pg of 1 (R = H) corresponds to a concentration of less than 1 pmol L-' in the blood ! Based on these results, the hope that SLeXcontaining oligosaccharides and their analogues may prove to be effective antiinflammatory drugs was borne. Disappointingly, a phase I1 clinical trial on the treatment of reperfusion injury following myocardial infarction with CylexinTM (a tetrasaccharide glycoside of SLeX) produced by Cytel Corporation was recently terminated. A scheduled interim analysis of results showed that CylexinTM was safe, but it had no benefit compared with a placebo. [17] The reason for this may be the low affinity of SLeXfor the selectins. A possible solution for this problem may be the administration of potent SLeX ligands. For example compound Arg-Gly-Asp-Ala-NH-SLeX was recently synthesized and proved to be a high affinity ligand of P-selectin [18]. In an assay employing P-selectin-IgG and HL- 60 tumor cells this glycopeptide have an ICSOvalue of 26 pM. A long-range goal continue to be the develpment of SLeX group with mimetics that are potent selectin ligands and are effective when taken orally. The discovery that the sulfooligosaccharides [19] 4 and 5 can serve as selectin ligands also indicates that the SLeX group may be replaced by simpler analogues that would be easier to synthesize. Crucial to the development of such carbohydrate mimetics may be the above mentioned determination of the SLeX bioactive conformation. A suitable molecule could then be created by attaching the structural units essential for recognition to an appropriate scaffold. Several rationally designed SLeX mimetics are shown in Scheme 2. As yet no realy potent selectin low molecular mass ligand with affinity in the low nanomolar range has been developed from SLeX pharmacophore.

348

Applications in Total Synthesis

H

O

O

C

d

I

0 6

5

7

8

HO

OH

9

Scheme 2.

Compound 5 [20] was recently designed and synthesized and proved to be a selectin ligand with weak affinity ( I C ~ O 0.5 mM for all three selectins). For its development the authors used conformational energy computations, high field NMR, and structure-function

-

studies in order to define distance parameters of critical functional groups of SLeX. This pharmacophore was used to search a threedimensional data base of chemical structures. Compounds that had a similar spatial relationship of functional groups were tested as in-

Analogues of the Sialyl Lewifl Group and of the N-Acetylneuraminic Acid

hibitors of selectin binding. Glycyrrhizin, a natural occuring triterpene glycoside, was identified and found to block selectin binding to SLeX in v i m . Subsequently they substituted different sugars for the glucuronic acids of glycyrrhizin and found the L-fucose derivative to be the most active in vitro and in vivo. A C-fucoside derivative, synthesized on a linker designed for stability and to more closely approximate the original pharmacophore, resulted in an easily synthesized, effective selectin blocker with anti-inflammatory activity in vitro. Other interesting and rationally designed selectin ligands with apparently little resemblance to the parent oligosaccharide SLeX are the monosaccharide derivatives 6 [21], 7 [22] and 8 [23] (Scheme 2). These compounds display critical elements for recognition by the selectins and have higher affinity to E- and P-selectin than SLeX. Another multivalent P-selectin ligand is the neoglycopolymer 9 [24] (IC50 = 7 pM). This compound was developed based on the fact that sulfatides (3-sulfogalactosylceramide) is a P-selectin ligand [25]. Finally, since the SLeX-induced leukocyte adhesion could also be blocked by inhibiting the enzymes responsible for the biosynthesis of this oligosaccharide group, intensive efforts are underway to develop such inhibitors [26]. In this context it is of interest that an inhibitor of NeuSAc biosynthesis has recently become available: the simple D-glucosamine derivative 10 (Scheme 3) is a specific and potent inhibitor of both GlcNAc kinase and ManNAc kinase (Ki = 17 and 80 pM respectively) and thus inhibits NeuSAc biosynthesis [27].

349

N-Acetylneuraminic Acid Analogues as Weapons against the Influenza Virus Infection Influenza virus infection (flu) is the most serious respiratory tract disease and is poorly controlled by modern medicine [28]. Influenza viruses are divided into several types on the the basis of antigenic differences between their nucleoproteins. Haemagglutinin and neuraminidase are two major glycoproteins expressed in the surface of influenza A and B viruses. Haemagglutinin is a trimeric protein that binds to terminal N-acetylneuraminic acid residues of cell surface glycoconjugates. Whereas its role in the pathogenesis of the influenza virus infection has been elucidated [29] the importance of the viral enzyme neuraminidase is not clear. Influenza neuraminidase is a glycoprotein consisting of four identical subunits held together by disulfide bonds [30]. It is a glycosylhydrolase that cleaves terminal sialic acid from several glycoconjugates (glycoproteins and glycolipids). It has been postulated that this enzyme helps the release of newly formed viruses from infected cells, and it may also assist the movement of viruses through the sialic acid containing glycoconjugates of the mucus within the respiratory tract. The determination of the crystal structure of the influenza sialidase opened interesting opportunities for the design of new drugs for the therapy as well as for the prevention of the influenza virus infection. Early studies revealed 2,3 -didehydro-2 deoxy-N-acetylneuraminicacid (NeuSAc2en, 13, Scheme 3) to be an weak and non-specific neuraminidase inhibitor [313 with a Ki value of 4 yM. Compound 13 represent a transition state analogue of the N-acetylneuraminyl cation during the enzymatic reaction (Scheme 3). According to a postulate by L. Pauling compounds that closely resemble the transition state have higher binding affinity toward the

350

Applications in Total Synthesis

HC1. -0+0R

OH

I

-OH

YOOH

U

I l a : R= H 11b : R= Oligosaccharide Neuraminidase

COOH

12

*

13

15: R= NH2

14

NH 16: R= N H A H 2

111 RODCOOH AcHN

R O n C O O H AcHN

AH*

NH2

14

17

target enzyme in comparison to the enzyme substrate [32]. On the basis of structural information obtained from X-ray crystallographic investigation [33] of influenza neuraminidase complexed with 13 the derivatives 2,3-di-

AcHN

NHp

18

Scheme 3.

dehydro-2,4-dideoxy-4-amino-N-acetylneuramink acid 15 and its guanidino analogue 16 were rationally designed and synthesized [34]. These compounds proved to be specific and potent highly potent inhibitors of the

Analogues of the Sialyl Lewi# Group and of the N-Acetylneuraminic Acid

influenza virus neuraminidase: the corresponding Ki values are lo-* and 10-lo M. The 4-amino group of compound 15 interacts with the carboxyl group of Glu 119 residue of the neuraminidase forming a salt bridge whereas the guanidine function of 16 interacts not only with Glu 119 but also with Glu 227 in a lateral bonding mode. Interestingly compound 16 (zanamivir) exhibited strong antiviral activity against several influenza A and B strains in the cell culture assay. Zanamivir is currently being in phase I1 clinical trials and has shown efficacy in in both prophylaxis and therapy of influenza virus infection. However do to its poor oral bioavailability this compound has to be administered directly to the upper respiratory tract by either intranasal spray or by inhalation. Because oral administration is a more convenient method the development of a new class of orally active neuraminidase inhibitors was recently initiated and succesfully completed [35]. Considering the flat oxonium ion in 12 as an double bond isostere, the cyclohexene scaffold was selected as a appropriate replacement of 12 which would keep the conformational changes to a minimum. Furthermore it was expected that the cyclohexenyl derivative would be chemically and metabolically more stable than the dihydropyran ring present in compounds 15 and 16 and easier for optimization of the pharmacological properties. The olefinic isomers 14 and 17 (R = H) were initially considered as two possible transitionstate analogues and subsequently synthesized. The isomer 14 is structurally closer to transition-state intermediate 12 than the isomer 17 which is related to the known inhibitors 13, 15 and 16. Compound 14 (R = H) proved to be a moderate neuraminidase inhibitor whereas compound 17 (R = H) was inactive. On the basis of the above discussed X-ray crystallographic investigations of influenza neuraminidase complexed with N-acetylneuraminic acid analogues it was revealed that the glycerol side chain makes hydrophobic contacts

35 1

with the hydrocarbon side chain of Arg-224 of the viral neuraminidase. This suggested that the C7 hydroxyl group of the known neuraminidase inhibitors could be replaced by lipophilic groups without loosing affinity to neuraminidase. Furthermore it was considered that in the transition-state intermediate, the oxonium double bond is electron deficient and highly polarized. For these reasons the glycerol side chain was replaced by an ether moiety at C3 position (cyclohexene numbering) to give compounds of the general formula 14 (R = Alkyl). Structure-activity studies identified the 3-pentyloxy moiety as an apparent optimal group at the C3 position: compound 18 proved to be a very potent inhibitor the influenza virus neuraminidase (IC50 = 1 nM). The X-ray crystallographic structure of 18 bound to viral neuraminidase clearly showed the presence of a large hydrophobic pocket in the region corresponding to the glycerol subsite of neuraminic acid. The high antiviral potency observed for 18 appears to be attributed to a highly favorable hydrophobic interaction in this pocket. The practical synthesis of 18 starting from (-)-quinic acid was also described. Finally the ethyl ester of derivative of this inhibitor (named GS4 104) exhibited good oral bioavailability in several animals. More interesting GS4 104 demonstrated oral efficacy in an animal influenza model. In a preclinical model, GS4104 was given orally to mice and demonstrated antiviral activity against multiple strains of influenza, increased survival, and decreased levels of the virus in lung tissue, without any reported toxicities. Do to these facts this compound has been selected as a clinical candidate for treatment and prophylaxis of influenza virus infection. The examples discussed above show clearly that “knowledge of carbohydrate synthesis, structure and function can serve the medicinal chemist well in the design of new drug candidates”. [36]

352

Applications in Total Synthesis

References [ 11 M. Fukuda, 0. Hindsgaul (Eds.) in Molecular

Glycobiology, Oxford University Press, New York, 1994. [2] M. von Itzstein, P. Colman, Cum Opin. Struct. Biol. 1996, 6, 703. [3] a) L. A. Lasky, Science 1992,258,964;b) T. A. Springer, L. A. Lasky, Nature 1991, 349, 196; c) T. A. Springer, Nature 1990, 346, 425; d) E. C. Butcher, Cell 1991, 67, 1033; e) R. 0. Hynes, A. D. Lander Cell 1992, 68, 303; f ) L. Stoolman, in Cell Surface Carbohydrates and Cell Development (Ed.: M. Fukuda), CRC, Boca Raton-FL, USA, 1992, p. 71; g) R. P. McEver, K. L. Moore, R. D. Cummings, J. Biol. Chem. 1995, 270, 11025. [4] Y. Imai, L. A. Lasky, S . D. Rosen, Nature 1993,361,555. [5] P. P. Wilkins, K. L. Moore, R. P. McEver, R. D. Cummings, J. Biol. Chem. 1995,270, 22677. [6] A. Etzioni, M. Frydman, S. Pollack, I. Avidor, M. L. Phillips, J. C. Paulson, R. GershoniBaruch, N. Engl. J. Med. 1992, 327, 1789. [7] Y. Ichikawa, Y.-C. Lin, D. P. Dumas, G.-J. Shen, E. Garcia-Junceda, M. A. Williams, R. Bayer, C. Ketcham, L. E. Walker, J. C. Paulson, C.-H. Wong, J. Am. Chem. SOC. 1992, 114, 9283. [8] B. W. Weston, R. P. Nair, R. D. Larsen, J. B. Lowe, J. Biol. Chem. 1992,267,4152. [9] S. D. Danishefsky, K. Koseki, D. A. Griffith, J. Gervay, J. M. Peterson, F. McDonald, T. Oriyama, J. Am. Chem. Soc. 1992, 114, 8331. [lo] S. A. DeFrees, F. C. A. Gaeta, Y.-C. Lin, Y. Ichikawa, C.-H. Wong, J. Am. Chem. SOC. 1992,115, 7549. [ 111 a) C.-T. Yuen, A. M. Lawson, W. Chai, M. Larkin, M. S. Stoll, A. C. Stuart, F. X. Sullivan, T. J. Ahem, T. Feizi, Biochemistry 1992, 31, 9 126. [I21 D. Tyrrell, P. James, N. Rao, C. Foxall, S. Abbas, F. Dasgupta, M. Nashed, A. Hasegawa, M. Kiso, D. Asa, J. Kidd, B. K. Brandley, Proc. Natl. Acad. Sci. USA 1991, 88, 10372. [13] B. J. Graves, R. L. Crowther, C. Chandran, J. M. Rumberger, S. Li, K. S. Huang,

D. H. Presky, P. C. Familletti, B. A. Wolitzky, D. K. Burns, Nature 1994,367, 532. [14] L. Poppe, G. S. Brown, J. S. Philo, P. V. Nikrad, B. H. Shah, J. Am. Chem. SOC.1997, 119, 1727. [15] S. Ushiyama, T. M. Laue, K. L. Moore, H. P. Erickson, R. P. McEver, J. Biol. Chem. 1993, 268, 15229. [161 M. S. Mulligan, J. C. Paulson, S. DeFrees, Z.-L. Zheng, J. B. Lowe, P. A. Ward, Nature 1993,364, 149. [I71 T. Feizi, D. Bundle, Curl: Opin. Struct. Biol. 1996, 6, 659. [18] U. Sprengard, G. Kretzschmar, E. Bartnik, C. Huls, H. Kunz, Angew. Chem. 1995, 107, 1104; Angew. Chem. Int. Ed. Engl. 1995, 34, 990. [19] Sulfatides 4 und 5 are already synthesized: K. C. Nicolaou, N. J. Bockovich, D. R. Carcanague, J. Am. Chem. SOC. 1993, 115, 8843. [20] B. N. Rao, M. B. Anderson, J. H. Musser; J. H. Gilbert, M. E. Schaefer, J. Biol. Chem. 1994, 269, 19663. [21] C.-C. Lin, M. Shimazaki, M.-P. Heck, S. Aoki, R. Wang, T. Kimura, H. Ritzen, S. Takayama, S.-H.-Wu, G. Weitz-Schmidt, C.-H. Wong, J. Am. Chem. SOC. 1996,118, 6826. [22] B. Duppe, H. Bui, I. L. Scott, R. V. Market, K. M. Keller, P. J. Beck, T. P. Logan, Bioorg. Med. Chem. Lett. 1996, 6, 569. [23] P. Sears, C.-H. Wong, Proc. Natl. Acad. USA 1996,93, 12086. [24] D. D. Manning, X. Hu, P. Beck, L. L. Kiessling, J. Am. Chem. SOC. 1997, 119, 3161. [25] A. Aruffo, W. Kolanus, G. Walz, P. Fredman, B. Seed, Cell. 1991, 67, 3161. [26] a) M. M. Palcic, L. D. Heerze, 0. P. Srivastava, 0. Hindsgaul, J. Biol. Chem. 1989, 264, 17174; b) S. Cai, M. R. Stroud, S. Hakomori, T. Toyokumi, J. Org. Chem. 1992, 57, 6693 and literature cited therein; c) C.-H. Wong, D. P. Dumas, Y. Ichikawa, K. Koseki, S. J. Danishefski, B. W. Weston, J. B. Lowe, J. Am. Chem. Soc. 1992, 114,7321. [27] R. Zeitler, A. Giannis, D. Danneschewski, E. Henk, T. Henk, C. Bauer, W. Reutter,

Analogues of the Sialyl LewisX Group and of the N-Acetylneuraminic Acid K. Sandhoff, Eul: J. Biochem. 1992, 204, 1165. [28] K. G. Nicholson, Curr Opin. Infect. Dis. 1994, 7, 168. [29] J. M. White, Science 1992, 258, 917. [30] J. N. Varghese, W. G. Laver, P. M. Colman, Nature 1983, 303, 35. [31] P. Meinal, G. Bodo, P. Palese, J. Schulman, H. Tuppy, Virology 1975,58,457. [32] L. Pauling, Chem Eng. News 1946, 24, 1375. [33] J. N. Varghese, J. L. McKimm-Breshkin, J. B. Caldwell, A. A. Kortt, P. M. Colman, Proteins 1992, 14, 327.

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[34] a) M. von Itzstein, W-Y. Wu, G. B. Kok, M. S. Pegg, J. C. Dyason, B. Jinn, T. van Phan, M. L. Smythe, H. F. White, S. W. Oliver, P. M. Colman, J. N. Varghese, D. M. Ryan, J. N. Woods, R. C. Bethell, V. J. Hotham, J. M. Cameron, C. R. Penn, Nature 1993, 363, 418; b) M. von Itzstein, W. Y. Wu, B. Jin, Carbohydl: Res. 1994, 259, 301. [35] C. U. Kim, W. Lew, M. A. Williams, H. Liu, L. Zhang, S. Swaminathan, N. Bischofberger, M. S. Chen, D. B. Mendel, C. Y. Tai, W. G. Laver, R. C. Stevens, J. Am. Chem. SOC. 1997, 119,681. [36] J. H. Musser, Annu. Rep. Med. Chem. 1992, 27. 301.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Peptidomimetics : Modern Approaches and Medical Perspectives Athanassios Giannis

Introduction A great variety of peptides acting as neurotransmitters, hormones, autocrine and paracrine factors has been discovered and characterized during the last decades [l, 21. After binding to their membrane-bound receptors, which belong mainly to the category of G-protein coupled receptors [3, 41 they elicit changes in cellular metabolism and control a series of vital functions such as blood pressure, digestion, immune defense, perception of pain, reproduction, behavior, tissue development, and cell proliferation. Furthermore, peptides as segments of proteins serve as recognition sites for enzymes, for the immune system, and are involved in cell-cell- and cell-extracellular matrix adhesion. Selective agonists and particularly antagonists of peptide receptors are indispensable for the investigation of peptidergic systems and are attractive starting points for drug development. Already most bioactive peptides have been prepared in larger quantities and made available for pharmacological and clinical investigations. Subsequently it became clear that the use of peptides as drugs is limited by the following factors a) their low metabolic stability towards proteolysis in the gastrointestinal tract and in serum; b) their poor transport from the gastrointestinal tract to the blood as

well as their poor penetration into the central nervous system, in particular due to their relatively high molecular mass or the lack of specific transport systems or both; c) their rapid excretion through liver and kidneys; and d) their side-effects caused by interaction of the conformationally flexible peptides with distinct receptors. In addition, a bioactive peptide can induce effects on several types of cells and organs, since peptide receptors and/ or isoreceptors can be widely distributed in an organism. In recent years intensive efforts have been made to develop peptidomimetics [5 -71 which display more favorable pharmacological properties than their endogenous prototypes. A peptidomimetic is a compound that, as the ligand of the corresponding peptide receptor, can mimic or block the biological effects of a peptide. In this chapter I will discuss basic principles of peptidomimetic design and discovery presenting selected examples of ligands developed for several G-protein coupled receptors as well as ligands for proteins involved in cell adhesion. Emphasis will be given to small nonpeptide ligands. For the development of modified peptides as ligands for peptide receptors and for the design of inhibitors of peptidases the interested reader is refered to several recent reviews.

Peptidomimetics: Modern Approaches and Medical Perspectives

Design of Peptidomimetics As for any drug a peptidomimetic must fulfill the following requirements: a) metabolic stability, b) good bioavailability, c) high receptor affinity and receptor selectivity, and d) minimal side-effects. For the rational design of such compounds knowledge of the bioactive conformation of the endogenous peptide (i. e. the receptor-bound conformation) is of crucial importance. In aqueous solution and in the absence of the receptor, the biologically active conformation may be poorly populated and is frequently quite different from the conformation obtained by, for example, X-ray or NMR methods [8, 91. However, due to the hydrophobic nature andlor size of most peptide receptors the detailed determination of the three-dimensional structures of receptorligand complexes has not yet been possible. The rational design of small nonpeptide ligands i.e. the transformation of a peptide into a nonpeptide ligand is one of the most challenging and exciting fields in medicinal chemistry. Two long known examples clearly demonstrate that it is possible in principle to find small nonpeptide compounds which act as agonists or antagonists for peptide receptors: First, the alkaloid morphine is a ligand for the opioid receptor (a G-protein coupled receptor) and imitates the pharmacological effects of 8-endorphin, an endogenous peptide composed of 31 amino acids, and of the tetrapeptide Met-enkephalin. On the other hand the structurally related morphine derivative naloxon represents an universal opioid receptor antagonist. From the study of many peptide analogues it became apparent that a) for receptor recognition the side-chains of the amino acid residues are of crucial significance whereas for proteolytic enzymes the peptide backbone of the substrate participates considerably in binding affinity [lo], b) frequently only a small number of three to eight amino acids in the peptide are responsible for the biological

355

activity (“message”), and c) conformationactivity studies of peptides suggested that their bioactive conformations are folded (turn-like) having molecular dimensions [ 111 in the range of 10 x 15 A. In this context it should be pointet out that 8-turns are the most frequently imitated secondary structures because they are a structural motif common to many proteins (including the complementarity determining region of antibodies) as well as cyclic peptides and has been postulated in many cases for the bioactive conformation of linear peptides [12]. Furthermore, p-turns are often localized at the surface of proteins where they serve as sites for molecular recognition. In linear biologically active peptides, turns arise mainly due to the tendency to form intramolecular hydrogen bonds. They may be also induced by interaction with biological membranes as well as by complexation with Ca2+which is present in millimolar concentration in the serum. A general rational approach to peptidomimetics is shown in Figure 1 (modified according to [13]). Using this approach it is possible to create a pharmacophore concept and to select an appropriate scaffold that cames the functional groups necessary for receptor binding andlor receptor activation in their correct spatial arrangement. However, despite of the emerging rational approaches it must be keept in mind that most of the peptidomimetics were discovered by screening of natural products and compound libraries. Recently very promising new techniques for the controlled synthesis of a great variety of compounds (combinatorial chemistry) have been established [ 141. Importantly, the rapid examination of compound libraries is also possible by the so called high-throughput screening (HTS). HTS is the process by which large numbers of compounds can be tested, in an automated fashion, for agonistic or antagonistic activity at a biological target, for example a cell-membrane receptor or a enzyme [15]. By the aid of these new techniques as well as

356

Applications in Total Synthesis Biologically Active Peptide

1 1

Alanine Scan

Critical Sidechain Residues

I

Reduce Size

Define Active Core D-Amino Acid Scan Unusual Amino Acid Scan

Define Local and Global ConformationalParameters Receptor Studies: (Determine Probable Turns) Seauencina Cloiing Expression Site Directed Mutagenesis

Cyclisation Introduce Turn Mimetics Amide Bond Modification

Generate Active ConstrainedAnalogs Identificationof receptor residues critical for peptide recognition

Conformational Analysis Physical Studies

Conformation Design Novel Compounds Wnich Mimic Critical Three-Dimensional Elements

IPEPTIDOMIMETIC I Figure 1. General approach to peptidomimetics.

tates a p-turn in the sequence Tyr-Ser-GlySer-Thr 3, a component of the hypervariable region of a monoclonal antibody against the reovirus type-3 receptor and is the first example of a low molecular mass immunoglobulin mimetic developed on the basis of an X-ray structure analysis of the antigen-antibody Biologically Active Mimetics complex. Cyclopeptide 3 is resistant towards proteases and imitates the binding and funcof P-Turns tional properties of the native antibody ! The macrocycle 1 resemble compounds of Compounds of the general formula 1 (Scheme 1) containing a hydrazine amino acid type 4 and 5 (Scheme 2 ) originally developed (Saragovi et al., 1991; Kahn, 1993) represent by Olson et al. [17] and Kemp and Stites [18], a landmark in the development of biologically respectively. A simple and efficient synthesis active p-turn mimetics [16]. Compound 2 imi- of a large library of chiral substituted hetero-

impressive advances in cell culture and molecular biology (cloning and expression of the target receptors) several lead structures can be identified and subsequently optimized.

Peptidomimetics: Modern Approaches and Medical Perspectives

o>;y

357

HO

HQ

1

4

3

2

1

cycles of the type 6 as p-turn mimetics containing the side-chains Ri+l and Ri+2 of the parent peptide was also reported [19]. For the same purposes macrocycles of the general formula 7 were designed 1201. A series of compounds containing the dipeptides AlaGly and cyclized with all stereoisomers of 6 -amino-3,5 -dimethylcaproic acid was prepared. A preliminary examination of these and other related compounds by NMR spectroscopy, circular dichroism and X-ray crystallography revealed that, depending on linker stereochemistry, different proportions of type I1 and type I exist in solution. Both type I and type I1 B-turns were observed also in the solid state. Although the use of synthetic linkers for the constraint of a dipeptide into various turns is not new, the ability of substituted linkers to affect the type of the turn is

w

R2

RI

R4

4

6

Scheme 2.

novel and may be useful in fine-tuning of biologically active peptidomimetics. Recently the design and synthesis of the 1,2,3-trisubstituted cyclohexane 9 (Scheme 3) as a analogue of the thyreotropin releasing hormone (TRH) with agonistic properties on the TRH receptor was reported [21]. On the basis of crystal and solution structures of TRH 8 (Scheme 3) they proposed a model for the pharmacophore which includes the lactam moiety of the pyroglutamyl group, the histidine imidazole ring, and the carboxamide function of the terminal prolineamide. For mimetic design they chose a starting conformation in which the peptide backbone approximates the Y-shaped X-ray structure of TRH. Subsequently the cyclohexane ring has been used as a scaffold for placing the pharmacophoric groups in the correct spatial arrangement. The most active compound was found to be the N-benzyl derivative 9. The rational design of this derivative clearly demonstrates a) the value of X-ray and NMR spectroscopical studies for generating a fruitful hypothesis concerning the bioactive conformation of a ligand which is not always different from the solution or crystal structure, and b) the possibility for the use of scaffolds for replacing the peptide backbone. One of the earliest examples of rationally designed low-molecular mass non-peptide compounds as turn mimetics is the bicyclic lactam derivative 11 [22]. This compound is a mimic of the immunosuppressing tripeptide Lys-Pro-Arg 10 which antagonizes the biolog-

RP 5

7

Scheme I .

358

Applications in Total Synthesis

8: TRH (pyroGlu-His-ProNH2)

9

10: Lys-ProArg

U

11

ical effects of the endogenous peptide tuftsin (Thr-Lys-Pro-Arg). This example clearly demonstrates that rational development of non-peptidal antagonists of peptide receptors is also possible using scaffolds carrying some critical side-chain groups of an endogenous peptide acting as agonist.

Scheme 3.

interested reader is reffered to several detailed reviews [S, 61.

Peptidomimetics for the Cholecystokin Receptor

Cholecystokinin (CCK) exists in numerous biologically active forms (CCK-58, CCK-39, CCK-33, CCK-8, CCK-4,) having a common Peptidomimetics for G-Protein C-terminus which is essential for biological activity [ 2 3 ] . It exists in the nervous system Coupled Receptors both centrally and peripherally. CCK-8 As mentioned above, most of the receptors for (Asp-Tyr( S03H)-Met-Gly-Trp-Met-Aspneuropeptides and peptide hormones belong Phe-NH2) is the most common neuropeptide to the seven-transmembrane spanning G-pro- in the brain. CCK was originally demonstrattein coupled receptors. Binding of the endo- ed to be one of the hormones responsible for genous peptide agonist results in a conforma- regulating the function of the digestive tract. tional change in the intracellular loops of the Peripherally cholecystokinin is released from receptor leading to activation of a trimeric nerve endings in many regions of the body. It G-protein [3]. This in turn activates phos- is also synthesized in neuroendocrine cells in pholipase C which cleaves phosphatidy- the upper gastrointestinal tract. In the latter it linositol-4,s -bisphosphate (PIP2) to inositol stimulates the contraction of the gall bladder 1,4,S-trisphosphate (IP3) and 1,2-diacylglyce- by simultaneous relaxation of the sphincter rol (DAG). IP3 causes release of Ca2+ from oddi, increases the release of insulin, enendoplasmatic reticulum leading to a cellular hances the secretion of enzymes from the pancresponse. Furthermore DAG activates protein reas, and inhibits the secretion of gastrin and kinase C which phosphorylates several inta- gastric emptying. In the central nervous cellular receptors and enzymes thereby in- system cholecystokinin acts as a neuromofluencing their activity. Below development dulatorheurotransmitter, has an anxiogenic of peptidomimetics for two representative (anxiety generating) and appetite-suppressing G-protein coupled receptors, namely the effect, whilst at the spinal level it antagonizes receptors for cholecystokinin and angiotensin the effect of opiates and thereby acts as an will be discussed. For further examples the antianalgesic [24]. Two receptor cholecystoki-

Peptidomirnetics: Modern Approaches and Medical Perspectives

erties in animal experiments. It has strong anxiolytic activity, but show no sedatory effects. Another, structurally related CCK-B receptor antagonist is compound 13 (PD-135666). Interestingly, the corresponding enantiomeric derivative (ent-13) is a potent and selective CCK-A receptor antagonist! [26] Using the substituted pyrrolidinone of the general formula 14 (Scheme 5 ) as scaffold and incorporating the side-chains of Trp, Asp, and Phe of the C-terminal region of the CCK peptides the derivative 15 which is a potent and orally active CCK-A antagonist = 16 nM) was developed [27]. For the antagonist activity the 3,4 -cis stereochemical arrangement is necessary.

12

* oD HOO

Scheme 4.

359

13

nin receptor subtypes have been identified: Angiotensin Receptor Antagonists the predominantly peripheral CCK-A receptor and the largely centrally located CCK-B The octapeptide angiotensin I1 (A 11: Aspexerts its receptor. The C-terminal tetrapeptide se- Arg-Val-Tyr-Ile-His-Pro-Phe) effects by interacting two receptors subtypes quence of CCK (Trp-Met-Asp-Phe-NH2) and particularly the side chains of Trp, Asp (AT1 and AT2). While AT2 receptors are and Phe are critical for biological activity. important in embryonic development, AT 1 Early studies identified the dipeptide deriva- receptors mediate the cardiovascular effects tive Boc-Trp-Phe-NHz as a weak CCK-B of angiotensin I1 and has been implicated in agonist. The modification of this structure, several cardiovascular diseases, including supported by investigations of conformational hypertension, cardiac hypertrophy, heart failure and myocardial infarction [28]. For these energy of the tetrapeptide Trp-Met-Asp-PheNH2, culminated in the synthesis of the orally reasons A I1 antagonists are of enormous active derivative CI-988 12 (Scheme 4), therapeutic potential. On the basis of physicochemical and specwhich proved to be a selective CCK-B antagonist [25] (IC50 = 1.7 nM). Compound CI-988 troscopical investigations of A I1 and the pepis the first example of a rationally developed tidic superagonist [Sar'IA I1 Matsoukas et al. nonpeptide ligand for a neuropeptide receptor [29] suggested a conformational model for and display interesting pharmacological prop- A11 characterized by clustering of the three

Phe14

15

8

Scheme 5.

360

Applications in Total Synthesis

aromatic rings and a charge relay system involving the triad Tyr hydroxyl-His imidazole-Phe carboxylate. According to these studies, the N-terminal domain of A I1 appears to play a crucial role in generating the biologically active charge relay conformation of the peptide hormone. In addition these investigations confirmed that a Tyr-Ile-His bend is a predominant feature of the conformation of A I1 and [SarlIA I1 in the relatively non-polar “receptor simulating” environment provided by dimethyl sulfoxide. The first potent, orally active nonpeptide antagonist of the AT1 receptor is losartan 16 (Lorzaar@,Scheme 6) with an ICso value of 19 nM [30]. Losartan was developed by overlaying the lead structure of 17 (S-8308), a weak but specific antagonist of the AT1 receptor discovered by screening, with the structure of A 11, using molecular modeling techniques. It was postulated that the imidazole moiety of 17 serves as a template to present mimetics of the Tyr [4] and Ile [5] side-chains as well as the C-terminal carboxyl group of A 11. Losartan blocks the vascular constrictor effect of Ang 11, the Ang 11-induced aldosterone synthesis and/or release, and the AIIinduced cardiovascular growth. In various models of experimental hypertension, losartan prevents or reverses the elevated blood pressure and the associated cardiovascular hypertrophy similar to angiotensin converting enzyme (ACE) inhibitors. Subsequently contolled clinical trials revealed that losartan is a new and valuable drug for treatment of hyper-

16

Scheme 6.

17

tension. It has been well tolerated [31] and, in contrast with ACE inhibitors, does not cause cough and is a promising drug.

Integrin Ligands as Modulators of the Cell Adhesion Integrins are noncovalently linked alp heterodimeric proteins which play a critical role in cell-cell adhesion as well as in cell-extracellular matrix adhesion and interaction 1321. Such interactions determine important biological phenomena such as cell differentiation and cell viability, cellular traffic and organogenesis, angiogenesis and blood clotting. 15 a subunits and 8 p subunits have been identified to date. Different ab complexes are expressed on different cells [33]. For example the integrins a& a d z , and a& are expressed only on leucocytes whereas the integrins a&, @ I , a&, a&, and avP3 are expressed on endothelial cells. In platelets, aII& (known also as GPIIb/IIIa) is the major integrin. Furthermore tumor cells as for example human melanoma cells express a& (vitronectin receptor). The Arg-Gly-Asp (RGD) sequence on several proteins such as fibrinogen, fibronectin, vitronectin, laminin, osteopontin, and von Willebrand factor serves often as an endogenous ligand for the integrins. The binding is Ca2+-dependent. The specificity of the RGDintegrin interaction is generated by a combination of variations in the RGD conformation in different proteins and contributions of sequences near the RGD moiety [34]. Structure-activity investigations have revealed that in linear RGD peptides small structural modifications such as the exchange of alanine for glycine or glutamic acid for aspartic acid abolish the binding of the resulting peptides by integrins [35]. RGD analogues are potential candidates for example for treatment of a) thromboembolic

Peptidomimetics: Modern Approaches and Medical Perspectives

diseases (GpIIb-IIIa receptor antagonists) and b) as antiangiogenic agents (vitronectin receptor antagonists) i.e. agents that prevent the formation of new blood vessels. The steroid derivative 18 was designed and synthesized as an analogue of a postulated [36] type I /3-turn 19 of the glycoprotein GpIIb-IIIa-bound sequence Arg-Gly-Asp of fibrinogen. Compound 18 binds to the GpIIb-IIIa receptor and shows an moderate IC50 value of 100 yM when fibrinogen is used as ligand. In comparison the peptide cyclo(Arg-Gly-Asp-Phe-D-Val), displays in ICS0value of 2 yM [37]. Apparently the glycoprotein GpIIb-IIIa bound RGD conformation is better imitated by the cyclopeptide. According to NMR spectroscopical investigations in dimethylsulfoxide solution, the Arg residue of this cyclopeptide lies in the i+2 position of an extended /3II’-turn, whereas the Asp residue lies in the central position of a y-turn, so that the Arg and Asp side chains are nearly parallelly oriented [38]. However it must be emphasized here that the receptor-bound conformation of RGD-containing peptides and RGD nonpeptide mimetics are still unknown. On the basis of an working hypothesis that the GpIIb-IIIa-bound conformation of the lead peptide Arg-GlyAsp-Phe includes either a /3- or a y-turn a

--.HN

+&

9 % OOH

18

Scheme 7.

OOH

19

36 1

y-lactam was used as template [39]. The critical side chains of the peptide groups were attached to the y-lactam via flexible linkers the length of which was optimized to afford a weakly active antagonist 20. After further optimization the very rigid lactam derivative 21 (BIBU 52) with an EC50 value of 80 nM was obtained. This drug candidate possesses a negatively and a positively charged group in the appropriate distance and is a high-affinity ligand for GpIIb-IIIa and is also active in vivo. In an animal thrombosis model 1 mgkg i.v. of BIBU 52 completely abolished thrombus formation for one hour. NMR studies of a rigid, potent GpIIbIIIa antagonist 22 (G4120) and molecular dynamic simulations of flexible active analogues suggested a cupped [40] (U-shaped) bioactive conformation of the RGD moiety of G4120. The D-Tyr side chain of this cyclopeptide is spatially positioned nearly in the middle between the Arg and Asp side chain. Subsequently the pyrrolo[ 1,4]benzodiazepine-2,5 -dione [4 11 was selected as a template to fit the contour and volume of the peptide backbone of G4120. This template enabled the attachment of the critical Arg and Asp sidechains. The rational approach led to the benzodiazepine derivative 23 with an ICSO value of 9 nM. The structural characteristics of G4120 suggested that a Arg-Tyr-Asp (RYD) group could be an alternative ligand for GpIIb/IIIa. Indeed the RYD mimetic lamifiban 24 (Ro 44-9883), which is currently in phase 3 clinical trials, is a potent inhibitor of the ADP-induced platelet aggregation determined in human platelet-rich plasma with an I C ~ O value of 30 nM [42, 431. b) Malignant metastases are highly dependent on blood supply. For their survival neovascularization is essential. Neovasculariza-

362

Applications in Total Synthesis

23

21

Scheme 8.

HO

‘COOH

24

tion begins with vasodilatation of the parent vessel (i. e. the vessel from which a new capillary sprout originates) followed by a protease-mediated degradation of the basement membrane of the vessel. Thereafter endothelial cells migrate toward the angiogenic stimulus [44, 451 (Fig. 2). Tumor cells promote vascular endothelial cells entry into the cell cycle and expression of integrin a&. After endothelial cells begin to move toward the angiogenic stimulus a& ligation provides a survival signal which finally results in differentiation and formation of mature blood vessel. A disruption of the a& liga-

tion may lead to apoptosis with subsequent tumor regression because of shortage in blood supply [46]. In order to test this hypothesis Brooks et al. [47] used the cyclopeptide RGDfV 25 which was previous identified as a potent inhibitor of a&-mediated cell adhesion [48]. The ICso value for the binding of 25 to both, soluble as well as immobilized a&integrin is 50 nM. A single intravascular injection of this peptide disrupts ongoing angiogenesis on the chick chorioallantoic membrane. This leads to the rapid regression of histologically distinct human tumors transplanted onto the chick cho-

Peptidomimetics: Modern Approaches and Medical Perspectives

363

- : lntegrin 0 :RGD

b : RGD-Analogue

Figure 2. av,!&-Integrinsand angiogenesis. The action of different growth factors stimulates the expression of integrin 4 3 on endothelial cells. During the subsequent migration of endothelial cells in the direction of the angiogenic stimulator (arrow), the integrin a& binds to RGD sequences present in multivalent form on the extracellular matrix (EM). As a consequence, integrin receptors aggregate on the cell membrane (A) and proteins of the cytoskeleton, like talin, paxilin, a-actinin, tensin, vinculin, and F-actin accumulate. This in turn results in maintenance of the migration process, serves as a signal for the survival of endothelial cells and finally leads to the formation of a new blood vessel. Prevention of integrin aggregation by soluble monovalent RGD analogues (B) leads to programmed cell death (apoptosis) of the migrating endothelial cells and therefore prevents vessel formation.

25

Scheme 9.

rioallantoic membrane (CAM assay). These results clearly demonstrate that a& antagonists may provide a new alternative approach for the treatment of malignancies or other diseases characterized by angioge-

nesis such as rheumatoid arthritis, psoriasis, haemangiomas and corneal neovascularization. In the past it has been shown that antiangiogenic therapy with agents such as platelet factor 4, angiostatin and the fumagilin derivative AGM 1470 generally has low toxicity and drug resistance does not develop. In the future further avP3 antagonists (particularly non-peptidal compounds) may be developed by optimization of known RGD analogues. In compound 25 a y-turn with glycine in the central position is formed by the RGD sequence. According to NMR-spectroscopic investigations in solution, this leads to a parallel arrangement of the side chains of arginine and aspartate. As expected, the D-amino acid occupies the i+l position of a PII’-turn. The distance between the P-carbon atoms of the Asp- and Arg-side chains within

364

Applications in Total Synthesis

peptide 25 was determined by NMR spectroscopy to be 0.69 nm. Therefore, it is considerably shorter than the distance that was thought to be optimal for recognition by the fibrinogen receptor (0.75-0.85 nm). Recently, Kessler et al. synthesized all possible stereoisomers of peptide 25 and of its retro-sequence (32 peptides). An important result of the subsequent biochemical and NMR-spectroscopic investigations was that the retro-inverso compound c(-vFdGr-) shows a drastically reduced affinity towards the a&-integrin. This is explained by a conformation different from that of peptide 25. More importantly, another peptide, c(-VfdGr-), shows nearly no affinity to the vitronectin receptor albeit its identical side chain orientation compared with 25. This means that not only the side chains but also the peptide backbone contribute to receptor binding, at least by formation of one hydrogen bond. It is shown in the same study that a sterically demanding group in position 4 (D-Phe) is necessary for the biological activity of cyclopeptide 25. In contrast to this, the Lvaline residue can be replaced by any other amino acid. These structure-activity relationships constitute a valuable basis for the rational development of potent small nonpeptide a 4 3 antagonists. In this regard one will certainly refer to the general principles in the design of peptidomimetics [5-71 and to the experience in the design of a& antagonists . In summary, after recognition of the importance of the RGD group for the integrin mediated cell adhesion several linear and cyclic RGD analogues were synthesized and their ability to act as alternative integrin ligands was investigated. On the basis of the subsequent pharmacological and physicochemical studies different hypotheses concerning the bioactive RGD conformation were generated leading to numerous interesting and exciting new

agents for the treatment of thromboembolic diseases. The design and synthesis of RGD mimetics was initiated after early studies in patients with the rare, inherited, autosomal bleeding disorder Glanzmann’s thrombasthenia revealed the role of GpIIb/IIIa in platelet aggregation. The GpIIb/IIIa antagonists will be probably the first clinically useful “anti-integrins” and should initiate the development of specific and potent low-molecular mimetics for other integrin for use in anti-adhesion therapy [49].

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[32] R. 0. Hynes, Cell 1992, 69, 11. [33] F. W. Lucinscas, J. Lawler, FASEB J. 1994, 8, 929. [34] E. Ruoslati, M. D. Pierschbacher, Science 1987,238,491. [35] E. Ruoslati, M. D. Pierschbacher, W. A. Border, in “The Liver: Biology, and Pathobiology”, 3rd ed. (Eds.: I. M. Arias, J. L. Boyer, N. Fausto, W. B. Jacoby, D. Schachter, D. A. Shafritz), pp. 889, Raven Press, New York, 1994. [36] R. Hirschmann, P. A. Sprengler, T. Kawasaki, J. W. Leahy, W. C. Shakespeare, A. B. Smith 111, J. Am. Chem. Soc. 1992,114,9699-9701. [37] M. Aumailley, M. Gurrath, G. Muller, J. Calvete, R. Timpl, H. Kessler, FEBS Lett. 1991, 291, 50. [38] G. Miiller, M. Gurrath, H. Kessler, R. Timpl, Angew. Chem. 1992, 104, 341; Angew. Chem. Int. Ed. Engl. 1992,31, 326. [39] V. Austel, F. Himmelsbach, T. Miiller, Drugs Fut. 1994, 19, 757. [40] R. S. McDowel, T. R. Gadek, J. Am. Chem. SOC.1992,114,9243. [41] R. S. McDowel, B. K. Blackburn, T. R. Gadek, L. R. McGee, T.Rawson, M. E. Reynolds, K. D. Robarge, T. C. Somers, E. D. Thorsett, M. Tischler, R. R. Webb, M. C. Venutti, J. Am. Chem. Soc. 1994,116,5077. [42] L. Alig, A. Edenhofer, P. Hadvm, M. Hurzeler, D. Knopp, M. Miiller, B. Steiner, A. Trzeciak, T. Weller, J. Med. Chem. 1992, 35, 4393. [43] T. Weller, L. Alig, M. Hurzeler-Muller, W. C. Kounus, B. Steiner, Drugs Fut. 1994, 19, 461. [44] a) J. Folkman, Nature Med. 1995, 1, 27; b) J. Folkman, N. Engl. J. Med. 1995,333, 1757. [45] A. Giannis, F. Rubsam, Angew. Chern. 1997, 109, 606; Angew. Chem. Int. Ed. Engl. 1997, 36, 588. [46] S. Miyamoto, S. K. Akiyama, K. M. Yamada, Science 1995, 267, 883. [47] P. C. Brooks, R. A. F. Clark, D. A. Cheresh, Science 1994, 264, 569. [48] M. Pfaff, K. Tangemann, B. Muller, M. Gurrath, G. Muller, H. Kessler, R. Timpl, J. Engel, J. Biol. Chem. 1994, 269, 20233. [49] J. Lefkovits, E. F. Plow, E. J. Topol, N. Engl. J. Med. 1995, 332, 1553.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

A New Application of Modified Peptides and Peptidomimetics: Potential Anticancer Agents R. M . J. Liskamp

Wide applications of (unmodified) peptides as drugs are limited by the disadvantages affiliated with their use in biological systems. An unmodified linear peptide is easily degraded by e. g. proteases, it is often too watersoluble to pass the cell membrane and therefore unable to pass the blood-brain barrier and rapidly excreted. In addition, a peptide is a flexible structure of which the bioactive conformation is usually hidden in a population of thousands of other conformers. The desire to remedy these disadvantages and therefore to be able to obtain meaningful pharmaceutical compounds led to the development of modified peptides and peptidomimetics. [l, 21 A relatively new promising application of modified peptides and peptidomimetics is as potential anticancer agents for the treatment of tumors in which oncogenic Ras proteins contribute to transformation and abnormal growth. Two aspects of this potential application are especially noteworthy: (1) the inhibition of malignant transformation is achieved on a level other than the DNA-level; and (2) the inhibition originates from inhibition of a post-translational modification process of proteins. In many conventional chemotherapeutic regimens of cancer, the drug displays its activity on the DNA-level. The interference with

or damage to the genetic material leads to the arrest of cellular growth and halting of uncontrolled cell division. However, these drugs are often deleterious for other rapidly dividing cells involved in the formation of e.g. bone marrow, gastrointestinal mucosa and hair follicles, causing the well-known side effects. In addition, interference with the genetic code means that these reagents are inherently carcinogenic and/or mutagenic. Therefore attempts directed towards the development of drugs acting on other cellular levels are especially interesting. Post-translational modification processes of proteins include phosphorylation [3] glycosylation, methylation, acetylation, fatty acid acylation and prenylation. Among the prenylation processes furnesylation is especially noteworthy since it is implicated in a considerable number of human cancers. As a consequence interference with the post-translational modification process of furnesylation seems a promising and perhaps even viable approach for the development of anticancer drugs. Eukaryotic polypeptides with a cysteine residue located at the fourth position counting from the C-terminus are in principle candidates for a post-translational modification involving the cysteine-SH. [4] In a reaction catalyzed by farnesyl protein transferase (FPTase) this SH can be alkylated

A New Application of Modified Peptides and Peptidomimetics

367

by farnesylpyrophosphate (FPP), an iso- gical effects. In case of the mutant Ras protein prenoid compound also involved in the bio- it appears to be required for efficient cell synthesis of cholesterol. The hydrophobic iso- transforming activity. Therefore a straightprenyl tail may be responsible for mem- forward, albeit elegant, approach to inhibit brane association of proteins. Alternatively, transformation would be to interfere with the isoprenyl tail and methyl ester may Ras membrane localization by preventing promote binding of the protein to specific farnesylation. [6] Tetrapeptides with amino acid sequences membrane associated receptors. [5] The closely related forms of Ras proteins identical to the COOH terminus of protein (H-Ras, N-Ras, K-Ras-A, K-Ras-B) are in- substrates for farnesylation by FPTase can triguing examples of eukaryotic proteins, compete with Ras for farnesylation. Selectivwhich are farnesylated (Scheme 1). Ras is a ity of inhibition of farnesylation as opposed guanosine triphosphate (GTP) binding pro- to inhibition of the other isoprenylation protein. When GTP is bound to Ras, the cell di- cess of attachment of a geranylgeranyl moiety vision is triggered. Normal Ras possesses can be obtained by using peptides of the GTPase activity, which hydrolyzes the bound consensus sequence CAAX in which C is GTP to GDP, so that the mitogenic signal is cysteine, A is an aliphatic amino acid and X timely terminated. There are however, mutant is serine, methionine or glutamine. Modified peptides containing reduced forms i.e. oncogenic versions of Ras, found in about 50% of human colon carcinomas amide bonds, i. e. compounds L-731,735 and and 90 % pancreatic carcinomas, which have L-731,734, were designed by the Merck an impaired GTPase activity. This impaired groups [7] (Fig. l), and have shown to be GTPase activity has as a consequence that potent inhibitors of partially purified FPTase, the mutant Ras protein remains constitutively the homoserine compound being the more complexed to GTP, leading to unregulated active inhibitor in vitro. Subsequent inhibitors cell proliferation and malignant transforma- include L-739,749 and L-739,750 [8] and tion. Farnesylation of both normal and onco- even truncated versions of the C-terminal genic Ras proteins is necessary for attachment tetrapeptide CAAX motif were prepared to the cell membrane and the resulting biolo- which do not have a C-terminal carboxyl normal cell division

t

I

---Y HH& ' J AO ' + OAH

H

0

-

'OH

-

I

H

O

A

H

0

KOH

normal Ras protein

membrane mutated Ras proteins

t

transformation

Scheme 1. Post-translational modification by farnesylation. The cysteine as part of the consensus sequence CAAX (C, cysteine; A, aliphatic amino acid residue; X, serine or methionine) near the C-terminus in the Ras protein is farnesylated by farnesylpyrophosphate (FPP) catalyzed by farnesyl protein transferase (FPTase). The farnesylated protein can then attach itself to the plasma membrane. If mutated Ras proteins are farnesylated and attached to the cell membrane this will lead to transformation.

368

Applications in Total Synthesis

Figure 1. Reduced amide containing modified peptides L-731,735, L-73 1,734, L-739,749, L-739,750 and a truncated CAAX - analog.

moiety, yet they inhibit farnesyltransferase. [91 The University of Texas and Genentech groups used the benzodiazepine skeleton to mimic a turn-like structure of the two middle amino acids in the consensus sequence, to which the N-terminal cysteine and a C-terminal methionine, serine or leucine were attached [lo, 111 (Fig. 2). Although the free acid (BZA-2B) was best in the in vitro assay, the

SMe

BZAPB: R = H BZA-5B: R = Me

Figure 2. BZA-2B and BZA-5B.

ester (BZA-SB) and to a somewhat lesser extent the amide were more active in a Chinese hamster ovary cell line, suggesting that the latter compounds may more easily penetrate into cells, because of their reduced polarity. This set the stage for the development of other peptidomimetic farnesyltransferase inhibitors and shortly thereafter a peptidomimetic in which the two aliphatic amino acids were replaced by a relative rigid aromatic spacer was introduced. [ 121 Other aromatic spacers were introduced [ 131 and it was even possible to replace the C-terminal amino acid ("X") by an aromatic residue containing a carboxylic acid moiety and to obtain potent inhibitors. [14] The synthesis of a potent representative of this class of farnesyltransferase inhibitors is delineated in Scheme 2. This approach of using an aromatic residue can be considered as a scaffold approach in which functional groups are attached to a relatively rigid core ('scaffold') thereby position-

A New Application of Modified Peptides and Peptidomimetics

Me

Me

1. COClp

-

2. tert- BuOH, n -BuLi

COOBu'

1. H,, 2. N Boc-STr-cysteinal PdE * 3. Na(CN)BH,

\

HZN

COOH

ing these groups with correct spatial orientations for the biomolecular interactions leading to inhibition. Another interesting scaffold in this respect turned out to be the piperazine ring leading to potent non carboxylic acid inhibitors of farnesyltransferase. [ 151 These inhibitors are accessible in a straightforward manner starting from an amino acid derivative (Scheme 3). One of the most conservative modifications and as a consequence perhaps one of the 'safest' structural modifications with respect to the biological activity is the replacement of an amino acid in the CAAX motif sequence by conformationally restricted amino acids. [I61 Despite the peptidic nature of these modified peptides, a number of them (Fig. 3) showed a considerable activity in vivo. [17, 181 However, if one wishes to reduce proteolysis and increase lipophilicity, replacement of

+q

COOH

BocNH

COOBu'

Scheme 2.

the amide bonds in the CAAX peptide by an isosteric replacement is an approach of considerable importance. The trans alkene moiety is a very suitable amide surrogate in terms of mimicking the rigidity, bond angles and bond length of the amide bond. [I91 The alkene moiety was incorporated through elegant approaches into peptidomimetic compounds in which one [20] (Scheme 4) or even two amide bonds were replaced by double bonds as is the case in compound B956 [21] (Fig. 4). In this way powerful inhibitors were obtained. Peptoids [22] form a particular promising class of oligomeric peptidomimetics, which consists of N-substituted-glycine derivatives. Thus, the concepts to translate a particular peptide sequence, in this case CAAX to a corresponding peptoid sequence is a perfectly suitable approach to obtain potential farnesyl inhibitors. This approach was adopted by 7

7

2. a. HCI b. NaHC03, HzO

1. N ~ B H ( O A C ) ~ ,

N(H)Boc

2. Et3SiH,TFA

369

Scheme 3.

370

Applications in Total Synthesis SMe I

A

HS

H

O

Figure 3. Farnesyltransferase inhibitors containing conformationally restricted amino acids. 0 W ( H ) N A

i

A

y'

l.H H H)'tMgBr

OMe

Me

2. NaBH4

3

*

1.03,Me2S

Boc(H)N

A

2. Ph3P=C(H)C0,Me 3. LiOH

CuCN, BF,.Et,O BnMgCl 2. MsCl

'

*

O

M

e

O \

SMe

h,,kOMe H O

& +*SBoc(H)N r T

1. HCI

HsL -

Boc(H)N s

2. NaCNBH,, 0 WH)N.A~

A.

1. Et,SiH, TFA * H2N

"i

2. NaOH

SMe

'STr

O

Scheme 4. Syntheses of an alkene moiety containing CAAX peptidomimetic.

Levitzki et al. who prepared a semipeptoid sequence by replacement of 'A' or 'AA' by a peptoid residue or dipeptoide sequence, respectively [23] (Scheme 5 ) . HZN A These examples show that state of the art organic chemistry is very effective in order to translate a peptide sequence into modified peptides or peptidomimetics having much Figure 4. B956.

\ /

O

i SMe

A New Application of Modified Peptides and Peptidomimetics MeS

MeS 1. Fmoc-N(Me)-VaCOH,

BrCH&OOH, DIC

* H

TrS

37 1

Me

0

H

O

IBCF

O HR-11

Scheme 5.

more favorable properties than the parent peptides. It is expected that the development of farnesyl inhibitors will continue to flourish. The preparation of tetrapeptides [24] and libraries of pentapeptides already led to nonthiol containing inhibitors of farnesyltransferase. [25] Furthermore, the isolation of naturally occurring farnesyltransferase inhibitors will undoubtedly lead to the synthesis of entirely new ones, [26] whereas the recent elucidation of the crystal structure of farnesyltransferase will surely lead to structurebased design of inhibitors. [27] The use of modified peptides and peptidomimetics to selectively inhibit Ras farnesylation and thereby transformation and ultimately possibly the carcinogenic process represents an important and recent application of these compounds. [28, 291 It also shows that they can be employed for a finely tuned intervention in complex biochemical and biological processes. It is therefore expected that as the understanding of cellular processes (e. g. protein trafficking, intracellular signal transduction) progresses, it will be possible to intervene in, or selectively inhibit these processes using modified peptides and peptidomimetics, which are obtained by structure based design and/or combinatorial chemistry approaches.

References [I] Modified peptides are being defined as peptides in which in essence the amino acid sequence is unchanged but the peptide contains e. g. some unnatural amino acids, a modification of a cysteine residue or a phospho amino acid. Peptidomimetics are compounds which imitate the structure andor imitate or block the biological effect of a peptide at the receptor level [2a]. As a consequence peptidomimetics span the whole range of compounds varying from peptide isosteres to compounds without an identifiable amino acid or peptide moiety., [2] For reviews on peptidomimetics see e.g.: a) A. Giannis, T. Kolter, Angew. Chem. lnt. Ed. Engl. 1993, 32, 1244-1267; b) R. M. J. Liskamp, Red. Trav. Chim. Pays-Bas, 1994, 113, 1-19; c) A. E. P. Adang, P. H. H. Hermkens, J. T. M. Linders, H. C. J. Ottenheijm, C. J. van Staveren, Recl. Trav. Chim. Pays-Bas, 1994, 113, 63-78; d) J. Gante, Angew. Chem. lnt. Ed. Engl. 1994, 33, 1699-1720; e) D. C. Rees, C u m Med. Chem. 1994, 1, 145-158. [3] Glycosylation see e. g.: M. A. Kukuruzinska, M. L. E. Bergh, B. J. Jackson, Annu. Rev. Biochem. 1987, 56, 915-944; acylation: D. A. Towler, J. I. Gordon, S. P. Adams, L. Glaser, Annu. Rev. Biochem. 1988, 57, 69-99; phosphorylation: E. G. Krebs, J. A. Beavo, Annu. Rev. Biochem. 1979, 48, 923959; isoprenylation: [6]

312

Applications in Total Synthesis

[4] S. Clarke, Annu. Rev. Biochem. 1992, 61, 355-386. [ 5 ] J. A. Glomset, M. H. Gelb, C. C. Farnsworth, Trends Biochem. Sci. 1990, 139-142. [6] J. B. Gibbs, Cell, 1991, 65, 1-4. [7] N. E. Kohl, S. D. Mosser, S. J. DeSolms, E. A. Giuliani, D. L. Pompliano, S. L. Graham, R. L. Smith, E. M. Scolnick, A. Oliff, J. B. Gibbs, Science 1993,260, 1934-1937; S. L. Graham, S. J. DeSolms, E. A. Giuliani, N. E. Kohl, S. D. Mosser, A. 1. Oliff, D. L. Pompliano, E. Rands, M. J. Breslin, A. A. Deana, V. M. Garsky, T. H. Scholz, J. B. Gibbs, R. L. Smith, J. Med. Chem. 1994,37,725-732. [8] N. E. Kohl, F. R. Wilson, S. D. Mosser, E. Giuliani, S. J. DeSolms, M. E. Conner, N. J. Anthony, W. J. Holtz, R. P. Gomez, Ta-Jyh. Lee, R. L. Smith, S. L. Graham, G. D. Hartman, J. B. Gibbs, A. Oliff, Proc. Natl. Acad. Sci. USA 1994,91,9141-9145. [9] S . J. DeSolms, A. A. Deana, E. Giuliani, S. L. Graham, N. E. Kohl, S. D. Mosser, A. I. Oliff, D. L. Pompliano, E. Rands, T. H. Scholz, J. M. Wiggins, J. B. Gibbs, R. L. Smith, J. Med. Chem. 1995,38,3967-3971. [lo] G. L. James, J. L. Goldstein, M. S. Brown, T. E. Rawson, T. C. Somers, R. S. McDowell, G. W. Crowley, B. K. Lucas, A. D. Levinson, J. C. Marsters, Science 1993, 260, 19371942; J. C. Marsters Jr, R. S. McDowell, M. E. Reynolds, D. A. Oare, T. C. Somers, M. S. Stanley, T. E. Rawson, M. E. Struble, D. J. Burdick, K. S. Chan, C. M. Duarte, K. E. Paris, J. Y. F. Tom, D. T. Wan, Y. Xue, J. P. Burnier, Bioorg. Med. Chem. Lett. 1994, 2, 949-957; T. E. Rawson, T. C. Somers, J. C. Marsters Jr, D. T. Wan, M. E. Reynolds, D. J. Burdick, Bioorg. Med. Chem. Lett. 1995,5, 1335-1338. [ l l ] For use of the benzodiazepine skeleton as B-turn mimetic see: W. C. Ripka, G. V. De Lucca, A. C. Bach 11, R. S. Pottorf, J. M. Blaney, Tetrahedron, 1993, 49, 3593-3608. [12] M. Nigam, C.-M. Seong, Y. Qian, A. D. Hamilton, S. M. Sebti, J. Biol. Chem., 1993, 268, 20695-20698; Y. Qian, M. A. Blaskovich, C.-M. Seong, A. Vogt, A. D. Hamilton, S. M. Sebti, Bioorg. Med. Chem. Lett. 1994, 4,2579-2584.

[13] Y. Qiam, M. A. Blaskovich, M. Saleem, C.-M. Seong, S. P. Wathen, A. D. Hamilton, S. M. Sebti, J. Biol. Chem. 1994, 269, 1241012413; A. Vogt, Y. Qian, Blaskovich, R. D. Fossum, A. D. Hamilton, S. M. Sebti, J. Biol. Chem. 1995, 270, 660-664; E. Lerner, Y. Qian, A. D. Hamilton, S. M. Sebti, J. Biol. Chem. 1995, 270, 26770- 26773. [14] Y. Qiam, A. Vogt, S. M. Sebti, A. D. Hamilton, J. Med. Chem. 1996,39, 217-223. [15] T. M. Williams, T. M. Ciccarone, S. C. MacTough, R. L. Bock, M. W. Conner, J. P. Davide, K. Hamilton, K. S. Koblan, N. E. Kohl, A. M. Kral, S. D. Mosser, C. A. Omer, D. L. Pompliano, E. Rands, M. D. Schaber, D. Shah, F. R. Wilson, J. B. Gibbs, S. L. Graham, S. L. Hartman, A. I. Oliff, R. L. Smith, J. Med. Chem. 1996,39, 1345-1348. [16] See e. g. [2b]. [17] K. Leftheris, T. Kline, G. D. Vite, Y. H. Cho, R. S. Bhide, D. V. Patel, M. M. Patel, R. J. Schmidt, H. N. Weller, M. L. Andahazy, J. M. Carboni, J. L. Gullo-Brown, F. Y. F. Lee, C. Ricca, W. C. Rose, N. Yan, M. Barbacid, J. T. Hunt, C. A. Meyers, B. R. Seizinger, R. Zahler, V. Manne, J. Med. Chem. 1996, 39, 224-236. [18] F.-F. Clerc, J.-D. Guitton, N. Fromage, Y. Lelibvre, M. Duchesne, B. Tocqu6, E. JamesSurcouf, A. CommerGon, J. Becquart, Bioorg. Med. Chem. Lett. 1995, 5, 1779-1784; G. Byk, M. Duchesne, F. Parker, Y. Lelievre, J. D. Guitton, F. F. Clerc, J. Becquart, J. Tocque, D. Scherman, Bioorg. Med. Chem. Lett. 1995, 5 , 2677-2682; G. Byk, Y. Leleivre, F. F. Clerc, D. Scherman, J. D. Guitton, Bioorg. Med. Chem. 1997,5, 115-124. [19] For other recent examples of incorporation of the alkene moiety into biologically active peptides, see e. g.: J. S. Kaltenbronn, J. P. Hudspeth, E. A. Lunney, B. M. Michniewicz, E. D. Nicolaides, J. T. Repine, W. H. Roark. M. A. Stier, F. J. Tinney, P. K. W. Woo, A. D. Essenburg, J. Med. Chem. 1990, 33, 838845; D. TourwB, J. Couder, M. Ceusters, D. Meert, T. F. Burks, T. H. Kramer, P. Davis, R. Knapp, H. I. Yamamura, J. E. Leysen, G. van Binst, Int. J. Pept. Prot. Res. 1992, 39, 131136; Y.-K. Shue, M. D. Tufano, G. M. Camera Jr., H. Kopecka, S. L. Kuyper, M. W. Holladay,

A New Application of Modified Peptides and Peptidomimetics C. W. Lin, D. G. Witte, T. R. Miller, M. Stashko, A. M. Nadzan, Bioorg. Med. Chem. 1993, I , 161-171; M. Gromm6, R. van der Valk, K. Sliedregt, R. Liskamp, G. Hiimmerling, J. 0. Koopmann, F. Momburg, J. Neefjes, Eur: J. Immunol. 1997,27, 898-904. [20] J. S. Wai, D. L. Bamberger, T. E. Fisher, S. L. Graham, R. L. Smith, J. B. Gibbs, S. D. Mosser, A. I. Oliff, D. L. Pompliano, E. Rands, N. E. Kohl, Bioorg. Med. Chem. 1994, 2 , 939-947. [21] M. D. Lewis, J. J. Kowalczyck, A. E. Christuk, R. Fan, E. M. Harrington, X. C. Sheng, Y. Hu, A. M. Carcia, I. Hishunuma, A. Et, Patent Application WO 95 -US3387, Chem. Abstx 124, 146855; T. Nagusu, K. Yashimatsu, C. Roweil, M. D. Lewis, A. M. Garcia, Cancer Res. 1995,55,5310-5314. [22] R. J. Simon, R. S. Kania, R. N. Zuckermann, V. D. Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg, C. K. Marlowe, D. C. Spellmeyer, R. Tan, A. D. Frankel, D. V. Santi, F. E. Cohen, P. A. Bartlett, Proc. Natl. Acad. Sci. USA, 1992, 89, 9367-9371; H. Kessler, Angew. Chem. Int. Ed. Engl. 1993, 32, 543-544; S. M. Miller, R. J. Simon, S. Ng, R. N. Zuckermann, J. M. Ken; W. H. Moos, Bioorgan. Med. Chem. Lett. 1994, 22, 2657-2662; R. N. Zuckermann, E. J. Martin, D. C. Spellmeyer, G. B. Stauber, K. R. Shoemaker, J. M. Kerr, G. M. Figliozzi, D. A. Goff, M. A. Siani, R. J. Simon, S. C. Banville, E. G. Brown, L. Wang, L. S . Richter, W. H. Moos, J. Med. Chem. 1994, 37, 26782685.

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[23] H. Reuvini, A. Gitler, E. Poradosu, C. Gilon, A. Levitzki, Bioorg. Med. Chem. 1997, 5, 85-92. [24] J. T. Hunt, V. G. Lee, K. Leftheris, B. Seizinger, J. Carboni, J. Mabus, C . Ricca, N. Yan, V. Manne, J. Med. Chem. 1996,39, 353-358. [25] D. M. Leonard, K. R. Shuler, C. J. Poulter, S . R. Eaton, T. K. Sawyer, J. C. Hodges, T.-Z. Su, J. D. Scholten, R. C. Gowan, J. S. Sebolt-Leopold, A. M. Doherty, J. Med. Chem,. 1997,40, 192-200. [26] R. Sekizawa, H. Iinuma, Y. Muraoka, H. Naganawa, N. Kinoshita, H. Nakamura, M. Hamada, T. Takeuchi, K. I. Umezawa, J. Nut. Prod. 1996,59,232-236. [27] H. W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, L. S . Beese, Science, 1997, 275, 1800-1 804. [28] J. Travis, Science 1993, 260, 1877-1878. [29] For recent reviews on inhibitors of Ras farnesyltransferases, including microbial products identified as such see: F. Tamanoi, Trends Biochem. Sci. 1993, 349-353; G. L. Bolton, S. Sebolt-Leopold, Hodges, Ann. Rep. Med. Chem. 1994, 29, 165-174; J.C.; S. AyralKaloustian, J. S. Skotnicki, Ann. Rep. Med. Chem. 1996, 31, 171-179; J. D. Scholten, K. Zimmerman, M. Oxender, J. Sebolt-Leopold, R. Gowan, D. Leonard, D. J. Hupe, Bioorg. Med. Chem. 1996, 4 , 1537-1543; D. M. Leonard, J. Med. Chem. 1997, 40, 29712990; Y. Qian, S. M. Sebti, A. D. Hamilton, Biopolym. 1997,43, 25-41.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Mechanically-InterlockedMolecular Systems Incorporating Cyclodextrins Sergey A. Nepogodiev and J. Fraser Stoddart

If any theme is beginning to dominate the development of synthetic chemistry these days, it must surely be self-assembly. [ l ] The spread of this concept, though somewhat belatedly, into all branches of chemistry is mainly W u-CD (n = 6) a result of the rapidly accelerating growth and p-CD ( n = 7) acceptance of supramolecular chemistry. [2] Long before chemists were thinking and prac- b) tising their own brands of chemistry beyond the molecule with wholly synthetic systems, nature had been extolling the virtues of molecular recognition in the production of sophisti- C) cated molecular assemblies and supramolecular arrays with linked forms and functions. If one class of compounds has provided the bridge between the worlds of natural and unnatural hosts, it has been the cyclodextrins Figure 1. Schematic representations of (a) a-cyclo[3] - or CDs (Fig. la) as the aficionados call dextrin (a-CD) and b-cyclodextrin (p-CD), (b) a them. Yet, even as they enter their second [2]rotaxane, and (c) a polyrotaxane. century [3b] of cultivation by chemists, they The self-assembly of CD rotaxanes is continue to fascinate the chemical community. [3c] The reason is quite simple: they are expected on account of the strongly pronounaesthetically-appealing molecules, and they ced ability of CDs to form inclusion complexes also lend themselves to novel experiments. with organic molecules. In principle, any The series of reports from different research through-ring CD complex can be considered laboratories [4-121 in recent years on the as a pseudorotaxane. Thus, polymethylene self-assembly of CDs into [2]rotaxanes [13] compounds, terminated with appropriate end and polyrotaxanes (Fig. lb,c) serves to groups such as pyridinium, [ 141 bipyridinium, remind us all that there is still a lot of inno- [ 151 or carboxyl groups [ 161 could form rather vation to be forged in and around CDs in the stable complexes with a-CD where the hydrocarbon chain is located inside the CD cavity. coming one-hundred years.

Mechanically-Interlocked Molecular Systems Incorporating Cyclodextrins

1

Extending the lifetime of such complexes may be achieved by using more bulky end groups like 4 -tert-butylpyridinium [ 171 stoppers and the slippage mechanism for rotaxane formation. However, even in this case, the formation of the rotaxane is reversible. Therefore, the task of creating CD rotaxanes comes down to the problem of putting bulky stoppers on the ends of a molecule threaded through the CD ring. This task is not a trivial one because of the necessity of carrying out reactions in aqueous media where the incorporation of guest molecules by CDs normally takes place. One of the solutions to the problem of capturing CDs on included dumbbell-shaped molecules lies in the construction of coordination linkages - an approach first reported by Ogino in 1981. [4] More recently, the construction of a series a-CD [2]rotaxanes, based on the attachment of stoppers to threads by means of metal complex formation, was described by Macartney et al. [5] They have shown that the self-assembly of rotaxanes of the a-CD } Fe(CN)5I4type [(NC)SFe{ R(CHZ)~R'. where R and R' are bipyridinium or pyrazinium (e. g., 1 in Scheme 1) happens irrespective of the order of the addition of the components to the aqueous solution. This observation infers a slow dissociation of one of the [Fe(CN)5I3- ions, followed by a-CD inclusion and the recomplexation of [Fe(CN)5I3- ion. Evidence for the formation of [2]rotaxanes is provided by the 'H NMR spectra, in which the signals of the symme-

375

complex 1 of Macartney et al. [5]

try-related protons of the [R(CH&R'I2+ unit are separated on account of the end-to-end asymmetry associated with the trapped a-CD ring. It is conceivable that this methodology could be applied to the preparation of a family of similar [alrotaxanes with different threads and a broad range of stoppers, such as [M(CN)#- and [M(NH3)51m+ions with redox active d6 metal (M) centers like Co, Ru, Os, and Fe.

iH*E-cD

3 (n=lI)

5a (n=11)

+

5b (n=11)

Scheme 2. The zwitterionic [2]rotaxanes 4 and 5 of Isnin and Kaifer [6]

Applications in Total Synthesis

376

1. p-CD i NaHC03 I H20 2. Aniline I NaHC03I H20

I

S03Na

I

Na03S

'S0,Na

6

In 1991, Isnin and Kaifer [6] announced the synthesis of the asymmetric zwitterionic [2]rotaxanes 4a, b and 5a, b incorporating aCD rings via amide bond formation promoted by the water-soluble coupling reagent - 1-[3dimethylamino)-prop yI] - 3 -ethylcarbodiimide (EDC) (Scheme 2). In these cases, a-CD first of all binds oligomethylene chains of 2 (n = 7) or 3 (n = 11) bearing carboxyl groups which were subsequently capped with aminonaphthyl residues to afford isomeric [2]rotaxanes 4a, b and 5a, b in 15 % yields. The isomers were subsequently separated

Scheme 3. The /?-CD [2]rotaxane 6 with a covalently-stoppered diaminostilbene dumbbell described by Nakashima et al. [7]

[ 181 and the relative orientations of the a-CD rings on the asymmetric dumbbell-shaped components have been established: one isomer is stable but the other one unthreads slowly! Another example of a CD [2]rotaxane in which the thread is capped with covalentlylinked stoppers have been reported by Nakashima et al. [7] Using a host-guest interaction between B-CD and stilbene and the reactivity of the cyanuric chloride whereby chlorine substituents are displaced with amines in aqueous solution, they performed

Figure 2. The p-CD rotaxanes 7 and 8 with ammonium tetraphenylborate stoppers synthesized by Lawrence et al. [8]

Mechanically-Interlocked Molecular Systems Incorporating Cyclodextrins

the two-step synthesis (Scheme 3) of the [2]rotaxane 6 . A very simple way of stoppering a bisammonium thread by using NaBPh4 was proposed by Lawrence and Rao. [gal They managed to obtain a “threaded molecular loop” - the per-2,6-dimethyl-b-CD [2]rotaxane 7 - in an excellent 71 % yield by doing the self-assembly in aqueous solution (Fig. 2). Furthermore, the same methodology has been employed successfully [8b] for the construction of the [3]rotaxane 8 incorporating a tetraarylporphyrin unit. The possibility of carrying out various chemical modifications on CDs has been used by Wenz et al. [9] for creating a series of lipophilic derivatives, which are not only readily

377

soluble in most organic solvents, but also can bind cationic species. A new CD host molecule was used (Scheme 4) for self-assembling the CD [2]rotaxanes 10a and 10b incorporating the 4,4’-bipyridinium unit. The formation of these rotaxanes occurs as a result of the quaternization of the pyridine nitrogen of the monocations 9a, b when they are complexed within the CD host. It has been proved that this process could take place only with a certain orientation of the CD ring with respect to the thread. Therefore, the selective formation of a single orientational isomer could be predicted in cases of [2]rotaxanes of the type 10 incorporating asymmetrical dumbbell units. The isomer phenomena literally takes on a further dimension in polyrotaxanes, for

9b X = COO

t

10aX=O

10b X = COO

Scheme 4. The lipophilic [2]rotaxanes

10 constructed by Wenz et al. [9]

378

Applications in Total Synthesis

Figure 3. Schematic representation of polyrotaxane constructed by Harada et al. [ 101

which the view has grown that the CDs might thread under conditions of equilibrium control with alternating orientations, wherein adjacent rings are matched head-to-headhail-to-tail in order to optimize hydrogen bonding between the neighboring CD units. In the knowledge that chains of poly(ethyleneglycol) (PEG) thread a-CD beads like a necklace, [19] Harada and co-workers [lo] have succeeded in capping the chain ends of a poly(ethyleneglyco1)diamine (PEG-DA, M , 3450) with dinitrophenyl stoppers. The reac-

tion was carried out in a solution of PEG-DA in dimethylformamide, saturated with a-CD and laced with a gross excess (46 mol equiv) of 2,4 -dinitrofluorobenzene. After an extensive purification procedure, full characterization of the product, which was obtained in high yield (60%), indicated average molecular weights of 23200 (by 'H NMR) and 24600 (by UV) that are commensurate with the respective threading of 20 and 23 a-CD rings per polyrotaxane molecule (Fig. 3). This type of molecular structure

b)

A

B 13

Figure 4. Structural units of CD polyrotaxanes 12 and 13 designed (a) by Wenz and Keller [ 111 and (b) by Osakada and Yamamoto [I21

Mechanically-Interlocked Molecular Systems Incorporating Cyclodextrins r

319

1

14

7 15

Scheme 5. Synthesis of [2]catenane 15 [22]

conjures up the image of a molecular abacus [20] in terms of both the structure and dynamics. Quite independently, Wenz and Keller [ 111 have demonstrated that threading of CD molecules on to polymeric secondary amines affords water-soluble polymeric inclusion complexes. The complex of the poly(iminetrimethyleneimino-decamethylene) 11 with P, = 23 f 5 is very stable: its equilibrium dialysis into separate components was far from complete after two weeks. When 11 (a-CD), was treated with nicotinoyl chloride to introduce at least two hydrophilic nicotonoyl blocking groups at arbitrary positions along the poly(iminooligomethy1ene) chain, a polyrotaxane 12 (Fig. 4a) of M , 55000 f 5000 (determined by laser light-scattering) was isolated with an average of 37 a-CD rings permanently threaded on to the chain, a number that corresponds to 67% of the monomer units with the polymer covered by CD. A similar type of polyrotaxane, with CD rings randomly clipped between blocking groups along the polymer chain, has been prepared by Osakado, Yamamoto and Yamaguchi. [ 121 Polycondensation of 3,3'-diaminobenzidine and 1,12-dodecanediol in the presence of aCD (1 :3 : 0.5 molar ratio), a reaction catalyzed by RuC12(PPh3)3, led to the irregular copolymer 13 containing structural units A and B in a 16 : 84 ratio (Fig. 4b).

Another possible way of forming interlocked molecular systems incorporating CDs involves in the macrocyclization of an acyclic guest threaded through a CD in a process which leads to catenated molecules. [21] In 1993, such a series of catenanes, based on dimethyl-B-CD (DM-/3-CD), was realized for the first time in our research laboratories. [22] Simple Schotten-Baumann condensation of terephtaloyl chloride with the diamine 14 in a basic aqueous solution of DM-p-CD afforded (Scheme 5) the [2]catenane 15 (see Fig. 5 for an X-ray crystal structure) and

Figure 5. A framework representationof the crystal structure of the catenated CD 15. The DM-p-CD ring component is shown black.

380

Applications in Total Synthesis

[7] M. Kunitake, K. Kotoo, 0. Manabe, T. Murarnatsu, N. Nakashima, Chem. Lett. 1993, 1033. [8] a) T. V. S. Rao, D. S. Lawrence. J. Am. Chem. SOC. 1990, 112, 3614; b) J. S. Manka, D. S . Lawrence. J. Am. Chem. SOC. 1990,112,2440. [9] G. Wenz, E. von der Bey, L. Schmidt, Angew. Chem. Int. Ed. Engl. 1992, 31, 783; G. Wenz, F. Wolf, M. Wagner, S . Kubik, New J. Chem. 1993, 17, 729. [lo] A. Harada, J. Li, M. Kamachi, Nature, 1992, 356, 325; A. Harada, T. Nakamitsu, J. Li, M. Kamachi, J. Org. Chem. 1993, 58, 7524; A. Harada, J. Li, M. Karnachi, J. Am. Chem. Soc.1994, 116, 3192. [ l l ] G. Wenz, B. Keller, Angew. Chem. Int. Ed. Engl. 1992,31, 197. [12] I. Yamaguchi, K. Osakada, T. Yamamoto, J. Am. Chem. SOC.1996,118, 1811. [ 131 For review on rotaxanes and other interlocked structures, see: D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995,95,2725. [14] H. Saito, H. Yonemura, H. Nakamura, T. Matsuo, Chem. Lett. 1990, 535. [15] H. Yonemura, H. Saito, S. Matsushima, H. Nakamura, T. Matsuo, Tetrahedron. Lett. References 1989, 30, 3143; H. Yonemura, M. Kasahara, H. Saito, H. Nakamura, T. Matsuo, J. Phys. [l] D. Philp, J. F. Stoddart, Angew. Chem. Int. Ed. Chem., 1992, 96, 5765. Engl. 1996,35, 1154. [ 161 M. Watanabe, H. Nakamura, T. Matsuo, Bull. [2] J.-M. Lehn, Supramolecular Chemistry, VCH, Chem. SOC. Jpn., 1992, 65, 164. Weinheim, 1995; J.-M. Lehn, Angew. Chem. [I71 D. H. Macartney, J. Chem. SOC., Perkin Trans. Int. Ed. Engl. 1988, 27, 89; ibid. 1990, 29, 2 1996,2775. 1304. [18] See the comments in an article by R. Dagani, [3] a) Comprehensive Supramolecular Chemistry; Chem. Eng. News, 1992, 70, (15) 39. J. L. Atwood, J. E. D. Davies, D. D. MacNicol, [I91 Complexes of CDs with different polymers F. Vogtle (Eds.), Cyclodextrins; J. Szejtli, T. have been reported: a-CD forms crystalline Osa (Eds.), Elsevier Sci.: Oxford, 1996, Vol. complexes with PEG: A. Harada, M. Kamachi, 3; b) J. F. Stoddart, Carbohydx Res. 1992, Macromolecules 1990, 23, 2821; p-CD and 192, xii; c) G. Wenz, Angew. Chem. Int. Ed. y-CD give crystalline and stoichiometric comEngl. 1994,33, 803. plexes with poly(propyleneglyco1): A. Harada, [4] H, Ogino, J. Am. Chem. SOC. 1981,103, 1303; M. Okada, J. Li, M. Kamachi, MacroH, Ogino, K. Ohata, Inorg. Chem. 1984, 23, molecules 1995, 28, 8406. 2312; H, Ogino, New. J. Chem. 1993,17,683. [20] M. V. Reddington, A. M. Z. Slawin, N. Spen[5] R. S. Wylie, D. H. Macartney, J. Am. Chem. cer, J. F. Stoddart, C. Vicent, D. J. Williams, SOC. 1992, 114, 3136; R. S. Wylie, D. H. J. Chem. SOC.Chem. Commun. 1991,630. Macartney, Supramol. Chem. 1993, 3, 29; [21] For recent review on catenanes see: M. BelohD. H. Macartney, C. A. Wadding, Inorg. radsky, F. M. Raymo, J. F. Stoddart, Collect. Chem. 1994,33, 5912. Czech. Chem. Commun. 1997, 62,527. [6] R. Isnin, A. E. Kaifer, J. Am. Chem. SOC.1991, [22] a) D. Armspach, P. R. Ashton, C. P. Moore, 113, 8188. N. Spencer, J. F. Stoddart, T. J. Wear, D. J.

three other catenanes - a [2]catenane and two [3lcatenanes involving the corresponding macrocyclic dimer. These exciting developments surrounding CDs [23] have been going on against a background of activity in other laboratories on self-assembling wholly synthetic rotaxanes, polyrotaxanes [24] and catenanes. This area was reviewed recently. [ l , 13,211 Self-assembly is the unifying concept in the construction of all these mechanically-interlocked molecular systems. As we begin to comprehend the rules of the game for different systems in a range of media, our fundamental understanding of molecular recognition benefits by leaps and bounds. Applications will begin to surface on a somewhat longer time-scale. Suffice it to say at present that there are high hopes for the advent of new materials with both novel forms and functions.

Mechanically-Interlocked Molecular Systems Incorporating Cyclodextrins Williams, Angew. Chem. Int. Ed. Engl. 1993, 32,854; b) D. Armspach, P. R. Ashton, R. Ballardini, V. Balzani, A. Godi, C. P. Moore, L. Prodi, N. Spencer, J. F. Stoddart, M. S. Tolley, T. J. Wear, D. J. Williams, Chem. Eur: J. 1995, I , 34. [23] Apart from the parent CDs, fully synthetic CD analogs may have some advantages in the construction of mechanically-interlocked systems. Thus, oh-alternating cyclic oligosaccharides designed and synthesized in our laboratories have S, symmetry and so behave as molecular cylinders rather than as molecular lampshades.

38 1

a) P. R. Ashton, C. L. Brown, S. Menzer, S. A. Nepogodiev, J. F. Stoddart, D. J. Williams, Chem. Eur: J. 1996, 2, 580; b) P. R. Ashton, S. J. Cantrill, G. Gattuso, S. Menzer, S. A. Nepogodiev, A. N. Shipway, J. F. Stoddart, D. J. Williams, Chem. EUKJ . 1997, 3, 1299; c) G. Gattuso, S. Menzer, S. A. Nepogodiev, J. F. Stoddart, D. J. Williams, Angew. Chem. Int. Ed. Engl. 1997, 36, 1451. [24] For examples of comb-shaped CD rotaxane polymers, see M. Born, H. Ritter, Macromol. Chem. Rapid Commun. 1991, 471; M. Born, H. Ritter, Adv. Muter. 1996, 8, 149.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Bolaamphiphiles: Golf Balls to Fibers* Gregory H. Escamilla and George R. Newkome

A bolaamphiphile is simply defined as a molecule in which two or more hydrophilic groups are connected by hydrophobic functionality (Scheme 1). Other terms such as bolaform amphiphile [ l ] or arborol [2] have been used to describe molecules possessing this general architecture. Bolaform electrolytes or bolytes, a term introduced [ 11 by Fuoss and Edelson in 1951, are structurally similar except the hydrophilic groups are ionic. [3] Since Fuhrhop and Mathieu [4] reported in 1984 the synthesis and self-assembly of several bolaamphiphiles, other researchers have explored the applications of this basic architecture to a variety of situations. A search of current literature demonstrates the potential of bolaphiles, short for bolaamphiphiles, for the preparation of ultrathin monolayer membranes and the disruption of biological membranes, which could lead to therapeutic agents, [5, 61 as well as their use as “antisense” agents; [7, 81 as catalysts in reactions; [9-111 and as models for the membranes found in thermophilic archaebacteria. [ 121 In natural membranes bolaform amphiphiles have chiral head groups, which are dif-

* Chemistry of Micelles, Part 76. Support for this work was provided by the National Science Foundation (DMR-92-1733 1; 92-08925, 96-22609).

ferent in size and thus react stereoselectively with guest molecules. [3] In non-natural membranes binding sites can also be present, [9,13] or other functional groups can be incorporated such as redox- andlor photoactive moieties. [4] The repertoire of bolaphiles is not limited to assemblies such as membranes and vesicles; specific two-directional arborols can form gels, [2, 14-16] and a-~-lysine-waminobolaphiles form rods and tubules. [ 171 When polymerizable functionalities are included either in the head groups or within the hydrophobic spacer, routes to extended covalently linked domains are created. [ 18, 191 Nontraditional structures (e. g., aqueous gels) result when non-covalent forces are coupled with a proper molecular architecture. The series of two-directional arborols, synthesized by Newkome et al., demonstrates this variation on the theme of the self-assembly of ordered arrays. [13, 141 In the proposed model of aggregated structure, or automorphogenesis, [20] one arborol is stacked upon the next; the hydrophobic chains overlap and the spherical, connecting hydrophilic hydroxyl termini are oriented out toward the aqueous solution (Fig. 1). Hydrogen bonding between the polar end groups and the water results in the formation of a thermoreversible gel. This proposed model is supported by the long fiber-like structures seen in electron micro-

Bolaamphiphiles: Golf Balls to Fibers

383

2

3 Scheme 1. Examples of bolaamphiphiles; the basic elements are hydyrophilic head groups (shaded) and the hydrophobic spacers (1 from [14], 2 from [ 5 ] , 3 from [3])

graphs of these molecular assemblages. [13, 21, 221 As with micelle formation, there is a minimum hydrophobic moiety needed for gelation to occur; for a saturated spacer this length is eight methylene units. [14] Aqueous N , N , N N"'-tetrakis[2-hydroxy-l,1-bis(hyI,

Side

TOP

Figure 1. Spatial (side and top) representations of the stacking pattern calculated for 1.

droxymethyl)ethyl]hexadec-8-yne-1,1,16,16tetracarboxamide formed a novel helical thread and macroassemblies; whereas with added [ 181 crown-6-ether, particles are formed rather than fibers, as evidenced in electron micrographs of resulting gels. [13] Related self-assembled, supramolecular assemblies have been reported by Jorgensen et al., [23] in which tetrathiafulvene (TTF) was synthetically incorporated into the inner hydrophobic region of the bolamphile. Aggregates, created from packed TTF-2-directional arborols, were shown to be thin string-like molecular stacks with lengths in the order of tens of microns and diameters of approaching 100 microns; it would appear that these superstructures are hydrogen bonded aggregates of the single strands.

384

Applications in Total Synthesis

4

Scheme 2. The unsymmetrical bolaphiles synthesized by Fuhrhop et al. [17] for the generation of monolayer rods and tubules.

The rods and tubules, described by Fuhrhop et al. [17] follow an analogous pattern to that of these the 2-directional arborols. When the racemic form of the lysine bolaphile 4 was used (Scheme 2), no rod or tubule formation was noted; in contrast, the racemate of the extended bolaphile 5 produced supramolecular assemblies identical to those formed by the pure enantiomers. The effect of configuration in molecular monolayers was shown to depend on membrane curvature in the same manner as in bilayers. [ 171 A related bipolar dodecane possessing Nbenzyloxycarbonyl-L-phenylalanine terminal units has been shown [24] to form bundles of braided tapes in a hexaneEtOAc mixture. In order to probe the function of the urethane moieties, deprotection afforded the corresponding bis(a-aminoamide), which gave solids lacking any microstructural character. Bolaphiles composed of straight chain alkane termini have been reported [25] to afford selfassembled supramolecular structures in water. Fuhrhop et al. demonstrated [26] that placing quinone moieties in either the head groups or within the hydrophobic spacer, formed redox-active membranes; thus, unsymmetrical bolaphile 6 (Scheme 3) is a model of electron acceptors in photosynthesis and forms vesi-

cles as shown by electron micrographs. In the anticipated membrane organization, it was assumed that all of the quinone moieties must be located on the vesicle exterior. This assumption was confirmed by quantitative reduction of the quinone moieties with borohydride; since the reagent does not diffuse through lipid membranes, these “membrane quinones” must be part of the vesicle exterior. The anthraquinone-based bolaphile 7 or 8 could not form homogeneous membranes due to steric interactions (Scheme 3); however, they could be integrated into host membranes formed by dihexadecylphosphate and dimethyldioctadecylammonium bromide. The bolaamphiphile fixed the quinone functionality in the center of the membrane and served as a model for pool quinones. [20] Electron transfer was further demonstrated by lightinduced charge transfer between cationic porphyrins dissolved in water and membranebound anthraquinone bolaphiles. [27] Bunton et al. proved that alkane a,w-bis(trimethylammonium) bolaphiles catalyze the spontaneous hydrolysis of 2,4 -dinitrophenylphosphates. [ l l ] The rate of hydrolysis was enhanced by micellar bolaphiles; this rate enhancement followed the greater organiza-

Bolaamphiphiles: Golf Balls to Fibers

385

0

8

Scheme 3. The unsymmetrical bolaphile 6 was used to fix the quinone functionality at the surface of the micelle; whereas, 7 and 8 were used to position the quinone moiety within the membrane.

tion seen in vesicles formed by surfactants Micelles generated from pyridine bolaphiles possessing longer spacers. Bolaphiles with (Scheme 4) and Cu" or Zn" enhanced the hexadecane and dodecane spacers did not rate of cleavage. As a comparison, the micelform micelles but rather small clusters instead, les generated from 6 -[ [(2-(n-hexadecy1)dimeand the rate enhancement achieved was much thylamino)ethyl]thio} methyl-2 -(hydroxymelower than that with micelle-forming surfac- thy1)pyridine bromide were not as effective tants. [ll] The aggregation and microstructure catalysts. Increased electrostatic repulsion of other alkane a,w-bis(ammonium) salts have between the ammonium group and the metal been studied. [28] ion site rationalized the difference in effecFornasier et al. used metallomicelles tiveness of the bolaform versus classical formed from bolaphiles and surfactants micelle. The crux of the catalytic process was with only one head group as catalysts for the formation of a ternary complex consisting of cleavage for para-nitrophenyl picolinate. [9] substrate, metal, and bolaphile, as ligand. [9]

386

Applications in Total Synthesis

9

10

These micelles demonstrate substrate discrimination, in other words, the correct substrate geometry is required for catalysis. Accordingly, no catalytic enhancement was found for the hydrolysis of the isomeric nicotinate or isonicotinate esters. Nolte and coworkers reported [29] the generation of a functional vesicle formed by an assembly of hosts (Scheme 5) capable of binding guests such as resorcinol and 4-(4'nitropheny1azo)resorcinol. In order to maintain the hydrophobic binding site at the exterior of the vesicle, two quaternary nitrogen atoms each having a long alkyl chain were utilized. The rigidity of the binding site held the

Scheme 4. The proximity of the charged head group to the binding site in 10 slows chelation of the metal relative to that of bolaphile 9. M=Cu", Zn"., R = para-nitrophenyl picolinate.

charged nitrogen atoms apart and fixed the binding site near the plane of the nitrogen atoms and therefore the vesicle surface. Typical for lipids, the hydrophobic alkyl chains served to form the membrane interior. Interactions of solvent, binding sites, charged nitrogen atoms, and hydrophobic alkyl chains together govern the vesicular morphology, which was likened to a golf ball because of its spherical shape and dimpled surface. [29] The golf ball analogy is completed by the concave shape of the binding site in the host. Examination of a cast film by X-ray diffraction yields a clear periodicity of 53 A, which is approximately the length of two fully ex-

Scheme 5. Representation of bolamphile 11 used by Nolte et al. [29] to prepare a functionalized vesicle.

Bolaamphiphiles: Golf Balls to Fibers

tended hexyldecylamine chains. Binding studies suggest that only half the total number of binding sites are able to interact with the guest. These data indicate a bilayer membrane with a thickness of approximately 53 A. Jayasuriya et al. [5] hypothesized that bolaform amphiphiles could be tailored to provide an optimal geometry for membrane disruption. Variation of either the head groups or spacer could provide a “tunability” to target certain microorganisms. The bolaphiles were proposed [5] to disrupt membranes by insertion of their hydrophobic spacers into the lipid layer, which would cause a mismatch of the preferred geometry of the bolaphile and lipid. When increased interruptions occur, the membrane would become more destabilized (Scheme 6). Spacers with central triple or double bonds were made with the expectation that these functionalities would increase the disruptive capability of the bolaform amphiphiles. Alkane spacers ranged from decane to eicosane, from which maximum activity was observed with pentadecane. In the olefinic analogues, the geometry and position of the double bond were less important in determining membrane disruption. Similarly, the position of unsaturation was not important for the acetylenic bolaphiles. [5] A general

387

trend was that maximum activity required an increase in spacer length when moving from saturated to olefinic to acetylenic spacers. The use of polymeric strings of bolaphiles in membrane disruption was described by Jayasuriya et al. (Scheme 7). [6] The membrane disruptive activity of the polymeric bolaamphiphiles or “supramolecular surfactants” is up to lo3 times greater than that of the monomeric analogues. The precise origin of this amplification is not yet understood; however, several factors were proposed. Since the polymeric bolaphiles have covalent linkages, the “bolaamphiphile defects” will be localized in the membrane and a high local concentration will be achieved. Domains of the supramolecular surfactant within the bilayer will be in equilibrium with nonaggregated membrane-bound polymers. Repeat unit defects in the polymer are intrinsically more disruptive than the free monomer. A polyester, very similar to these “supramolecular surfactants”, exhibited substantial protection for human CD4+ lymphocytes against HIV-1 during in vitro studies. [6] Thus a new route into nonionic membranedisrupting agents is opened, in which activity and specificity could be tailored by molecular design.

phospholipid monolayer

llllllllllll

IIllllllIIII

4 \

hydrophillic A/

111111111111

111111111111

\

hydrophobic

Scheme 6. Mechanism proposed by Jayasuriya et al. [6] for the destabilization of a membrane by the insertion of the hydrophobic spacer of a bolaphile into the phospholipid layer and the resulting local defect.

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Applications in Total Synthesis

&

CH2)"

. .

-(C H~)x-HC=CH-(CH~)

(4

(b)

Hudson and Damha have succeeded in making branched RNA in a convergentgrowth approach (Scheme 8). [8] The resulting compound composed of oligothymine units, modified adenosine spacers, and terminal nucleotides as head groups fits the description of a bolaamphiphile. These branched RNA molecules could be useful in capturing and binding matching nucleotide sequences.

(3) Scheme 7. Membrane-disruptive bolamphiles (a) and their polymeric analogues (b).

This would allow access to potential antisense agents or ligands for affinity purification of the branch recognition factors, which catalyze the maturation or splicing of precursor messenger RNA. [8] Beyond these initial examples, basic questions remain concerning the conformation of bolaamphiphile within micelles. [30] There is evidence that a bent conformation is adopted, TTTT

TTT

T TTTf

{ATTTTTTTTT

ATTTT T T f

Scheme 8. An RNA-based bolamphile synthesized by Hudson and Damha [8]

~ T T T

Bolaamphiphiles: GolfBalls to Fibers

[31] but micelles have been observed with very small hydrophobic cores and others are sometimes seen on electron micrographs with diameters that correspond to the length of the bolaphile. [30, 321 Among the many subjects for further exploration in the area of molecular self-assembly are the naturally occurring bolaamphiphiles found in thermophilic bacteria with their stereochemistry and stability in harsh environments. More robust membranes or chiral bolaphiles with their resulting chiral membranes could provide avenues to molecular recognition based on stereochemistry not only at one site, but over an entire membrane. [3] Rhizoferrin, N',N4-bis(4-0x0-3 -hydroxy3,4-dicarboxybutyl)diaminobutane, isolated from an organism associated with mucormycosis observed in dialysis patients [33] and occurs in Zygomycetes strains of fungus [34] has been recently synthesized [35] and may possess bolaphilic properties. Bolaamphiphiles, [36] like dendritic macromolecules, [37] have gained increasing attention recently, since they offer insight to micellar systems that can mimic enzymes, act as therapeutic agents, or as tools to investigate molecular recognition and assemblages. Nolte's golf ball [29] and the other specifically shaped examples described here illustrate the goal Lehn set forth for supramolecular chemistry - structures alone are not the goal but rather the expression of a desired chemical, biological, or physical property. [20]

389

[4] J.-H. Fuhrhop, J. Mathieu, Angew. Chem. 1984, 96, 124; Angew. Chem., Int. Ed. Engl. 1984, 23, 100. [5] N. Jayasuriya, S. Bosak, S. L. Regen, . I Am. . Chem. SOC. 1990,112,5844. [6] N. Jayasuriya, S. Bosak, S. L. Regen, J. Am. Chem. SOC.1990,112,5851. [7] I. Amato, Science 1993, 260, 491. [8] R. H. E. Hudson, M. J. Damha, . I Am. . Chem. SOC. 1993, 115, 2119. [9] R. Fornasier, P. Scrimin, P. Tecilla, U. Tonellato, J. Am. Chem. SOC. 1989, 111, 224. [ 101 A. Cipiciani, M. C. Fracassini, R. Germani, G. Savelli, C. A. Bunton, J. Chem. SOC., Perkin Trans. 1987, 547. [ l l ] C. A. Bunton, E. L. Dorwin, G. Savelli, V. C. Si, Recl. Trav. Chim. Pays-Bas. 1990, 109, 64. [12] J.-M. Kim, D. H. Thompson, Langmuir 1992, 8, 637. [13] G. R. Newkome, G. H. Escamilla, M. J. Saunders, 1997, unpublished results. [14] G. R. Newkome, G. R. Baker, S. Arai, M. J. Saunders, P. S. Russo, K. J. Theriot, C. N. Moorefield, J. E. Miller, K. Bouillon, J. Am. Chem. SOC. 1990, 112, 8458. [15] G . R. Newkome, X. Lin, C. Yaxiong, G. H. Escamilla, J. Org. Chem. 1993,58, 3123. [16] G. R. Newkome, C. N. Moorefield, G. R. Baker, R. K. Behera, G. H. Escamilla, M. J. Saunders, Angew. Chem. 1992, 104, 901; Angew. Chem., Int. Ed. Engl. 1992, 31, 917. [17] J.-H. Fuhrhop, D. Spiroski, C. Boettcher, J. Am. Chem. SOC. 1993,115, 1600. [I81 L. Gros, H. Ringsdorf, H. Schupp, Angew. Chem. 1981, 93, 311; Angew. Chem., Int. Ed. Engl. 1981,20, 305. [ 191 J.-H. Fendler, P. Tundo, Acc. Chem. Res. 1984, 17, 3 . [20] J.-M. Lehn, Angew. Chem. 1990, 102, 1347; References Angew. Chem., Int. Ed. Engl. 1990,29, 1304. [21] T.-P. Engelhardt, L. Belkoura, D. Woermann, [I] R. M. Fuoss, D. J. Edelson, J. Am. Chem. SOC. Bel: Bunsenges. Phys. Chem. 1996,100, 1064. 1951, 73, 269. [22] K. H. Yu, P. S. Russo, L. Younger, W. G. Henk, [2] G. R. Newkome, G. R. Baker, S. Arai, M. J. D.-W. Hua, G. R. Newkome, G. R. Baker, Saunders, P. S. Russo, V. K. Gupta, Z.-Q. J. Polym. Sci.-Polym. Phys. 1997, 35, 2787. Yao, J. E. Miller, K. Bouillon, J. Chem. SOC., [23] M. JGrgensen, K. Bechgaard, R. Bjarnholm, P. Chem. Commun. 1986, 752. Sommer-Larsen, L. G. Hansen, K. Schaum[3] J.-H. Fuhrhop, D. Fritsch, Acc. Chem. Res. burg, J. Org. Chem. 1994, 59, 5877. 1986, 19, 130.

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Applications in Total Synthesis

[24] S. Bhattacharya, S. N. Ghanashyam, A. R. Raju, J. Chem. Soc., Chem. Commun. 1996, 2101. [25] T. Shimizu, M. Masuda, J. Am. Chem. Soc. 1997, 119, 2812; M. Masuda, T. Shimizu, J. Chem. Soc., Chem. Commun. 1996, 1057. Also see: F. Brisset, R. Garelli-Calvet, J. Azema, C. Chebli, I. Rico-Lattes, A. Lattes, A. Moisand, New. J. Chem. 1996,20, 595; D. Lafont, P. Boullanger, Y. Chevalier, J. Carbohydr. Chem. 1995, 14, 533; P. Goueth, A. Ramez, G. Ronco, G. Mackenzie, P. Villa, Carbohyydr. Res. 1995, 266, 171; A. Mueller-Fahrow, W. Saenger, D. Fritsch, P. Schneider, J. H. Fuhrhop, Carbohydr. Res. 1993, 242, 11; R. Garelli-Calvet, F. Brisset, I. Rico, H. Lattes, Synth. Commun. 1993, 23, 35. J.-H. Fuhrhop, H. Hungerbuhler, U. Siggel, Langmuir 1996,6, 1295. U. Siggel, H. Hungerbuhler, J.-H. Fuhrhop, J. Chim. Phys. 1987, 84, 1055. D. Danino, Y. Talmon, R. Zana, Langmuir 1995, 11, 148; M. Frindi, B. Michels, H. Levy, R. Zana, Langmuir 1994, 10, 1140; E. Alami, G. Beinert, P. Marie, R. Zana, Langmuir 1993, 9, 1465; E. Alami, H. Levi, R. Zana, A. Skoulios, Langmuir 1993, 9 , 940. 1291 A. P. H. J. Schenning, B. de Bruin, M. C. Feiters, R. J. M. Nolte, Angew. Chem. 1994, 106, 1741; Angew. Chem., Int. Ed. Engl. 1994, 33, 1662.

[30] J.-H. Fuhrhop, R. Bach in Advances in Supramolecular Chemistry, Vol. 2 (Ed.: G. W. Gokel) JAI Press, Greenwich, 1992, p. 25. [31] R. Zana, S. Yiv, K. M. Kale, J. Colloid Interface Sci. 1980, 77, 456. 1321 S. Yiv, R. Zana, J. Colloid Interface Sci. 1980, 77, 449. [33] H. Drechsel, J. Metzger, S. Freund, G. Jung, J. R. Boelaert, G. Winklmann, B i d . Mat. 1991, 4, 238. [34] A. Thieken, G. Wienkelmann, FEMS Microb i d . Lett. 1992, 94, 37. [35] R. J. Bergeron, M.-G. Xin, R. E. Smith, M. Wollenweber, J. S. Mmanis, C. Ludin, K. A. Abboud, Tetrahedron 1997, 53, 427. [36] J.-H. Fuhrhop, W. Helfrich, Chem. Rev. 1993, 93, 1565; G . H. Escamilla, “Dendritic Bolaamphiphiles and Related Molecules”, in Advances in Dendritic Macromolecules, Vol. 2, (Ed.: G. R. Newkome) JAI Press, Greenwich, 1995, 157. [37] G. R. Newkome, C. N. Moorefield, F. Vogtle, Dendritic Molecules: Concepts, Syntheses, Perspectives, VCH, Weinheim, 1996.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Dendrimers, Arborols, and Cascade Molecules : Breakthrough into Generations of New Materials Andreas Archut, Jorg Issberner and Fritz Vogtle

The initial impetus can be traced to our cascadelike synthesis of noncyclic, branched polyamines in 1978. [4] Thereafter DenkeWalter, Newkome, Tomalia, and others expanded this theme considerably. [ 1, 51 The extremely branched molecules are mainly synthesized from identical building blocks that contain branching sites, and often have a variety of functional groups on the periphery. These dendrimers are constructed in stages in repeatable synthetic steps (repetitive strategy). Each reaction cycle creates a new “generation” of branches. Unlike the divergent method, i.e. the dendrimer is built up shellwise from the core, the convergent approach is to create larger fragments first and then to couple these in a final step to the core building block. Polypropylene amines, poly(amidoamines) (PAMAM) and silicon dendrimers set “records” for the number of generations, whereas the polyacetylene dendrimer prepared by Moore et al. [6] with the formula C1398H1278 and a mass of 18079.53 holds the “heavyweight championship title” of pure hydrocarbons. Mullen et al. have recently published a series of aromatic hydrocarbon dendrimers 1984 1986 1988 1990 1992 1994 1996 consisting of phenylene-bridged benzene Figure 1. The number of publications on dendri- rings. [7] Interestingly, these species form mers has increased almost exponentially within two-dimensional planes rather than threedimensionally extended structures. the last decade.

When a new idea in science is particularly appealing or “contagious”, activity in that area may rapidly reach epidemic proportions. A recent example is the development of dendrimer research in the past few years. [ l , 21 CAS online searches [3] shows that the number of publications in this field has increased nearly exponentially over the past decade, and the limit has not yet been reached (Fig. 1).

392

Applications in Total Synthesis

The nomenclature of cascade molecules according to the common rules has its difficulties. The names became extremely long and the fundamental structure of the molecule cannot be quickly derived from them. Newkome et al. therefore proposed a new nomenclature that reflects the structure in the sense that it names the molecule from the core towards the periphery. [8] Furthermore, the class of compound becomes clear, since the names begin with “Z-Cascade”, where Z is the number of functional groups on the periphery.

Today research does no longer focus on the dendrimer itself but on the multiplication of functional components attached to a dendritic skeleton and new materials with specific properties (redox, ligand, and liquid crystalline properties, biochemical activity ...) are anticipated. [9] Industry has also shown increasing interest in functional cascade molecules for applications in diverse areas such as medical engineering, agrochemistry, and the development of photocopier toner additives. Concrete applications include nunoscale catalysts [2a],

I

I

Figure 2. Moore et al. [6] have built up the heaviest pure hydrocarbon dendrimer known to date with a molecular weight larger than 18 000 u.

Dendrimers, Arborols, and Cascade Molecules

reaction vessels for chemical reactions [lo], biomimetics of cells [ 111, diagnostic imaging [12], radio therapy [13], immunoassays [14], antiviral drugs [15], drug targeting [16, 171, sensors [ 181, conducting polymers [ 191, coolant additives [20], column materials [2a], metal absorbers [21], calibration standards of submicron apertures [22] and molecular antennas [2a,fl as documented by many patents. The birth of cascade construction and cascade molecules was in 1978 when we reported the first preparation, separation, and mass spectrometric characterization of dendritic structures by repetition of certain synthetic steps. [4] Treating primary amines with acrylonitril and using a Michael-type addition afforded dendritic polynitriles with twice as many functionalities as the starting amines. After reduction and purification the product of the first reaction cycle was subject to the same sequence to generate the next-generation cascade molecule again with the doubled number of functional groups. Meanwhile the reduction conditions that are reliable if properly applied have been modernized by using

393

diisobutylaluminum hydride (DIBAH) supporting the original structural conclusions. [23, 241 In a further attempt we later prepared readily soluble dendrimers with large monomeric units up to the third generation. This general synthesis can be extended to other core units and to higher generations. [25] In addition it is possible to easily functionalize these dendrimers. Tomalia, Denkewalter and Newkome followed the cascade synthesis for the preparation of “Starburst” polyamidoamines, polylysines, and “arborols” during the 80’s and developed the dendrimer chemistry to a high skill. [l] FrCchet et al. employed the convergent method for the first time to synthesize highgeneration dendritic polyethers. [26] The attraction of the convergent method is the small number of molecules that are involved in the reaction steps to give each successive generation. Large excess of reagents can be avoided resulting in good yields. However, for higher generations the yields decrease because of increasing steric hindrance at the reacting functional groups. Also the multiple CN \

NC

NC

H2C= CH -CN L

Figure 3. The first cascade synthesis of dendrimers by iterative cycles of Michael-type addition of acrylonitril and reduction to the amine.

394

Applications in Total Synthesis

Frkchet et al. [26] have reported the first fullerene dendrimer.

benzylic ether bonds require non-acidic conditions which narrows chemical handling of this type of dendrimers. [27b] The preparation of the first fullerene dendrimer by FrCchet et al. combined two topics of supramolecular chemistry when they linked C ~ and O a dendritic benzylic bromide by Williamson ether synthesis. [28] Just recently, Hirsch et al. managed to use C ~ as O the core building block of a dendrimer with as many as 12 dendritic branches attached to the fullerene center. [29] Shinkai et al. have reported the synthesis of potential complexing arborols bearing crown

ether units in the core and on the periphery. [30] The synthesis of a dendrimer with a complexing inner core (hexacyclene = hexaaza[ 181crown-6) succeeded in Bonn; hexacyclene was linked with a branching unit which was obtained in a convergent manner. [3 I] In most cases the functional units are located on the dendrimer surface, but dendrimers are now accessible containing a nucleus capable of performing special functions (luminescence, complexation) which are influenced to some extent (sterically or electronically) by the periphery. Inoue et al. were the first to

Dendrimers, Arborols, and Cascade Molecules

describe a dendrimer with a metal porphyrin at its center. The convergent synthetic method of FrCchet was used to prepare a dendrimer in which the photoactive metal porphyrin center is sterically shielded. [32] Diederich et al. investigated the influence of the surface groups on the electrochemical behavior of metal porphyrins. Following a divergent synthesis devised by Newkome et al. they prepared the third generation porphyrin

395

dendrimer shown in Figure 5 , which has a molecular weight of over 19000. The redox chemistry of this dendritic porphyrin strongly contrasts that of non-dendritic zinc porphyrins. [33] The porphyrin nucleus is shielded by a core of electronegative oxygen atoms such that reduction by electrons from the outside is hindered. [34] We ourselves have explored several strategies to prepare Ru(I1) complexes of

Figure 5. A zinc porphyrin serves as core unit of this dendrimer prepared by Diederich et al. [33]

396

Applications in Total Synthesis

dendritic bipyridine ligands by an analogous way. [27] Such complexes exhibit the well known absorption and emission properties of Ru(I1)-polypyridine complexes. However, their excited state lifetime in air-equilibrated solutions is longer than expected. Indeed the dendrimer branches protect the Ru-bipy based core from oxygen quenching. A long lifetime of the luminescent excited state is important e.g. for immunoassay applications since the signal of the label can be read after the decay of the background fluorescence of the sample, whose lifetime usually is on the nanosecond time scale. The first studies on dendritic metal and nonmetal complexes demonstrate that dendrimers/arborols can be attached to metal centers for the preparation of “supramolecular aggregates”. The controlled complexation of metal ions at specific binding sites in dendrimer cavities was achieved by Newkome et al., who prepared a dendrimer framework containing triple bonds, which could be complexed by dicobalthexacarbonyl units. [35] Puddephatt et al. described the synthesis of dendrimers containing metal ions by coordinating bipyridine derivatives to transition metals, in analogy to the synthetic strategy developed by Balzani et al. In a convergent synthesis, in other words by repetition of alternating steps, (oxidative addition of benzylic bromides to platinum with bipyridine) Puddephatt et al. obtained a cluster with 28 Pt centers (Fig. 6), which is sterically that crowded that further conversion to yield a Pt30 cluster has failed. [36] The attachment of natural products or drugs to a dendritic skeleton is a promising concept as well. Multiplication of specific sugar epitopes in one molecule results in highly increased avidities [37] in adhesion processes and is called the “cluster effect”. [38] This is of importance where carbohydrate-protein interactions are under investigation. Sugar units were multiply built into polymers via copolymerization or telomerization to give glucomimetica. Den-

drimers are currently more and more used as core building blocks of taylor-made cluster glucosides. Roy et al. [39], Lindhorst et al. [40], and Stoddart et al. [41] have published new gluco dendrimers. In another study Roy et al. prepared a second generation poly(1ysine) dendrimer functionalized with disaccharides. [39] Preliminary tests with the influenza A virus indicate that the dendritic cluster depicted in Figure 7 is a strong inhibitor of erythrocyte hemagglutination. Similar systems among the star polymers were synthesized with peptide residues. Even nucleic acids can be constructed in a dendritic way, as Hudson and Damha have shown. [42] In an automated procedure the nucleic acid chains were first prepared and then divergently connected to give a cascade molecule containing 87 nucleic acid residues and having an approximate molecular weight of 25000. It was necessary to use longer branches for the inner core of the dendrimer than for the periphery. Rao and Tam proved that even peptides can be connected in a dendritic manner. [43] An octameric peptide dendrimer, which could be useful as a synthetic protein, was prepared and characterized by laser-desorption mass spectrometry. First investigations with cell cultures showed that certain dendrimers support the transfection of mammalian cells by plasmids. The controlled synthesis, low toxicity, and pH buffering effect of dendrimers are the main criteria for dendrimers suitable for gene-transfer experiments. [44] Seebach et al. met the challenge of synthesizing chiral dendrimers to investigate the influence of chiral building blocks on the chirality of the whole molecule and to determine whether enantioselective complexation was possible. [45] They achieved dendrimers with a chiral nucleus as well as dendrimers with additional chiral branches. The optical activity of dendrimers with only a chiral nucleus decreases with increasing

Dendrimers, Arborols, and Cascade Molecules

size of the dendrimer whereas the optical activity of dendrimers that are “fully chiral” correspond to the optical activity of the nucleus. These dendrimers also form quite stable clathrates. Meijer et al. recently reported the synthesis of dendrimers thereof with chiral terminal

397

units. [46] When only the chiral surface unit contains a stereogenic carbon atom the dendrimers exhibit low or vanishing optical activity with increasing generation number. In contrast, dendrimers with rigid chiral units show increasing optical activity with increasing generation number.

%

Figure 6. 28 platinum centers are clustered in this metal-complex dendrimer (Puddephatt et al.) [36]

398

Applications in Total Synthesis

Figure 7. Roy et al. have designed artificial glyco clusters based on dendrimers.

We were able to synthesize chiral dendrimers with stable planar-chiral building blocks to avoid racemisation. [47] In contrast to the results of Seebach et al. these dendrimers show increasing chirality with inreasing gene-

rations. In addition, the circular dichrograms clearly indicate that chiral dendrimers based on derivatives of [2.2]paracyclophanes can be employed for complexation of certain metal cations.

Dendrimers, Arborols, and Cascade Molecules

Figure 8. A polyamine dendrimer bearing planar-chiral cyclophane units (Vogtle et al.)

These dendrimers are precisely built nanoscopic molecules with physical characteristics such as size, solubility and dispersity of complexation sites. The chiral information should be useful for further reactions, e. g. in the field of homogeneous catalysis. There is a strong interest in the developing of new materials that combine the advantages and/or minimize disadvantages associated with individual homogeneous and heterogeneous catalysts. [48] Dendrimer construction might offer a Figure 9. Majoral et al. [50] have devised the synthesis of a new class of phosphorus-containing dendrimers.

399

400

Applications in Total Synthesis

better means of controlling the disposition of pendant metal-containing catalytic sites in soluble, polymer-based catalysts. [49] Catalytic dendrimers with nanoscale dimensions may be recycled by using simple filtration methods to remove the catalyst from the reaction mixture.

Majoral et al. have prepared the first neutral phosphorus-containing dendrimers. The forthgeneration dendrimer (Fig. 9) was obtained by reacting PSC13 and the sodium salt of para-hydroxybenzaldehyde and H2NN(Me)P(S)CClz. [50] Analogous reactions with POC13 instead of PSCl3 are possible as

Figure 10. Meijer et al. [53]have discovered the “dendritic box”, a fifth-generation polyamine dendrimer with bulky substituents, that can be used to include various types of guest molecules (amide hydrogen atoms have been omitted in the picture).

Dendrimers, Arborols, and Cascade Molecules

well. The only byproducts are sodium chloride and water, and the dendrimer is formed almost quantitatively. The monodispersity of the products could be easily monitored by phosphorus NMR. In addition to forming clathrates, dendrimers have been found to encapsulate guest molecules inside their cavities (“dendritic box”, “container dendrimers”). Suitable methods for inclusion of even large molecules (dyes, spin markers, fluorescence markers) have been developed. [51] After a guest has been bound in a certain generation of the dendrimer, the next generation is covalently linked closing the remaining gaps in the surface and thus confining the guest molecule in the dendrimer’s inner cavities. Such dendrimers are clearly supramolecular hosts. If the outer shell that closes the cavities containing guests is linked to the dendrimer supramolecularly (e.g. via hydrogen bonding), this linkage could later be broken more easily. [52, 531 Thus even without guests inside dendrimers can be supramolecules. Dendrimers that release guests upon changing pH hold

40 1

promise for the directed application of pharmaceuticals (drug release, drug targeting). Newkome et al. successfully prepared dendrimers with terpyridine units as linkers that are able to form supramolecular network assemblies. [54]The same authors have suggested recently to incorporate H-bonding moieties within a dendrimer to allow supramolecular network formation. 1551 Zimmerman et al. have disclosed the convergent preparation of dendritic wedges possessing tetraacid moities that self-assemble into the hexameric, disk-like network. [56] The tetraacid unit is known to form cyclic as well as linear structures in solution via carboxylic-acid dimerization. It is postulated that the cyclic structure forms predominantly since it is sterically less demanding than the linear aggregates would be. This suggestion has been supported by size-exclusion chromatography (SEC). Above all, the synthesis of large, branched molecules bordering on polymers challenges synthetic and analytical chemists alike. A large number of reaction centers or considerab-

R

-

W43h

Figure 11. Newkome et al. [54]have shown that dendrimer building blocks can be combined to give supramolecular dendrimer networks.

402

Applications in Total Synthesis

R-Y. R - H

/

Figure 12. A supramolecularcluster consisting of six dendritic wedges has been reported by Zimmermar et al. [56]

Dendrimers, Arborols, and Cascade Molecules

le steric congestion hinders the synthesis of monodisperse molecules, i.e. having all exactly the same structure. The classical methods of analysis in organic chemistry are sometimes pushed to their limits. NMR spectra and elemental analysis are becoming increasingly less informative, and mass spectrometry of very heavy molecules creates problems as well. The variety of the examples listed above documents that dendrimer chemistry has attained increasing interest. In this compilation of recent results the trend towards functional and application-oriented molecules including biochemically active, photoswitchable, and polymerlike dendrimers is particularly apparent. Dendrimers cross the boundaries of classical organic chemistry and as new materials will penetrate deeper into the topical fields of “nanostructures”, supramolecules and polymers in the future. Increasing industrial research on dendrimers and the commercial availability of PAMAM and polyamine dendrimers should stimulate further investigations in this field.

References [ 11 G. R. Newkome, C. N. Moorefield, F. Vogtle in

Dendritic Molecules, VCH, Weinheim, 1996. [2] a) R. Dagani, Chem. Eng. News 1996, June 3, 30-38; b) R. F. Service, Science 1995, 267, 458-459; c) T. W. Bell, Science 1996, 271, 1077-1078; d) M. GroB, Spektrum der Wissensch. 1995, 6, 30-32; e) J. Breitenbach, Spektrum der Wissensch. 1993, 96-97; R . Dagani, Chem. Eng. News 1993, February 1, 28-32; V. Balzani, S. Campagna, G. Denti, A. Juris, S. Serroni, M. Venturi, Acc. Chem. Res. 1998, 31, 26-34.. [3] The CAS online search was done with the terms “dendrimer” or “cascade molecule” or “cascade polymer” or “starburst dendrimer” or “arborol” or “dendritic molecule” or repetitive synthes? or “pamam” (1986-1993) and “dendrimer” (1994-1996).

403

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Applications in Total Synthesis F. Moll, C. Ferzil, S. Lin, P. Singh, K. Koshi, P. Cronin (Dade International Inc.), WO

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C. J. Hawker, J. M. J. FrCchet, J. Am. Chem. Soc. 1991, 113, 4252-4261; d) I. Gitsov, K. L. Wooley, J. M. J. FrCchet, Angew. Chem. 1992, 104, 1282-1285; Angew. Chem. Int. Ed. Engl. 1992, 31, 1203; e) J. W. Leon, M. Kawa, J. M. J. FrCchet, J. Am. Chem. SOC. 1996,118, 8847-8859. [27] a) J. Issberner, F. Vogtle, L. De Cola, V. Balzani, Chem. Eul: J., 1997, 3, 706-712;

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Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches Russell N. Grimes

Introduction

agents, and as carriers for radioactive metals in radioimmunodetection and radioimmunoCarboranes - polyhedral boranes containing therapy. Although polyhedral carboranes having as carbon in the framework - have been known for over 35 years, and their intrinsic stability, few as five and as many as twelve vertices (fourversatility, structural variety, and electronic teen if metal atoms are included) are known, properties have been put to use in a number [2] most research and applications have cenof diverse areas, [ 11for example in the synthe- tered on the exceptionally stable 7- and 12-versis of extraordinarily heat-stable polymers, in tex cage systems. Largely for reasons of BNCT (boron neutron capture therapy), as accessibility, the 12-vertex C2B 10H12 icosaligands in metallacarborane catalysts, as com- hedral carboranes have been most widely plexing agents for extraction of metal ions, as studied. The three known isomers, in which precursors to ceramics, conducting polymers, the carbon atoms occupy ortho (1,2), meta and nonlinear optical materials, as anticancer (1,7), or para (1,12) vertices (Fig. la-c), are

2-

Figure 1. Icosahedral boron clusters: (a) 112-CzB10H1z; (b) ~ , ~ - C Z B ~ O H (c)I Z1,12; C~BIOHIZ; (d) CB11HlZ-; (e) B1zH1zZ-. In these nonclassical electron-delocalized molecules, the connecting lines show bonding interactions, but do not necessarily represent electron pairs.

Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches

white solids that are among the most stable molecular compounds known. Together with the isoelectronic anions CBllH12- and B12H1z2- (Fig. Id and e), these clusters are three-dimensional “superaromatic” systems in which 26 electrons fill the 13 bonding molecular orbitals on the polyhedral framework; moreover, the cage volume approximates that displaced by a benzene molecule rotating on one of its twofold axes. The very high intrinsic stability of the C2B1oH12 isomers, together with the acid character of the hydrogens bound to the cage carbon atoms (which allows facile introduction of functional groups at carbon), is the basis of extensive development of icosahedral carborane chemistry over three decades and its application to practical problems. [ 1, 21

Metallacarborands The remarkable versatility of carboranes presents an almost limitless range of possible roles in designed synthesis, a fact that is drawing increasing attention in organic and inorganic chemistry, materials science, engineering, and biologically related areas. Particularly elegant examples in recent years have been afforded by the construction of novel carborane-based macrocycles, in which both the electron-withdrawing character of the car-

H

2 nBuLi

407

borane cage and the close geometric relationship of icosahedral C2BloH12 to planar CsH6 are exploited. In recent work, Hawthorne and his associates have synthesized a series of novel complexes that feature host “mercuracarborands”, which are metallacycles incorporating three or four CzBloHlo cages linked by an equal number of mercury atoms. [3] As shown in Figure 2, the reaction of 1,2-dilithio-o-carborane (Li2C2BloH10) with mercury(I1) halides generated C1-, B r , or I- complexes of the (C2BloH10)4Hg4 host tetramer whose structure is illustrated in Figure 3a. This species binds to C1- in nearly squareplanar geometry (Fig. 3b), an unprecedented coordination mode for halide ions. [3a] The mercury-chloride binding is proposed to involve a pair of orthogonal 3-center, 2-electron Hg-Cl-Hg bonds, [3a] involving overlap of two filled p orbitals on C1- with four empty Hg orbitals, as pictured in Figure 3c. All of the mercuracarborand halide complexes react with silver acetate to form the silver halide and liberate the free macrocycle. X-ray crystallography on the THF complex of the host tetramercuracarborand [3d] and on an octa-B-ethyl derivative (prepared to facilitate solubility in hydrocarbon solvents) has revealed that both species have saddleshaped & symmetry with the centers of the icosahedra well outside the plane of the four mercury atoms. [3a, d] The square planar conformation that is found in the chloride com-

Li

-2 nBuH

X = CI, Br; n = 1

X = I ; n = l o r 2

Figure 2. Synthesis of mercuracarborand halide complexes from 1,2-LizCzBloHlo and mercury(I1) halides. [3a]

Applications in Total Synthesis

408

1

8

1

O H g O O C 1O O H g 4

l t l 3(4

cos \

/

(d)

Figure 3. (a) Structure of the host tetramer (1,2-CzB 10H10)4Hg4 in its planar conformation. [3a] (b) Structure of the tetramer with a bound chloride ion. [3a] (c) 3-Center, 2-electron Hg-CIHg bonds in the mercuracarborand-4 chloride ion complex. [3a] (d) Structure of [12]-crown-4.

plex suggests that the halide anion functions been found in chloride complexes of this as a template, enforcing the planar geometry. mercuracarborand. [3b] Other electron-rich substrates also coordiThe carborane macrocycle is a Lewis acid and coordinates nucleophiles; it is therefore nate to mercuracarborands, as illustrated by an “anti-crown”, [4] i. e., a charge-reversed the complexation of a polyhedral BloHlo2analogue of the well-known family of nucleo- guest dianion that is bound to the four Hg philic hosts such as [12]-crown-4 (Fig. 3d) atoms in (9,12-Et2-1,2-C2B10H&Hg4 via 3that have figured prominently in molecular center, 2-electron B-H-Hg bonds. [3a] Figure recognition studies. [5] Bromide ion forms a complex analogous to that of the chloride, but treatment of the 1,2dilithiocarborane with HgI2 generated the dianionic species (C2B10H10)4Hg4(I)z2-inwhich the two iodide ions are bound on each side of the Hg4 plane. [3c] In contrast, the corresponding reaction of the 3 -phenyl-l,2-dilithiocarborane gave a cyclic tetramer with only one I- bound in the sterically encumbered cavity (Fig. 4); [3b] the only steroisomer formed was that having two phenyls directed “up” and two “down” with respect to the cavity. In this case the bulky phenyl groups prevent the macrocyclic host from accommodating more Figure 4. Structure of the (3-Ph-1,2-C2BloH9)4than one iodide. Similar steric effects have Hg4 . I- anion (H atoms omitted). [3b]

Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches

(a>

(b)

@

c.

Hg

O B

Figure 5. (a) Interaction of two BloHlo2- dianions with the four mercury atoms in the (1,ZC2B 10H~Et2)4Hg4host. [3a] (b) Space-filling view of the complex from above the Hg4 plane.

5a presents a schematic view of this interaction, with a space-filled drawing of the structure as seen from above one of the BloHlo2dianions shown in Figure 5b. In contrast to its reactions with mercuric halides, the treatment of dilithiocarborane with mercuric acetate [3e] yielded a trimer (Fig. 6) which coordinates acetonitrile in a

most unusual manner: the solid-state structure features two cocrystallized adducts having three and five CH3CN-bound molecules, respectively. This anti-crown is analogous to trimeric ophenylene mercury, but its mean Hg-Hg distance of more than 3.7 implies a larger central cavity than that of the latter compound. [3e] The reaction of ( C ~ B ~ O H I O ) ~ H ~ ~ with LiCl produced an anionic chloride complex whose C1- ion is proposed to reside at the center of the Hg3 triangle. The binding ability of these mercuracarborands toward Lewis bases implies that nitrogen-containing bases of biological relevance - adenine, guanine, and the like - may be similarly bound. [3e]

Carboracycles The geometries of the outward-pointing (exopolyhedral) carbon orbitals in the 0- and mcarborane cages can similarly be exploited to construct nonmetallic macrocycles. In a synthetic tour de force that combined chemistry with art, Wade and co-workers [6] prepared the aesthetically appealing molecule shown in Figure 7. In this case the starting reagent was the dicopper m-carborane, 1,7C U ~ C ~ B ~which O H ~reacted ~, with m-diiodobenzene to give the desired trimeric product in low yield. As revealed by X-ray crystallography, the carborane cages are tilted away by 17 from the plane defined by their carbon atoms, while the benzene rings are tilted in the opposite direction by the same amount; consequently, the molecule has a dish-shaped structure whose central cavity is defined by three inward-directed carborane hydrogen atoms (mean separation 3.16 A) and three phenylene hydrogens that lie almost in the same plane; three other carborane hydrogens are much further apart (ca. 4.48 A). It may be possible to remove the boron atoms on the O

Figure 6. Structure of (1,2-C2B10H10)3Hg3 (bound CH3CN molecules not shown). [3e]

409

410

Applications in Total Synthesis

P

Figure 7. Structureof (1,7-C2B10H10)3(1’,3’-C6H4)3. [6]

inside of the macrocycle and replace them with metals, [6] opening intriguing possibilities for catalysis and other applications wherein the three metal centers act in concert. Macrocycles incorporating the 1,2C ~ B I O Hcage ~ O and linked by trimethylene or 1,3-xylyl groups have been prepared in Hawthorne’s laboratory, and include both trimers and tetramers (Fig. 8). [7] The crystallographically determined structure of a xylyl-linked tetramer that features an unusual 28-membered ring is shown in Figure 8c.

Figure 8. (a) Structure of (1,2-C2BloHl&(C3H&. [7cl (b) Structure of (1,2-C2BloHlo)4(C3H6)4. [7cl (c) Structure of ( ~ , ~ - C Z B I O H I O ( l)’ ~, 3’CHzCdbCHzh. Val

bons at opposite ends of the polyhedron and is ideally suited for the assembly of rigid linear “carborods” via direct C-C connections, as has been demonstrated in two research groups. [8] The synthesis of carborods via C-lithio or C-silyl p-carborane intermediates produced isolable products having up to four carborane units, such as that shown in Figure 9, but longer rods proved insoluble and could not be made in this way. Carborods This problem has been alleviated by the use While the geometries of the 1,2- and 1,7- of B-alkylated carboranes which afford C2Blo cages are made to order for the syn- greater solubility in hydrocarbon solvents thesis of macrocycles via substitution at car- and allow the synthesis of higher molecular bon, the 1,12 isomer @-carborane) has car- weight carborod products. [8c]

Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches

4 11

decker complexes (and no species with more than three decks) bridged by C5H5, C6H6, or other monocyclic hydrocarbons. [ 111 The formal R ~ C Z B ~ and H ~ R3C3B2R’13~ring ligands (R, R‘ = alkyl) and their Bsubstituted derivatives are isoelectronic analogues of C5H5- and form strong covalent bonds with metal ions, creating species that can be described equally well as metal sandwich complexes or as electron-delocalized polyhedral metallacarboranes linked via metal vertices. [9] Like their larger (e. g., icosahedral) metallacarborane homologues, [ 121 these carborane-metal sandwiches are considerably more robust than most metallocenes, Figure 9. allowing much greater versatility in their synStructure of thesis and modification. This has led to the (n-C4H9)3Sipreparation of a wide range of “molecular skyscrapers” that typically are air- and waterstable crystalline solids that dissolve in organic media, can accommodate first-, second, or third-row transition metals, and are readily derivatized via introduction of substituents. [9] Significantly, many of these complexes Multidecker Molecular are paramagnetic mixed-valence species, whose electron-delocalization over several Sandwiches metal centers suggests potential utility as As the foregoing examples illustrate, the building-block units for conducting polymers special stereochemistry of the icosahedral car- and other applications. [9, 131 Synthetic routes to the CzB3-bridged comboranes can be used to advantage in the synthesis of structurally novel molecules. Mole- pounds are based on pentagonal-pyramidal cular engineering employing non-icosahedral nido-2,3-R2C&&I6 carboranes, which are carborane or organoborane units is also deprotonated with lithium alkyls in THF and under active investigation, as in stacked metal ions inserted to generate 7-vertex assemblies that incorporate 7-vertex MC2B4 clusters. [9, 141 Removal of the apex MC2B3M’ or MC3B2M’ pentagonal bipyra- BH unit (decapitation) affords open-cage midal cages where M and M’ are transition (nido) MC2B3 complexes which serve as buildmetals. [9, 101 Planar, aromatic C2B3 and ing-blocks for the synthesis of higher-decker C3B2 (diborolyl) rings have a remarkable sandwiches via coordination to metal ions or ability to bind in q5 fashion to metal atoms metal-hydrocarbon units such as CpCo2-. on both sides of the ring plane, allowing the Diborolyl-bridged sandwich complexes that construction of stable, neutral multidecker incorporate MC3B2M’ cluster units are presandwich complexes such as those dipicted pared directly from the neutral 1,3-diborolyl in Figure 10. [9] This type of double-metal ring ligands. [lo] coordination is rare for hydrocarbon ligands; Work in the author’s laboratory and in that there are only a few reported isolable triple- of W. Siebert, both separately [9, 101 and in

4 12

Applications in Total Synthesis

0 BH.

8-alkyl. 6-halo

CH, C-olkyl. C-SiMej

M

= CO, Fe,

Ru. Rh, 0s

M'

= CO, Ni.

collaboration [ 151 over the past decade, has produced numerous triple- to hexadecker sandwiches, many of which have been examined in detail via electrochemistry, EPR, correlated paramagnetic NMR, [15] and other techniques designed to probe their electronic character. Spectroelectrochemical studies on these compounds in cooperation with W. E. Geiger and his students have been particularly illuminating. [ 161 Larger systems have also been investigated, such as the linked-tetradecker oligomer [ 131 shown in Figure 11a and the nickel-diborolylpolymer [ 171inFigure 11b. The electronic properties of the multidecker sandwich compounds vary considerably depending on structure, metals, external substituents, and other factors, suggesting that they can be tailored to suit particular needs. For example, in the fulvalene-bridged complex in Figure l l a , each tetradecker unit has one formal Co(1V) paramagnetic metal center, and exhibits electrochemical behavior that indi-

Ru, Rh, P t

Figure 10. Multidecker metallacarborane sandwich complexes. [9] The rotational orientations of the C2B3 rings vary in different complexes, and are arbitrarily depicted here.

cates electron-delocalization throughout the chain, [18] However, if the fulvalene units are replaced by 1,4-(Me&)zC6H4 linking groups, electrochemical data indicate that delocalization of the unpaired electrons ocurs within, but not between the individual tetradecker units because the connecting phenylene rings are rotated out of coplanarity with the cyclopentadienyls, preventing effective TCconjugation. [19] Still different is the polydecker sandwich in Figure l l b , which is an insoluble semiconducting solid; the corresponding rhodium polymer is an insulator. ~171 A basic theme of the chemistry highlighted in this article is the exploitation of the distinctive features of icosahedral and planar carborane units in order to generate new types of stable molecular structures that are generally inaccessible via conventional organic or organometallic approaches. Many other examples of creative and imaginative synthesis in

Carboranes, Anti-Crowns, Big Wheels, and Supersandwiches

I

(b)

borane and carborane chemistry can be cited, and the reader is referred to a series of comprehensive recent reviews in this area. [20] A notable aspect of much of the work described here is its essential simplicity - for example, the generation of pre-organized cyclic host molecules in one or two steps from readily available reagents - an advantage not afforded by crown ethers and cryptands. These synthetic advances illustrate the rapidly evolving art of “designer chemistry” in which inorganic and organometallic assemblies of specified architectures are obtained in directed reactions from available building-block molecules. [211 Because of their unique steric and electronic properties and synthetic versatility, carboranes and other boron clusters seem destined to play a significant role in this field. Philosophically

413

Figure 12. (a) Structure of a fulvalene-bridged linked-tetradecker oligomer. [12] (b) Structure of a diborolyl-nickel polydecker sandwich. [17]

and historically, designed synthesis derives from organic chemistry; but for inorganic chemists, given the entire periodic table of elements to work with, the scope of possibility seems far larger and the ultimate achievements hardly imaginable at present.

References [ l ] J. Plesek, Chem. Rev. 1992, 92, 269. [2] (a) V. I. Bregadze, Chem. Rev. 1992, 92, 209. (b) B . Stibr, ibid. 1992, 92, 225. (c) R . N. Grimes, Carboranes, Academic Press, New York, 1970. [3] Leading references: (a) X. Yang, C. B. Knobler, Z. Zheng, M. F. Hawthorne, J. Am. Chem. SOC. 1994, 116, 7142. (b) Z. Zheng,

414

Applications in Total Synthesis

C. B. Knobler, M. F. Hawthorne, J. Am. Chem. SOC. 1995, 117, 5105. (c) Z. Zheng, C. B. Knobler, M. D. Mortimer, G. Kong, Hawthorne, M. F., Inorg. Chem. 1996, 35, 1235. (d) X. Yang, S. E. Johnson, S. I. Khan, M. F. Hawthorne, Angew. Chem. Int. Engl. 1992, 31,893. (e) X. Yang, Z. Zheng, C. B. Knobler, M. F. Hawthorne, J. Am. Chem. SOC. 1993, 115, 193. [4] For a summary of published reports on anion complexation by multidentate Lewis acid hosts, see [3a]. [5] (a) D. J. Cram, Science 1983, 219, 1177. (b) F. Vogtle, E. Weber, Host-Guest Complex Chemistry/hfacrocycles, (Eds.: I. Vogtle, E. Weber), Springer, Berlin, 1985. (c) L. F. Lindoy, The Chemistry of Macrocyclic Ligands, Cambridge University Press, Cambridge, 1989. [6] W. Clegg, W. R. Gill, J. A. H. MacBride, K. Wade, Angew. Chem. Int. Engl. 1993, 32, 1328. [7] (a) I. T. Chizhevsky, S. E. Johnson, C. B. Knobler, F. A. Gomez, M. F. Hawthorne, J. Am. Chem. SOC. 1993, 115, 6981. (b) W. Jiang, I. T. Chizhevsky, M. D. Mortimer, W. Chen, C. B. Knobler, S. E. Johnson, F. A. Gomez, M. F. Hawthorne, Inorg. Chem. 1996,35,5417. [8] (a) X. Yang, W. Jiang, C. B. Knobler, M. F. Hawthorne, J. Am. Chem. SOC. 1992, 114, 9719. (b) J. Muller, K. Base, T. F. Magnera, J. Michl, Ibid. 1992, 114, 9721. (c) W. Jiang, C. B. Knobler, C. E. Curtis, M. D. Mortimer, M. F. Hawthorne, Inorg. Chem. 1995, 34, 3491. (d) W. Jiang, D. E. Harwell, M. D. Mortimer, C. B. Knobler, M. F. Hawthorne, Inorg. Chem. 1996, 35, 4355. [9] (a) R. N. Grimes, Applied Organometallic Chemistry 1996, 10, 209, and references therein. (b) R. N. Grimes, Chem. Rev. 1992, 92, 251. [lo] (a) W. Siebert, Adv. Organometal. Chem. 1993, 35, 187. (b) W. Siebert, in Current Topics in the Chemistry of Boron, Kabalka, G. W., Ed., Royal Society of Chemistry, 1994, 275, and references therein. [ I l l Notable examples: (a) H. Werner, A. Salzer, Synth. React. Inorg. Met. Org. Chem. 1972, 2, 239. (b) A. W. Duff, K. Jonas, R. Goddard,

H.-J. Kraus, C. Krueger, J. Am. Chem. SOC. 1983, 105, 479. (c) W. M. Lamanna, J. Am. Chem. SOC. 1986, 108, 2096. (d) A. R. Kudinov, M. I. Rybinskaya, Yu. T. Struchkov, A. I. Yanovskii, P. V. Petrovskii, J. Organometal. Chem. 1987, 336, 187. (e) J. J. Schneider, R. Goddard, S. Werner, C. Kruger, Angew. Chem. Int. Engl. 1991, 30, 1124. ( f ) G. E. Herberich, U. Englert, F. Marken, P. Hofmann, Organometallics 1993, 12, 4039. [ 121 M. F. Hawthorne, Accounts Chem. Res. 1968, I , 281. [13] X. Meng, M. Sabat, R. N. Grimes, J. Am. Chem. SOC. 1993,115,6143. [14] N. S. Hosmane, N. S., J. A. Maguire, J. Cluster Science 1993, 4 , 297. [15] (a) M. Stephan, P. Muller, U. Zenneck, H. Pritzkow, W. Siebert, R. N. Grimes, Inorg. Chem. 1995, 34, 2058. (b) M. Stephan, J. Hauss, U. Zenneck, W. Siebert, R. N. Grimes, Inorg. Chem. 1994, 33, 4211, and references therein. [16] (a) J. Merkert, J. H. Davis, Jr., W. E. Geiger, R. N. Grimes, J. Am. Chem. SOC. 1992, 114, 9846. (b) T. T. Chin, S. R. Lovelace, W. E. Geiger, C. M. Davis, R. N. Grimes, J. Am. Chem. SOC. 1994,116, 9359. [17] W. Siebert, Pure Appl. Chem. 1988, 60, 1345. [ 181 W. E. Geiger, private communication. [19] J. R. Pipal, R. N. Grimes, Organometallics 1993,12,4459. [20] (a) G. E. Herberich, in E. Abel, F. G. A. Stone, G. Wilkinson (Eds.), Comprehensive Organometallic Chemistry II, Pergamon Press: Oxford, England, 1995; Volume 1, Chapter 5 , pp. 197-216. (b) T. On&, ibid., Chapter 6, pp. 217-255. (c) L. J. Todd, ibid., Chapter 7, pp. 257-273. (d) L. Barton, D. K. Srivastana, ibid., Chapter 8, pp. 275-372. (e) R. N. Grimes, ibid., Chapter 9, pp. 373-430. (f) A. K. Saxena, N. S. Hosmane, Chem. Rev. 1993,93, 1081. [21] For a beautifully illustrated brief account of this subject, see: M. F. Hawthorne and M. D. Mortimer, Chem. in Britain, 1996, 32, 32.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Framework Modifications of [60]Fullerene : Cluster Opening Reactions and Synthesis of Heterofullerenes Andreas Hirsch

The accessibility of the fullerenes [l] in macroscopic quantities [2] opened up the unprecedented opportunity to develop a rich “three-dimensional”chemistry of spherical and polyfunctional all carbon molecules. [3-81 A large multitude of fullerene derivatives like exohedral covalent addition products, salts, cluster opened and defined degradation products, heterofullerenes and endohedral derivatives can be imagined and numerous examples, especially of covalent adducts have been synthesized and characterized. [3-81 Within a few years the fullerenes became essential building blocks in organic chemistry. Most of the chemistry of fullerenes has so far been carried out with c60 (1)with little work on C ~ and O few experiments with c76 and c84. This is simply due to the fact that c60 (1) is the most abundant as well as the most symmetrical fullerene. The first period of preparative fullerene chemistry was dominated by the development of defined addition reactions to the unsaturated n-system of the fullerene cage, [3-41 like nucleophilic and radical additions, cycloadditions, hydrogenations, transition metal complex formations, halogenations, oxygenations and others, which together with the careful examination of the structural and electronic properties of c 6 0 (1) allowed to deduce principles of fullerene chemistry. [3-41 The systematic development of

covalent fullerene chemistry provides a rich diversity of tailor-made three-dimensional building blocks for technological interesting materials. The various aspects that are associated with covalent fullerene chemistry, including the regioselective synthesis of multiple adducts, in which the fullerene serves as a versatile structure determining tecton, as well as the synthesis of fullerene derivatives with potential biological or materials applications have been summarized in a variety of monographs and reviews. [3-81 Here, a first review is provided which summarizes the more recent development frumework modijied jkllerenes like cluster opened structures and heterofullerenes. The key steps for such framework modifications are always defined activations of the fullerene cluster due to specific covalent addition reactions. Therefore, the principles of covalent fullerene chemistry [3-81 will be considered first:

416

Applications in Total Synthesis

Each fullerene contains 2(10 + M ) carbon atoms corresponding to exactly 12 pentagons and M hexagons. This building principle is a simple consequence of the Euler’s theorem. Starting at C 2 0 any even-membered carbon cluster, except C 2 2 , can form at least one fullerene structure. With increasing M the number of possible fullerene isomers rises dramatically. The soccer-ball shaped c 6 0 isomer with icosahedral symmetry (Zh) is the smallest stable fullerene, because it is the first to obey the isolated pentagon rule (IPR) [3]. Three properties, which are due to the structure of c60 largely govern its chemical behavior:

the ease of reversible one-electron reductions up to the hexaanion. The following rules of reactivity, which are based on these properties, can be deduced from the multitude of chemical transformations that have been carried out with C60:

1. The reactivity of c60 is that of a fairly localized electron deficient polyolefn. The main type of chemical transformations are therefore additions to the [6-61 double bonds, especially, nucleophilic-, radicaland cycloadditions and the formation of r2transition metal complexes; but also, for example, hydroborations and hydrometalations, hydro-genations, halogenations 1. The bonds at the junctions of two hexagons and Lewis acid complex formations are ((6-61 bonds) are shorter than the bonds possible. at the junctions of a hexagon and a pentagon ((5-61 bonds). As a consequence, 2. The driving force for exohedral addition reactions is the relief of strain in the fulamong the 12.500 possible, the lowest lerene cage. Reactions leading to saturated energy KekulC structure of c60 is that with tetrahedrally hybridized sp3 C-atoms are all the double bonds located at the junctions of two hexagons ([6-61 double strongly assisted by the strain of pyramidabonds) and the single bonds at the junctions lization. In most cases, addition reactions of a hexagon and a pentagon ([5-61 single to c 6 0 are exothermic. The exothermicity of subsequent additions depends on the bonds). Therefore, c 6 0 can be considered size and the number of addends already a sphere built up of fused [5]radialene and bound and decreases at a certain stage. cyclohexatriene units and a complete deloTherefore, adducts with a high degree of calization of the conjugated n-system addition become eventually unstable (elileading to a reactivity closely related to mination) or do not form at all, since new aromatics can be ruled out., types of strain, for example, steric repul2. The highly pyramidalized sp2 C-atoms in sion of addends or introduction of planar spherical c60 cause a large amount of cyclohexane rings are increasingly built strain energy within the molecule. Mainly up. The interplay of these strain arguments due to this strain energy, which is about largely determines the number of energe80% of its heat of formation (AHf), c 6 0 tically favourable additions to the fullerene (AHf = 10.16 kcallmol per C-atom) is thercore. Also the reduction of CF~O can be modynamically less stable than graphite regarded as a strain-relief process, because (AHf = 0 kcallmol). many carbanions are known to prefer pyra3. c60 is an electronegative molecule, which midal geometries. can be easily reduced but hardly oxidized. This is reflected theoretically by the MO 3. The regiochemistry of exohedral addition reactions is governed by the minimization diagram of C ~ showing O low lying triply degenerate LUMOs and five-fold degeneof (5-61 double bond within the fullerene framework. The exclusive mode for typical rate HOMOS as well as experimentally by

Framework Modifications of [tiO]Fullerene

cycloadditions and the preferred mode for additions of sterically non demanding segregated addends is 1,2 (addition to a [6-61 double bond), since in this case no unfavourable double bonds within five membered rings have to be formed. The introduction of each [5-61 double bond costs about 8.5 kcal/mol. In 1,2-additions, however, eclipsing interactions between the addends are introduced. Thus, if bulkier segregated addends are allowed to react with C60, a 1,4-mode avoiding eclipsing interactions may occur simultaneously or exclusively. In 1,4 additions eclipsing 1,2 interactions are avoided but the introduction of [5-61 double bonds is required.

4 17

and closed [5,6]-adducts can be imagined. So far, only the closed [6,6]-bridged adducts 2 and the open [5,6]-bridged adducts 4 have been found. Computational investigations [8, 221 confirm the experimental finding, that 2 and 4 are the most stable isomers. The simple rationale for this behaviour is that only in the structures 2 and 4 no unfavorable double bonds within five-membered rings have to be included. The [5,6]-bridged methano- and iminofullerenes were the first examples of cluster opened derivatives. The entire 60-nelectron chromophore remains intact and the fullerene cage contains a bridged nine-membered ring, whereas in closed [6,6]-bridged adducts one double bond of the cages is removed. As a consequence the electronic Among the cycloadducts of c60 [3-81 the properties of [5,6]-bridged methano- and methano- [S] and imino derivatives [9-221 ex- imino[60]fullerenes are very similar to those O hibit a special case, since the bridging of the of C ~ itself. The first syntheses of cluster open [5,6]addend can take place not only on the junctions between two six-membered rings but bridged methano- and iminofullerenes were also on the junctions between a five-mem- elaborated by Wudl and co-workers [7, 91 bered and a six-membered ring. The resulting by allowing diazo compounds or alkyl azides . scope of constitutional isomers are denoted as [6,6]- thermally to react with C ~ OThe and [5,6]-adducts. Without considering the the thermal addition reaction of diazo specific properties of the fullerene moiety compounds is quite broad. In addition to the one could propose that in analogy to methano- parent and substituted diazomethanes, diaand iminoannulenes [23] the corresponding zoacetates, diazomalonates and diazoamides transannular bonds can, for example, depend- have been employed. [3-81 In general next ing on the addend, either be open or closed. to the [5,6]-bridged isomers the corresponAs a consequence, four different types of ding closed [6,6]-bridged systems are formed isomers (2-5) of monoaddition products, the as side products. Whereas the open iminofulopen and closed [6,6]- as well as the open lerenes are stable, many of the [5,6]-bridged

R'X

@ ' \ / ' \

2

0

3

4

X

-

5 N, CH, CR'

418

Applications in Total Synthesis R-R'

R-R'

m

7a CRR"2

1

___, R-R' 6

L 4 2

8

R, R' = H, alkyl, aryl, alkoxycarbonyl,aminocarbonyl

methano fullerenes undergo a facile isomerization to the closed [6,6]-adducts upon thermal or photochemical activation. [3-81 The first step of the addition of diazo compounds is the formation of pyrazolines 6. In the case of the parent diazomethane the corresponding pyrazoline intermediate could be isolated and characterized. The thermal extrusion of N2 out of pyrazolines 6 in general leads to a mixture of [5,6]- and [6,6]-bridged structures 7 and 8 in different ratios. In the case of the reaction of the parent diazomethane with c60 the [6,6]-adduct 8 was formed only in trace. Here no thermal conversion of 7 to 8 was observed. O The addition of alkyl azides to C ~ proceeds similarly via intermediate triazolines 9, which after extrusion of NZ rearrange to [5,6]adducts 10 as major and the [6,6]-adducts 11 as the minor monoaddition products. [3, 4, 9-22] These reactions were carried out for example in refluxing chlorobenzene. Under such conditions azidoformiates react prefer-

ably to [6,6]-adducts 11 since in this case stabilzed nitrenes can be formed, which undergo in a competing pathway [2+1]-cycloadditions with the [6,6]-double bonds to form directly the corresponding aziridines 11. [18] If the reactions are carried out in highly concentrated solutions at temperatures not exceeding 6OoC the triazolines can be isolated and characterized regardless of the nature of R. [18, 19, 241 The introduction of two [5,6]-aza bridges shows a remarkable regioselectivity even if segregated alkyazides are used, [ 191 since bisadducts 13 are by far the major products and only traces of one other bisadduct 14 with unidentified structure are found, if, for example a twofold excess of azide is allowed to react with c60 at elevated temperatures. To obtain further information on this most regioselective bisadduct formation process in fullerene chemistry a concentrated solution of 10 was treated with methyl azidoacetate at room temperature. [ 191 Under these conditions, in

Framework Modifications of [4O]Fullerene

@ N

1

N

/

,- \

4 2

9

10

addition to a small amount of bisadducts 13 and 14, only one mixed [6,6]-triazoline/[5,6]iminofullerene isomer 12 was formed. The exclusive formation of 12 is explained by the fact that 10 behaves as a strained electronpoor enamine what the reactivity of the bonds between C1 and C2 as well as between C5 and C6 is concerned. The significantly highest Mulliken charge of 0.06 (AM1) is located at C1 and C6, and the lowest of -0.07 at C2 and C5. The most negatively polarized N-atom of the azide (AMI) is that bearing R. A kinetically controlled attack of the azide, therefore, leads predominantely to 12. The further ring expanded doubly bridged bisiminofullerenes 13 exhibit three seven membered rings and one eleven membered ring within the fullerene cage. One Catom is already halfway decoupled from the spherical carbon core. The pronounced relative reactivity of the vinylamine type double bonds within [5,6]-bridged iminofullerenes was also demonstrated by the facial addition

-

of mild nucleophile such as water and amines. For example, the first stable fullerenol was synthesized by treatment of a toluene solution of 10 in the presence of water and neutral alumina and a almost quantitative reaction. [19b] This finding that the reactivity of the vinylamine type [6,6]-double bonds in 10 is dramatically enhanced over the remaining [6,6]-bonds turned out to be a key for further cluster opening reactions and the formation of nitrogen hetereofullerenes as will be shown below. Subsequent attacks to [6,6]bonds within [6,6]-adducts and also to [6,6]bonds within the [5,6]-bridged methano-fullerenes 7 are by far less regioselective. [3, 41 Bis-[5,6]-bridged iminofullerenes with another addition pattern can only be obtained in good yields if a tether directed synthesis is applied. If the tether between two azide groups is rigid enough than the second addition is forced to occur at specific regions of the fullerene cage. Using this approach Luh et al. [20] synthesized the doubly cluster

-

1 equiv. N,R chloronaphthalene

toluene

RT

10

11

R

R. NNR

419

reflux

+

- N2

12

13

14

420

Applications in Total Synthesis

/Ydn

which was synthesized by allowing the corresponding azidoformiate to react with C ~ inO N N 1,1,2,2-tetrachloroethaneor l-chloronaphthalene at high temperatures (conditions for generation and [2+1]-additions of nitrenes). If 11 is allowed to react with another equivalent of the azidoformiate but under conditions, which would be typical for the formation of [5,6]-bridged adducts via intermediate triazolines (highly concentrated solutions, moderate 15 temperatures), of the large number of regioisomeric bisadducts (doubly [6,6]-bridged as openend adducts 15 by allowing an excess well as mixed [6,6]/[5,6]-bridged isomers), of N ~ ( C H Z ) ~(nN=~2,3) to react with C ~ in O the most polar bisadducts 18 are formed as refluxing chlorobenzene. The addition occurs major products (> 50 % yield). In addition to at two non adjacent [5,6]-bonds of the same a directing effect into cis-] positions caused five membered ring. by the attachment of the first addend [25] A new type of cluster opened iminoful- this result can be understood with a mechalerenes was recently described by Hirsch et al. nism based on the AMl-calculated bond pola[22] with the synthesis of the bisiminoful- rizations of the starting materials. [22] The lerenes 18. The comparatively regioselective reaction intermediate leading to 18 is the formation of 18 can be achieved starting from mixed triazolinehminofullerene 16, formed the closed [6,6]-bridged iminofullerenes 11, in a [3+2]-cycloaddition, where the negatively

ii)

d

11

R

R i) 2 equiv. N,R, 1-chloronaphthalene, 6OoC, 4d

ii) toluene, reflux, 30 min.

-

18

COOEt. COOtBu

Framework Modifications of [60]Fullerene

42 I

polarized nitrogen (R-N-N2) of the azide mates or amides) are the open forms more group forms a bond with the positively polar- stable than the closed forms. [22] These are ized C-atom (e. g. C4) of a cis-l bond. The the first chemical modifications of the fulthermal extrusion of N2 leads to the diradical lerene core, which allow the synthesis of intermediate 17. open as well as of closed valence isomers Due to the location of the first addend in the with the same addition pattern. The following same six-membered ring the usual delocaliza- conclusions can be deduced: tion of spin density within the six-membered ring, [3, 41 like transfer of spin density to C5 1. With the exception of a cis-1 adduct, where is impossible and radical recombination can upon the two-fold ring opening due to the only take place at C3. Hence, the formation location of the imino bridges in the same of a heterotropilidene like structure (1,2,4,5 six-membered ring only three [5,6]-double bisimino[60]fullerene) is suppressed. The bond have to be introduced, six of these ring opening from the non isolable closed energetically unfavourable bonds would be form to 18 occurs via an inter ring retrorequired for the hypothetical open structures of the other seven regioisomers (transDiels-Alder reaction. These compounds represent the first examples of [60]fullerene 1 to cis-2). In the latter regioisomers the transannular [6,6]-bonds are always closed. derivatives with open transannular [6,6]bonds. Characteristic features within in the 2. In a cis-l adduct a closed valence isomer bears a strained planar cyclohexene ring fullerene framework of these valence isomer but the introduction of a unfavourable are the presence of i) a doubly bridged 14[5,6]-double bonds is avoided, whereas in membered ring with a phenanthrene perimeter an open valence isomer no strained planar and ii) a eight membered 1,4-diazocine hecyclohexene but three [5,6]-double bonds terocycle. Upon changing the addition pattern, are present. as demonstrated by the investigation of the 3 . For the cis-1 adducts open valence isomers other possible regioisomers of C~O(NCOOR)~ are favoured for imino addends with planar “regular” behaviour with closed transannular imino bridges like carbamates and the [6,6]-bonds is observed. [22] The fullerene cage can be re-closed again via an intra ring closed isomers are favoured for imino addends with pyramidalized imino bridges Diels-Alder reaction [22] by transferring cislike alkylimines or HN. Z-C60(NCOOt-BU)2 18a into CiS-l-C6o(NH)2 4. Carbamates or amides prefer planar ar19 as cluster closed valence isomer. rangements of the nitrogen due to resulting The latter phenomenon clearly reveals the favourable conjugation of the free electron role of the addend. An extensive AM1- and pair with the carbonyl group. This has conDFT study revealed that only in cis-1 adducts sequences for imimo-[60]fullerenes, since that prefer planar imino bridges (e. g. carba‘BuOOC,

COO‘Bu

CF3COOH

___, toluene, RT

18a

19

422

Applications in Total Synthesis

the planar arrangement of the carbonate Natoms and the required enlargement of the bond angles between C1, N, C2 or C3, N, C4 are most favourably realised if the transannular [6,6]-bonds are open.

enter the cage. Some flexibility in the keto and lactam moieties at elevated temperatures is expected and should increase the size of the opening, also, removal of the MEM protecting group should further increase access to the cavity. A major breacktrough in the field of cluster Another oxidative opening of the a fulopening reactions was achieved by Hummelen lerene derivatives was achieved by Taylor et et al. who allowed 10 to react with singlet al., [28] who observed that the [70]fullerene oxygen, which afforded the ring-opened keto- derivative C70Phs sponataneously oxidizes in lactam 21. [26] This synthesis takes advantage air to form a bis-lactone C70Ph804, having from 1) the pronounced susceptibility of the an eleven membered hole in the fullerene vinylamine type double bonds of 10 to ad- cage. The reaction is believed to proceed via dition reactions and 2) the ability of c60 and insertion of oxygen into [5,6]-double bonds C60-adducts to efficiently sensitize the photo- followed by oxidative cleavage of the adjacent chemcially induced formation of singlet oxy- double bond. This process has precedent in gen. [27] The reaction, using 1,2-dichloroben- the spontaneous oxidations of vinyl ethers to zene (ODCB) as the solvent and a Kapton esters. Triple scission of a six-membered ring on 500HN (DuPont) filtered flood lamp as the light source, is virtually complete within 3 h the surface of c60 via consecutive pericyclic at 25-30 "C. The Kapton filter is a convenient reactions and oxidative cobalt insertion was alternative for the commonly used aqueous achieved by Rubin et. al. [29] This work origidichromate solution filter. It is assumed that nated from the discovery that diene 22 underthe reaction proceeds via a 1,2-dioxetan inter- goes a very facile photochemically promoted mediate 20. This cluster opening reaction rearrangement to the stable doubly [5,6]seems to be general, as analogous iminoful- bridged bismethano fullerene 23, which is lerenes give the corresponding products. The the first example for this adduct type. In 23 a ketolactams are stable under the reaction con- twelve membered ring within the fullerene ditions. No new products were detected after 4 cage is open. The formation of 23 out of 22 h of photooxygenation in ODCB at 25-30 "C. occurs via an initial [4+4] photoadduct (not Molecular modelling investigations suggest observed), which undergoes a thermally that at its minimum energy conformation, allowed [2+2+2] cycloreversion to afford the ketolactam 21 does not have an opening bis-methano[ 12lannulene structure within 23. large enough to allow any guest molecule to The treatment of 23 with CpCo(CO):! afforded

hv

'0,

10

20

21 R = CHzOCH&HzOCHs (MEM)

Framework Modifications of [60]FuElerene

423

I_\

hV

[4+41

PhCl

23

22

24

the stable compound 24, whose structure was determined by X-ray crystallography. The bond within the five-membered ring adjacent to the bismethano[ 12lannulene ring of 24 has been broken by oxidative insertion of the cobalt. The “trismethano[ 15lannulene” opening within the c60 framework is the largest annulene ring created thus far in a fullerene. At about the same time the groups of J. Mattay, [30] A. Hirsch [31] and F. Wudl[32] indenpently provided the first convincing mass spectrometric evidence for the formation of the heterofullerene ions C59NH+,C59NHz+, C59N+ and C69N+ by fragmentation reactions of the [6,6]-bridged CmNH (25), [30] Ma, [31] the n-butylamine adducts of 13a [31] and 30 [31] as well as of 21. 1321The first synthesis of the heterofullerene ‘(259” as its dimer (C59N)2 in macroscopic quantities was

achieved by J. C . Hummelen and F. Wudl. [32] When 21 was treated with a large excess (15 to 20 equivalents) of p-toluenesulfonic acid monohydrate in ODCB at reflux temperature under nitrogen a very fast reaction occurs with the formation of the very apolar 29 as major product accounting for 85 % of starting material. The absence of an ESR signal as well as the other spectroscopic results excluded the possibility that the product is a stable free radical. During the formation of 29 the acid protonates the MEM moiety, inducing the loss of 2-methoxyethanol. The presence of the reaction intermediate 26 was proven by trapping experiments with nucleophiles and characterization of the corresponding products. [33] 26 rearranges to the four-membered 1,3-0xazetidinium ring compound 27, which in turn loses formaldehyde and carbon

PTsOH,H20 ODCB, A CHZOCHZCHZOCH,

21

26

- CHZO - co

27

28

29

424

Applications in Total Synthesis

monoxide to yield the azafulleronium ion 28. tion of 29 and 31 was found to occur only if The azafulleronium ion, expected to be a the substituents of the imino bridges can be very strong oxidant, can apparently be reduc- easily removed by acids. For example, heteroed by either (2-methoxyethanol or water) to fullerenes were not obtained using the the azafullerenyl radical, which dimerizes to CHzC02Me analogue of 13a as starting mateyield bisazafullerenyl 29. The parent hydro- rial. This implies that during heterofullerene azafullerene C59HN was synthesized either formation, which is accompanied by the elimiby the thermal treatment of 21 with p-tolue- nation of one C-atom of the fullerene cage as nesulfonic acid monohydrate in presence of an isonitrile or a carbodiimide species unhydroquinone as reducing agent or by irradia- protected imino bridges are required. Next to tion of (C59N)z (29) through a Kapton filter in the dimers 29 and 31 derivatives 32 and 33 ODCB in the presence of tributyltin hydride. are formed as by-products. Presumably, derivatives 32 and 33 are formed by trapping [331 A new rout to nitrogen heterofullerens and of the expected but unstable C59N+ or the first synthesis of (C69N)z was achieved C69N+-intermediateswith the acetal cleavage by Hirsch et al. [34] starting from 13a and 30 product HO(CH2)zOMe. via their n-butylamin monoadducts. Forma-

2.) TsOH, ODCB, A

13a

(C59N)2

+

29 32

Framework Modifications of [60O]Fullerene

425

References [I] H. W. Kroto, J. R. Heath, S. C. O’Brien, R. F. Curl, R. E. Smalley Nature 1985, 318, 162. [2] W. Kratschmer, L. D. Lamb, K. Fostiropoulos, D. R. Huffman Nature 1990,347, 354. [3] A. Hirsch, The Chemistry of the Fullerenes, Thieme, Stuttgart, 1994. [4] A. Hirsch, Synthesis 1995, 895. [5] F. Diederich and C. Thilgen, Science 1996, 271. [6] The Chemistry of Fullerenes, R. Taylor (Ed.), World Scientific, Singapore, 1995. 171 F. Wudl, Acc. Chem. Res. 1992, 25, 157. [8] F. Diederich, L. Isaacs, D. Philip, Chem. SOC. Rev. 1994,243. [9] M. Prato, Q. Li, F. Wudl, V. Lucchini, J. Am. Chem. SOC. 1993,115, 1148. [lo] M. R. Banks, J. I. G. Cadogan, I. Gosney, P. K. G. Hodgson, P. R. R. Langridge-Smith, D. W. H. Rankin, J. Chem. SOC.;Chem. Commun. 1994, 1365. [ l l ] M. R. Banks, J. I. G. Cadogan, I. Gosney, P. K. G. Hodgson, P. R. R. Langridge-Smith, J. R. A. Millar, A. T. Taylor, Tetrahedron Lett. 1994, 35, 9067. [ 121 T. Ishida, K. Tanaka, T. Nogami, Chem Lett. 1994, 561. [13] C. J. Hawker, K. L. Wooley, J. M. J. Frechet, J. Chem. SOC.;Chem. Commun., 1994,925. [I41 M. Yan, S. X. Cai, J. F. W. Keana, J. Org. Chem. 1994,59, 5951. [15] J. Averdung, H. Luftmann, J. Mattay, K.-U. Claus, W. Abraham, Tetrahedron Lett. 1995, 36, 2957. [16] M. R. Banks, J. I. G. Cadogan, I. Gosney, P. K. G. Hodgson, P. R. R. Langridge-Smith, J. R. A. Millar, J. A. S. Parkinson, D. W. H. Rankin, A. T. Taylor, J. Chem. SOC.; Chem. Commun. 1995, 887. [17] M. R. Banks, J. I. G. Cadogan, I. Gosney, P. K. G. Hodgson, P. R. R. Langridge-Smith, J. R. A. Millar, A. T. Taylor, J. Chem. SOC.; Chem. Commun. 1995, 88. [18] G. Schick, T. Grosser, A. Hirsch, J. Chem. SOC.; Chem. Commun. 1995,2289.

[19] a) T. Grosser, M.Prato, V. Lucchini, A. Hirsch, F. Wudl, Angew. Chem. 1995, 107, 1462; Angew. Chem. Int. Ed. Engl. 1995, 34, 1343, b) T. Grosser, A. Hirsch, unpublished results. [20] L.-L. Shiu, K.-M. Chien, T.-Y.Liu, T.-I. Lin, G.-R. Her, T.-Y. Luh, J. Chem. SOC.; Chem. Commun. 1995, 1159. [21] G.-X. Dong, J . 3 . Li, T.-H. Chang, J. Chem. SOC.; Chem. Commun. 1995, 1725. [22] G. Schick, A. Hirsch, H. Mauser, T. Clark, Chem. Eu,: J. 1996, 2, 935. [23] a) E. Vogel, Aromaticity, Spec. Publ. No. 21, The Chemical Society, London, 1967, 113; b) E. Vogel, Pure Appl. Chem. 1969,20, 237; c) E. Vogel, Is,: J. Chem. 1980, 20, 215; d) E. Vogel, Pure Appl. Chem. 1993, 65, 143. [24] B. Nuber, F. Hampel, A. Hirsch, J. Chem. SOC.;Chem. Commun., 1996, 1799. [25] F. Djojo, A. Herzog, I. Lamparth, F. Hampel, A. Hirsch, Chem. Eu,: J. 1996, 2, 1537. [26] J. C. Hummelen, M. Prato, F. Wudl, J. Am. Chem. SOC.,1995, 117, 7003. [27] X. Zhang, A. Romero, C. S . Foote, J. Am. Chem. SOC., 1993, 115, 11024. [28] P. R. Birkett, A. G. Avent, A. D. Darwish, H. W. Kroto, R. Taylor, D. R. M. Walton, J. Chem. SOC.;Chem. Commun. 1995, 1869. [29] M.-J. Arce, A. L. Viado, Y.-Z. An, S. I. Khan, Y. Rubin, J. Am. Chem. SOC. 1996, 118, 3775. [30] I. Lamparth, B. Nuber, G. Schick, A. Skiebe, T. Grosser, A. Hirsch, Angew. Chem. 1995, 107, 2473; Angew. Chem. Int. Ed. Engl. 1995,34, 2257. [31] J. Averdung, H. Luftmann, I. Schlachter, J. Mattay, Tetrahedron, 1995, 51, 6977. [32] J. C. Hummelen, B. Knight, J. Pavlovich, R. Gonzalez, F. Wudl, Science 1995,269, 1554. [33] M. Keshavaraz, R. Gonzalez, R. G. Hicks, G. Srdanov, V. I. Srdanov, T. G. Collins, J. C. Hummelen, C. Bellavia-Lund, J. Pavlovich, F. Wudl, K. Holczer. Nature, 1996, 383, 147. [34] B. Nuber, A. Hirsch, J. Chem. SOC.; Chem. Commun. 1996,1421.

Organic Synthesis Highlights I l l Johann Mulzer and Herbert Waldmann ConvrinhtaWILEY-VCH Verlan GmhH 1998

Index

A absolute configuration 28, 92 28 abzymes 170 ACE see angiotensin converting enzyme acepentalene - dilithium salt 254 acetaldehyde 216 acetogenins 98 a-acetoxy ketones 3 19 N-acetylenamides 52 ff. - BJ3-disubstituted 52 ff. - enantioselective hydrogenation 52 acetylenes - chemistry 256 - cyclic 256f. N-acetylhydrazones 52 - enantioselective hydrogenation 52 N-acetylneuraminic acid 342, 349 - 2,3 -didehydro-2,4 -dideoxy-4-amino 350 a-acids 218 activation parameters 258 active-site 186 N-acylindoles 212 acyloxy boranes (CAB) 45 ff. adamantane 140 2-adamantanylidene 25 1 additions - [4+3] 110 - [4+4+4] 110 - [6+2] 110 - [6+4] 110 - [6+6] 110 - control of

asymmetric 23, 79 cyclovinylogous 109 - enantioselective 8 1 adenosine, modified 388 adhesion receptors 342 aerogels 214 affinity labeling 242 aggregates 18, 217 - lithium amidelhalide 18 aglycons 306 - 1,3-diol unit 306 - erythronolides A and B 306 - B-hydroxycarbonyl unit 306 - lactonization 306 - seco acids 306 agonists 354,358 akuammicine 273 alanine scan 356 aldehydes - a-branched 15 - borocrotylation 307 Alder ene reaction 98 aldol reactions 24, 47, 205 - asymmetric 47 - enantioselective 47 - Lewis acid catalyzed addition 290 alkanes 212 - oxidation 140ff. alkenes 369 - aminohydroxylation 57 ff. - epoxidation 144 alkyl azides 4 18 ff. alkylation 3, 15, 20 alkylidene carbenoids 253 alkylperoxo complex 135 -

428

Index

alkynes 103 allenediradical 250 allylation 8, 275 - asymmetric 45 - enantioselective 45 - palladium-catalyzed 8 allylic - ligand 98 - 1,3-strain 310 allyllithium, chiral 70 amide - bond formation 376 - enolates 20 - hydrolysis 185 p-amidinophenyl esters 169 amination - allylic 60 - of aryl halides 126 ff. - intramolecular 130 amines, primary 5 a-amino acids - conformationally restricted 369 f. - derivatives 16 - synthesis 13 amino alcohols 57, 69, 114 2-aminobutadienes 28 - chiral 28 - synthesis 29 2-amino-2’-hydroxy-l ,l’-binaphthol 24 aminohydroxylation, asymmetric 57 ff. a-amino ketones 319 aminomercuration 29 a-amino oxime ethers 3 19 aminopyridines 129 ammonium hexafluorophosphate 98 amplification, asymmetric 80 ff. - autocatalysis 80 - synthesis 80 angiogenesis 363 angiotensin 359 - converting enzyme 360 - receptor 359 angular methyl group 323 annulenes - imino 417 - methano 417

antagonists 354, 358 anti-Bredt double bond 296 anti-integrins 364 antiadhesion therapy 342 antibiotic 3 14 anticancer agents 366 antimony pentafluoride 141 antisense agents 388 antitumor activity 318 ff., 323 apoptosis 363 aptamer 173 ff. aqueous solution 205 arborols 382, 391 ff. - synthesis 394 - two-directional 382, 384 aromatic spacer 368 aryl fluoride 316 N-arylpiperazines 128 aspidospermidine 237 (+)-asteriscanolide 108 asymmetric - addition 23, 79 - autocatalysis 79 ff. - benzylation 3 - catalysts 35 - catalytic deprotonation 4 - catalytic hydrogenation 6 - induction 19 f. - absolute synthesis 84, 89 ff. atherosclerosis 282 atomic force microscopy (AFM) 90 ff. atropisomerism 3 14 autocatalysis, asymmetric 79 ff. autoinduction, enantioselective 79 automorphogenesis 382 automultiplication 8 1 autoseeding 89 auxiliary group 15, 37 aza-Cope rearrangemenmannich cyclization 273 azafulleronium ion 424 ff. a-azido ketones 320, 323 azirines 320 azobis(isobutyronitri1e) 2 13 azulenes 206, 212

Index

B

B I ~ H & ion 406 f. baccatin I11 295 ff. basic pancreatic trypsin inhibitor (BPTI) 170 benzenediazonium - azide 265 - diazoazide 266 - ion 266 benzodiazepines 246 f., 368 benzoin condensation 205 benzophenone 212 benzyl - bromide 213 - chloride 213 - ketones 212 benzylation 4 biaryl ether 3 15 bicyclo[3.1 .O]hexanones 37 bicyclo[4.2.0] systems 301 - fragmentation 301 bimolecular process 259 BINAP 9, 53ff., 121, 129 binding site 194, 283 bio-Diesel 2 17 bioactive conformation 347, 355 biomesogen systems 201 biopolymer mimetics 246, 248 biosynthesis 156 ff. - aromatic compounds 156 - aspidosperma alkaloids 159 - endiandric acids 158 - fatty acids 164 - iboga alkaloids 159 - polyketides 164 - steroids 162 biotin 75 bipentazole 269 bipyridine 193, 396 - dendritic ligands 396 bipyridyl complex 2 12 bis(a-aminoamide) 384 bisazafullerenyl 424 2,2’-bis(dipheny1phosphino)-1,l’-binaphthyl 121

429

1,l ’-bis(diphenylphosphin0)-ferrocene 129 bis-homodiene 96 bisoxazolines (BOX) 5 , 10 N , O-(bistrimethylsily1)-acetamide) 11 bis(tri-o-toly1phosphine)-palladium(0) 127 bitropenyl 2 13 blocked quadrants 55 bolaamphiphiles (bolaphiles) 382 ff. - acetylenic 387 -

alkane-a,w-bis(trimethy1ammonium)

384 f. anthraquinone-based 384 - a-l-lysine-w-amino- 382 - lysine 384 - RNA-based 388 - unsymmetrical 385 bolytes 382 bond fixation 258 bond-alternation 259 boranes - polyhedral 406 boron clusters - icosahedral 406 ff. BPE 51 ff. branched molecules 391 Bredt’s rule 296 bromination 94, 213 bromine atoms 2 13 bromoetherification 322 bromonium ion 256 l-bromo-l-phenylethane 21 3 N-bromosuccinimide 2 13 4 -bromotoluene 2 13 BSA see N ,O-(bistrimethyl-sily1)acetamide building blocks 222 - chiral 222 - planar-chiral 398 - vicinal diols 222 Burgess’ reagent 298 Burgi-Dunitz trajectory 302 butadiene - highly hindered 256 butenolide synthesis 98 n-Bu4NBH4 254 butyrolactones 13, 2 16 butyrylcholinesterase 158 -

430

Index

C C-H bonds enantioselective insertions 42 - oxidation 140 C-N coupling reactions 126 ff. C - 0 coupling reactions 131 C2 symmetry 10 C2Sz 250 c402 250 CAAX sequence 367, 369 cage effect 212 (-)-camphor 297 CAN see ceric ammonium nitrate cancer - breast 295 - ovarian 295 Cane-Celmer-Westley hypothesis 230 cantharidin 206 capillary electrophoresis 167 carbanion - chemistry 254 - structures 254 - a-sulfonyl-substituted 254 carben(oid) reactions 40 carbene 43,251 - diduryl 252 - dimesityl 252 - diphenyl 252 - propynylic 328 carbenoid - chiral 67 - intermediates 327 carbocation 254 f. - ally1 255 - benzene 255 - CH5+ 255 - chemistry 254 - internally H-bridged 255 carbocyclic rings 103 carbometallation 97 - intramolecular 97 carbon dioxide, supercritical 54, 2 11 ff. - for chemical reactions 21 I - in extractions 211 - industrial application 2 19 -

phase diagram 220 polarity 211 carbonate 298 ff. - cyclic 216 - fragmentation 298 - phenyllithium addition 298 - protecting group 298 carbonyl oxide 252 carbonyl-ene reactions - asymmetric 23 - titanium-catalyzed 23 carboracycles 409 f. carboranes 406 ff. - anti-crown macrocycles 408 ff. - metal complexes 406 ff. carborods 4 10 carboxy inversion 2 12 carboxyl groups 283 ff. - activation 309 carboxylic acids - a-branched 15 cascade molecules 391 ff. - nomenclature 392 - synthesis 393 cascade synthesis 393 catalysis 186 - asymmetric 79 - enantioselective 40, 100 - two-phase 119 catalyst control 42 catalytic - activity 80 - antibodies 156ff., 170f., 188 - efficiency 187 catenanes 379 Caulton’s reagent 115 CB11H12- ion 406f. C2B10H12 isomers 406f. CBS reagents 44 CCK see cholecystokinin cell adhesion 362 cembrene 108 Cephalodiscus gilchristi 318 f., 323 cephalostatins 3 18 - isolation 318 - synthetic studies 322 ff. -

Index

ceric ammonium nitrate 32 chelation control 290 chemical selectivity 97, 147 chick chorioallantoic membrane 362 chiral - auxiliary, C2-symmetric 30 - base 4 - crystals 89ff. - induction 20 - pool 286, 303 - recognition 85ff. - space group 89ff. chirality 396 Chiraphos 9 N-chloramine-M 58 N-chloramine-T 57 f. N-chloro-benzylcarbamate 58 N-chloro-ethylcarbamate 58 chloroallylphosphonic acid amide 37 m-chloroperbenzoic acid 143 cholecystokinin 358 - Areceptor 359 - B receptor 359 cholesterol 217, 282 - high level 282 - oxidase 217 chrysanthenone 302 circular dichroismus 194 ff. citric acid 283 citronellol 2 17 - oleate 217 cladinose 3 10 Claisen reaction - intramolecular 276 Claisen rearrangement 156ff., 205 Clar’s hydrocarbon 253 clathrates 397, 401 cloud point 121 cluster 396 - dendritic 396 - effect 396 - glucosides 396 - supramolecular 402 CMP-Neu5Ac-synthetase 345 cocaine 158 combinatorial libraries 325

-

B-cyanhydrin 65

- epoxide opening with trimethylsilyl cyanide 65

- screening 65

combinatorial synthesis 129 n-complex 255 f. complex formation 82 conformation 247 f., 298 ff. - taxoids 298 conformer 91 ff. conjugate addition 27 1 conocurvone 33 1 Conospermum teretifolium 332 consensus sequence 367 f. container dendrimers 40 1 convergent-growth 388 cooperativity 147 coordination chemistry 192 Cope rearrangement 32,37, 108, 158 corannulene - tetralithium salt 254 cosolvents 17 coupled cluster (CC) theory 266 coupling - branched 97 - linear 97 - palladium-catalyzed 99 p-cresol 217 critical - density 211 ff. - pressure 211 ff. - temperature 211 cross-coupling 129 - carbonylative 275 cryptophanes 25 1 crystal packing 94 crystal structure analyses 17 Cu(I1) binding 193 cumene 213 [3]cumulenes 253 cyclization 91 ff. - 6-ex0 237 cycloadditions 103, 212 ff., 415 ff. - enantioselective [2+1] 39 - intramolecular [2+1] 36 - [2+2] 109f., 231

431

432

Index

ruthenium-catalyzed [2+2] 99 [4+2] 28, 96, 158ff. enzyme-catalyzed [4+2] 162 - [4+3] 206 - [4+4] 106ff. - metal-catalyzed [4+4] 106 - photochemical [4+4] 106, 108 - thermal [4+4] 106 [2+2]-cycloaddition-cycloreversion 206 1,3-cyclobutadiene 25 1 cyclobutanone 302 - cleavage 302 cyclodextrins 189, 374 cyclohepta-1,4-dienes 32, 103 cyclohepta-2,4 -dien-1-ones - synthesis 104 cycloheptanes - functionalized 37 cycloheptanones 104 cyclohexane 2 16 - oxidation 142 cyclohexatriene 259,416 cyclohexene oxide 2 17 1 3-cyclooctadiene (COD) 96 cyclooctanoids 106 f. cyclooctatetraene 258 - planar 259 cyclopentadienone complexes 100 cyclopentadienyl ruthenium complexes 96 - cationic 96f. cyclophanes 399 cy clopropanation - antibody-induced 37 - asymmetric 48 - enantioselective 41, 48 - intramolecular 35 f., 42 cyclopropanes 35,40, 141 cyclopropenation 42 cyclopropylidene 250 Cylexin 347 cytochrome - model 195 - P-450 140 -

D decalin

- oxidation 142

p-dehydrobenzene 258 dehydrobufetenine 130 2,4 -dehydrophenol 25 1 dendrimer - branches 396 - building blocks 401 - cavities 396 - construction 399 - framework 396 - periphery 394,396 - surface 394 dendrimers 391 ff. - aromatic hydrocarbon 391 - chiral 396f. - complexing inner core 394 - core units 395f. - enantioselective complexation 396 - fullerene 394 - gluco 396 - guest molecules 400f. - hydrocarbon 392 - metal complex 397 - metalporphyrin 395 - nanoscale catalysts 392, 400 - peptide 396 - phosphorus-containing 399 f. - polyacetylene 391 - polyamine 399 f., 403 - polyether 393 - polymerlike 403 - poly(1ysine) 396 - polynitrile 393 - Pt-complex 397 - silicon 391 - supramolecular networks 401 dendritic - box 400f. - wedges 401f. density function theory (DFT) 266 1-deoxynojirimycin 114 deoxyribozymes 173 ff., 181 ff.

Index

deprotection silyl groups 298 deprotonation - enantioselective 67 design 192 desosamine 3 10 desymmetrization 32 1 1,2-diacylglycerol 358 dialkyl zinc addition - asymmetric 45 - enantioselective 45 dialkynes, cyclic 258 1,2-diamination 60 diastereoselectivity 17 diazide 267 diazoacetates 417 diazoamides 4 17 1,4-diazocine 42 1 diazomalonates 4 17 diazomethanes 417 ff. dicarbonyl compounds 114 Diels-Alder cycloaddition - asymmetric 46 - enantioselective 46 Diels-Alder reaction 28, 103, 110, 157 ff., 188 f., 205,421 - hetero 31, 205 - - asymmetric 205 - intramolecular 278 - pyrone 298 Diels-Alder-ase 159 dienes - bicyclic 258 - chiral 28 dienophiles 28 - chiral 28 1,l-difluoroethylene 214 dihydroindoles 129 dihydroquinolines 129 2,2’-dihydroxy-l,1 ’-binaphthyl 85 dihydroxylation - asymmetric 57 diisobutylaluminium hydride 393 diisocyan 250 dilithioacetylene 254 di-n-methane rearrangement 90 -

dimethylamine 2 16 dimethyldioxirane 141 dimethyl fumarate 58 dimethyl malonate 11 (S,S)-3,5-dimethylmorpholine 3 1 1,2-diols 113 ff. DIOP 9 dioxabicyclo[3.2. lloctane 284 dioxaborolidine - catalysts 44 1,2-dioxetan 422 dioxirane 252 di(perfluoroalky1)-oxaziridines 143 diphenyldiazomethane 212 2 -(diphenylphosphino) - aniline 9 - benzoic acid 9 diphosphines 76 1,3-dipolar cycloadditions - asymmetric 47 - enantioselective 47 distillation, enantioselective 84 ff. diversomers 245, 247 divinylcyclopropane 32 DNA cleavage 258 DNA intercalator 328 double bond shift 258 double stereoselection 41 drug design - irrational 242 - rational 242 dumbbell-shaped molecules 375 DuPHOS 51ff.

E effective molarity 187 eight-membered rings 106 ff., 296 - strained 296 electrocyclic reactions 158 electrolytes - bolaform 382 electrophilic addition - halogens to olefines 255 electrospray mass spectrometry 194 ff.

433

434

Index

elimination, reductive 97 enamides 5 1 ff. - enantioselective hydrogenation 5 1 ff. - prochiral 215 enamines 30 - a-chloro 30 - reactions 29 enamino ketones 320 enantiomers 85 enantiomorphic crystal 92 enantioselectivity 42, 79, 151, 217 B-endorphin 355 endothelial cells 362 ene reactions 23 - enantioselective 25 enediynes 327 ff. - antibiotic 256 - cyclic 327ff. - heterocyclic 328 - steroid conjugates 328 energy - barrier 266 - density 269 - hypersurface 266 - minimum 268 enolate reactions 15 enzymatic reactions 217 enzyme - engineering 168 - inhibitors 242 - mimetics 185 enzyme-catalyzed evolution 201 L-(-)-ephedrine 15 epoxidation 144 - asymmetric 49, 57ff. - - allylic alcohols 62 - - other reactions 62 - - unfunctionalized alkenes 62 - chelate-directed 298, 302 - enantioselective 49 epoxides 4, 15 erythromycins 306 ff. ethane 216 ethenylmagnesium bromide 100 ethylbenzene 2 13 ethylene carbonate 2 16

(R)-ethyl lactate 215 ethyl pyruvate 215 EuIer’s theorem 416 Evans copper complex 36 external quench 21 extravasation 343

F farnesyl inhibitors 369 protein transferase 366 ff. - transferase 368f. - - inhibitors 368, 371 farnesylation 366 f. femtosecond spectroscopy 259 ferrocene 7 1 , 7 3 - chiral 71 - planar-chiral 73 ferroceny1 - amides, lithiation 71 - substituent 255 - phosphines 100 ferromagnetism 252 fibrinogen 361 Fischer carbene complexes 32 FK 506 324 fluorescence microscopy 243 fluorinated polymer 21 3 fluorine 143 a-fluorketimines 143 fluoroalkene 213 fluorous biphase system 122 formic acid 2 15 fragmentation 27 1, 397 ff. Fritsch-Buttenberg-Wiechell rearrangement 253 FT-IR studies 148 Fuc transferase 344 fullerene dendrimer 394 fullerenes 251, 415 ff. - imino 417 ff. - KekulC structure 416 - methano 417 ff. fusicoccin 108 -

Index

G G-protein coupled receptors 354 galactosyl transferase 344 gaslsolid reaction 21 1 GDPFuc 345 gel, thermoreversible 382 Gif systems 140 Glanzmann’s thrombasthenia 364 GlcNAc kinase 349 glucomimetica 396 d-glucosamin 349 glycerine 223 - desymmetrization 223 glycinamides 16 glycoconjugates 336 glycolate complex 136 glycoproteins 228, 344 glycosides - allylglycoside 338 f. - 2-isobutenylglycoside 338 - phenylthioglycoside 337 - selenodisaccharide 340 - selenoglycoside 339 - thioglycoside 336 f. - 2-(trimethylsily1)-ethylglycoside 336 glycosphingolipids 344 glycosyl donors 209, 225, 310 - armed 225 - disarmed 225 glycosyl fluorides 209, 336 f. glycosyl trichloroacetimidate 209, 339 glycosylation 3 10, 336 glycyrrhizin 349 GPI anchor 227 graphite 416 greenhouse warming potential (GWP) 122 p-guanidinophenyl ester 169 H haemagglutinin 349 halide effects 4 halogenations 415 ff. hapten 156ff., 188 hazards, environmental 84

Heck reaction 126, 278, 300 hetero 126 intramolecular 278 hecogenin 320 ff. helical thread 383 helix 91 f. heme 195 hemicarcerand 25 1 heterofullerenes 4 15 ff. heterotropilidene 42 1 hexaazabenzene 267 hexacarbene 253 hexafluoropropene oxide (HFPO) 123 hexamethylphosphoric acid triamide 17 3-hexyne 217 HIV 331 - proteases 115 homoallylic alcohols 23 homodimer 3 18 ff. hops extracts 218 horseradish peroxidase 217 humulone 218 hydride transfer - intramolecular 147 hydroazulene 206 hydrocarbon - in-out- 255 - oxidation 140 hydroformylation 120, 123, 146, 2 13ff. - regioselective 123 hydrogen - bonding 378 - bonds 87 - migration 93, 218 hydrogenations 51 ff., 213 ff., 415 ff. - asymmetric 75 - enantioselective 5 1 ff. - - N-acetylenamides 52 - - N-acetylhydrazones 52 - - enamides 51 ff. - - imines 53 - - ketones 51 ff. hydroperoxides 133 f. hydrophobic - association 190 - effect 205 -

435

436

Index

a-hydroxy-pamino acids 58 P-hydroxy esters 24 hydroxy groups - selective protection 300 y-hydroxy ketones 15 hyperlithiation 254 - methane 254 hypertension 282,360

I imines 5, 53 enantioselective hydrogenation 53 hydrogenation 76 iminium ions 205 - cyclization 271 immobilization 119, 122 in vitro - evolution 173 - selection 173, 177, 180, 182f. inclusion - complexes 374, 379 - compound 84 - crystallization 85 - enantioselecitve 85 - gas-solid 86 - solid-solid 86 indium trichloride 99 influenza 349 inhibition - mitotic 109 inositol-1,4,5 -trisphosphate 358 integrins 343, 362 f. intermediates - reactive 250 interstellar space 250 intersystem crossing 267 intramolecular reactions 187 iodonium salts 256 - structure 256 ion pairs - contact 254 - solvens-shared 254 - solvent-separated 254 iron(II1) chloride 141 -

irradiation 89 ff. a-isoacids 2 18 isobenzene 257 isocarbacyclin 25 trans-isohumulone 218 isoprene 215 isoprenylation 367 isosteric replacement 369 isostrychnine 276 ff. ISQ effect 19

J Josiphos 75

K ketodiols 24 ketoimine reduction - asymmetric 45 - enantioselective 45 ketolactam 422 ketolides 3 12 ketones 51ff., 113 - a-branched 15 - a,,&unsaturated 99 - b,,y-unsaturated 98 - y,d-unsaturated 98 - asymmetric reduction 44 - enantioselective hydrogenation 51 ff. - enantioselective reduction 44 keto-oximes 114 ketyl radicals 114 kinetic resolution of racemic epoxides 64 - B-azido silyl ethers 64 - opening with trimethylsilyl azide 64 kinetic stabilization 252

L y-lactones 15 lactonization 306 f. lamifiban 361

Index

laser flash spectroscopy 258 lead compounds 247 leukocyte adhesion deficiency 344 Lewis acids - chiral 23 libraries 245 ff. - DNA 181 - nucleic acid 173 - peptide 245 - random 175 - RNA 174f., 177 ligands - cyclopentadienyl 100 - smart 121 - tailoring 122 ligation 176 ff., 182 light-induced charge separation 252 light-scattering 379 ortho-lithiation - diastereoselective 73 - enantioselective 74 lithium - amides, chiral 4 - bases 18 - bromide 4 - carbenoid 68 - chloride effect 19 - diisopropylamide (LDA) 4, 17 - enolates 3 - halides 4, 17 - hexamethyldisilazane 18 - perchlorate-/dichloromethane 208 - - /diethy1 ether 205 - tetramethylpiperidide 18 - trifluoromethane-sulfonimide (LiNTf2) 209 Lochmann bases 254 losartan 360 low conversion 93

M macroassemblies 383 macrocycles 357 - carborane ligands 407 ff.

-

431

enantioselective synthesis 36

- lactones 35

macrolactonization 309 - Yamaguchi’s 311 macrolide antibiotics 306 ff. - aglycons 306 - 6-deoxyerythronolide 307 - erythromycins A and B 306 ff. magnetic field 89 main-chain chirality 154 ManNAc kinase 349 Mannich reaction 275 many-body perturbation theory (MBPT) 266 Marker - degradation 322 - ring-opening 322 material science 256 matrix - halogen-doped 253 - isolation 250 - spectroscopy 250 McMurry pinacol coupling 113, 298 MCPBA see rn-chloroperbenzoic acid membrane - disruption 387 - quinones 384 - redox-active 384 (lS,3S,4R)-menthyl diazoacetate 41 mercury - in metallacarborand complexes 407 ff. meso epoxide opening, enantioselective 63 - chiral boron Lewis acids 63 - Cr-Salen catalysts 63 - /3-cyanohydrin 65 - /3-halohydrins 63 - heteroatom nucleophiles 62 - /3-hydroxy benzoates 64 - C3-symmetry 63 - with silyl azides 63 - with trimethylsilyl cyanide 65 - zirconium complex 63 mesoporphyrin 179 f., 183 Met-enkephalin 355 metal - carboran sandwich complexes 411 ff. - complexes, dendritic 396

438

Index

diborolyl sandwich polymers 411, 413 oxiranes 115 salts 17 metalla - carborands 407ff. - carboranes 406, 411 ff. - cycles, eight-membered 104 - cycloheptadiene 100 - cyclopentene 97, 100 - oxetane 230 metallocenes 153 metalloenzymes 192 metallopeptide 193 metastases 344, 361 methamphetamine 84 (S)-2-methoxymethyl-pyrrolidine 29 ff. 3 -methyl-y-butyrolactone 42 methylenation 298 methylenecyclopropanes 104, 253 methyl pyrrolidone-5 -carboxylate (mepy) 41 methyl(trifluoromethy1)-dioxirane 142 methyltrioxorhenium 133 (S)-Metolachlor 76 Meyer-Schuster redox isomerization 99 Meystre’s hypoiodite reaction 323 micelles 189 Michael addition 393 Michaelis-Menten analysis 164 microtubuli 295 - stabilization 295 migratory insertion 136 mixed complexes 79 molecular - abacus 379 - assemblies 374, 383 - cylinders 381 - lampshades 381 - movement 90 ff. - recognition 188, 374, 380, 389 - self-assembly 389 - systems, mechanically interlocked 374, 380 Mgiller-Plesset perturbation theory 266 monensin A 230 ff. monoclonal antibody 247 monodisperse molecules 403 -

monodispersity 40 1 morphine 355 Mucor miehei lipase 217 Mukaiyama aldol reactions 24 Mukaiyama-Michael aldol reaction - asymmetric 47 - enantioselective 47 Mulliken charge 419 multidecker metal sandwich complexes 411 ff. myocardiac infarction 282

N naloxone 355 nanoscopic molecules 399 natural products 235 - total synthesis 295 neovascularization 361 f. Neu5Ac transferase 344 neuraminidase 349 new materials 380, 391 f., 399, 403 NF-KB 324 niobium reagents 116 nitroalkenes 30 nitrogen rings 265 nitrostyrenes 30 NMR spectroscopy 18 non-KekulC hydrocarbons 253 nonacarbene 253 nonmetal compIexes - dendritic 396 nonstoichiometric effect 19 norbornadiene 97, 99 f. norbornen 99, 259 - retro-Diels-Alder reaction 259 nucleophile - hardsoft 8 nucleophilic - additions 5, 415 ff. - catalysis 190 nucleosides 13

Index

0 octaazacubane 269 1-octene 215 oleic acid 217 a-olefin polymerization 153 oligo - carbamate 245ff. - nucleotides 242 - peptides 242 - saccharides, cyclic 381 - - synthesis 225, 336 - sulfones 248 - tetrahydrofurans 23 1 - thymine 388 - ureas 248 Oppenauer oxidation 100 organic ferromagnets 253 organolithium compounds 3, 19, 291 organometallic chemistry 238 orientational isomers 377 orthogonal glycosylation 336 osmium tetroxide 57 oxa-di-z-methane rearrangement 218 oxaldie 189 oxazaborolidine - catalysts 44 oxen complex 133 oxenoid 135 oxetanes 217, 296 ff. oxidation 133ff., 216 - adamantane 14Off. - alkanes 140ff. - alkyl zinc reagents 137 - allylic 136 - arenes 134 - autoxidation 155 - Baeyer-Villiger 134 - cyclohexane 142 - decalin 142 - Dess-Martin 290 - enantioselectivity 135 - enolate 298 - - with benzeneseleninic anhydride 298 - - with oxygen or air 302

439

- epoxidation 134

- hydrocarbons 140 - anti hydroxylation 134 - syn hydroxylation 134 - mechanism 133 - organometallic intermediates

- osmylation 136

133

oxametalla-cyclobutane intermediate 136 withoxygen 140 oxygen transfer 134 withozone 141 photooxygenation 137 - pyridines 144 - regioselective 299 - - with pyridinium chlorochromate 299 - sulfides 144 - syn-oxidative 230 - trialkylsilanes 144 oxidative coupling 3 14 oxirane 216 oxofunctionalization 140 0x0 process, Ruhrchemie/Rh6ne-Pouienc 119 oxygenations 415 ff. ozone depletion potential (ODP) 122 ozonization 252 -

P paclitaxel 295 ff. palladacycles 129 palladium 300 - catalyzed processes 126 - Heck coupling 300 pancratistatin 236 pantolactone 86 [2.2]paracyclophanes 298 ,8-patchoulene oxide 297 pentazole 265 - ah initio calculations 266 - aromatic ring 266 - kinetic stability 266 - Lewis structure 266 - natural bond orbital analysis 266 pentazolyl acetic amidrazone 265 (R)-pentolactone 70

440

Index

PEPSCAN 247 peptide 19, 192ff. - dendrimer 396 - helical 194 - ligases 167 peptide synthesis 167 - abzyme-catalyzed 170 - chemical 167 - cryoenzymatic 169 - enzyme-catalyzed 167 - protease-catalyzed 168 f. - solid-phase 167 - trypsin-catalyzed 169 - zymogen-catalyzed 170 peptides, modified 366 ff. - post-translational 366 - reduced amide 367 f. peptidomimetics 354, 356, 366 - design 355 - for G-potein coupled receptors 358 - oligomeric 369 peptidophosphoramidates 248 peptidosulfonamides 248 peptoids 248, 369f. pepzymes 185 ff. pericyclic reactions 156 perlithiomethane 254 peroxo complex 134 pharmacophore 355 phase rebuilding 85, 90 ff. phase-transfer catalysis 213 phenanthrene 421 phenol oxidation 332 phenollquinone addition 334 phenolic resins 217 phenylpentazole 265 pheromone 158 phosphatidylinositol-4,5 -bisphosphate 358 phospholanes 5 1 phospholipase C 358 phosphorimidazolide 176 [2+2]photodimerization 89 photo electron spectroscopy 258 photochemical processes 260, 302 - ally1 shift 302 photolithography 242

photooxygenation 422 phthalazine ligands 58 pinacols 113 ff. - coupling 113 ff. - rearrangement 113 a-pinene 302 piperazine ring 369 piperidones 3 1 planar-chirality 73 platelet-activating factor 343 poly(2-hydroxypropyl-methacrylate) poly(amidoamines) 391, 393 poly(ethyleneglyco1) 378 polyacrylamide 214 polycarbonates 2 16 polycyclization 230 polyepoxidation 230 polyepoxide cascade 230 polyesters 214 polyethers - biosynthesis 230 - dendritic 393 polyisobutylene 214 polyketide synthase (PKS) 164 polylysines 393 polymerization 2 13 polymethylmethacrylate 214 polynitriles, dendritic 393 polyolefin, optically acitve 153 polypropylene amines 39 1 polyrotaxanes 374, 377 ff. polystyrene 2 14 polyvinylalcohols 2 14 porphyrin dendrimer 395 prebiotic 198 - evolution 177 Prins reaction 3 19 product inhibition 157 promoter ligands 120 1,3-propanediyl 253 propargyl alcohols 23, 99 propargylene 250 protecting group - amino 246 - cyclohexane-1,2-diacetal (CDA) 222

214

Index -

dispiroketal(Disp0ke) 222

- Fmoc 246 - nitroveratryloxycarbonyl

protein 192 ff. - artificial 192 - denovo 192 - engineering 188 - mimetics 192 D-(+)-pseudoephedrine 15 pseudoknot 177 pseudopterosine A 238 pseudorotaxane 374 Pummerer reaction 271 pyrazine synthesis - symmetrical 3 19 ff. - unsymmetrical 320 ff. pyrazolines 418 ff. pyridines - oxidation 144 pyridones 106, 108 - tethered 108 a-pyrone 106, 251 pyrrole 266

Q quaternary center 290 pinones - cyclo-trimeric 332 - virostatic 332

R racemate 84 ff. racemization 167 [5]radialene 416 radical - additions 415ff. - cyclization 235 - - tandem 238 - reactions 213, 235 rapamycin 25 Ras proteins 367 - mutant 367

246

rearrangement [1,2,3,4] 218 [3,3lsigmatropic 275 regioselectivity 100, 146, 151, 291 resolution, optical 84 ff. resorcinol 214 retro-Diels-Alder reaction 99, 259 - concerted 259 - non-concerted 259 - real-time dynamics 259 - stereospecifity 259 retroaldoValdo1reactions 297, 302 retrosynthesis 284 RGD sequence 360, 363 rhizoferrin 389 rhodium - acetate 40 - catalysis 104 - catalysts 40f., 51 ff., 215 ff. - cationic complexes 104 - dinuclear intermediates 148 - MEPY catalyst 36, 41 - phosphan complexes 215 rhodopsin 260 - cisltruns-isomerization 260 ribonuclease A 167 ff. ribozymes 173 ff. ring inversion 258 ring opening processes 268 ritterazines - isolation 319 - synthetic studies 322 f. Ritterellu tokioku 3 19 RNA - branched 388 - world 176ff., 183 - Hoogsteen strands 202 rocket fuels 269 rolling 343 [6]rotane 141 rotaxane 374 ff. - formation 375 - metal complex 375 - self-assembly 375 ruthenium - catalysts 53 ff., 97 ff. -

441

442 -

Index

- [CPRU(COD)CI] 96 - [Cp*Ru(COD)Cl] 99 - Cp*Ru(IV) 100

polypyridine complexes 396 tetraoxide 141

S salts, diastereomeric 84 samarium diiodide 114 ff. sandwich complexes 41 1 ff. - molecular metal-carborane 41 1 ff. - multidecker 411 ff. scaffold 368 f. Schotten-Baumann condensation 379 screening 247, 249 - high-throughput 355 seco acids 306f. seeding 89 selectins 342 - E 342 - L 342 - P 342 selector - optical 87 - structural 87 self-assembly 374, 377, 380, 382 - molecular 389 self-reproduction models 199 selfreplicating system 8 1 semiconines 10 - copper complex 36 semiempirical PM3 calculations 92 semisynthesis 296 - taxol 296 sequence space 173 sesterterpenes 107 SET reactions 143 seven-membered rings 32 Shapiro reaction 298, 300 Sharpless dihydroxylation 285, 289 8-sheet 193 sialyl LewisX 342, 344 - chemoenzymatic synthesis 345 - mimetics 347 - pharmacophor 346f.

1-silacyclopropylidene 257 silanols 144 siloxydienes 29 N-silylimines 3 1 Simmons-Smith reaction - asymmetric 48 - enantioselective 48 singlet 252 - stability 252 SLeX see sialyl LewisX slippage mechanism 375 slurry technique 86 SMP see (S)-2-methoxymethyl-pyrrolidine SOH10 process 136 solid-phase synthesis 129, 242, 245 solid/solid reaction 21 1 solid support 247 soy flakes 217 sparteine 5, 68, 74 spiroketals 322 squalen synthase 283 squalestatin 283 squaric acid 104 star polymers 396 stereoelectronic effects 8 stereoregularity 153 stereoselectivity 80 stereospecifity 90, 109 steric - effects 296ff. - hindrance 393 steroids 361 stilbene - aminohydroxylation 59 Stille coupling 275 strain 296 strained molecules 35 Streptococcus 228 structure-acitvity relationsships (SAR) 295 Strychnos alkaloids 270 ff. - akuammicine 273 - isostrychnine 276 ff. - strychnine 270ff. - - unnatural 275 - Wieland-Gumlich aldehyde 270 ff.

Index

styrene 41 substrate - control 42 - mimetics 169 succinic acids 13 sugar - epitones 396 - nucleotides 346 - protecting group 222 sulfatides 346 sulfide oxidation 144 sulfones 144 sulfoxides 144 supersandwiches - carborane-based 41 1 ff. supported aqueous phase catalysis (SAPC) 121, 123 supported liquid phase catalysis (SLPC) 121 supramolecular - aggregates 396 - arrays 374 - assemblies 383 - chemistry 85,374,389,394 - cluster 402 - hosts 401 - network 401 - surfactants 387 surface features 90 ff. suspension technique 85 Suzuki coupling 124 symmetry principles 89 synthesis - aspidospermidine 235 - camptothecin 235 - cascadelike 391 - convergent 391, 393 ff., 401 - dactomelyne 235 - divergent 39 1 , 395 - 7-deoxypancratistatin 235 - light-directed parallel 246 - pseudopterosine A 235 - regioselective 4 15

443

T 2,4,5-T 218 tartaric acid 290 taxanes 107 ff. taxol 58, 107 ff., 295 ff. - amino acid side chain 58 taxotere 295 ff. teicoplanin 3 16 teretifolion B 332 terpenoid 295 tetraazatetrahedrane 268 tetraaziridine 268 tetrahydrofurans 217, 230 ff. 1,2,3,4 -tetramethyl-5 -(trifluoromethyl)cyclopentadienide 100 tetraphosphorus ligand 146 tetrathiafulvene 383 tetrazole 266 tetrazole-carbonitrile 265 thermophilic bacteria 389 threo selectivity 115 thromboembolic diseases 360 f. thyretropin releasing hormone (TRH) 357 tin amides 127 titanium - catalysis 23 - low-valent compounds 113 ff. - [TiX2BINOL] 25 a-tocopherol 212 Toda method 86 f. toluene 213 total synthesis 106, 282 Townsend-Basak-McDonald hypothesis 230 transamination 127 transfer hydrogenation 53 transferases 346 transition metal - catalysis 103 - catalyst 153 - complex formation 415 ff. - complexes, chiral 62 transition state 185, 250 - analog 178ff., 188 transition structure 268 TRAP 54

444

Index

trialkylsilanes

- oxidation 144

triangulen 253 triaziridine 268 triazolines 418 ff. tributyltin hydride 114 trichloroethoxycarbonyl chloride (TrocC1) 302 tricyc10[4.2.2.0~~~]dec-7-ene96 n-tridecafluorooctane 215 triimide 268 trimethylenemethane 253 - palladium complexes 104 triphenylphosphine trisulfonate (TPPTS) 119 triple bonds - differentiation 96 triplet - stability 252 - state 267 Trommsdorff effect 213 tropones 206 Trypanosoma 227 TSA see transition state analog TTF see tetrathiafulvene tuftsin 358 turnover - numbers 215 ff. - frequency 215 ff. p-turns 355f.

U Ullmann coupling 3 15 unimolecular process 259 unnatural biopolymer 246

vinyl

- azides 320

cyclopropanes 37, 103 ethers 23, 25 selenides 25 sulfides 25 vinylidene complex 98 vitamin D3 156

-

W Wacker oxidation 124 Wadsworth-Emmons reaction 322 Wagner-Meerwein shift 3 19 waste treatment 216 water as solvent 205 Wieland-Gumlich aldehyde 270 ff. Wieland-Miescher ketone 300 Wilkinson’s catalyst 103 f. Williamson ether synthesis 394 Wittig olefination 30 Wittig-Homer reaction 273

X X-ray crystallography 18 X-ray structure 93

Y Yamaguchi macrolactonization 3 11 a,p-ynals 23 2

V

vanadium compounds low-valent 115 vancomycin 3 14 vesicular morphology 386 -

Zanamivir 35 1 zaragozic acids 282 - A 283 - C 283,286,290 - retrosynthesis 284 ZEKE-photoelectron spectroscopy 255 zinc prophyrins 395

Organic Synthesis Highlights IV Edited by Hans-Giinther Schmalz

Related Titles from WILEY-VCH:

J. Mulzer / H. Wuldmann (eds.)

Organic Synthesis Highlights I11 1998. X. 412 pages with 302 figures Softcover. ISBN 3-527-29500-3 K. C. Nicoluou / E. J. Sorensen Classics in Total Synthesis 1996. XXIII. 792 pages with 444 figures Softcover. ISBN 3-527-2923 1-4 H. Hopf Classics in Hydrocarbon Chemistry 2000. XI. 547 pages with 434 figures Hardcover. ISBN 3-527-30216-6 Softcover. ISBN 3-527-29606-9 J. Otera

Modern Carbonyl Chemistry 2000. XX. Approx 600 pages with 542 figures and 102 tables Hardcover. ISBN 3-527-2987 1- 1 A. Ricci

Modern Amination Methods 2000. Approx 400 pages Hardcover. ISBN 3-527-29976-9 J. A . Gewert et al.

Problem Solving in Organic Chemistry 2000. Approx 278 pages with 284 figures Softcover. ISBN 3-527-30 187-9

Organic Synthesis Highlights IV Edited by Hans-Gunther Schmalz

@WILEYVCH Weinheim . New York . Chichester . Brisbane

. Singapore

. Toronto

Prof. Dr. Hans-Gunther Schmalz Institut fur Organische Chemie dcr Universitat zu Koln Greinstrasse 4 D-50939 Koln Germany

This book was carefully produced. Nevertheless, authors, editor and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

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Preface

During the past century, the world has changed to an unprecedented extent, and the development of the chemical sciences has greatly contributed to this change. The ability of chemists to synthesize complex organic molecules such as dyes, drugs, fragrances and crop protection agents is largely responsible for the high standard of living we enjoy today. Moreover, synthesis as a key discipline is contributing to the development of modern life sciences and materials technology. However, while the power of synthesis has led to remarkable achievements, the technology and art of organic synthesis is still far from being fully developed. Many problems remain unsolved concerning, for instance, the efficiency and atom-economy of syntheses. Organic synthesis continues to offer multifarious academic and technological challenges, and a tremendous amount of research is carried out worlwide in this field. This fourth volume of Organic Synthesis Highlights (OSH) comprises a collection of more than 40 articles reflecting some more recent developments and achievements of organic synthesis. About half of the contributions have their origin in the review section “Synthese im Blickpunkt” in Nachrichten aus Chemie, Technik und Labnratorium (1994- 1998), the members’ journal of the GDCh; most of the others have been selected from the “Highlights” of Angewandte Chemie (1997- 1998). The first half of the present volume concerns synthetic methodology, with emphasis on stereoselective synthesis, transition metal organometallic methods,

and enantioselective catalysis. The second part focuses on applications in total synthesis of natural products and non-natural compounds and materials. In addition, a few articles reflect the recent renaissance of solid-phase synthesis and the growing importance of combinatorial chemi stry. The articles taken from “Synthese im Blickpunkt” have all been carefully updated and translated by the authors (U. Koert, 0. Reiser, M. Reggelin, C. Ruck-Braun). I would like to express special thanks to these colleagues and their co-workers. I am also grateful to all the other authors for their excellent and up-to-date contributions. I also have to thank the team at WileyVCH, especially Dr. A. Eckerle, Dr. G. Walter, Dr. A. Kessinger and P. Biel for their excellent, professional support and their patience with the editor. I hope this new volume will find as much acceptance in the scientific community as the first three volumes of this series and will help to stimulate the interest of, in particular, young chemists in the field of synthesis.

Cologne, February 2000 Hans-Giinther Schmalz

Contents

Part I. Synthetic Methods A. New Methods in Stereoselective Synthesis Stereocontrolled Simmons-Smith Cyclopropanation Julia Schuppan and Ulrich Koert

..............................

3

Oppolzer Sultams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Reiser

11

Oxazolines: Chiral Building blocks, Auxiliaries and Ligands . . . . . . . . . . . . . . . . . . . . . . . . Martin Glos and Oliver Reiser

17

New Sequential Reactions with Single Electron Transferring Agents . . . . . . . . . . . . . . . . . . . 34 Troels Skrydstrup Deracemisation by Enantiodifferentiating Inversion in 1,3- and I ,2-Diols . . . . . . . . . . . . . . . 40 Anthony I? Davis Non-Biaryl Atropisomers: New Classes of Chiral Reagents, Auxiliaries and Ligands? . . . . . . 48 Jonathan Clayden Amino Acid Derivatives by Multicomponent Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gerald Dyker

53

New Polyol Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christoph Schneider

58

Stereoselection at the Steady State: The Design of New Asymmetric Reactions . . . . . . . . . . . Thomas Wirth,

67

B. Transition Metal Organometallic Methods Photolysis of Fischer Carbene Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Kiehl and Hans-Gunther Schmalz

71

Zr-Catalyzed Carbomagnesation of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Florian Blume and Hans-Gunther Schmalz

77

VIII

Contents

Intramolecular Alkoxypalladation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Geis and Hans-Giinther Schmalz Ring-closing Olefin Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Michael Kurle and Ulrich Koert Metal-Catalyzed Hydroformylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Reiser Rare Earth Metal Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patrick Amrhein and Kurola Ruck-Bruun Dithioacetals as an Entry to Titanium-Alkylidene Chemistry: New and Efficient Carbonyl Olefination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bernhurd Breit New Developments in the Pauson-Khand Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Geis and Huns-Giinther Schmalz

83 91

97 104

110

116

Multicomponent Catalysis for Reductive Bond Formations . . . . . . . . . . . . . . . . . . . . . . . . Alois Fiirstner

123

Natural Product Synthesis by Rh-mediated Intramolecular C-H Insertion . . . . . . . . . . . . . . Douglass I? Taber and Suluh-E. Stiriba

130

C. Enantioselective Catalysis Enantioselective Heck Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marku.5 Jachmann and Hans-Giinther Schmalz

136

Catalytic Asymmetric Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rolf Krauss and Ulrich Koert

144

Binaphthyls: Universal Ligands for Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tobias Wubnitz and Oliver Reiser

I55

Fluorotitanium Compounds - Novel Catalysts for the Addition of Nucleophiles to Aldehydes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rudolf 0. Duthaler and Andreas Hufner

166

Enzymes and Transition Metal Complexes in Tandem - a New Concept for Dynamic Kinetic Resolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ruiner Stiirmer

172

Non-Enzymatic Kinetic Resolution of Secondary Alcohols . . . . . . . . . . . . . . . . . . . . . . . . Peter Somfai Copper-Catalyzed Enantioselective Michael Additions: Recent Progress with New Phosphorus Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Norbert Krause C,-Symmetric Ligands for Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mark Mikula's and Kurola Ruck-Bruun Highly Enantioselective Catalytic Reduction of Ketones Paying Particular Attention to Aliphatic Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renat Kadyrov and Riidiger Selke

175

182 187

194

IX

Contarits

Part 11. Applications

A. Total Synthesis of Natural Products Total Synthesis of Ikarugamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oliver Schwarz and Hans-Gunther Schmulz

207

Palladium-Catalyzed Synthesis of Vitamin D-Active Compounds . . . . . . . . . . . . . . . . . . . . Sandra Kruuse and Huns-Gunther Schmnlz

2 I2

Syntheses of Oligo(thiazo1ine) Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Subine Hoppen and Ulrich Koert

2 18

Camptothecin - Synthesis of an Antitumor Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stcfun Biiurle and Ulrich Koert

232

Polycyclic Guanidines From Nature's Shaped Cations to Abiotic Anion Hosts . . . . . . . . . . . Hans-Dieter Arndt und Ulrich Koert

241

Synthetic Access to Epothilones - Natural Products with Extraordinary Anticancer Activity . 25 I Ludger A. Wessjohunn und Giinther Scheid Total Syntheses of the Marine Natural Product Eleutherobin . . . . . . . . . . . . . . . . . . . . . . . Thonius Lindel

268

Selectin Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

275

Murkiis Riisch und Kurola Riick-Bruun

Crossing the Finishing Line: Totdl Syntheses of the Vancomycin Aglycon . . . . . . . . . . . . . . Holger Herzner and Kurola Riick-Braun

281

B. Synthesis of Non-Natural Compounds and Materials An Update on the New Inductees in the ,,Hall of Phane" Graham -1. Bodwell

-

No Phane, No Gain! . . . . . . . . .

289

Well-Rounded Research: Nanotubes through Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . Burkhurd Kiinig

30 1

From Random Coil to Extended Nanocylinder: Dendrimer Fragments Shape Polymer Chains Holger Frey

306

C. Solid Phase Synthesis and Combinatorial Chemistry Combinatorial Methods - Prospects for Catalysis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reinhard Racker and Oliver Reiser

3 I4

The Renaissance of Soluble Polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

322

M. Reggelin

Polymeric Catalysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M. Reggelin

328

Combinatorial Chemistry for the Synthesis of CarbohydrateKarbohydrate Mimics Libraries Prubhat Arya, Robert N . Ben and Kristina M. K. Kutterer

. 337

Combinatorial Biosynthesis of Polyketides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kui Donsbuch and Kamla Ruck-Braun

343

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

351

List of Contributors

Dr. P. Arya Steacie Inst. f. Mol. Sciences Nat. Research Council of Canada 100 Sussex Drive CanadaKlA OR6 Ottawa

Prof. Dr. G. Dyker FB6-Inst. f. Synthesechemie der Universitat-GH Duisburg Lotharstr. I 47048 Duisburg

Dr. G. J. Bodwell Department of Chemistry Memorial University of NF KanadaAlB 3 x 7 St. John’s

Dr. H. Frey Inst. fur Makromolek. Chemie (FMF), Universitat Freiburg Stefan-Meier Str. 21/31

Priv.-Doz. Dr. B. Breit Organisch-Chemisches Institut der Universitat Heidelberg Im Neuenheimer Feld 270 69120 Heidelberg

Prof. Dr. A. Fiirstner Max-Planck-Institut fur Kohlenforschung Kaiser-Wilhelm-Platz I 45470 Miilheim

Dr. J. P. Clayden Department of Chemistry University of Manchester Oxford Rd. M13 9PL Manchester

Prof. Dr. N. Krause Lehrst. fur Organische Chemie Universitat Dortmund 44221 Dortmund

Prof. A. P. Davis Department of Chemistry (University of Dublin Trinity College Ir-2 Dublin Dr. R. Duthaler Novartis Pharma AG WSJ-507.109 Postfach 4002 Base1

Prof. Dr. U. Koert Institut fur Chemie der Humboldt-Universitat Hessische Str. 1-2 10115 Berlin Prof. Dr. B. Konig Inst. fur Organische Chemie der Universitat Regensburg Universitatsstr. 3 1 93053 Regensburg

XI1

List

of Contributors

Dr. T. Lindel Pharmazeut.-chem. Institut der Universitat Heidelberg Im Neuenheimer Feld 364 69 120 Heidelberg

Prof. Dr. T. Skrydstrup Department of Chemistry University of Aarhus Langelandsgade I40 DK-8000 AarhudDenmark

Dr. M. Reggelin Institut fur Organische Chemie Universitat Mainz Dusbergweg 10- 14 55099 Mainz

Prof. Dr. R. Selke Ifok, ,,Asymmetrische Katalyse" an der Universitat Rostock Buchbinderstr. 5-6 18055 Rostock

Prof. Dr. 0. Reiser Institut fur Organische Chemie der Universitat Regensburg Universitatsstr. 3 1 93053 Regensburg

Dr. P. Somfai Dept. of Organic Chemistry Stockholm University Arrhenius Laboratory 10691 StockholmE Dr. R. Sturmer BASF AG Hauptlaborat., ZHF/D A30 67056 Ludwigshafen

Dr. K. Ruck-Braun Institut f. Organische Chemie J. Gutenberg-Universitat Mainz Duesbergweg 10- 14 55099 Mainz Prof. Dr. H.-G. Schmalz Inst. fur Organische Chemie Universitat Koln GreinstraRe 4 50939 Koln Dr. C. Schneider Institut fur Organische Chemie der Universitat Tammannstr. 2 37077 Gottingen

Prof, Dr. D. F. Taber Dept. of Chemistry and Biochemistry University of Delaware USA 19716 Newark Prof. Dr. L. A. Wessjohann Faculty of Chemistry (N 348) Vrije Universiteit Amsterdam de Boelelaan 1083 HV 1081 Amsterdam PD Dr. T. Wirth Institut fur Organische Chemie Universitat Basel St. Johanns-Ring 19 4056 Basel

Part I. Synthetic Methods

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

A. New Methods in Stereoselective Synthesis Stereocontrolled Simmons-Smith Cyclopropanation Julia Schuppan and Ulrich Koert Institut .fur Chemie, Humboldt Universitat Berlin, German);

The cyclopropyl subunit is a frequent structural element in natural and non-natural products. In FR-900848 (1) [ 11, a natural product with fungicide bioactivity even five cyclopropane rings are found, which make its structure remarkable and its synthesis a challenging issue. Other representatives of naturally occurring cyclopropanated compounds are ah-coronamic acid (2) [2] and cis-chrysanthemic acid (3) [3]. Among the nonnatural products containing cyclopropane rings the perspirocyclopropanated [3]-rotaxane (4) [4] and the trifunctional fullerene ( 5 ) [ 5 ] are worth mentioning.

AH

* COOH

aNo -coronamic acid 2

cis -chrysanthemic acid

C02Et

bpEt

4

Figure I

5

3

From the multitude of synthetic work in the field of cyclopropanation, we will focus on the asymmetric synthesis of cyclopropanes. Besides the known \tereocontrolled addition of diazocompounds to olefins (diazo-method) [6] the stereocontrolled Simmons-Smith cyclopropanation has received significant attention in the last ten years. The latter will be discussed further. The reaction of activated zinc and CH,I, results in the formation of a zinc carbenoid reagent “IZnCH,I”, which, originally introduced to literature by Simmons and Smith, converts alkenes into cyclopropanes [7]. For a successful reaction the activation of zinc metal is essential. Apart from the originally applied Cu [7] by Simmons and Smith the activation may be accomplished using Ag [8], TiCI, [9] or TMSCI/BrCH,-CH,Br (Knochel-zinc) [ 101. Highly activated zinc can also be obtained by the reduction of zinc salts (Rieke-zinc ( 1 I], Furstner-zinc [ 121). Concerning commercially available zinc, the purity is of great importance. Electrolytically prepared zinc is highly pure, but pyrometallurgically made zinc, which is obtained by distillation, contains traces of lead. which can inhibit the cyclopropanation reaction [13]. Despite the various methods for activation of i n c metal, the Simmons-Smith reaction remains a heterogeneous reaction, holding all known preparative disadvantages. Hence, many efforts have been directed towards the development of homogeneous reaction conditions. Among others, two particularly successful methods will be highlighted here: the Furukawa-procedure (Et,Zn + CH,I,) [ 141 and the Sawada-procedure (EtZnI + CH,I,) 1151 [Eq. (1)l.

4

A. New Methods in Stereoselective Syithesis

Although the Simmons-Smith cyclopropanation has attracted increased attention during recent years, the exact structure of the cyclopropanating reagent is still uncertain. NMR-spectroscopic investigations revealed a Schlenk equilibrium between IZnCH,I and ICH,ZnCH,I [Eq. (2)] 1151.

Simmons-Smith 61% CH212+Zn Furukawa-method CH212+ EtpZn 79% Sawada-method CH212+ EVnl 92%

0 -

(1)

Another approach in the preparation of zinc carbenoids has been developed by Wittig [ 161. It involves the reaction of diazomethane with a Zn(I1) salt, but the delicate preparation of diazocompounds has hindered the wide spread preparative application so far (scheme I). DIAZO-METHOD

/=

-

%OMe

M L*

+

$0.

M = CU, Rh

NZ

R

b

ZINC CARBENOID-METHOD Furu kawa

Simmons-Smith act. Zn

+ CHZIz

EtpZn +CH2I2

Sawada EtZnl

+ CH212

Scheme f. Diazo method and zinc carbenoid method for cyclopropanation

The advantages of the homogeneous procedure are evident: mild conditions and low temperatures cause increased compatibility with other functional groups. The control of stoichiometry is simplified compared to the heterogeneous case by the application of an organo-zinc solution of known molarity. Furthermore, the homogeneous reaction also proceeds in non-coordinating solvents, which is of great importance especially for asymmetric synthesis. Finally, compared to a heterogeneous reaction the homogeneous procedures afford higher yields in most cases.

2 IZnCH21

F - ICH2ZnCH21+ Znl2 (2)

Denmark et al. studied the effect of zinc iodide on the catalytic, enantioselective cyclopropanation of allylic alcohols with bis(iodomethy1)zinc as the reagent and a bismethanesulfonamide as the catalyst [ 171. They found significant rate enhancement and an increased enantiomeric excess of the product cyclopropane upon addition of 1 equivalent zinc iodide. Their studies and spectroscopic investigations showed that the Schlenk equilibrium appears to lie far on the left (IZnCH,I). Charette et al. used low temperature "C-NMR spectroscopy to differentiate several zinc-carbenoid species [IS]. They also found evidence that in the presence of zinc iodide, bis(iodomethy1)zinc is rapidly converted to (iodomethy1)zinc iodide. Solid-state structures of (halomethy1)zinc species have been described by Denmark for a bis(iodomethy1)zinc ether complex (6a) [19] and Charette for an (iodomethy1)zinc iodide as a complex with 18crown-6 (6b) [20] (Fig. 2). However, future work will show whether the cyclopropanating species actually is IZnCHJ or ICH2ZnCH,I. Regarding the addition of a carbenoid 7 to an olefin 8, resulting in the formation of cyclopropane 9, theoretical calculations point towards a concerted mechanism involving a transition state 10 (Scheme 2) [21]. For a better understanding of the transition state of cyclopropanation with zinc carhenoids a reflection on the well-studied lithium carbenoids is profitable. Hoffmann et al.

Me 6a

Figure 2

I CHpl

6b

5

Stereocontrolled Simmons-Smith Cyclopropanution

studied the stereochemical course of the intramolecular cyclopropanation for the carbenoids 11 and 12, utilizing an internal stereocentre as a reference (Scheme 2) [23]. The stereochemically defined lithium carbenoid 11 forms the bicyclus 13 by intramolecular cyclopropanation even at - 1 10 "C. In contrast, no conversion of the epimeric lithium carbenoid 14 into diastereomeric bicyclus 16 is observed under similar conditions. These results are explained on the basis of the transition state structures 12 and 15ah. Structure 12 allows complexation of the lithium atom by ether oxygen. This leads to activation of the carbenoid and accelerates the cyclopropanation (11 + 12 13) by a transition state choreography of type 10. In structure 15a the ether group is in equatorial position, which

does not allow the complexation of the lithium atom. Accordingly, this carbenoid is less reactive and cyclopropanation does not proceed at -110°C. Hoffmann et al. suggest that for this case (14 15b + 1% + 13) the carbolithiation competes with the concerted mechanism. In theoretical studies on the cyclopropanation of ethylene with lithium and zinc carbenoids Nakamura et al. found two competing pathways: methylene transfer and carbometallation 1221. For the lithium carbenoid, both pathways have similar activation energies and may compete in cyclopropanation, which is consistent with the results of Hoffmann's experiment [23]. However, for the zinc carbenoid, methylene transfer is found to be favored, because of a much lower activation energy compared to the carbometallation. --f

--f

r

-

tEuMe2SiO

-11ooc

13

SiMeptBu

14

~ ~

~

15b

15c

~

M H

e

13

Scheme 2. Mechanistic studier on carbenoid mediated cyclopropanation

p

S B

~

~

6

A. New Me1hod.v in SrereoJelertive Synthesis CHzk

H

O

Zn(Cul

G

H

O

O

75%

d s > 99:l

17

18

1.3-allylic strain

OH

19

20

2 ds>99:1

21

Scheme 3. The stereodirecting influence of OH-groups in cyclic and acyclic systems

-

BnO

CH&, EtpZn

Ac

H6

HO"'

Scheme 4. The stereodirecting influence of NH-groups

As found for lithium carbenoids, an activating and directing influence of intramolecular O-donators is also known for zinc carbenoids [21]. Alcohol-groups in cyclic systems seem to have

HL

C

O

?

M

e

a strong syn-directing influence (17 + 18) (Scheme 3) [24]. High stereocontrol in acyclic systems is achieved only if conformational control restricts the rotation of single bonds. This is found for example in the cyclopropanation reaction (19 + 21) (Scheme 3) [25]. Herein, due to 1,3- allylic strain, the three-dimensional arrangement of the directing OH-groups in relation to the double bond is fixed. A directing effect has also been found for intramolecular NH groups. When an OH and an NH group are in competing allylic positions, the cyclopropanation is completely directed by the NH groups. The directing influence by the OH group only comes forward after protection of the amide hydrogen (Scheme 4) [26]. For the enantioselective synthesis of cyclopropanes using zinc carbenoids, two different approaches are possible: first, by using a covalent bound chiral auxiliary or, second, by application of a chiral catalyst. Numerous chiral auxiliaries are known today. For instance, acetals derived from tartaric acid enable the preparation of enantiomerically pure cyclopropanated aldehydes (22 + 23 + 24 + 25) (Scheme 5 ) . Aldehyde 25 is a key intermediate in the synthesis of leucotriene inhibitor 26 [27]. The chiral acetonide 27 has been stereoselectively transformed into 28 by cyclopropanation. This reaction serves as the key step in the synthesis of 29 (Scheme 6) 1281. Cyclopropanated nucleosides such as 29 are interesting drug candidates for HIV therapy.

H&CO,Me

24

23

C02Me

26

Scheme 5. Chiral acetals serving as covalent-bound auxiliaries

7

Stereocontrolled Simmons-Smith Cyclopropanation

54% 55% de

28

27

29

Scheme 6. Stereocontrolled cyclopropanation in the synthesis of cyclopropanated nucleosides

Carbohydrates have been used as chiral auxiliaries in cyclopropanation reactions using zinc carbenoids. The conversion of acetal 30 affords the cyclopropanated compound 31 with high diastereoselectivity [Eq. (3)] [ 291.

Enol ethers may also be cyclopropanated using zinc carbenoids stereoselectively. Furukawa cyclopropanation of enol ether 32 proceeds with high stereoselection, and the obtained cyclopropyl ether 33 can be easily transformed into the enantiomerically pure cyclopropyl alcohol 35 [30]. In this case, high stereoselectivity is achieved by employing the chiral diol 36, which is not commercially available. Using the commercially available enantiopure diol 37, the level of stereoselectivity is significantly lower (Scheme 7). Asymmetric Simmons-Smith cyclopropanation using no covalent-bound auxiliary but a chira1 catalyst have only been successful with allylic alcohols so far. Fujisawa had shown that allylic alcohols such as 38 are converted into the corresponding alcoholate by Et,Zn (1.1 equivalents) first [3 11. Addition of diethyltartrate ( 1 . 1 equivalents) results in the formation of an intermediate 39, which is cyclopropanated under Furukawa conditions (Et,Zn + CH,I,) to give compound

1. EIZZn 2. (+)-dieihyltartraie

31

30

HO

I

0 oc

60H86% 99% de

Zn

EtpZn, CHpIp.

32

CICH2CH2CL -12%

33

ph-v

___)

1. PCC 2. KzCO3

,-'OH

54% 79%ee

I

40

1. E t g n 2. (+)-dieihyllanrate

34

35

OH

OH

36

41

OH

37

Scheme 7. Stereocontrolled cyclopropanation of enol ethers

42

1. E@n 2. (c)-diethyitariraie 3. Etgn, CH&

""Pf OH

70% ee

43

88% 92% ee

44

Scheme 8. Asymmetric cyclopropanation according to Fujisawa

8

A. New Methods in Stereoselective Synthesis

93% ee

38

41

80%ee

ent-40

42

51

Scheme 10. Asymmetric cyclopropanation according 1. 2 eq n-BuLt 2. E'

48

u

A

to Charette

.u

49

Scheme 9. Asymmetric cyclopropanation according to

Kobayashi

40. No significant influence of the double bond geometry on the stereoselectivity was found. Both stereoisomers the E-allylic alcohol 38 and the corresponding Z-configured compound 41 are converted with similar enantioselectivity (ee 70- 80 %). Using silyl-substituted olefins an enantiomeric excess above 90 % has been reached (Scheme 8). Kobayashi et al. successfully performed asymmetric cyclopropanation using substoichiometric amounts of catalyst 45 (Scheme 9). [32] The levels of enantioselectivity achieved are in the 70-90 % range. Both, E- and Z-allylic alcohols are readily converted. Vinylstannanes 46 are also appropriate substrates. The resulting enantiomerically pure cyclopropanated stannanes hold great synthetic potential [33]. Thus, the cyclopropanated stannane 48 can be converted into the substituted cyclopropane 49 after successful tinlithium exchange and electrophilic substitution.

In an extensive study of the effect of experimental variables on the rate and selectivity of this reaction, Denmark et al. found the independent formation of ethylzinc alkoxide and bis(iodomethyl)zinc to be crucial for effective cyclopropanation [34]. They also detected an autocatalytic behavior of the reaction due to the generation of zinc iodide. High enantioselectivity (> 90 %) and excellent yields are observed employing a method developed by Charette et al. (Scheme 10). [35] Herein, a chiral, amphoteric, bifunctional boron acid ester 50 serves as the catalyst. For example, allylic alcohol 38 can be efficiently transformed into compound ent-40 with high enantioselectivity (ee 93 %). Unfortunately, stoichiometric amounts of 50 are necessary. With an acidic binding site at boron and a basic binding site at the carbonyl group, a transition state 51 may be reasonable. The alcoholate of the allylic alcohol and the boron acid ester form an ate-complex where the zinc carbenoid reagent now coordinates at the alcoholate-oxygen and at one of the carbonyl groups. Attack on the double bond proceeds from the direction indicated by the arrow (Scheme 10)

Stereocontrolled Simmons-Smith Cyclopropanation

H

CH&, Ef2Zn, SO, CH2C12.0 ‘C,

OH W

O

9

__f

H

89%

52

O

W

o

H

4 -

53

ds r 99; 1 CH& Eln&, 50. CH2C12.0aC

OH --t

OH

54

93% ds > 99:l CH&. Et2Zn, 50,

OH

57

OTES

56

OTBS

90% ds > 99:l

Scheme 11. Construction of the cyclopropanc rings of FR-900848 (1) according to Barrett CH&, EtzZn, 50, CH2CI2,rt B u 3 S n q Bu3Sn*

OH 58

-

OH

98%

59

l)TBDPSCI, ImH, DMF (88%))

OTBDPS

2)s-BuLi, [ICUPBU~)~. 02

OTBDPS

60

(73%)

s-BuLi

61

75%

62

~TBDPS

Scheme 12. Construction of the cyclopropane rings of FR-900848 (1) according to Falck

[ 3 5 ] . The formation of ate-complexes by those tailor-made ligands of type 50 was proven by X-ray crystallographic investigations [36]. With regard to the synthesis of the oligo-cyclopropane natural product FR-900848 (1) multiple and consecutive cyclopropanation reactions using zinc carbenoids have been applied. Thus, in the total synthesis of 1 by Barrett et al. the Furukawa-procedure was used for the conversion of 52 into the biscyclopropane 53 (Scheme 11). [37] After bidirectional elongation of the molecule, another double cyclopropanation of diene 54 using Charette’s catalyst gave tetracyclopropane 55 in 93 % yield as one stereoisomer only. Finally, the olefin 56 is cyclopropanated at -40 “C to yield the desired pentacyclopropane alcohol 57. Thus, all five cyclopropane rings of

FR-900848 (1) are introduced with Charette’s modified Furukawa method. In the total synthesis of FR-900848 (1) published by Falck et al. a cyclopropane coupling strategy was successfully applied for the preparation of the tetracyclopropane backbone (Scheme 12) [38).

Summary The examples mentioned above illustrate the progress in the field of stereocontrolled cyclopropanation. Nowadays, the asymmetric Simmons Smith cyclopropanation may well be mentioned in the line with other asymmetric reactions like epoxidation or dihydroxylation. High enantioselectivity and diastereoselectivity can be

10

A . New Methods in Stereoselective Synthesis

achieved applying chiral catalysts. Unfortunately, in most cases only allylic alcohols are successfully cyclopropanated using a chiral catalyst in equimolar amounts. Further work upon these problems has to be done and newly developed methods regarding the usage of substoichiometric amounts of the chiral catalyst and the application to other systems than allylic alcohols is to be expected soon. Still, great progress has been achieved so far, which is nicely represented in the recently published total syntheses of

FR-900848 (1).

References [ 11 M. Yoshida, M. Ezaki, M. Hashimoto, M. Yama-

shita, N. Shigematsu, M. Okuhara, M. Kohsaka, K. Horikoshi, J. Antibiot. 1990, 43, 748. [2] K. Burgess, K.-K. Ho, D. Moye-Sherman, Synlett 1994, 575. [3] K. A. Hassal, The Chemistry ofPesticides, Verlag Chemie, Weinheim, 1982, 148. [4] S. I. Kozhushkov, T. Haurnann, R. Boese, A. de Meijere, Angew. Chem. 1993, 105, 426; Angew. Chem Int. Ed. Engl.. 1993, 32, 401. [5] A. Hirsch, I. Lamparth, H. R. Karfunkel, Angew. Chem. 1994, 106, 453; Angew. Chem. Int. Ed. Engl. 1994, 33, 437. [6] M. P. Doyle in Catalytic Asymmetric Synthesis (Ed.: I. Ojima), VCH, Weinheim, 1993, 63; A. Pfaltz, Arc. Chem. Rex 1993, 26, 339; C. Bolm, Angew. Chem. 1991, 103, 556; Angew. Chem. Int. Ed. Engl. 1991, 30, 542; G. Maa, Top. Curr: Chem. 1987, 137, 75. [7] H. E. Simmons, R. D. Smith, J . Am. Chem. Suc. 1958, 80, 5323; H. E. Simmons, T. L. Cairns, S. A. Vladuchick, C. M. Hoiness, Org. React. 1973, 20, 1. 181 J. M. Denis, C. Girard, J. M. Conia, Synthesis 1972, 549. 191 E. C. Friedrich, S. E. Lunetta, E. J. Lewis, J. Org. Chem. 1989, 54, 2388. [lo] P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 2117. [ I l l R. D. Rieke, P. T.-J. Li, T. P. Burns, S. T. Uhm, J. Org. Chem. 1981, 46, 4323. [ 121 A. Fiirstner, Angew. Chem. 1993,105,171;Angew. Chem. Int. Ed. Engl. 1993, 32, 164. [13] K. Takai, T. Kakiuchi, K. Utimoto, J . Org. Chem. 1994,59, 2671. [14] J. Furukawa, N. Kawabata, J. Nishimura, Tetrahedron Lett. 1966, 3353. [15] S. Sawada, Y. Inouye, Bull. Chem. Japn. 1969,42, 2669.

[ 161 G. Wittig, K. Schwarzenbach, Angew. Chem. 1959,

71, 652. [I71 S. E. Denmark, S. P. O’Connor, J. Org. Chem. 1997, 62, 3390. [I81 A. B. Charette, J.-F. Marcoux, J. Am. Chem. SOC. 1996, 118, 4539. [I91 S. E. Denmark, J. P. Edwards, S. R. Wilson, J . Am. Chem. SOC. 1992, 114, 2592. [20] A. B. Charette, J.-F. Marcoux, F. BClanger-GariCpy, J. Am. Chem. SUC. 1996, 118, 6792. [21] A. H. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307; E. Nakamura, A. Hirai, M. Nakamura, J . Am. Chem. SOC.1998, 120, 5844. [22] A. Hirai, M. Nakamura, E. Nakamura, Chem. Lett. 1998, 927. [23] H. C. Stiasny, R. W. Hoffrnann, Chem. Euru. J. 1995, I , 619. [24] S. Winstein, J. Sonnenberg, J. Am. Chem. SOC. 1961, 83, 3235. [25] M. Ratier, M. Castaing, J.-Y. Godet, M. Pereyre, J. Chem. Res. ( S ) 1978, 179. [26] P. Russ, A. Ezzitonni, V. E. Marquez, Tetrahedron Lett. 1997, 38, 723. [27] I. Arai, A. Mori, H. Yamamoto, J. Am. Chem. SOC. 1985, 107, 8254. [28] Y. Zhao, T.-F. Yang, M. Lee, B. K. Chun, J. Du, R. F. Schinazi, D. Lee, M. G. Newton, C. K. Chu, Tetrahedron Lett. 1994, 35, 5405. [29] A. B. Charette, B. Cote, J.-F. Marcoux, J. Am. Chem. SOC.1991, 113, 8166. [30] T. Sugimura, T. Futagawa, M. Yoshikawa, A. Tai, Tetrahedron Lett. 1989, 30, 3807. [31] Y Ukaji, M. Nishimura, T. Fujisawa, Chem. Lett. 1992, 61; Y. Ukaji, K. Sada, K. Inomata, Chem. Lett. 1993, 1227. [32] H. Takahashi, M. Yoshioka, M.Ohno, S. Kobayashi, Tetrahedron Lett. 1992, 33, 2575; N. Imai, K. Sakomato, H. Takahashi, S. Kobayashi, Tetrahedron Lett. 1994, 35, 7045; N. Imai, H. Takahashi, S . Kobayshi, Chem. Lett. 1994, 177. [33] E. J. Corey, T. M. Eckrich, Tetrahedron Lett. 1984, 25, 2419; G. Boche, H. Walborsky in Cyclopropane Derived Reactive Intermediates (Eds.: S. Patai, Z . Rappoport), Wiley, Chichester, 1990. [34] S. E. Denmark, B. L. Christenson, D. M. Coe, S . P. O’Connor, Tetrahedron Lett. 1995, 36, 2215; S. E. Denmark, B. L. Christenson, S . P. O’Connor, Tetrahedron Lett. 1995, 36, 2219. [35] A. B. Charette, H. Juteau, J. Am. Chem. SOC.1994, 116, 2651; A. B. Charette, H. Juteau, H. Lebel, C. Molinaro, J. Am. Chem. SOC.1998, 120, 11943. [36] M. T. Reetz, C. M. Niemeyer, K. Harms, Angew. Chem. 1991, 103, 1515; Angew. Chem. Int. Ed. Engl. 1991, 30, 1472. [37] A. G. M. Barrett, K. Kasdorf, J. Am. Chem. SOC. 1996, 118, 11030. [38] J. R. Falck, B. Mekonnen, J. Yu, J.-Y. Lai, J . Am. Chem. SOC. 1996, 118, 6096.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Oppolzer Sultams Oliver Reiser Institut ,fur Organische Chemie, Universitat Regensburg, Germany

On March 15, 1996, Wolfgang Oppolzer, Professor at the University of Geneva, Switzerland, died. Of his numerous important contributions to organic synthesis, the sultams, derived from campher sulfonic acid, have found widespread application especially as chiral auxiliaries. Camphor-I 0-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [ 1, 21. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the n,P-unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-

4

&=Re

5

most all resulting N-acyl derivatives are stable and can be purified by crystallization. Moreover, diastereomeric mixtures can be enriched this way. The chiral auxiliary can be cleaved under mild conditions, without erosion of the induced chirality, by saponification or reduction and subsequently reisolated in high yields and purity [3, 41. One of the most notable properties of sultammodified substrates is that they undergo highly selective reactions in Lewis-acid-catalyzed as well as in thermal processes. There are a number of investigations into the basic selection mechanisms of the sultam auxiliary [S], which were carried out mainly by the groups of W. Oppolzer and D. Curran. In summary, the following model has arisen, which is described here giving the

Scheme I

12

A. New Methods in Stereoselective S ~ n t h e s i s

example of the acryl sultams 4 and 5. It has to be noted that the following discussion relies on the assumption that the conformations of the ground states are similar to the conformations of the transition states. For a side-selective reaction with the CC double bond three conditions have to be fulfilled: The reactive conformation of the possible rotamers (rotation around the OC-CC bond) has to be unambiguous. Of the two possible planar conformations, which allow conjugation with the n-systems, the s-cis-orientation of C = O/ C,=Cp is favored based on steric reasons (0 < NR,, analogously to the well-known fact that (a-enolates of amides are more stable than (E)-enolates). The orientation of the carbonyl group has to be unambiguous, which can be parallel or antiparallel to the nitrogen-sulfur bond. Other orientations are energetically less favored because of the missing mesomeric stabilization with the amide nitrogen. In the most favored conformation, one side of the double bond has to be effectively blocked by the chiral auxiliary to allow an unambiguous attack of the reagent. By choosing the reaction conditions appropriately, the orientation of the carbonyl group can be influenced. Addition of a Lewis acid with mo open coordination sites (e.g. TiCI, or EtAICI,) results in the formation of a chelate 4. It is important to note that the two oxygen atoms connected to sulfur are not equivulenr but that one is positioned pseu-

9

10

do-axial and the other pseudo-equatorial in the five-membered ring. As X-ray structure analyses show [6], the Lewis acid coordinates selectively with the equatorial oxygen atom, since this way an almost planar chelate is formed allowing one to preserve the conjugation of the n-system. In 4, the upper side of the double bond is blocked by the camphor structure, and the attack has consequently to take place from the lower side of the molecule (chelate model). In the absence of Lewis acids or with Lewis acids having only one free coordination site (e.g. BF,) no chelation is possible. Therefore, the unti-position of C = 0 and NSO,, as shown in 5, is favored based on steric and in particular stereoelectronic reasons (minimization of the dipole moment). In this conformation the camphor structure is too far away from the double bond to shield it effectively. However, the axially positioned oxygen atom of the SO, group can now take over that role, so that attack occurs mainly from the top side. Therefore, in Lewis-acid-catalyzed as well as in thermal reactions the same stereoselectivity is induced according to that model. The direction of the induction that is shown in the following examples can be understood in almost all cases with the model described above. Only typical examples of different reaction types can be given; to comprehensively cover the vast number of applications of the sultams is beyond the scope of this article.

11

Scheme 2

Oppolzer Sillturns

Diels-Alder Reactions

13

1,4-Additions

+

Sultam-modified acrylates undergo [4 21-cycloadditions with 1.3-dienes with excellent endo- and side-selectivity in the presence of EtAICI, or TiCI, [7-91. This feature could be used for an effective synthesis of the loganinaglycon 9 (Scheme 2) [lo]: The Diels-Alder reaction between cyclopentadiene and the crotylsultam (S)-6 and the subsequent reductive cleavage of the auxiliary gave rise to 7 in diastereo- and enantiomerically pure form, in which already three stereocenters (C5, C8 and C9) have the right configuration for the final product. Especially elegant is the subsequent regioselective opening of the norbornene structure: epoxidation with concurrent intramolecular epoxide opening of 7 followed by oxidation leads to 8. After reductive opening of the tetrahydrofuran ring and oxidation/ketalization of the resulting CH2-OH group at C9, the breaking point into the norbornane structure is introduced by a regioselective Baeyer-Villiger oxidation of the more highly substituted C-C bond leading to 11. Saponification of the lactone resulted in the highly functionalized cyclopentane derivative 10, in which its "wrong" configuration at C7 is fixed by a Mitsunobu-Inversion. The dihydropyran 9 was finally formed by formylation at C4 and Lewis-acid-catalyzed ring closure.

v

. R' MgX

Acryl sultams such as (R)-12 and (R)-15 are also excellently suited for stereoselective 1,4-additions of various nucleophiles (Scheme 3) [ 1 1- 131. Even simple Grignard reagents can be added with excellent 1,4-regio- and good diastereoselectivity according to the chelate model [ 141, which seems especially useful from a preparative point of view. The resulting (a-enolates 13 and 16 can be captured with electrophiles, which proceeds also with high stereocontrol. It should be noted, that 13 reacts with opposite selectivity to that of 16 in this second step. The additional methyl substituent in (R)-15 is sterically repelled by the camphor structure. Nevertheless, coplanarity of the acryl amide is a necessary condition for the nucleophilic addition. Therefore, despite the unfavorable interactions in the reactive conformation, chelation occurs and attack of the nucleophile takes place from the side away from the auxiliary. For the trapping of the enolate, conjugation is not necessary any longer, resulting in the formation of the more favorable enolate 16, which is attacked from the front.

O

H

C, > 97% de Cp = 82-90% de

13

14

Scheme 3

14

A. New Methods in Stereoseleciive Synihe.yi.7

Enolate Reactions It became apparent from the previous examples that sultam auxiliaries could be used in stereoselective enolate reactions. Indeed, acyl derivatives (R)-18 or (R)-20 can be alkylated in a highly diastereoselective manner [ 151, which was applied e.g. for the synthesis of u-amino acids (Scheme 4) [16-181. After deprotonation of the glycinate (R)-18 with n-butyllithium, the resulting (2)-enolate can be trapped with alkyl-, allyl- or benzylhalides according to the chelate model with selectivities of > 90 % de (> 99 % de after recrystallization). After acidic hydrolysis and cleavage of the auxiliary, enantiomerically pure amino acids (S)-19 are obtained. A complementary method is the highly selective electrophilic amination of (R)-20 with 1 -chloro1-nitrosocyclohexane, which - again according to the chelate model - leads to (R)-19 1191. Syn-, anti- and acetate aldol derivatives can be synthesized by choosing appropriate enolization protocols (Scheme 5) [20]. With lithium, boron and tin Lewis acids, syn-aldols can be obtained via (Z)-enolates [21]. If enolization is carried out with lithium or tin, there are enough open coordination sites available to position the aldehyde and the enolate in accordance with the chelate model for the sultam auxiliary and with the Zimmermann-Traxler model. The combination of these models predicts the formation of 22, which is indeed experimentally obtained. If Lewis acids with only two open coordination sites are used

%,N37FSMe

N

2 ) n-BuLi 1) R'X, HMPA*

3) HCI 0 2

(4-18

(e.g. Et,BOTf), chelatization is only possible between the enolate oxygen and the aldehyde. Such reactions should therefore occur through a transition state which is analogous to 5 and should also lead to 22. However, aldol reactions catalyzed by dialkylboron triflate lead with excellent selectivities to 24. A plausible transition state that reflects this result is depicted in 23, in which the aldehyde reacts with the enolate from the lower face being sterically disfavored. Stereoelectronic reasons (antiperiplanar position of I,, to the aldehyde) could be decisive. If another equivalent of titanium(1V) chloride is added to the boronenolates and only subsequently the aldehyde is introduced, the reaction proceeds via the open transition state 25 and leads to the anti-aldols 26 [22]. The aldehyde attacks the enolate from the sterically favored lower face, and the group R is oriented away from the auxiliary. The asymmetric synthesis of (-)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the meso-aldehyde 27 and (S)-28, the hydroxyaldehyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an u-chiral aldehyde to react to the anti-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 251.

H02C

4) LiOH

(S)-l9

Scheme 4

Oppolzer Sultarns

1) n-BuLi 12) Bu3SnCI]

15

*

3) RCHO

OH

or

0.. -L

64 to 85% de

Li

(R)-21

22

r

9'

-

*xoc+"

OH 98% de

94 to

L 23

24 CI,Ti.

:0

b

antifelkin 27

99% de

89 to

25

26

( S)-28

29

OSiR,

30: (-)-Denticulatin A

The synthesis of heteroarornatic side-chain analogs masked as p-lactarns of paclitaxel was efficiently accomplished by a cyclocondensation strategy between sultam-modified ester enolates and irnines, demonstrating yet another strategy in sultam-enolate chemistry [26].

Scheme 5

QSiR3

31

Scheme 6

Radical Reactions Also for stereoselective radical reactions such as radical additions or radical cyclizations, the camphor sultarn 2 is suitable as an auxiliary (Scheme 7). The acyl radical which was gener-

16

A. New Methods in Stereoselective Synthesis r

1

1 33

(5)-32

b

84% de bei +80”C

34

Scheme 7

ated from the iodo compound (S)-32 can be allylated even at +80 “C with remarkable selectivities [27]. Alkyl radicals also add highly selectively to camphor sultam derivatives of oxime ethers to provide a convenient method for the preparation of enantiomerically pure n,/5dialkyl-/l-amino acids [28]. There are many more applications of the sultams of camphor-sulfonic acid that could have been described in this article. Finally, it should be noted that recently structurally simpler sultams 35, which are available from saccharin, have also been successfully applied as a chiral auxiliary [29].

(035

Figure 1

Without doubt, with the discovery of the sultam auxiliaries W. Oppolzer has earned himself a place in the hall of fame of chemistry. With this contribution he will never be forgotten, even by people who, like the author of this article, have never had the chance to meet him personally. Acknowledgement: The author thanks the Fonds der Chemischen Industrie for financial support.

References [I] W. Oppolzer, C. Chapuis, G. Bernardinelli, Helv. Chim. Actu 1984, 67, 1397-40 1. [2] F. A. Davis, J. C. Towson, M. C. Weismiller, S. Lal, J. P. Caroll, J. Am. Chem. Soc. 1988, 110, 8477. [3] W. Oppolzer, Pure Appl. Chem. 1990,62, I241 -50. [4] W. Oppolzer, Tetrahedron 1987, 43, 1969-2004. [S] B . H. Kim, D. P. Curran, Tetrahedron 1993, 49, 293-3 18. [6] W. Oppolzer, 1. Rodriguez, J. Blagg, Helv. Chirn. Act0 1989, 72, 123-30. [7] W. Oppolzer, D. Dupuis, Tetrahedron Letf. 1985, 26, 5437-40. 181 W. Oppolzer, M. Wills, M. J. Kelly, Tetrahedron Letf. 1990, 31, 5015-18. [9] W. Oppolzer, B. M. Seletsky, Bernardinelli, Tetrahedron Lett. 1994, 35, 3509- 12. [lo] M. Vandewalle, J. Van der Eycken, W. Oppolzer, C. Vullioud, Tetrahedron 1986, 42, 4035 -43. [ 1 I ] W. Oppolzer, G. Poli, Tetrahedron Left. 1986, 27, 4717-20. [ 121 W. Oppolzer, A. J. Kingma, Helv. Chim. Acta 1989, 72, 1337-45. 1131 W. Oppolzer, A. J. Kingma, G. Poli, Tetrahedron 1989, 45, 479-88. [I41 W. Oppolzer, G. Poli, A. J. Kingma, Helv. Chim. Acta 1987, 70, 2201 - 14. [I51 W. Oppolzer, R. Moretti, S. Thomi, Tefruhedron Left. 1989, 30, 5603-6. [ 161 W. Oppolzer, R. Moretti, C. Zhou, Helv. Chim. Actu 1994, 77, 2363-80. [I71 W. Oppolzer, R. Moretti, S. Thomi, Tetrahedron Lett. 1989, 30, 6009- 10. I181 K. Voigt, A. Stolle, J. Saliun, A. de Meijere, Sjnlett 1995, 226. [ 191 W. Oppolzer, 0. Tamurd, Tetrahedron Lett. 1990, 31, 991 -4. 1201 W. Oppolzer, C. Starkemann, Tetrahedron Left. 1992, 33, 2439-42. [21] W. Oppolzer, J. Blagg, I. Rodriguez, J. Am. Chem. Soc. 1990, 112, 2767-72. 1221 W. Oppolzer, P. Lienard, Tetrahedron Lett. 1993, 34, 4321 -4. 1231 W. Oppolzer, J. De Brabander, E. Walther, B. G., Tetrahedron Lett. 1995, 36, 44 13- 16. 1241 W. R. R0ush.J. Org. Chem. 1991,56,4151-4157. 1251 A. Mengel, 0. Reiser, Chern. Rev. 1999, YY, I191 1223. 1261 G. I. Georg, G. C. B. Harriman, M. Hepperle, J. S. Clowers, D. G. V. Velde, R. H. Himes, J. Org. Chem. 1996, 61, 2664-76. 1271 D. P. Curran, W. Shen, Z. Zhang, T. A. Heffner, J . Anz. Chem. Soc. 1990, 112, 6738. [28] H. Miyabe, K. Fujii, T. Naito, Org. Left. 1999, 1 , 569-572. 1291 W. Oppolzer, M. Wills, C. Starkemann, Tetrahedron Lett. 1990, 31, 4117-20.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Oxazolines: Chiral Building blocks, Auxiliaries and Ligands Martin Glos and Oliver Reiser Institut fur

Orgunische Chemie, Universitat Regensburg, Germany

Do you need a chiral starting material which can be converted into a number of enantiopure products? Or a chiral auxiliary to perform an asymmetric transformation at a certain point of a complex molecule? Would you like to have a protecting group for an acid, which activates the orthoposition of an aromatic ring? Or do you need an easy-to-synthesize chiral catalyst? For all these problems oxazolines can be the solution. Oxazolines [ I ] can be synthesized by several routes; two common methods are described below (Fig. 1). Readily available p-amino alcohols 1 can be coupled with an acid chloride to yield the amide 2 which is then cyclized to the oxazoline 3 in the presence of zinc(I1) chloride. Alternatively a one step synthesis of 3 can be achieved by reacting 1 with nitriles. Both methods are reliable

and give good yields. Twofold cyclization which leads to bis(oxazo1ines) 4 is also possible, giving access to a most important class of ligands for asymmetric catalysis. An obvious advantage of oxazolines is their simple synthesis; however, the synthesis of oxazolines depends on the availability of the corresponding amino alcohols, which are generally accessible from the chirul pool in only one enantiomeric form. The recent development of the Sharpless aminohydroxylation [2] makes it possible to synthesize an amino alcohol in both optical antipodes (Fig. 2). For example, starting from 2-vinylnaphthalene (S), the amino alcohol 6 is readily synthesized by the aminohydroxylation protocol [ 3 ] .After deprotection, the free amino alcohol 8 was coupled with dimethylmalonic acid di-

R R’COCI

*

2 R’CN

1 R2 R2 c i o c ~ c o c l

3 R’ R

R 4

Figure 1. Synthesis of oxazolines from p-amino alcohols and carboxylic acid derivatives

18

A. New Methods in Stereoselective Synthesis

BnOCONClNa 4% K20~02(0H), (DHQD)zPHAL

5

6 H2, PdlC

7

8

Figure 2. Use of the Sharpless aminohydroxylation to generate chiral amino alcohols.

Oxazolines as Chiral Auxiliaries

chloride and subsequently cyclized to the corresponding bis(oxazo1ine) 7 which was used as chiral ligand for the Diels-Alder reaction of cyclopentadiene (54) with the acrylamide 55 yielding 56 in 94% ee (ct Fig. 9).

The oxazoline l1 developed by MeYers is a versatile building block for the synthesis of chiral carboxylic acids (Fig. 3). Its synthesis is based

OH 9

1

OMe 11

10

OMe 12

73

R ’ = P h ‘Bu

75.85% ee

NU= Alkyl. CN.

z

=

(

~

~

16 45 to > 95%

de

’

~

~

~

Ph

15

Figure 3. Asymmetric synthesis of carboxylic acids.

17

Oxazolines: Chirul Building blocks, Auxiliaries and Ligands

on the amino alcohol 10 which is accessible from serin [4]. Metallation of 11 followed by quenching with electrophiles was done in numerous variations. One example is the alkylation of 11 which leads to 13 in good optical yields. Probably the reaction proceeds through the highly ordered intermediate 14 in which a Z-enolate is formed and the 1,3-allylic strain (H/Li vs. R/Li) is minimized. Lithium is coordinated by oxygen and nitrogen and directs the electrophile R' X to the lower side of the double bond. The phenyl group is shielding the upper side of the double bond from unwanted non-coordinated attacks of R'X. The auxiliary is hydrolyzed to the carboxylic acid 12 by heating in dilute hydrochloric acid. When R and R' are introduced in the reverse order the enantiomer of 12 is also accessible.

Conversion of the auxiliary into other funcional groups is also possible. For example, 13 can be reacted with methyl triflate, reduced with sodium borohydride and then hydrolyzed with acids to yield the corresponding aldehydes [ 5 ] . 1 ,4-Additions of nucleophiles to a, ,&unsaturated oxazolines of the type 15 are generally conducted with high diastereoselectivity [6]. Good results are obtained with organolithium compounds [7] and silyl enol ethers [8a], while the addition of cyanide seems to be problematic [8b]. For these reactions it is not necessary to have a chelating moiety R' in the auxiliary in order to obtain good selectivities. However, there is a loss of activity, which can in some cases be compensated by activating the oxazoline with acetic anhydride [9].

Me0

-:I:$:?p, ,

MeO& \

Me0

90% M~

Me0

Me0 OMe

Br

OR

Me0

\ '

O

Me0 19

18

20 96%de

Cu-pyridine ____)

-110°C

E = C02Me

21

22 98:2

23

R

R ,

n

n

0 /N

24

25

19

26 up to > 98% ee

Figure 4. Reactions of aromatic systems involving chiral oxazolines.

20

A. New Methods

it1

Stereoselective Swthesis

In aromatic systems, oxazolines can have three different functions (Fig. 4). Firstly, they can be used as protecting groups for carboxylic acids. Secondly, they activate even electron-rich aromatic systems for nucleophilic substitution. Fluorine or alkoxy groups in the ortho position can be substituted by strong nucleophiles such as Grignard reagents. Thirdly, when biaryl compounds with axial chirality are synthesized in these reactions, oxazolines can induce the formation of only one atropisomer with excellent selectivity. These three qualities were all used in the synthesis of 20, a precurser of the natural product isochizandrine [lo]. It is also possible to conduct a diastereoselective Ullmann coupling using 1-bromo-2-oxazolylnaphthalene (21). Binaphthyloxazolines 22 are generated in up to 98 % de and can be further converted to chiral binaphthoic esters 23 [ I I]. Addition of alkyllithium compounds at the ortho-position of oxazolines is possible with heteroarenes as well as naphthalenes 24 (benzene derivatives usually tend to ortho-metallations) [ 121. After reductive cleavage of the auxiliary, enantiopure aldehydes 26 are obtained, which have found wide application as versatile chiral precursers for complex polycyclic natural products.

Oxazolines as Ligands for Chiral Catalysts Oxazolines are excellently suited for the complexation of metals. Based on this knowledge, a variety of metal-oxazoline complexes have been synthesized in recent years and used with outstanding results. In 1986 Pfaltz developed the semicorrin ligands 27 and thereby laid the foundation for future developments [ 131. However, the more recently developed bis(oxazoline) ligands are more easily accessible and have therefore found wider application (Fig. 5 ) . In the beginning, the interest was focused on C,-symmetric bis(oxazo1ines) such as for example 4 and 28-30 [14], and one of the first applications was the rhodium-catalyzed hydrosilylation of ketones. The generally successful concept of C,-symmetry also proved to be advantageous here. The conversion of aromatic or aliphatic ketones 33 to the alcohols 34 was conducted with higher selectivities in the presence of ligand 30 [ 151 than with ligand 31 [ 161, although with the latter 86 % ee could be reached in the reduction of acetophenone (Fig. 6). Copper-bis(oxazo1ine)complexes were used for cyclopropanations [ 171 and aziridinations [ 181 with great success. The latter reaction performs especially well

CN

R’

A

R

R 27

29a: R’ = CN 29b: R’ = H

28

pa----“$3 A

N

R

93-3

N

N

R

X

N

R

R X = OR, SR, SeR, NR2, PPh3

30

31

32

Figure 5. Semicorrin- and oxazoline-ligands for asymmetric catalysis.

Oxazolines: C h i d Building blocks, Auxiliaries and Ligands 1) Ph2SiH2 RhCI3 4 0 (1 mol%)

H 3 C y R

*

0

2) ti+

R = Ar, Alkyl

33

34

Ts

35

97% ee

+ Phl=NTs

37

36

Re

OBz

CuOTf.4,

38 up to 84% ee

+ PhCOiBu

40

39

,Ar

R’

AH

HN’Ar

4 ( 1 eq)

R2Li (2eq))

RIbR2

41

42 57-91% ee

TMSCN

RCHO 43

OTMS R ~ C N

29b (12 rnol%)

esting application of the bis(oxazo1ine)-ligands was shown by Denmark. Alkyllithium compounds can be added enantioselectively to imines, but equimolar quantities of ligand 4 are necessary [2 I]. A catalytic system involving two bis(oxazo1ines) was developed by Corey and Wang [22] for the enantioselective conversion of aldehydes 43 to cyanhydrins 44. One bis(oxazo1ine) (29a) served as ligand for magnesium which coordinates the aldehyde, while the second bis(oxazo1ine) (29b) together with TMSCN provided a source for a “chiral cyanide”. The optical yields were modest for a,punsaturated and aromatic aldehydes (52 % ee for benzaldehyde) and high for aliphatic aldehydes (95 % ee for heptanal). The Mukaiyama aldol reaction could be catalyzed by chiral bis(oxazo1ine) copper(I1) complexes resulting in excellent enantioselectivities (Fig. 7) 1231. A wide range of silylketene acetals 46 and 49 were added to (benzy1oxy)acetaldehyde 45 and pyruvate ester 48 in a highly stereoselective manner. The authors were also able to propose a model to predict the stereochemical outcome of these reactions. Chiral bis(oxazo1ines) 51 with an oxalylic acid backbone were used for the Ru-catalyzed enantioselective epoxidation of truns-stilbene yielding truns-l,2-diphenyloxiranein up to 69 % ee [24]. Thc asymmetric addition of diethylzinc to several aldehydes has been examined with ferrocene-based oxazoline ligand 52 [25], resulting in optical yields from 78-93 % ee. The imide 53 derived from Kemp’s triacid containing a chiral oxazoline moiety was used for the asymmetric protonation of prochiral enolates [26]. Starting from racemic cyclopentanone- and cyclohexanone derivatives, the enantioenriched isomers were obtained in 77-98 % ee. MetalLbis(oxazo1ine) complexes were widely used as effective catalysts for enantioselective Diels-Alder reactions. Two research groups could achieve excellent diastereo- and enantioselectivity for the reaction of cyclopentadiene (54) and the acrylamide 55 (Fig. 9) [27]. Yet the decisive feature is only recognizable when both studies are analyzed together. In both cases the endo products are obtained in high selectivities using either the magnesium- or the coppercontaining catalyst. However, despite the same

H3CYR OH 27-95% ee

44

Figure 6. Application of bis(oxazo1ines) in asymmetric catalysis.

with cinnamic acid esters such as 35. The aziridine 37 was obtained with excellent enantioselectivity and could be further converted to a-amino acid derivatives 1191. Oxidations are also possible with these complexes as two research groups [20] showed in recent developments. The copper(1)catalyzed allylic oxyacylation (Kharasch reaction) of cyclic and acyclic olefines by peracidesters was conducted in the presence of 4 with enantioselectivities up to 84 % ee. Another inter-

21

22

A. New Methods in Stereoselective Synthesis

BnOJ

H

+

0.5-10 mol% A,

R+SEi

0

OH

OTMS

BnO,),/,

S-'Bu R

R=H. 98%ee (95%) R=Me: 97%ee 97:3 sywanti

45

47

46

OTMS

+

f,sJBu

Me
I-lOrnol%B,

~~o,/,/, O

0

SJBu R

R=H: 99%ee (96%) R=Me: 96%ee 94 6 syn:anti

49

48

=A

N-CU-N Ph

50

Ph 2SbFe-

20Tf -

Figure 7. Enantioselective Mukaiyama aldol reaction.

51

52

53

Figure 8. Oxazoline-ligands in asymmetric catalysis.

chirality of the ligands, products of opposite absolute configuration were obtained. These results can be explained assuming the dienophile being coordinated tetrahedrally in the magnesium complex and in square planar configuration in the cop-

per complex. In 57 the acrylate is turned by 90" compared to the coordination in 58. The attack of the diene at the dienophile, which reacts from an s-cis configuration, takes place from the less hindered side opposite the bulky groups (Ph and 'Bu).

Oxazolines: Chiral Building blocks, Auxiliaries and Ligands

54

55

Mgl2* 4 C u (OTf),.

56

(ent)-56

'95

45

<2

'98

4

(ent)-56

56

Figure 9. Asymmetric Diels-Alder reaction with metal-bis(oxazo1ine) complexes.

5

2 mol% A +

foEt

molecular sieve ( 3 4

X THF, 0°C

0 X=OEt R=Ph, 'Pr, Me, OMe, OEt, SBn

59

~

.& 0 ee=97-99%

60 61

20Tf

- '

2H20

Figure 10. Hetero-Diels-Alder reaction catalyzed by chiral bis(oxazo1ines).

23

24

A . New Methods in Stereoselective Synthesis Pd(0) * 32

JR RdR\

‘

X =NuH PPhZ *

s

Nu = Nphth

-

Nu R’02CAR

up to > 99% ee

X = AC, C02Me

62

Ph

RuCI3 / NalOl

64

63

E

02/‘BuCH0 CUL?

(raci-65

66 (69%ee)

,,+Ph

(S)-65

67

Figure 12. Non-C,-symmetric oxazoline-ligands in asymmetric catalysis.

For the enantioselective hetero Diels-Alder reaction, very similar bis(oxazo1ine) complexes proved to be highly efficient [28]. The conversion of several unsaturated keto-esters 59 with ethyl-vinyl ether 60 gave cycloaddition products 61 in 91-99% e e . The enantioselective cycloaddition of thiabutadienes with the acrylate 55 yielding dihydrothiopyranes was conducted with optical yields up to 98 % e e using a C,-symmetric bis(oxazo1ine) ligand derived from 1-amino-indan-2-ol 1291. Three research groups discovered almost at the same time that non-C,-symmetrical oxazolines of the type 3 2 can be even more effective ligands for asymmetric catalysis than type 4 ligands (Fig. 11). For the palladium-catalyzed allylic substitutions on 62, record selectivities could be reached using 32 (X = PPh,) [30]. It seems that not only steric but also electronic factors, which cause different donorhcceptor qualities at the coordination centers of the ligand, seem to play a role here [31]. The reaction products can subsequently be converted to interesting molecules, for example 63 (Nu = N-phthalyl) can be oxidized to the amino acid ester 64 1321.

Optically active lactones can be obtained by a kinetic resolution catalyzed by the copper(I1)catalyst 67 in a Baeyer-Villiger-type oxidation. Molecular oxygen is used as oxidizing agent and an aldehyde has to be added in stochiometric amounts as oxygen acceptor. Again, a ligand of the type 32 proved to be better in this reaction than a bis(oxazo1ine)-ligand; however, the ligand had to be modified with additional groups [33]. The Diels-Alder reaction of 54 and 55 (Scheme 9) is also catalyzed in excellent enantioselectivities (92 % e e ) [34] by a catalyst made of MeMgBr and (ent-32) (X = NTs). lnterestingly the product is 56. This suggests that the chirality transfer is - other than postulated by the authors - not analogous to the model for Mg12*4. The examples described here should give an impression of the numerous applications of oxazolines in organic synthesis. The easy accessibility combined with the excellent qualities in transferring chirality will surely lead to many more applications of oxazolines. Acknowledgement: The authors thank the Fonds der Chemischen Industrie for financial support.

Oxuzolines: Chiral Building blocks, Auxiliaries and Ligands

References [ l J T. G. Grant, A. I. Meyers, Tetrahedron 1994, 50,

2297. 121 G. Li, H.-T. Chang, K. B. Sharpless,Angew. Chem. 1996, 108. 449. [31 S. Crosignani, G. Desimoni, G. Faita, P. Righetti, Tetrahedron. 1998, 54, 1572 I . (41 A. I. Meyers, G. Knaus, K. Kamata, M. E. Ford, J. Am. Chem. Soc. 1976, 98, 567. 1.51 M. Reurnan, A. I. Meyers, Tetrahedron 1985, 41, 837. 161 A. I. Meyers, C. E. Whitten, J. Am. Chem. Soc. 1975, 97, 6266. [7] A. 1. Meyers, M. Shipman, J. Org. Chem. 1991,56, 7098. [8] (a) F. Michelon, A. Pouihes, N. v. Bac, N. Langlois, Tetrahedron Letr. 1992, 33, 1743. (b) N. Dahuron, N. Langlois, Synlert 1996, 51. [9] N. Langlois, N. Dahuron, Tetrahedron Lett. 1990, 31, 7433. [lo] A. I. Meyers, A. Meier, D. J. Rawson, Tetrahedron Lett. 1992, 33, 853. [ I I] T. D. Nelson, A. 1. Meyers, J . Org. Chem., 1994, 59, 2655. [ 121 D. J. Rawson, A. I. Meyers, J. Org. Chem. 1991, 56, 2292. [ 131 (a) A. Pfaltz, Synletr, 1999, 835. (b) H. Fritschi, U. Leutenegger, A. Pfaltz, Angew. Chem. 1986, 98, 100.5. [I41 C. Bolm, Angew. Chem. 1991, 103, 556. 1151 H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Horihata, M. Kondo, K. Itoh, Organometallics 1989, 8, 846. [ 161 H. Brunner, U. Obermann, Chem. Ber: 1989, 122, 499. [I71 (a) R. Lowenthal, A. Abiko, S . Masamune. Tetrahedron Lerr. 1990,31,6005. (b) D. A. Evans, K. A. Woerpel, M. M. Hinman, M. M. Fad, J. Ant. Chern. Soc. 1991, 113, 726. (c) A. Pfaltz, Acc-. Chem. R e x 1993, 26, 339. [ 181 (a) D. A. Evans, M. M. F a d , M. T. Bilodeau, J. Am. Chem. Soc. 1994, 116, 2742. (b) R. E. Lowenthal, S. Masamune, Tetrahedron Lett. 1991, 32, 7373.

25

[191 D. A. Evans, M. M. F a d , M. T. Bilodeau, B. A. Anderson, D. M. Barnes, J. Am. Chem. Soc. 1993, 115, 5328. [20] (a) A. S . Gokhale, A. B. E. Minidis, A. Pfaltz, Tetrahedron Lett. 1995,36, 1831 . (b) M. B. Andrus, A. B. Argade, X. Chen, M. G. Pamment, ihid. 1995, 36, 2945. (211 S. E. Denmark, N. Nakajima, 0. J.-C. -. Nicaise, J. Am. Chem. Soc. 1994, 116, 8797. (221 E. J. Corey, 2. Wang, Tetrahedron Lett., 1993, 34, 4001. 1231 a) D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R. Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc., 1999,121,669. b) D. A. Evans, C. S. Burgey, M. C. Kozlowski, S. W: Tregay, J. Am. Chem. Soc., 1999, 121, 685. [24] N. End, L. Macko. M. Zehnder, A. Pfaltz, Chem. Eur: J., 1998, 4, 818. [25] C. Bolm, K. Muniz-Fernindez, A. Seger, G. Raabe, K. Giinther, 1. Org. Chern., 1998, 63, 7860. [26J A. Yanagisawa, T. Kikuchi, T. Kuribayashi, H. Yamamoto, Tetruhedron, 1998, 54, 10253. [27] (a) E. J. Corey, K. Ishihara, Tetrahedron Lett. 1992, 33, 6807. (b) D. A. Evans, S. J. Miller, T. Lectka, J. Am. Chem. Soc. 1993, 115, 6460. [28] (a) D. A. Evans, E. J. Olhava, J. S . Johnson, J. M. Janey, Angew. Chem., 1998, 110, 3554. (b) M. Johannsen, K. A. Jergensen, Tetrahedron 1996, 52, 732 I . [29] T. Saito, K. Takekawa, T. Takahashi, Chem. Comnz., 1999, 1001. [30](a) P. v. Matt, A. Pfaltz, Angew. Chem. 1993, 105, 614. (b) J. Sprinz, G. Helmchen, Tetrahedron Left. 1993,34, 1769. (c) G. J. Dawson, C. G. Frost, J. M. J. Williams, ihid. 1993, 34, 3149. (d) H. Rieck, G. Helmchen, Angew. Chem. 1995, 107,2881. [ 3 I] (a) J. Sprinz, M. Kiefer, G. Helmchen, G. Huttner, 0. Walter, L. Zsolnai, M. Reggelin, Tetrahedron Lett. 1994, 35, 1523. (b) 0. Reiser, Angew. Chem. 1993, 105, 576. (c) J. M. J. Williams, Synleft, 1996, 705. (d) H. Steinhagen, M. Reggelin, G. Helmchen, Angew. Chem., 1997, 109, 2199. [32] R. Jumnah, A. C. Williams, J. M. J. Williams, Synleft 1995, 82 I . [33]C. Bolm, G. Schlingloff, K. Weickhardt, Angew. Chem. 1994, 106, 1944.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

New Strategies to a-Alkylated a-Amino Acids Thomas Wirth Universitat Basel, Institut fur Orgunische Chemie, Switzerland

Nonproteinogenic a-alkylated a-amino acids are playing an important role in natural products and for biological investigations. Because of the tetrasubstituted asymmetric carbon atom they possess high stability at the stereogenic center. They exert a remarkable influence on the conformation of peptides into which they are incorporated [ 11. They can therefore be used for the investigation of enzymatic mechanisms and as enzyme inhibitors. Furthermore, they are interesting building units for the synthesis of natural products, which has already been demonstrated by several impressive examples [2]. In 1872 the simplest a,a-disubstituted amino acid (2-aminoisobutyric acid, Aib) was described [3]. In 1908 the first optically active representative of this class of compounds, (R)-2-ethylalanine (D-isovaline), was isolated by microbial racemic resolution [4]. Synthetic chemists have therefore been interested in the enantiopure synthesis of a-alkylated a-amino acids for some time. Their powerful methods for the construction of chiral a-amino acids can in some cases also be used for the synthesis of the a-alkylated derivatives which has been the topic of recent reviews ~51. In most of the procedures the stereogenic center is constructed by alkylation of chiral, nonracemic enolates. The established methods, which have been reviewed several times [6], are mentioned only briefly here. One of the classics is the Schollkopf synthesis via bislactim ethers [7]. Beside efficient methods for the preparation of bislactim ethers [8], a derivative of 1 with R = C0,Et has been used for the synthesis of a-alkylated serines [9], and a derivative of 1 with R = H has been used in a

tin-mediated aldol-type reaction to serine compounds as well [lo]. The chirality of an amino acid, mostly valine, is used to create a second stereogenic center by the addition of an electrophile to the deprotonated bislactim ether 1. Acidic cleavage of the bislactim ether makes it possible to synthesize a variety of natural and unnatural amino acids in good yields and optical purities. Similar diastereoselective alkylations of other heterocyclic enolates such as 2 can also lead to a-alkylated amino acids in high optical purities [ I 1, 121. The Seebach method likewise employs a chiral, cyclic enolate 3 (n = 0) (Bz = benzoyl) [ 131. The required imidazolidinones are synthesized by condensation of the corresponding amides with pivalaldehyde. The tert-butyl group is directing the electrophile in a 1,3-induction and determines the configuration of the new stereogenic center. If six-membered heterocycles 3 (n = 1)

E+

1

3 (n =O,l)

Figure 1

2 (X = 0, N-BOC)

4

New Strategies lo a-Alkylated a-Amino Acids

27

BH3-

Me

Me

6

7

BH3-

6

-

Base

Bn ,,,,

'

A

aq. NH&l Bn'

Me +E & 2 ~ e

MO

9

8

are employed in this reaction, it is possible to synthesize a,a-disubstituted p-amino acids as well [14]. If a ferrocenyl substituent is used instead of the tert-butyl group as a directing group, the alkylation proceeds again with excellent stereoselectivities [ 151. Deprotonated oxazaborolidinones 4 can also serve as chiral equivalents of amino acid enolates [ 161. It was found recently that changing the phenyl moiety to a naphthyl moiety on the boron atom in 4 resulted in a further improvement of this methodology [17]. Starting from amino acids, these compounds can be prepared in a few steps in enantiomerically pure form. As in the Seebach method, the chirality of the amino acid is used to control the stereochemistry of a second center, which then directs the attack of the electrophile at the enolate. An interesting version of this concept was published recently [ 181. After reaction of the alanine ester 5 with borane, the mixture of the diastereomers 6 and 7 could be separated (Scheme 1). The chiral nitrogen atom directs the attack of the electrophile at the enolate. The direction of the attack can be explained by the Felkin - Anh model, because the electrophile approaches anti to the largest (benzyl) substituent. The enolate shown

p h y C 0 2 E t

Me/ N, Boc

in 8 should be preferred because of the repulsion of the boron and the carboxy group. The boron is removed by aqueous work-up and the a-methylated amino acid 9 is obtained in enantiomeric purities up to 82 %. The chirality of the phenylalanine derivative 10 is used for a direct. stereoselective a-alkylation (Scheme 2) [19]. After treatment with base and reaction with an electrophile the a-alkylated amino acid 11 is obtained in up to 88 % ee. It is not yet clear whether the deprotonated species is an enolate with a chiral nitrogen atom (12) or a chiral, a-metallated compound (13). The protecting groups on the nitrogen seem to play an important role. It is not yet possible to alkylate other phenylalanine derivatives by means of this reaction. A fast access to a-alkylated amino acids is also possible by the Claisen rearrangement of chelated enolates [20].Esters of type 14 rearrange after treatment with base and chelation with a metal salt. The products 15 are obtained in good yields and with diastereoselectivities up to 99 YO(Scheme 3). Other rearrangements have been used as well to create quaternary stereocenters of a,a-disubstituted amino acids. The rearrangement of O-acylated azlactones 16, described by Steglich in 1970

- ph3CozEt Ph

1. Base 2. E+

Me0

Boc

Boc

tE; ; , -h P Me-N

: \

10

Scheme 1. Synthesis of a,a-disuhstituted amino acids from a-methylated amino acids (Bn = Benzyl).

11

:

)so

t-BuO

13

Scheme 2. Asymmetric aalkylation of a substituted phenylalanine (Boc = terfhutoxycarhonyl).

28

A. New Methods in Stereoselective Synthesis

R'

1. Base YHN

2. MXn 0

R2

14

0

:;A

coo H

Y

Y=

A,,

Sclzeme 3. a-Alkylated amino acids by Claisen rearrangement.

15

[21], has been developed into an efficient stereoselective method using the chiral catalyst 17. Protected serine derivatives of type 18 are accessible in high yields and with excellent stereoselectivities as shown in Scheme 4 [22]. A Lewis acidcatalyzed rearrangement of epoxides, first reported by Jung et al. for the asymmetric synthesis of a-alkylated amino acids 1231, was used recently for the synthesis of similar derivatives [24]. The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, u-alkylated amino acids are obtained in high yields and optical purities [26]. A new variant of this reaction reported recently employs valine to build a cyclic imine [27]. The cyclic imine 19 is obtained by conden-

sation of hydroxyacetone with valine, which reacts with cyanide to yield amino nitrile 20. With tert-butyl hypochlorite and triethylamine an imine is formed, which gives after acidic hydrolysis enantiopure a-methylserine 21 in an overall yield of about 55 % (Scheme 5 ) . The stereochemical information for the asymmetric Strecker reaction can even be located outside the heterocycle, as demonstrated with the compounds 22 [28] and 23 [29] as precursors for the synthesis of serine derivatives. Because of the intramolecular protection of the hydroxy group this method allows a rapid and efficient access to hydroxy amino acids. Alternative methods of synthesizing optically active a-methyl serine derivatives have been reported recently 1301. b-Lactams are also suitable intermediates en route to u,a-disubstituted amino acids 1311. In a 1,2-induction the chiral center in 24 is created. After reductive cleavage of the C-N bond enan-

2 mol% 17

BnOKO

'OH iundAr

Ar

16

Ar

18

Scheme 4. Enantioselective rearrangement of 0-acylated azlactones.

New Strategies to a-Alkybted a-Amino Acids

29

Me*' I I

CN-

19

21

20

ko 3

O , Bn N

O

Scheme 5. Asymmetric variants of the amino acid 22

23

tiomerically pure a-alkylated amino acids are obtained. Two directing stereogenic centers are found in oxazinones 25 (Cbz = carbobenzyloxy), which can also be used advantageously in the synthesis of disubstituted amino acids [32]. However, during the reductive liberation of the amino acids the chiral auxiliary is destroyed. Another conventional approach, the addition of electrophiles to enolates of chiral esters, has been

24

25 Me

Me

26

Figure 2

Ph

2

27

synthesis according to Strecker (Bn = Benzyl).

applied successfully by several groups. The 8phenylmenthol ester of N-benzoyl alanine can be deprotonated twice (26) and, after addition of various electrophiles, a-methylated derivatives are obtained. After cleavage of the chiral auxiliary they can be transformed into the enantiomerically pure a-methylated amino acids [33]. Other directing groups such as oxazolidinones 27 [34], imidazolidinones [35] or sultames [36] have been used as well. If a chiral directing group is connected to the N-terminus of a peptide, a stereoselective alkylation of the terminal amino acid is possible [37]. With racemic u-alkylated amino acids an enzymatic racemate resolution is possible. There are several methods to access racemic a-alkylated amino acids in high yields [38]. Different microorganisms have been applied, and the products are obtained in very high enantiomeric purities [39:. Because a-alkylated amino acids are used as building blocks for different active substances, methods for the synthesis of large quantities have been developed, especially in industry [40]. Other effective racemic resolution techniques have been described recently. Disubstituted azlactones of type 28 can react with the phenylalanine derivative 29 [4 I]. The diastereomers of the protected dipeptide 30 are then separated. The easy access of compounds of type 28, together with the optimized reagent 29, ensures

30

A. New Methods in Stereoselective Synthesis

Scheme 6. Synthesis of optically pure Ph

0

0

28

30

29 Me

-

33 C02Me

1. m-CPBA

2. PdlHCO2H

P

h Me

T NHTs

34

I

Me

PQ

32

31

a,a-disubstituted amino acids by treatment of racemic azlactones 28 with 29 and subsequent diastereomer separation of 30.

Scheme 7. Aziridines as intermediates in the synthesis of n,a-disubstituted amino acids (p-Tol: p-tolyl, Ts: p-toluenesulfonyI).

'

OMe

35

36

Ph

37

that the method is powerful for the synthesis of optically pure a,a-disubstituted amino acids (Scheme 6). Nitrogen heterocycles such as azirines and aziridines are also used effectively as building blocks for the synthesis of a,a-disubstituted amino acids. The aziridine derivative 33 is prepared in optically pure form by addition of the lithium enolate 32 to the chiral sulfinimide 31 (Scheme 7) 1421. After oxidation of the sulfoxide to the sulfone and subsequent hydration, the a-methylated phenylalanine derivative 34 is obtained in good overall yield. The introduction of apdisubstituted amino acids into peptides is sometimes troublesome. A recent, easy access to enantiomerically pure 3-amino-2H-azirines offers an elegant way for

Scheme 8. Incorporation of u,a-disubstituted amino acids into peptides on treatment of diastereochemically pure azirines 30 with an amino acid and

scission on the chiral residue.

the incorporation of a,a-disubstituted amino acids into peptides [6b, 431. The amide 35 is treated with phosgene and a base to yield a ketene iminium salt, which then reacts with sodium azide to afford azirine 36 with loss of nitrogen (Scheme 8). Because of the chiral substituent a separation of the diastereomers is possible (only one diastereomer shown here). After reaction with the carboxylic group of an amino acid and acidic cleavage of the chiral auxiliary the dipeptide 37 is obtained. Other conformationally restricted a,a-disubstituted amino acids have been resolved and investigated also by computational methods [44]. Stoichiometric amounts of sometimes cheap chiral reagents have to be used for most of the

New Strategies to a-Alkyluted a-Amino Acids

31

AILi-BINOL. complex (5-10 mol%)

J C 0 2 B n

+

-

qR 0

30

0

R =Me, Et, Ph

39

1.

40 (10 rnol%) R'Br, NaOH 2.

P h A N G o 0R

*

6NHCL 41

R = Me, i-Pr, t-Bu

(7.5 mol%)

Ph

Ph

42

synthetic methods shown above. Very recently first reactions for the synthesis of enantiomerically enriched a-alkylated amino acids have been published in which only catalytic amounts of chiral auxiliaries are needed. Catalytic Michael additions of a-nitroesters 38 catalyzed by a BINOL (2,2'-dihydroxy- 1,1 '-binaphthyl) complex were found to yield the addition products 39 as precursors for u-alkylated amino acids in good yields and with respectable enantioselectivities (8-80 %) as shown in Scheme 9 [45]. Asymmetric PTC (phase transfer catalysis) mediated by TADDOL (40) as a chiral catalyst has been used to synthesize enantiornerically enriched a-alkylated amino acids 41 (up to 82 % ee) [46]. A similar strategy has been used to access a-amino acids in a stereoselective fashion [47]. Using azlactones 42 as nucleophiles in the palladium catalyzed stereoselective allylation addition, compounds 43 were obtained in high yields and almost enantiomerically pure (Scheme 9) [48]. The azlactones 43 can then be converted into the a-alkylated amino acids as shown in Scheme 4.

Ph

Ph

43

Scheme 9. Synthesis of aalkylated amino acids with only catalytic amounts of chiral auxiliaries.

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32

A. N e w Methods in Stereoselective Synthesis

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[22] J. C. Ruble, G. C. Fu, J . Am. Chem. Soc. 1998, 120, 11532-11533. [23] M. E. Jung, D. C. D’Amico, J . Am. Chem. Soc. 1995, 117, 7379-7388. [24] M. Matsushita, H. Maeda, M. Kodama, Tetrahedron Lett. 1998, 39, 3749-3752. [25] A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27. (261 a) K. Weinges, H. Blackholm, Chem. Ber: 1980, 113, 3098-3102; b) P. K. Subramanian, R. W. Woodard, Synth. Commun. 1986, 16, 337-342; c) D. Ma, H. Tian, G. Zou, J . Org. Chem. 1999, 64, 120-125. 1994, [27] a) S.-H. Moon, Y. Ohfune, J. Am. Chern. SOC. 116, 7405-7406; b) Y. Ohfune, S.-H. Moon, M. Horikawa, Pure Appl. Chem. 1996, 68, 645648; c) M. Horikawa, T. Nakajima, Y. Ohfune, Synlett 1997,253-254; d) Y. Ohfune, M. Horikawa, J . Synth. Org. Chem. Jpn. 1997, 55, 982-993. [28] J. A. Marco, M. Carda, J. Murga, R. Portoles, E. Falomir, J. Lex, Tetrahedron Lett. 1998, 39, 3237-3240. [29] a) J. A. Marco, M. Carda, J. Murga, S . Rodriguez, E. Falomir, M. Oliva, Tetrahedron: Asymmetty 1998, 9, 1679-1701; b) M. Carda, J. Murga, S. Rodriguez, F. Gonzilez, E. Castillo, J. A. Marco, Tetruhedron: Asymmetry 1998, 9, 1703- 17 12. [30]a) P. Wipf, S. Venkatraman, C. P. Miller, Tetruhedron Lett. 1995,36,3639-3642; b) D. Obrecht, M. Altorfer, C. Lehmann, P. Schonholzer, K. Muller, J . Org. Chem. 1996, 61, 4080-4086; c) R. Grandel, U. Kazmaier, Eul: J. Org. Chem. 1998, 409-417. 1311 I . Ojima, Ace. Chem. Rex 1995, 28, 383-389. 1321 a) R. M. Williams, M.-N. Im, J. Am. Chern. Soc. 1991, 113, 9276-9286; b) J. E. Baldwin, V. Lee, C. J. Schofield, Synlett 1992, 249-25 1. 1331 D. B. Berkowitz, M. K. Smith, J. Org. Chem. 1995, 60, 1233- 1238. 1341 S . Wenglowsky, L. S. Hegedus, 1.Am. Chenz. SOC. 1998, 120, 12468- 12473. [35] G. Guillena, C. Najera, Tetrahedron: Asymmetry 1998, 9, 3935-3938. [36] A. Lbpez, R. Pleixats, Tetrahedron: Asymmetry 1998, 9, 1967- 1977. 1371 K. Miyashita, H. Iwaki, K. Tai, H. Murafuji, T. Imanishi, Chem. Commun. 1998, 1987- 1988. [38] a) D. L. Griffith, M. J. O’Donnell, R. S. Pottorf, W. L. Scott, J. A. Porco, Tetrahedron Lett. 1997, 38, 8821-8824; b) P. Dauban, R. H. Dodd, Tetrahedron Lett. 1998, 39, 5739-5742; c) S. W. Kim, Y. S. Shin, S. Ro, Bioorg. Med. Chem. Lett. 1998, 8, 1665- 1668. [39] S. Sano, K. Hayashi, T. Miwa, T. Ishii, M. Fujii, H. Mima, Y. Nagao, Tetrahedron Lett. 1998, 39, 5571 -5574.

New Strategies to a-Alkylated a-Amino Acids

[40] a) W. H. Kruizinga, J . Bolster, R. M. Kellogg, J. Kamphuis, W. H. J . Boesten. E. M. Meijer, H. E. Schoemaker, J. Urg. Chem. 1988, 53, 18261827; b) J. J. Lalonde, D. E. Berghreiter, C.-H. Wong, J . Org. Chem. 1988, 53, 2323-2327; c ) J. Kamphuis, W. H. J. Boesten, B. Kaptein, H. F. M. Hermes, T. Sonke, Q. B. Broxterman, W. J. J . van den Tweel. H. E. Schoemaker, in Chirality in Industry, Eds. A. N. Collins, G . N. Sheldrake, J. Croshy, Wiley, 1992, 187-208; d) W. Liu, P. Ray, S. A. Benezra, J. Chem. Soc., Perkin Trans. I , 1995, 553-559; e) B. Westermann, 1. Gedrath, Synlett 1996, 665-666. [41] a) D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P. Schonhoker, C. Spiegler, K. Muller, Helv. Chim. Acta 1995, 78, 563580; b) D. Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A. Grieder, M. Kleber, P. Pfyffer, K. Mdller, Helv. Chim. Acta 1996, 79, 1315-1337. 1421 F. A. Davis, H. Liu, G. V. Reddy, Tetrahedron Lett. 1996, 37, 5473-5476.

33

[431 C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1995, 78, 935-946. 144J a) A. Avenoza, J. H. Busto, C. Cativiela, J. M. Peregrina, F. Rodriguez, Tetrahedron 1998, 54, 11659-11674; h) A. Avenoza, P. J. Campos, C. Cativiela, J. M. Peregrina, M. A. Rodriguez, Tetrahedron 1999, 55, 1399- 1406. [45] E. Keller, N. Veldman, A. L. Spek, B. L. Feringa, Tetrahedron: Asymmetry 1997, 8, 3403-3413. 1461 Y. N. Belokon, K. A. Kochetkov, T. D. Churkina,

N. S. Ikonnikov, A. A. Chesnokov, 0. V. Larionov, V. S. Parmir, R. Kumar, H. B. Kagan, Tetrahedron: Asvmmetry 1998, 9, 85 1 - 857. 1471 a) E. J. Corey, F. Xu, M. C. Noe, J . Am. Chem. Soc. 1997, 119, 12414-12415; b) E. J. Corey, M. C. Noe, E Xu, Tetrahedron Lett. 1998, 39, 53415350. [48] B. M. Trost, X. Ariza, Angew. Chem. 1997, 109, 2749-2751; Angew. Chem. Int. Ed. 1997, 36, 263.5 -2637.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

New Sequential Reactions with Single Electron Transferring Agents Troels Skrydstrup Department of Chemistry, University

of Aarhus, Denmark

The construction of complex organic compounds via sequential transformations is by far the most impressive and efficient synthetic strategy to be reported, clearly demonstrating the imaginative and creative abilities of the synthetic chemist. The advantages in the use of such tandem reactions are many and have been thoroughly discussed by Tietze and Beifuss in a review on the subject in Angew. Chem. from 1993 [l]. Now through the work of the groups of Molander and Murphy three newly discovered sequential reactions may be added to this growing list of transformations making use of single-electrontransferring agents such as samarium diiodide and tetrathiofulvalene. These new sequential reactions provide an effective and elegant route to a series of polycyclic compounds. Of the plethora of contemporary organic synthetic reagents now at our disposal, perhaps the most remarkable to stand out in this last decade is the divalent lanthanide reagent, samarium diiodide [ 2 ] . This unique and polyvalent reducing agent has been applied to a multitude of important individual synthetic transformations which are generally associated with high levels of stereochemical control. The secret to the success of this one-electron-donating agent lies in its inr

-

1

Smlz (2.1 eq)

m

88%

I

Scheme 1. Sm1,-induced nucleophilic acyl substitution

termediate reducing potential, such that one of either a radical or carbanionic reaction may be efficiently performed through the judicious choice of both reactants and conditions. As has been demonstrated by several groups, these two reaction types may furthermore be combined in a tandem process, known as a radical/polar sequence [3].That is, an initial Sm1,-induced radical cyclization may be succeeded by a second electron transfer from an additional equivalent of SmI, affording a corresponding organosamarium with concomitant reactions such as P-elimination and intermolecular nucleophilic addition or substitution [3]. Radical cyclizations are thereby terminated by the addition of functionalization rather than its loss, as is characteristic for normal tin hydride-ring forming chemistry. In an extension of this chemistry, Molander and Harris have recently demonstrated that SmI, may additionally be employed in either one of an anionidanionic or an anionichdical sequential reaction for the stereocontrolled construction of complex bicyclic and tricyclic ring systems, which enhances even further the versatility and possibilities of this reagent [4, 51. The Molander team, having greatly contributed to the popularity of this reagent over the last de-

9H

New Sequential Reactions with Single Electron Transferring Agents

35

Hal'

U Second anionic cyclization

H+

1 -

THF.HMPA 68%

aoH Mk

S d 2 (4 eq)

THF, HMPA 83%

Scheme 2. Several examples of sequential anionickanionic reactions promoted by Sml,.

cade, had previously observed that nucleophilic acyl substitution reactions proceed exceptionally well to afford cyclic or acyclic ketones, as exemplified in Scheme 1 161. Bearing in mind the ability of SmI, to promote Barbier-type cyclization reactions with alkyl halides, it seemed possible that these two transformations might be combined in a sequential manner. This was exactly the case when simple-to-prepare substrates as illustrated in Scheme 2 were subjected to four equivalents of SmI, rather than the usual two, leading to a diverse array of cyclic products depending on the substitution pattern chosen [4]. The mechanism proposed for these reactions involves a tetrahedral intermediate which is formed upon nucleophilic addition of an organosamarium generated upon SmI, addition. Libera-

tion of the ketone is then followed by an additional intramolecular attack upon reduction of the second alkyl halide side chain. Crucial to the success of some of these reactions is the sequenced formation of the organosamarium intermediates, controlled by the different reduction rates of alkyl halides displayed by SmI, (krcd(R-,)> kred(R-c,!). In the other cases employing the same halide in the two side chains, it is apparently their length which determines the sequence of attack to the carbonyl functionality. A wide variety of ring systems are made available by this methodology including seven- and eight-membered rings. Highly impressive are the efficient transformations of the last two examples in Scheme 2 to the corresponding tricyclic systems, related to certain naturally occurring sesqui- and sesterterpenes, respectively.

36

A. New Methods in Stereoselective Synthesis

H

48%(41,ds)

Scheme 3. An example of an intermolecular sequential anioniclanionic reaction promoted by Sml,.

-

o

4 Sml,

THF, HMPA

81% TMS \

TMS I

4 SmI,

THF, HMPA 58%

(6 : I )

4 Sm12

OH

49%

Scheme 4. Several examples of sequential anionichdical reactions promoted by SmIz.

An interesting intermolecular version of this reaction has likewise been put forward for the preparation of seven-, eight-, and nine-membered carbocycle, as illustrated with a sole example in Scheme 3 [7]. In contrast to the above, these reactions begin with a carbonyl addition reaction of chloroiodoalkanes to cyclic or acyclic keto esters leading to the formation of an intermediate lactone. An intramolecular nucleophilic acyl substitution then terminates the sequence. The example in Scheme 3 represents a simple method for the construction of the 5: 8 5 tricyclic ring system. In another series of papers, the Molander team demonstrate the efficiency of the Sm1,-promoted anionidradical sequence as a viable approach to similar ring systems [ 5 ] .Basically the same starting materials are exploited again, with the minor but important modification that one of the alkyl halide side chains has been replaced with that of an alkenyl. The logic behind these examples is that in the absence of a second alkyl halide reduction step, the intermediate ketone formed after acyl substitution is reduced to its corresponding ketyl radical with subsequent cyclization onto the unsaturation. As shown by the substrates in Scheme 4, this approach also provides an efficient and facile access to numerous substituted carbocycles, including heterocycles, and in general with high diastereoselective display. However, the best yields of this bicyclization process were noted with substrates possessing activating groups on the alkene. A slight variation of this class of tandem reactions was reported employing a cyanide group as the ketyl radical trap rather than an unsaturated alkane, as shown in the last example in Scheme 4 [8]. In this way, access to bicyclic hydroxy ketones is allowed via one step. A nice extension of this chemistry to sequential anionic/radical/anionic sequence was also provided [5, 91. Normally after acyl addition and radical cyclization onto a C = C bond, the newly formed carbon radical is reduced to an organosamarium intermediate which is subsequently protonated. However, as depicted in Scheme 5 , this organosamarium may be trapped in the presence of a ketone substrate, thus terminating this three-step process. In another demonstration of how such anions may be further exploited, substrates possessing vinyl ethers as the radical acceptor were found to under-

New Sequrntiul Reuctions with Single Electron Transferring Agents

THF, HMPA acetone 67%

M)E J

1,Sm

Y-

Scheme 5. Examples of sequential anionic/radical/ anionic reactions promoted by Sml,.

go a final B-elimination step resulting in the transfer of an alkenyl side chain. These examples certainly suggest the possibility of extending these Sm1,-induced sequential reactions even further.

37

Another impressive array of radical/polar sequential reactions have likewise been in the developmental stage employing an alternative one-electron-transferring agent, which previously has not been exploited in organic synthesis, namely tetrathiafulvalene (TTF). In contrast to the traditional radical/polar reactions induced by SmI, [3], Murphy and collaborators have demonstrated that radical cyclizations promoted by TTF may be terminated by S,I -type nucleophilic substitution at the new exocyclic center [lo]. The principles of this sequence are illustrated in Scheme 6. After single-electron reduction of a suitable substrate A by TTF and subsequent radical cyclization as with the Sm1,-promoted reactions, the newly formed carbon radical center is formally oxidized by combination with the TTF'. radical cation and formation of the corresponding sulfonium ion, rather than being reduced by a second TTF, as is the case when employing divalent samarium. Substitution at the sulfonium ion-bearing carbon center with external nucleophiles (solvents) such as H,O, MeOH or CH,CN were found to follow S,I-type kinetics. These reactions have so far only been applied to aryl diazonium salts and are hence restricted to aryl-type radical cyclizations. Nevertheless an intriguing facet of this chemistry is the ability of this radical/polar sequence to be carried out in the presence of a catalytic amount of TTF, as the one-electron transferring agent is regenerated after nucleophilic attack. This represents a clear distinction from the samarium(I1)induced chemistry, where two equivalents are necessary for the radical/anionic process. Further

A

Scheme 6. Comparison of SmL- and TTF-induced radical/polar sequential reactions.

38

1 "

A. New Methods in Stereoselective Synthesis

-

H H

"

Aspidospermidine

NHZ

I

NH2

Scheme 7. Examples of sequential radicallcationic reactions promoted by TTF with internal nucleophiles.

studies along this line are necessary, as the best yields, as well as appreciable reaction times, were obtained when one equivalent of TTF was employed. A more interesting application of this chemistry involves substrates containing internal nucleophiles allowing the construction of more complex ring systems such as the first two examples shown in Scheme 7 [ 111. In these cases, radical cyclization is terminated by a substitution reaction with the appending primary hydroxyl group. A cunning demonstration of this approach was provided by the Murphy group in their model studies for the preparation of the ABCE tetracyclic substructure of the Aspidosperma alkaloids, such as aspidospermidine and strychnine [ 121. Diazotization of precursors B and C and their subsequent reaction with TTF were performed in situ and furnished the desired tetracyclic ring systems in good yields (Scheme 8). Most importantly, complete stereochemical control at the three contiguous stereocenters was observed affording the all cis product and providing further evidence for the S, I substitution reaction with the sulfonium ion intermediate. This radicaVpolar sequential reaction therefore nicely complements the tandem radical cyclization approach reported by the same group [ 131. However, in order to prepare the E ring of aspidospermidine containing the correct heteroatom, it was found that the use of internal nitrogen nucleophiles was not efficient for such TTFmediated cyclizations. To overcome this problem, these reactions were performed in moist acetone in order to introduce a hydroxyl group at the C ring (Scheme 9) [ 141. Manipulations of this com-

B (R=SOzPh) C (R =S02Me)

R = SOZPh, 68% R = SOZMe, 75%

t

&HO

\

R H

T f""

CLy) R H

R H

Scheme 8. Synthesis of the ABCE tetracyclic structure of aspidospermidine.

pound then allowed for the introduction of both the E and D rings, thus completing the total synthesis of this natural product. This example represents the first application of this new and powerful ring-forming methodology for the efficient synthesis of a complex natural product. Other examples will no doubt follow. NHCOCF,

/NHcocF3

Scheme 9. Application of the radicallpolar crossover reaction to the total synthesis of aspidospermidine.

New Sequential Reactions with SingIe Electron Transferring Agents

References [I1 L.F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137; Angew. Chem., Int. Ed. Engl. 1993, 32, 131. [21 For several reviews, see: a) A. Krief, A.-M. Lava], Chem. Rev. 1999, 99, 745: b) G.A. Molander, C.R. Harris, Tetrahedron 1998, 54, 3321; c) G.A. Molander, C.R. Harris, Chem. Rev. 1996, 96, 307; d) G.A. Molander in Organic Reactions, Vol. 46, (Ed.: L.A. Paquette), Wiley, New York, 1994, p. 21 1; e) G.A. Molander, Clzent. Rev. 1992, 92, 29; f) D.P. Curran, T.L. Fevig, C.P. Jaspersen, M.L. Totleben, Synletf 1992, 943: g) H.B. Kagan, J.L. Namy, Tetruhedron 1986, 42, 6573. 131 For some applications of this sequential reactions, see: a) G.A. Molander, L.S. Harring, J. Org. Chem. 1990, 55, 6171; b) D.P. Curran, T.L. Fevig, M.L. Totleben, Synlett 1990, 773; c) D.P. Curran, M.L. Totleben, J. Am. Chem. Soc. 1992, 114, 6050. d) M.L. Totleben, D.P. Curran, P. Wipf, J. Org. Chem. 1992, 57, 1740; e) G.A. Molander, J.A. McKie, ibid. 1992, 57, 3132; f) G.A. Molander, J.A. McKie, ibid. 1994,59,3186; g) G.A. Molander, J.A. McKie, ibid. 1995, 60, 872; h) G.A. Molander, C. Kenny, ibid. 1991, 56, 1439; i) G.A. Molander, S.R. Shakya, ibid. 1996, 61, 5885; j ) G.A. Molander, J.C. McWilliams, J. Am. Chern. Soc. 1997, 119, 1265; k) E.J. Enholm, A. Trivellas, Tetrahedron. Lett. 1994, 35, 1627: 1) Z. Zhou, S.M. Bennett, Tetrahedron. Left. 1997,38, 1153: m) D.P. Curran, B. Yoo, Terruhedron. Letr. 1992, 33, 693 I ; n) G.A. Molander, C.R. Harris, J , Org. Clzem. 1998, 63, 812; o) M. Sasaki, J. Collin, H.B. Kagan, Tetrahedron. /.err. 1988, 29, 6105. [4] G.A. Molander, C.R. Harris, J. Am. Chem. Soc. 1995. 117, 3705. [5] a) G.A. Molander, C.R. Harris, J. Am. Chem. Soc. 1996, 118. 4059; b) G.A. Molander, C.R. Harris, J , Org. Chem. 1997, 62, 2944.

39

[61 a) G.A. Molander, J.A. McKie, J. Org. Chem. 1993, 58, 7216; b) G.A. Molander, S.R. Shakya, ibid. 1994, 59, 3445. [7] G.A. Molander, C. Alonso-Alija, J. Org. Chem. 1998, 63, 4366. [Sl G.A. Molander, C.N. Wolfe, J. Org. Chem. 1998, 63, 903 I . 191 G.A. Molander, C.R. Harris, J. Org. Chem. 1998, 63, 4374. I101 a) C. Lampard, J.A. Murphy, N. Lewis, J. Clzem. Soc., Chern. Commun. 1993, 295; b) R.J. Fletcher, C. Lampard, J.A. Murphy, N. Lewis, J. Chem. Soc. Perkin Trans. I 1995,623; c) J.A. Murphy, M. Kizil, C. Lampard, Tetrahedron. Lett. 1996,37,2511;d)T. Koizumi, N. Bashir, J.A. Murphy, Tetruhedron. Lett. 1997, 38, 7635; e) N. Bashir, 0. Callaghan, J.A. Murphy, T. Ravishanker, S.J. Roome, Tetrahedron, Lett. 1997, 38, 6255; f) 0. Callaghan, X. Franck, J.A. Murphy, Chem. Commun. 1997, 1923; g) J.A. Murphy, F. Rasheed, S , Gastaldi, T. Ravishanker, N. Lewis, J. Chem. Soc. Perkin Trans. 1 1997, 1549. [I]] a) J.A. Murphy, F. Rasheed, S.J. Roome, N. Lewis, J. Chern. Soc., Chem. Commun. 1996, 737: b) J.A. Murphy, F. Rasheed, S.J. Roome, K.A. Scott, N. Lewis, J. Chem. Sor. Perkin Trans. I 1998, 2331. [ 121 a) R.J. Fletcher, D.E. Hibbs, M. Hursthouse, C. Lampard, J.A. Murphy, S.J. Roome, J. Chem. Soc., Chem. Commun. 1996, 739; b) R.J. Fletcher, M. K i d , C. Lampard, J.A. Murphy, S.J. Roome, 1.Chem. Soc. Perkin Trans. I 1998, 2341. [ 131 M. Kizil, J.A. Murphy, J. Chem. Soc., Chem. Commun. 1995, 1409;This work has been reviewed in a recent Highlight: U. Koert, Angew. Chem. 1996, 108, 441; Angew. Chem., Int. Ed. Etigl. 1996, 35, 405. [ 141 0. Callaghan, C. Lampard, A.R. Kennedy, J.A. Murphy, Termhedron. Lett. 1999, 40, 161.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Deracemisation by Enantiodifferentiating Inversion in 1,3- and 1,2-Diols Anthony P. Davis Department of Chemistry, Trinity College, Dublin, Ireland

The conversion of achiral molecules into enantiomerically pure chiral compounds [I] is generally accomplished using one of two types of method. On the one hand, the application of a chiral reagent, catalyst or auxiliary may be used to effect an enantioselective synthesis, in which asymmetric induction desymmetrises the starting material to give molecules which are chiral in predominantly one sense. On the other, the use of simple achiral reagents gives a racemic mixture of chiral molecules, which may then be resolved by interaction with a chiral agent. While the first of these methods may give, in principle, 100 % conversion of achiral educt into enantiomerically pure product, the second is limited to 50 % conversion in most cases. Only certain circumstances allow “deracemisation”, whereby a racemate may be converted to a single enantiomer in up to 100 % yield. One possibility is “dynamic resolution”, wherein equilibration of the starting enantiomers permits the enantiodifferentiating reagent, catalyst or complexing agent to deliver a quantitative yield of enantiomerically pure product (e.g. Scheme 1) [2]. An alternative involves destruction of the asymmetric centre in the race-

A

*

P

Scheme 1. Dynamic resolution of an equilibrating mixture of enantiomers. S, and S, represent substrate enantiomers, A represents the resolving agent (reagent, catalyst or complexer) and P, the enantiomerically pure product.

mate, followed by enantioselective regeneration [3]; this is, however, only trivially different from conventional enantioselective synthesis. More distinctive, conceptually, are methods for deracemisation in which enantiomers are differentiated in an initial step and then carried along separate paths to the same enantiopure final product. Such methods may be unwieldy if separations are required, but elegant and practical if the material can be kept together throughout the procedure.

la

Ib

2

While most of these “divergent-convergent’’ deracemisations rely on biocatalysis [2a, b], there is no reason why chemical methodology should not be used, provided selectivities are sufficiently high. An impressive example was provided by Harada, Oku and co-workers 141, in research leading up to a landmark paper in 1995 [4c]. The methodology developed by the Japanese group was based on the chemistry of menthone-derived spiroketals 1 [4a]. The [6, 61 bicyclic framework of this system sets up interactions and dispositions which rigorously control the stereochemistry of many of its reactions. The major source of stereochemical bias is the isopropyl group, which determines the conformation of the menthone-derived ring (see la) and also fixes that of the 1,3-dioxane ring (see lb) by prohibiting 2. Important consequences are that (a) substituents at positions 2 and 4 of the dioxane must take just one of the two possible

Deracemisation by Enantiodifferentiating Inversion in 1,3- and 1,2-Diols

v-vR . .

R

. .

. .

Me3SiO

R

MeaSiOTf, CH2C12

+

OSiMe3

OoC,6h

41

- &J,, '" R

3

5

4

Tick CH2CI2, -85 OC

I R

\

a) dihydropyran, pyH'Ts0-

R

O

W

R

O

H

<

OTHP

OH

b) t-BuOK. t-&OH, 50 oC, 0.5 h

%Fh'

8

orientations (marked eq. in l b ) to avoid 1,3diaxial interactions with a menthone ring carbon, and (b) the dioxane oxygens occupy very different steric environments, the equatorial oxygen (see la) being far more accessible to an approaching electrophile. The well-defined preferences of 1 offer various opportunities for the development of stereoselective methodology, not least the desymmetrisation of meso-1,3-diols which proceeds as shown in Scheme 2 [ 5 ] . Ketalisation of TMS ethers 3 with L-menthone 4 under thermodynamic control leads exclusively to dioxanes 5, in which both groups R are equatorial. When 5 are treated with silyl enol ether 6 and TiCl, at low temperature, the less-hindered equatorial ketal oxygen is attacked preferentially by the Lewis acid. The resulting oxonium ion is quenched selectively from the equatorial direction [6] to give "monoprotected diol" 7 as a single stereoisomer. Derivatisation of the free hydroxyl group followed by base-induced removal of the chiral auxiliary can give the alternative protection pattern as in 8. Notably, this sequence can be carried out on meso- 1,3-diols even when contaminated by the D,L-diastereomer. The latter can only form "eq.-ax." acetals such as 9 in the initial step, and therefore prefer to remain unreacted.

7

Scheme 2

R&oQ

A

9

This procedure is elegant and useful, but conventional in that, like most enantioselective syntheses, it involves an achiral starting material desymmetrised by a chiral reagent. However, as shown in Scheme 3, the methodology was extended in a remarkable and unusual direction through the application of similar chemistry to racemic starting materials [7]. To allow a generalised discussion of this and subsequent procedures, it is helpful to introduce special stereochemical descriptors for use with 1,3-diols and their de-

&" &" 0

0

0

0

Figure. 1. C and P centres in 1 Jdioxygenated molecules, as defined for the purposes of this article. External substituent K takes lower priority than central carbon C(2).

42

A. New Methods in Stereoselective Synthesis

4 Me3SiOTf, Me3Si0

OSiMe3

*

CH2C12,4 0 oC. 18 h

&2,<+&> 11

10

12

R

R

14

13

1

PhCOzH. DEAD,

I

PPh3,THF

R I

(Y" *aq OH

OH

NaoH, MeoH /

O

15

A Ph

" W OH R OH

+

/

R-R' OH

16 Scheme 4

OAPh

Scheme 3

rivatives. P and C asymmetric centres are defined as equivalent to R and S with the proviso that the central carbon of the 1,3-dioxygenated system is assigned higher priority than all external substituents (see Fig. I ) 181. Turning to Scheme 3, when TMS ethers 10 are derivatised with I-menthone diaxial interactions can be avoided only if C-10 reacts to give 11, while P-10 reacts to give 12.

OH

R

OH

OH

Accordingly, 11 and 12 are the only stereoisomers detectable [7]. Now if this mixture is treated with enolsilane 6/TiCI,, the course of reaction is again dictated by the conformation of the bicyclic system. Only the equatorial C - 0 bonds are cleaved, so that 11 leads to 13 and 12 leads to 14 [4b]. The diol enantiomers have been differentiated, such that the secondary hydroxyl groups in C and P isomers are respectively exposed and protected. A Mitsunobu reaction inverts the former, while performing a "stereoneutral" displacement in 14. On base-induced deprotection, the products (now regioisomers) convergc on P-diol 15, which is formed in 2 95 % enantiomeric excess. The essential basis of this method is that the equatorial oxygen in an L-menthone derivative must be attached to a Z centre while the axial oxygen must be connected to a P centre. As the equatorial C - 0 is cleaved in the second

Derucemisation by Enuntiodifferentiuting Inversion in 1,3- and 1,2-Diols

P Y

43

Z

O E OH OH 0

t

+ + EtOzC

OH

OH

0

17 a) LiAIH, b) NaH, BnBr c) 6, TiCI4, CH2Clz

10

OH

20

OBn

BnO

OH

0

P-OZNC~H~CO~H, Ph3P, DEAD, THF

\0 %Ph

OCOAr

BnO

+

23

1

10

OCOAr Ar = pCsHdN02

%Ph

24

aq. NaOH, MeOH

w OH

OH

OBn

25

step, the C centre is selectively exposed and converted to P , resulting in deracemisation. This analysis encourages consideration of racemates 16, in which both Z and P centres are present. If the ,L centres in both enantiomers could be converted to P , deracemisation would again be possible (Scheme 4). A remarkable tour de force by the Japanese group showed that this process could indeed

Scheme 5

be effected [4c]. In an initial demonstration (Scheme 5 ) , diol enantiomers 17 were converted directly to menthonides 19 and 20 by treatment with silyl enol ether 18 and Me,SiOTf. After conversion of the esters to benzyloxy groups, the Z centres were revealed using 6/TiCI, to give 2 1 and 22. Mitsunobu inversion of this mixture gave 23 + 24, which on deprotection gave enantiopure (> 95 96 ee) diol 25.

44

A. New Methods in Stereoselective Synthesis

n M

a) EtZBOMe.NaBH, b) 18, Me3SiOTf

f menthonide

OEt 0 O x 0

0

a) LiAIH4, THF b) KN(SiMe&, BnBr c) CHz=CHCH>SnBu3,TiCI4

/

O x 0

28

J

OR

OH

OH

OR

OBn

29

I

a) CH~SOZCI, Et3N b) AcO-Cs', DMF

c) NaOH d)CF&OZH

e )Ac& DMAP, py

30

The scope of the strategy was then extended in spectacular fashion (Scheme 6). The mixture of 19 and 20 was transformed into the corresponding aldehydes 26 through reduction/oxidation of the ester groups. Treatment with the dianion derived from ethyl acetoacetate then led to hydroxyketones 27. Chelation-controlled, sqnselective reduction 191 of this mixture followed by menthonide formation gave 28 as four diaste-

Scheme 6

reomers, each containing two C and two P centres. After ester reduction and 0-benzylation, the stage was set for C-selective unmasking, inversion and convergence. The usual conditions employing 6 were unsuccessful, but the combination of TiC1, with allyltributylstannane produced the desired effect. Equatorial-selective ring-opening yielded the mixture of compounds 29, i n which all the hydroxyl groups were derived

Derucemisation Ov EnantiodiSSererztiuting Inversion in 1,3- and l,2-Diols

R*R

x

x

-

R+R

d

X

31

Y

x

x

X

Y

RIFRz x x 35

34

Rz*R1

x

x

-

x 33

32

x

37

“I

Rz*R’

X

Y

- RzY+R’ x

36

from Zcentres in 28. Hydroxyl inversion, deprotection (including acidic cleavage of the menthylderived tertiary ethers) and reacetylation yielded 30 as a single diastereomer. The enantiomeric purity of 30 was not confirmed, but may be inferred with confidence from the diastereoselectivity and the previous record of the methodology. Intellectually this methodology is elegant and distinctive, especially in its uninhibited use of complex mixtures as intermediates. Judgement

x

Scheme 7

on its practicality is best delayed, but it undoubtedly contributed to an area of real importance in organic synthesis. The 1,3-diol substructures generated are relevant to important classes of natural products [ 101 most notably the polyene macrolide antibiotics [ I l l . Indeed, 30 contains a stereochemical pattern present in several such targets, including rotaxicin and mycoticin A and B. From another perspective, the work further demonstrated the value of organo silicon- and orga-

OEt P

R,.

h

A

R

>.

(

OEt

M

oyo

TsOH (cat.)

38

I

L

w

OH

.R

R.

M

HO

Ijl Ph

=(sBu‘ B.->; Ph

Ph OTMS

39

Ts

40

Ph

P

R,

A

HO

i,protection 4

OP

ii, LDA

41

45

)i-SBut 0

Scheme 8

46

A. New Methods in Stereoselective Synthesis

39

Ph

R‘

43

ii, KOAc, DMF, 85 OC

40

Ph \OHOH R2

0

no- tin-based nucleophiles in organic synthesis [ 121. Their comparatively low reactivity often generates the need for catalysis, providing a dimension of control which may be exploited to various stereochemical ends [ 13I. The application in this case was delightfully oblique (C-C bond formation is not usually employed to elaborate a protecting group in a synthetic intermediate), and nicely illustrated the versatility of these widely-used reagents. The progression from desymmetrisation (Scheme 2) to derdcemisation (Schemes 3-6) leads to a useful general insight. The desymmetrisation of a-symmetric difunctional compounds (31 + 32, Scheme 7) is a common approach to asymmetric synthesis 1141, and there may be various circumstances where the regeneration of functional symmetry, but with stereoinversion, is also possible (32 + 33). If 31 is now allowed to “mutate” into the asymmetrical 34, present as a racemate, it is likely that the desymmetrising reaction will yield 35 + 36, converging on 37 after the final step. Any desymmetrisation of a-symmetric (e.g. meso) diols may thus be extended, potentially, to deracemisation, and other substrates may lend themselves to analogous sequences. Harada, Oku et al. have themselves illustrated this point by developing a second deracemisation,

R’

0

Scheme 9

this time of I ,2-diols. The desymmetrisation method shown in Scheme 8 relies on chiral reagent 39, rather than a covalently-bonded chiral auxiliary, and proceeds to give a range of asymmetrically protected products 41 in > 70 % yields and 2 95 92 ee [IS]. Having been applied to meso-diols 38, the methodology was then extended to racemates 42 (Scheme 9). The necessary inversion was achieved via an intramolecular displacement, to give epoxides 43 in, for most cases, > 90 % ee [16].

Reference [ I ] General reference: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann (eds.), Hoiiben- Weyl Methods of’ Organic Chemistry, Vol. E 21, Stereoselective Synthesis, Thieme, Stuttgart, 1995. See also: R. Noyori, Asymmetric Catalysis in Organic Synthesis, John Wiley, Chichester, 1994; M. Nbgridi, Stereoselective Synthesis, VCH, Weinheim, 1995; R. S. Atkinson, Stereoselective Synthesis, John Wiley, Chichester, 1995; G. Procter, Asymmetric Synthesis, OUP, Oxford, 1996. [ 2 ] For leading references, see: a) U. T. Strauss, U. Felfer, K. Faber, Tetrahedron-Asym. 1999, 10, 107; b) H. Stecher, K. Faber, Synthesis 1997, 1; c) R. S. Ward, Tetrahedron-Asym. 1995, 6, 1475; d) M. Kitamura, M. Tokunaga, R. Noyori, J . Am. Chem. Soc. 1993, 115, 144.

Derucemisation by Enuntiodifferentiuting Inversion in 1,3- and 1,2-Diols

[3] For examples involving deprotonation-protonation, see: C. Fehr, Angew. Chem. 1996, 108, 2726; Angew. Chem. Int. Ed. Eiigl. 1996,35,2567. [4] a) T. Harada, A. Oku, Synlett 1994, 95; b) T. Harada, H. Kurokawa, A. Oku, Tetrahedron Lett. 1987, 28, 4847; c) T. Harada, T. Shintani, A. Oku, J. Am. Chem. SOC. 1995, 117, 12346. [ S ] T. Harada, K. Sakamoto, Y. Ikemura, A. Oku, Tetrahedron Lett. 1988, 29, 3097. [6] T. Harada, T. Hayashiya, I. Wada, N. Iwa-aki, A. Oku, 1.Am. Chetn. Soc. 1987, 109, 527. [7] T. Harada, H. Kurokawa, A. Oku, Tetrahedron Lett. 1987, 28, 4843. [8] Note that in polyoxygenated systems a given centre may be both Z and P, depending on which 1,3-dioxygenated fragment is under consideration. [9] K.-M. Chen, K. G. Gunderson, G. E. Hardtmann, K. Prasad, 0. Repic, M. J . Shapiro, Chem. Lett. 1987, 1923. [lo] T. Oishi, T. Nakata, Synthesis 1990, 635. [ I l l S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021. [ 121 E. W. Colvin, Silicon Reagents in Organic Synthesis., Academic Press, New York, 1988; M. Pereyre, J.-P. Quintard, A. Rahm, Tin in Organic Synthesis., Butterworths, London, 1987.

47

[ 131 Leading references: D. A. Evans, M. C. Kozlowski,

J. A. Murry, C. S. Burgey, K. R. Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999, 121, 669; H. Groger, E. M. Vogl, M. Shibasaki, Chem. Eur. J.l998,4,1137; A. P. Davis, S . J. Plunkett, J. E. Muir, Chem. Commun. 1998, 1797; K. Iseki, S. Mizuno, Y. Kuroki, Y. Kobayashi. Tetrahedron Lett. 1998, 39, 2767; I. Fleming, A. Barbero, D. Walter, Chem. Rev. 1997, 97, 2063; R. 0. Duthaler, A. Hafner, Angew. Chem. 1997, 109, 43; Angew. Chem. Int. Ed. Engl. 1997, 36, 43; G. Stork, J. J. LaClair, J. Am. Chem. Soc. 1996, 118, 247; M. P. Sibi, J. G. Ji, Angew. Chem. 1996, 108, 198; Angew. Chem., Int. Ed. Engl. 1996, 35, 190; L. F. Tietze, C. Schiinke, Angew. Chem. 1995, 107, 1901; Angew. Chem., Int. Ed. Engl. 1995, 34, 1731; L. F. Tietze, K. Schiemann, C. Wegner, J. Am. Chem. Soc. 1995, 117, 5851; T. Bach, Angew. Chem. 1994, 106,433; Angew. Chetn., Int. Ed. Engl. 1994, 33, 417.

[I41 For a selection of methods applicable to diols, see H. Fujioka, Y. Nagatomi, N. Kotoku, H. Kitagawa, Y. Kita, Tetrahedron Lett. 1998, 39, 7309, and references therein. [IS] M. Kinugasa, T. Harada, A. Oku, J. Am. Chem. Soc. 1997, 119, 9067; M. Kinugasa, T. Harada, A. Oku, Tetrahedron Lett. 1998, 39, 4529. [I61 T. Harada, T. Nakamura, M. Kinugasa, A. Oku, Tetrahedron Lett. 1999. 40, 503.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Non-Biaryl Atropisomers: New Classes of Chiral Reagents, Auxiliaries and Ligands? Jonathan Clayden Department of Chemistry, University of Manchestev, I/.K.

While many chemists are familiar with the problems posed by abnormally large barriers to rotation about single bonds when it comes to interpreting NMR spectra, few have sought to make use of these barriers as tools for stereoselective synthesis. A renewal of interest in this prospect followed Fuji’s remarkable observation, published in 1991, of stereospecific alkylation of ketone 1. The stereochemistry of the starting material was retained in the product 2 despite the intermediacy of an apparently achiral enolate (Scheme 1) [I].

& -& Ph

Ph

OEt

’

OEt

KH, 18-crown-6 Me1

OEt

OEt

1 93% ee

2 66% ee

&lEt OEt

3

Scheme I

Et3N.

MeOH. A

4

Scheme 2

5 65%

The conveyor of “chiral memory” in the reaction turned out to be restricted rotation in the enolate intermediate, and Fuji was able to show that the enol ether 3, formed as a by-product in the reaction, was chiral because of restriction to rotation about the arrowed bond, and could be recovered enantiomerically enriched. The enantiomeric excess of 3 decayed with a half-life of about 1 h at ambient temperature, and the enantiomers of 3 are atropisomers [2]. A similar phenomenon was observed by Stoodley and co-workers in the stereospecific cyclisation of 4 to a single isomer of 5 [3]. Again, the most likely explanation was an intermediate with a barrier to racemisation sufficiently high to prevent it interconverting with its enantiomer on the timescale of the reaction (Scheme 2). Reactions like these, in which stereoselectivity is the consequence of steric hindrance to bond rotation, are most well known among the biaryls, and derivatives of binaphthyl have provided chemists with a valuable range of chiral ligands [4-61. But the biaryls are only a small subset of axially chiral compounds containing two trigonal centres linked by a rotationally restricted single bond. Many others are known, some with much greater barriers to rotation than Fuji’s enol ether [7]. Yet until quite recently there were no reports of reactions in which nonbiaryl atropisomers were the source, conveyor, or product of asymmetric induction. An early attempt to exploit the atropisomerism inherent in aromatic amides [S] drew inspiration from the suggestion that the orientation of nicotinamide’s C = 0 bond was fundamental to the stereoselectivity of hydride transfer to or from NADH [9]. Ohno and his co-workers managed

Non-BiuTl Atropisnmers: New Classes of Chiral Reagents, Auxiliuries and Ligands?

to separate a quinolinamide from its atropisomeric diastereoisomer and showed that the face-selectivity of hydride transfer to its methiodide salt 6 was stereoselective (Scheme 3) [lo]. When the diastereoisomer of 6 with the opposite configuration about the C-CO bond was used as the starting material, the diastereoselectivity was inverted, so the configuration of 7 must be controlled by the axial chirality of 6. Similar experiments on enantiomeric atropisomers of dihydropyridines have confirmed this [ I I]. The resulting dihydroquinoline 7 turned out to be an enantioselective reducing agent, since it transformed methyl benzoylformate to methyl(S)-mandelate with 99 % ee. This reaction is

not controlled by axial chirality because with an sp3 hybridised C4 atom there is free rotation about the C-C = 0 bond of 7. Yet the re-oxidised quinolinium salt 6 returned by these reactions recovers its axial chirality with almost complete stereospecificity, making this reaction the first example of an asymmetric synthesis of a non-biaryl atropisomer. The compound is also unique in being what we could term a "chiral shuttle", in which chirality is transferred from the C-CO bond to the chiral centre at C4 and vice versa, with the source of asymmetric induction being destroyed each time. There are as yet no reports of successful translation of non-biaryl axial chirality directly into

CON&

~ * y' Q yo I'

.

9 7 3 diastereoselectivity

Me

Me

vc

H

9 4 5 diastereoselectivity

,

Me

Me

7

6 OH

Scheme 3

99% ee

8 93:7 diastereoselectivity

0

9

83%; 2 5 1 atroposelectivlty

>97:3diastereoselectivity

Scheme 4

87%; 1 diastereoisomer only

Scheme 5

0

10 > 9 7 3 diastereoselectivity

11

49

A. New Methods in Stereoselective Synthesis

50

chiral centres in other molecules. However, some recent publications indicate the potential of nonbiaryl atropisomers, and in particular atropisomeric amides, for intramolecular asymmetric induction. Curran (121 showed in 1994 that maleimides bearing ortho-substituted aryl groups could react diastereoselectively, favouring a single atropisomer of the product (Curran termed these reactions "atroposelective"). Racemic maleimide 8 underwent radical reactions and cycloadditions from the face unshielded by the tert-butyl group, as shown in Scheme 4. Acyclic compounds will also react atroposelectively: amide 9 gave the isoxazoline 10 with >97 : 3 diastereoselectivity [ 121, and only one diastereoisomer was obtained from the alkylations or aldol reactions of 11 [I31 (Scheme 5). These high stereoselectivities bode well for the use of axially chiral anilides as chiral auxiliaries,

provided they can be made in enantiomerically pure form. One approach [ 131 employs a kinetic resolution: enolate formation is faster from one enantiomer of the starting anilide 12 than from the other (Scheme 6). An alternative employs classical resolution using lactic acid as the source of asymmetry. Amide formation from (Sj-0-acetyllactic acid and 13 gave a separable mixture of 14 [14, 151. The lactanilides could be eliminated or reduced [ 161 to remove the stereogenic centre to give optically active analogues of 9 and 11. Nonetheless, a serious problem with the effective use of anilides as auxiliaries is their recovery in enantiomerically pure form. In our own group, we [ 171 have shown that rotationally restricted aromatic amides (ArCONR,) can be functionalised atroposelectively, both by nucleophiles and electrophiles [ 181. Atroposelective additions to carbonyl groups are possible:

0

12

up to 88% ee

Scheme 6

Scheme 7 i-Pr,

15

i-Pr.

99.3:0.7 anti selectivity

CPr,

16

97:3syn selectivity

Scheme 8

Non-Biaryl Atropisomers: New Classes of Chiral Reagents, Auxiliaries and Ligands? CPr,

&

51

i-Pr,

1. s-EuLi, THF, -78

OY"-"'

'C

x = Et Me3Si PhMeZSi

1

2. RX or R3SiX or MeOD or R,C=O

\

D

/

MeZ(0H)C

>97:3syn selectivity

Scheme 9

reduction of keto-naphthamides such as 15 with bulky reducing agents gives very high selectivities for attack anti to the bulky N,N-dialkyl group (Scheme 8). Interestingly, reaction of the aldehyde 16 with phenylmagnesium bromide generates the other diastereoisomer atroposelectively. Lateral benzylic lithiation of 2-alkylnaphthamides gives a single atropisomer of the configurationally stable benzylic organolithium, and can be used to introduce electrophiles atroposelectively (Scheme 9). This class of amides has been made enantioselectively - albeit in low yield and low ee by an ortholithiation reaction (Scheme 10). More successful is Uemura's demonstration [ 191 that the arene-chromium tricarbonyl complex chemistry that works with atroposelectivc biaryl couplings is also successful with atroposelective amide-forming reactions (Scheme 11).

These reactions, and other successful resolutions (both classical [20, 211 and on chiral stationary phase IS, 22, 231) of atropisomeric aromatic amides means that this class of non-biaryl atropisomers are now available enantiomerically enriched. Atropisomers should be suited to enantioselective synthesis using thermodynamic control, and Curran has proposed using anilides as "prochiral auxiliaries", responding to stereochemistry within

n-Hex,

n-Hexs

N - n-Hex 1. sec-BuLi. (-)-sparteine

30% yield, 50% ee

Scheme 10

O V N E t 2

Scheme 11

1. LiTMP t-BuOK_MeokQ-O 2. ally1 bromide

MeO+& l

L

87%

17

Scheme 12

A. New Methods in Stereoselective Synthesis

52

0

0

the

Me

21

22

Scheme 13 a molecule and relaying stereochemical information from one centre to another [24]. Taguchi [25] has demonstrated this idea (Scheme 12), with the stereogenic centre of 17 exerting control over the axis of 18 during a cyclisation reaction. T h e axis can now control the enolate chemistry of the product: 19 is formed stereoselectively as the syn stereoisomer. It was possible to remove the anilide portion reductively (with loss of axial chirality) to give the pyrrolidone 20. T h e search for a general synthesis of enantiomerically pure non-biaryl atropisomers has been given added impetus by the discovery [26, 271 that the absolute configuration of some atropisomeric amides affects their biological activity. T h e enantiomeric atropisomers 21 and 22 (Scheme 13) differed in activity at the tachykinin N K , receptor by a factor of 6- 13, with 21 being the more active. Atroposelectivity must now be an important new consideration in drug synthesis. T h e contrasted electronic properties of the carbonyl oxygen atom and steric bulk of the dialkylamino group suggest that these amides would make good candidates as asymmetric ligands for metals, and it should not be long before we see novel classes of ligands based on these structures.

References II ] T. Kawabata, K. Yahiro, K. Fuji, J . Am. Chem. Soc. 1991, 113, 9694. 121 M. Oki, Topics in Srereochein. 1983, 14, I .

[3] B. Beagley, M. J. Betts, R. G. Pritchard, A. Schofield, R. J. Stoodley, S. Vohra, J. Chern. SOC.,Perkin Truns. I 1993, 1761. 141 K. Tomioka, Synthesis 1990, 541. IS] C. Rosini, L. Franzini, A. Raffaelli, P. Salvadori, Synrhesis 1992, 503. [6] R. Noyori, A.symmetric Catalysis in Orgunic Synthesis, Wiley, New York 1994. 171 E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds, Wiley, New York 1994. [8] M. A. Cuyegkeng, A. Mannschreck, Cheni. Ber: 1987, 120, 803. 191 M. C. A. Donkersloot, H. M. Buck, J . Am. Chem. Soc. 1981, 103, 6549, 6554. [ 101 A. Ohno, M. Kashiwagi, Y. Ishihara, S. Ushida, S. Oka, Tetruhedron 1986, 42, 961. 1111 P. M. T. de Kok, L. A. M. Bastiaansen, P. M. van Lier, J . A. J. M. Vekemans, H. M. Buck, J. Org. Chem. 1989, 54, 13 13. [I21 D. P. Curran, H. Qi, S. J. Geib, N. C. DeMello, J . Am. Chem. Soc. 1994, 116, 3 I3 I . [ 131 A. D. Hughes. D. A. Price, 0.Shishkin, N. S. Simpkins, Terrahedron Lett. 1996, 37, 1601. [ 141 0. Kitagawa, H. Izawa, T. Taguchi, M. Shiro, Terruhedron Lett. 1997, 38, 4441. [IS] 0. Kitagawa, H. Izawa, K. Sato, A. Dobashi, T. Tagichi, J . Org. Chem. 1998, 63, 2634. [I61 A. D. Hughes, N. S. Simpkins, Synlett 1998, 967. [I71 J. Clayden, N. Westlund, F. X. Wilson, Tetrahedron Lett. 1996, 37, 5517. [ 181 J . Clayden, Synlett 1998, 8 10. [ 19 I H. Koide, M. Uemura, J. Chem. Soc.. Chenz. Cominun. 1998, 2483. [20] J. H. Ackerman, G. M. Laidlaw, G. A. Snyder, Tetruhedron Lett. 1969, 3879. I211 P. M. T. de Kok, M. C. A. Donkersloot, P. M. van Lier, G. H. W. M. Meulendijks, L. A. M. Bastiaansen, H. J. G. van Hooff, J. A. Kanters, H. M. Buck, Tetrahedron 1986, 42, 941. [22] C. Kietl, H. Zinner, T. Burgemeister, A. Mannschreck, Rec. Trav. Chim. Pnys-Bas 1996, 115, 125. [23] W. H. Pirkle, C. J. Welch, A. J. Zych, J. Chromutogruphy 1993, 648, 101. [24] D. P. Curran, G. R. Hale, S. J. Geib, A. Balog, Q. B. Cass, A. L. G. Degani, M. Z. Hernandes, L. C. G. Freitas, Tetrahedron Asyminetty 1997. 8, 3955. [25] M. Fujita, 0. Kitagawa, H. Izawa, A. Dobashi, H. Fukaya, T. Taguchi, Terruhedron Lett. 1999, 40. 1949. [26] Y. Ikeura, Y. Ishichi, T. Tanaka, A. Fujishima, M. Murabayashi, M. Kawada, T. Ishimaru, I. Kamo, T. Doi, H. Natsugari, J. Med. Chem. 1998, 41,4232. [27] Y. Ikeura, T. Ishimaru, T. Doi, M. Kawada, A. Fujishima, H. Natsugari, 1. Chern. Soc., Chem. Conzmun. 1998, 2141.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Amino Acid Derivatives by Multicomponent Reactions Gerald Dyker Institut ,fur Synthesechemie, Universitut Duisburg, Germany

Amino acids constitute one of the most important classes of naturally occurring substances and possess a variety of biological functions. The areas of application of the amino acid derivatives range from sweeteners through pharmaceuticals to crop and plant protection. Widely applicable methods for the synthesis of a-amino acids [ I , 21 are of great interest, especially for the construction of compound libraries by combinatorial chemistry. Multicomponent reactions, as a special case of a domino process 131, are particularly fascinating since they facilitate rapid syntheses from simple building blocks. A classic example of such a reaction is the Strecker synthesis, which has been known for almost 150 years but is still as topical as ever 141: an aldehyde 1 (or a ketone) is condensed, using an acid catalyst, with an amine 2 and an alkali metal cyanide such as 3 to give an a-aminonitrile 4, which can be hydrolyzed to the amino acid 5. In recent investigations on the

Strecker synthesis attempts have been made to optimize the reaction conditions [4b] and to achieve stereoselective syntheses [4c-h]. Usually chiral amines such as 7 have been employed, which can, for example, on reaction with 6 be converted to the thiophene-substituted amino acid 8 [4c]. In Ugi's four-component condensation, imine formation from an aldehyde 1 and an amine 2 is likewise the initiating step [ S , 6); a carboxylic acid 9 and an isonitrile 10 are the other reaction components, which finally yield the bisamide 11. Both for this reaction and the Strecker synthesis, the galactosylamine 12 is particularly suitable for carrying out a stereoselective reaction (synthesis of 13) [4d-e, Sf]. With an aminoglucopyranose as a chiral auxiliary, the stereoselectivity of the reaction can be further increased [5b]. Amino acids as condensation components yield particularly impressive results. For instance, the imino-

RI-CHO

NaCN

R'ACO2"

R~--NH~

4

5

2

6

7

8

Scheme I

54

A. New Methods in Stereoselective Synthesis

R'-CHO

+

R3-C02H

+

9

0

R4-NC

11

10

+1 + HCOlH

OPiv NH2 opiv

PivO

0 R?.N,4R3

2

1

+

R~-NH~

ZnCl2. OEtz

PivO

NHR4

12

13 (-90% de)

14

room temp.

+

a C O 2 H

YI3

I

H

_

CO~CH~

2d 17 (98%, 88% de)

16 dicarboxylic acid 17 can be synthesized from components 14- 16 at room temperature and obtained in excellent yield and with remarkable diastereoselectivity [ k ] . Readily available reagents were used exclusively in both the Strecker synthesis and the Ugi reaction. A convincing reaction from organometallic chemistry was a long time coming. Petasis and Zavialov now report [7a-b] that vinylboronic acids 18 [7c-d], which are readily accessible and easy to handle, can participate in a three-component reaction with primary and secondary amines 19 and with a-keto acids 20. The process, which proceeds at room temperature, leads to P,y-unsaturated a-amino acids 21 in good yields. The reaction of vinylboronic acid 22 with the chiral amino alcohol 23 and glyoxylic

Scheme 2

acid hydrate 24 illustrates that the reaction is not sensitive to air or humidity, can be carried out under mild conditions, and has impressive diastereoselectivity. Conceptually this new three-component reaction resembles the methods applied by Steglich, Enders et al. [Sa] and Yamamoto et al. [8b], who treated the preformed iminoesters 26 and 29 at low temperature with the electron-rich olefins 27 and 30, respectively [9]. However, the use of boronic acid derivatives appears to be a versatile method with a great deal of potential. As Petasis and Zavialov note at the end of their paper, unprotected amino acids and peptides, aryl boronic acids, and chiral boronates can also participate in their three component condensation [7a]. Transition metal catalysis also

Amino Acid Derivatives by Multicomponent Reactions

55

R' R

1s

3

x

F

R2

21

H

19

20

OH PhbB'OH

23

Ph

24 Scheme 3

0

PhKN

26

29

provides surprising solutions for the synthesis of amino acids by multicomponent reactions [ 101. More than 25 years ago Wakamatsu et al. [ 1 1 a] found that aldehyde 1 could be coupled with carboxamides 32 and carbon monoxide under pressure to give N-acylamino acids 33, a process catalyzed by octacarbonyldicobalt and known as

Scheine 4

amidocarbonylation [ 11b]. In the presence of hydrogen, the reaction conditions are suitable for hydroformylation; thus, alkenes 34 could be used in place of the aldehyde 1 [llb]. Although amidocarbonylation appears to be very favorable from an economic point of view, it has not yet been realized in industry. The main problem con-

56

A. New Methods in Stereoselective Synthesis

0 R'-CHO

+

~

32

1

yR +

R

34

0

co2(Co)S (3-5mol 9'0)

R?

0 A,,

YH

RtAC02H

CO, pressure I 00-I 60OC

33

COZ(CO)~ (3-5 mol %)

0

R?"KR3

CO, H2, pressure R+C02H 100-160°C R

32

35 0

(0.25 mol %)

36

37

60 bar CO 12OoC. 12 h N-methylpyrrolidone

(Ph3PhPdBrz

38 (99%)

(0.25 mol 5%)

39

40

cat. H2S04, LiBr 60 bar CO 100°C, 12 h N-methylpyrrolidone

0

9-N

FH3

H

41 (86%) Scheme 5

cerns low catalyst efficiency, but in addition it does not appear to be possible to run the enantio/diastereoselective process with the previously applied cobalt catalysts. Beller et al. have now found [ 121 that amidocarbonylation of aldehydes can also be achieved by using palladium catalysts with sulfuric acid and halide ions as cocatalysts, as shown by the reaction of isovaleraldehyde 36 with acetamide 37. This palladium-catalyzed synthesis is superior to that catalyzed by cobalt in many respects. Both the catalytic efficiency and the attainable yields are considerably higher. Several components,

such as aromatic aldehydes and monoalkyl amides [ 1lc], which the cobalt-catalyzed method failed to convert, can now be used without any problems, and even ureas such as 40 are suitable coupling components, opening up an efficient access to hydantoins (for instance 41) [ 12el. In addition, the reaction conditions required are milder: very good yields can be obtained at 80 "C and a CO pressure of only 10 bar. Most importantly, perhaps, the change of catalyst allows the possibility of controlling the process through choice of ligand and of running an enantio/diastereoselective process.

Amino Acid Derivatives by Multicomponent Reactions

References [I] Current examples of the synthesis of a-amino acids: a) J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig, Organic Synthesis Highlights, VCH, Weinheim, 1990, pp. 300-305; b) R. 0. Duthaler, Tetruhedron 1994, 50, 15391650; c) U. Kazmaier, Liebigs Ann./Recueil 1997, 285-295; d) M . Braun, K. Opdenbusch, ibid. 1997,141-154; e) L. S. Hegedus, Acc. Chenz. Res. 1995, 28, 299-305; f) D. Enders, R. Funk, M. Klatt, G. Raabe, E. R. Hovestreydt, Angew. Chem. 1993, 105, 418-420; Angew. Chem. lnt. Ed. G i g l . 1993, 32, 418-420. [2] Current examples of the synthesis of p-amino acids: a) D. Enders, .I.Wiedemann, Liebigs Ann./ Recueil 1997, 699-706; b) J. Voigt, M. Noltemeyer, 0. Reiser, Synlett 1997, 202-204; c) H. Kunz, A. Burgard, D. Schanzenbach, Angew. Chem. 1997, 109, 394-396; Angew. Chem. hit. Ed. Engl. 1997, 36, 386-387; d) G. Cardillo, S. Casolari, L. Gentilucci, C. Tomasini, ihid. 1996, 108, 1939-1941 and 1996, 35, 1848-1849; e) J. Podlech, D. Seebach, ihid. 1995, 107, 507-509 and 1995, 34, 471-472; f) J. Podlech, DSeebach, Liebigs Ann. 1995, 1217-1228; g ) P. Gmeiner, E. Hummel, C. Haubmann, ihid. 1995, 1987- 1992; h) J. Escalante, E. Juaristi, Tetrahedron Left. 1995, 36, 4397-4400; i) D. C. Cole, Tetrahedron 1994, 50, 9517-9582. 131 L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137- 170; Angew. Chem. lnt. Ed. Engl. 1993, 32. 131 - 163. [4] a) A. Strecker, Justus Liebigs Ann. Chem. 1850, 75, 27: b) M. P. Georgiadis, S . A. Haroutounian, Synthesis 1989, 616-618; c) K. Weinges, H. Brachmann, P. Stahnecker, H. Rodewald, M. Nixdorf, H. Irngartinger, Liebigs Ann. 1985, 566-578; d) H. Kunz, W. Sager, D. Schanzenbach, M. Decker, ibid. 1991, 649 -654; e) H. Kunz, K. Ruck, Ang e w Chem. 1993, 105, 355-377; Angew Chem. lnt. Ed. Engl. 1993, 32, 336-358; f) F. A. Davis, P. S. Portonovo, R. E. Reddy, Y. Chiu, J . Org. Chem. 1996, 61, 440-441; g) T. K. Chakraborty, K. A. Hussain, G. V. Reddy. Tetruhedron 1995, 51, 9179-9190; h) M. S. lyer, K. M. Gigstad, N. D. Namdev, M. Lipton, J . Am. Chem. SOC.1996, 118, 4910-4911. IS] a) I. Ugi, Angew. Chem. 1982, 94, 826-835; Angew. Chem. Int. Ed, Engl. 1982, 21, 810-819; b) S. Lehnhoff, M. Goebel, R. M. Karl, R. Klosel, I . Ugi, ibid. 1995, 107, 1208-1211 and 1995, 34, 1104-1107; c) A. Demharter, W. Horl, E. Herdtweck, Ugi, ibid. 1996, 108, 185-187 and 1996, 35, 173-175; d ) A. Domling, M. Starnecker, I. Ugi, ibid. 1995, 107, 2465-2467 and 1995, 34, 2238-2239; e) T. Yamada. T. Yanagi, Y. Omote, T. Miyazawa, S. Kuwata, M. Sugiura,

57

K. Matsumoto, J. Chem. Soc. Chem. Commun. 1990, 1640-1641; f) H. Kunz, W. Pfrengle, J. Am. Chem. SOC.1988,110,651 -652; g) P. A. Tempest, S. D. Brown, R. W. Armstrong, Angew. Chem. 1996, 108,689 -691; Angew. Chem. lnt. Ed. Engl. 1996,35,640-642; h) T. A. Keating, R. W. Armstrong, J. Am. Chem. Soc. 1996, 118, 2574-2583; i) H. Quast, S. Aldenkortt, Chem. Eur: J. 1996, 2, 462-469. [6] Synthesis of an amino acid derivative by using a seven-component reaction: A. Domling, I. Ugi, Ang e w Chem. 1993, 105, 634-635; Angew. Chem. lnt. Ed. Engl. 1993, 32, 563-564. [7] a) N. A. Petasis, I. A. Zavialov. J. Am. Chem. Soc. 1997, 119, 445-446; b) N. A. Petasis, A. Goodman, I. A. Zavialov, Tetrahedron 1997, 53, 16463- 16470; c) Tetrahedron Lett. 1996, 37, 567-570; d) N. A. Petasis, I. Akritopoulou, ibid. 1993, 34, 583-586; e) for a related synthesis of chiral /5aminoalcohols, see: N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1998, 120, 1179811799. [8] a) R. Kober, K. Papadopoulos, W. Miltz, D. Enders, W. Steglich, H. Reuter, H. Puff, Tetrahedron 1985, 41, 1693-1701; b) Y. Yamamoto, W. Ito, K. Maruyama, J . Chem. Soc. Chem. Commun. 1985, I131 - 1132. 191 Further examples of amino acid syntheses starting with glyoxylic acid derivatives: a) P. Munster, W. Steglich, Synthesis 1987, 223-225; b) M. J. 0 Donnell, W. D. Bennett, Tetruhedron 1988, 44, 5389-5401; c) E. C. Roos, M. C. Lopez, M. A. Brook, H. Hiemstra, W. N. Speckamp, B. Kaptein, J. Kamphuis, H. E. Schoemaker, J. Org. Chetn. 1993, 58, 3259-3268. [lo] M. Beller, B. Cornils, C. D. Frohning, C. W. Kohlpaintner, J . Mol. Cat. 1995, 44, 237-273. [ 1 I] a) H. Wakamatsu, J. Uda, N. Yamakami, J . Chem. Soc. Chem. Commun. 1971, 1540; b) “Amidocarbonylation”: J. F. Knifton in Applied Honiogeneous Catalysis with Metal Complexes (Eds.: B. Cornils, W. A. Herrmann), VCH, Weinheim, 1996, pp. 159-168; c) P. Magnus, M. Slater, Tetrahedron Lett. 1987, 28, 2829-2832. [ 121 a) M. Beller. M. Eckert, E Vollmuller, S. Bogdanovic, H. Geissler, Angew. Chem. 1997, 109, 15341536; Angew. Chem. Int. Ed. Engl. 1997, 36, 1494- 1496: b) M. Beller, M. Eckert, F. Vollmuller, J. Mol. Cat. A 1998, 135, 23-33; c) M. Beller, M. Eckert, E. W. Holla, J. Org. Chem. 1998, 63, 5658-5661; d) M. Beller, M. Eckert, W. A. Moradi, Synlett 1999, 108- 110; e) M. Beller, M. Eckert, W. A. Moradi, H. Neumann, Angew. Chem. 1999, 111, 1562- 1565: Angew. Chern. lnt. Ed. Engl. 1999, 38, 1460- 1463.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

New Polyol Syntheses Christoph Schneider Institut fur Organische Chemie, Universitat Gottingen, Germany

Among the natural products of polyketide origin the polyene macrolide antibiotics have only recently attracted attention from synthetic chemists [ 11. More than 200 members of this class of natural products have been identified, but the constitution and configuration of many have only been partially elucidated. Best known are probably amphotericin B and nystatin, which are used clinically for the treatment of systemic fungal infections. Their biological activity rests on their ability to damage cytoplasmic membranes of eucaryotic cells by various mechanisms with consequent loss of ions, amino acids, and carbohydrates. Structurally they consist of a polyene moiety with up to seven, mostly conjugated double bonds and a polyol moiety with nine secondary, mainly 1,3-orientated hydroxy groups. New strategies for the stereoselective synthesis of the polyol structures are of great interest to synthetic chemists. Rychnovsky and his group have recently developed new synthetic methods that lead to the total syntheses of the polyene macrolides roxaticin [2], roflamycoin [3], and filipin 111 [4]. The polyol chains of all three natural products were constructed by iterative, stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation, illustrated here by the synthesis of the polyol framework of filipin I11 (1) (Scheme 1). The bifunctional cyanohydrin acetonide 2, prepared by rutheniudBINAP catalyzed enantioselective hydrogenation of the corresponding P-keto ester (BINAP = [ 1,l’binaphthyl]-2,2’-diylbis(diphenylphosphane)), is deprotonated with LiNEt, and alkylated with 2benzyloxy- 1 -iodoethane. The alkylation product 3 is converted by a Finkelstein reaction into the iodide 4, which is used to alkylate a second

molecule of 2. After a second Finkelstein reaction, the protected tetraol 6 is coupled with the lithiated cyanohydrin acetonide 7 in a third alkylation to form the complete polyol segment 8 of filipin 111. Each alkylation step proceeds in good yield (70-80 %), and the 1,3-dioxanes 9, in which the slim cyano group assumes the axial position, are formed with high stereoselectivity. Once they have fulfilled their role for the alkylations, the three cyano groups are removed with Li/ NH, with retention of configuration to afford the 1,3-syn-diol acetonides 11 (Scheme 2). Control experiments revealed, however, that the reductive decyanation always gives 1,3-syn configured diol acetonides irrespective of the cyanohydrin acetonide configuration. The reason is that the intermediate radical 10 prefers a configuration in which the unpaired electron assumes the axial position at the anomeric center. The carbanion formed by the next electron transfer is protonated at this position so the H atom is also in an axial position. Protected I ,3-anti-diols 14 are accessible by the highly stereoselective Lewis acid promoted addition of dialkylzinc compounds to 4-acetoxy-1,3-dioxanes 13 (Scheme 3) [5]. The two cis-orientated alkyl substituents at C2 and C6 fix the carboxonium ion 15 in the half-chair conformation, which undergoes preferential axial attack by the dialkylzinc under stereoelectronic control. The 4-acetoxy- 1,3-dioxanes 13 may be synthesized from the Seebach 1,3-dioxan-4-ones 12 by reduction with diisobutylaluminum hydride (DIBAH) and acetylation. Since dialkylzinc compounds are now readily available and are compatible with many functional groups, this

59

New Polyol Syntheses

O K ,

1. LiNEt,

NC

2.

*

B"O&X

BnO-'

CN

70-80%

34: :xX= =c l1

J

KI

1. LINE!,

2.4, 7040%

7

6:X=l LiNEt,

70-80%

8a: X = CN, R = Bn

8b: X = H, R = H

z]

Li/NH3

~

OH OH OH . OH _ OH .OH

-

-

-_ _

_

_

_

_

_.

_

_

Scheme 1. Synthesis of the C(1)-C( 15) polyol fragment 8b of filipin I11 (1) according to Rychnovsky et al. Bn = benzyl, TBS = rert-butyldimethylsilyl.

method should be widely applicable to the preparation of 1,3-anti-diols. The most direct method for the preparation of polyol frameworks is without doubt the aldol reaction. The diastereofacial selectivity of the reaction can be controlled by P-alkoxy groups in both the methylketone enolate and the aldehyde. As investigations by Evans [6] and Paterson [7] and their groups have demonstrated, the correct selection of enolization conditions and the protective group for the P-hydroxy group are important for the stereocontrol of the reaction.

The boron-aldol reaction of the p-methoxybenzyl(PMB)-protected methylketone 16 proceeds with excellent 1,5-anti-selectivity (Scheme 4). In cases where the asymmetric induction is lower it may be improved by a double stcreodifferential aldol reaction with chiral boron ligands [7].The reason for this high stereoselectivity is currently unknown. Ab initio calculations suggest the involvement of twisted boat structures rather than chair transition structures [6]. If the chiral information is contained within the aldehyde, a Mukaiyama aldol reaction is the

60

A. New Methods in Stereoselective Synthesis

11

Scheme 2. Reductive decyanation of the cyanohydrin acetonide 9 according to Rychnovsky et al.

R’no -R’moAc 1, D~BAH

T

RZ2Zn,TMSOTf

e

T

2’Ac20

CH2C12. -78% 70-90%

antikyn > 99:1

13

12 r

14

1

15

method of choice [8]. The BF,-catalyzed addition of the silyl enol ether 18 to the chiral aldehyde 19 affords the 1,3-unti product 20 in high yield and stereoselectivity. Evans has developed a modified Felkin-Anh model as a working hypothesis in which repulsive interactions between the carbonyl group and the p-alkoxy group and steric interactions between the carbonyl group and the p-alkyl group are minimized. The complementary reaction conditions permit selective product formation in a double stereodifferential aldol reaction of a chiral ketone and a chiral aldehyde, even in the mismatched situation [6]. Thus the boron enolate 21 adds to the aldehyde 22 with excellent stereoselectivity and forms almost exclusively the 1,5unti product 23 (enolate control). In the Mukaiyama reaction of the corresponding silyl enol ether 24, however, the aldehyde 22 exercises stereochemical control, and the 1,5-.syn product 25 is the main product. The ketone carbonyl function

Scheme 3. Preparation of the I ,.?-antidiol acetal 14 by dialkylzinc addition to 4-acetoxy-1,3-dioxanes 13 according to Rychnovsky et al. TMSOTf = trimethylsilyltrifluoromethane sulfonate.

of the aldol products can be reduced with high diastereoselectivity to the 1,3-syn-diols with Et,BOMe/NaBH, [9] and DIBAH [lo], and to the 1,3-unri-diols with Me,NBH(OAc), [ 111 and SmI,/RCHO[ 121. A catalytic, enantioselective approach towards the synthesis of polyol chains has recently been reported by Carreira et al. and has been applied in a synthesis of the polyol subunit of amphotericin B (Scheme 5) [ 131. Aldol addition of the silyl dienolate 26 to furfural (27) catalyzed by the TolBINAP-CuF,-complex (2 mol-%) gives rise to the addition product 28 in 95 % yield and >99 96 ee after one recrystallization. Spectroscopic evidence indicates that a copper dienolate is formed in situ from the silyl dienolate 26 and is actually the active nucleophile [ 141. Standard transformations including a syn-selective reduction of the @hydroxy ketone by the method of Prasad and the oxidative conversion of the furan ring to the car-

New Polyol Syntheses boxyl group with subsequent reduction furnish the aldehyde 29 as one half of the target molecule. The other subunit 30 is assembled from the enantiomeric aldol product by the same set of transformations and conversion to the alkyne. Both fragments are then joined through the addition of the lithium salt of 30 to the aldehyde 29 which gives a 78 : 22 mixture of diastereomers with thc wrong stereoisomer predominating. Subsequent hydrogenation of the triple bond and installation of the correct stereochemistry at the central hydroxyl-bearing carbon atom through an oxidation-reduction sequence produce the complete polyol fragment 32 of amphotericin B.

PMBO Bn&

OBBU, +

H

0 &Bn

-..?,+Bn-

61

Bruckner and et al. use the oxidative degradation of butyrolactnnes by a Criegee rearrangement as the key step in the synthesis of different polyol systems (Scheme 6) [ 151. In their convergent route to the pentamethyl ether 33 from Tolypothrix conglutinata they synthesize the homoallylic alcohols 34 and 36 by catalytic, enantioselective allylstannane additions and convert them into the two central building blocks 35 and 37 by ozonolysis and syn-selective ketone reduction. Coupling of these two fragments to form the complete carbon framework 38 of the polyol chain is achieved by Peterson olefination and stereoselective hydrogenation of the conjugated double

PMBO

0

OH

-

Bn

85%

16

17 (1,5-anti/syn = 982)

OTMS

OPMB

18

OH

OPMB

20

19

(1,3-anti/syn = 92:8)

-

ph

O h ,

OBBU~

a)

TrO

Ph

O n 0 :

OH OPMB

0

:

OBn

81%

21

23

OPMB

(1,5-anfi/syn = 96:4)

HLOBn 22 Ph

OAO

OTES

OBn

66%

25

24

(1,5-syn/anfi= 82:18)

Scheme 4. Stereocontrolled aldol reaction according to Evans et al. a) Et,O, -115'C; b) BF, . OEt,,

CH,CI,, -78 C. TES = triethylsilyl, methylsilyl, Tr = triphenylmethyl.

TMS = tri-

62

A. N e w Methods in Stereoselective Synthesis

~ 27

O

T

M

S95% >99% ee

26

t'r

28

81%

29

-

x

0

3 steps 67%

T

x

0

0

B

S OH

0 O OTBS

~

32 Scheme 5. Catalytic, enantioselective synthesis of the polyol fragment of amphotericin B according to Carreira et al. a) 2 mol % TolBINAP-CuF,, -78'C, then CF,COOH; b) nBuOH, IIO'C; c) Et,BOMe,

NaBH,, THF, -78°C; d) Me,C(OMe),, PPTS; e) LiAIH,, THF; f) TBSCI, imidazole, DMF: g) O,, CH2CI,, -78 'C; h) Me,SiCHN,; i) LiAIH,, THF: k) Dess-Martin periodinane.

bond. The butyrolactone 38 is now converted into the peroxosulfonate 39 by addition of MeLi, oxidation with H,O,, and reaction with p-nitrobenzenesulfonyl chloride. This sulfonate undergoes a Criegee rearrangement at room temperature to form the resonance-stabilized, cyclic carboxonium ion 40 by cleavage of the unstable peroxo compound and stereospecific migration of the neighboring carbon atom. Alkaline hydrolysis yields the syn-diol 41, and standard methods then give the natural product in a few steps.

Smith et al. have developed a very elegant route to complex polyol structures by sequential dithiane-epoxide coupling reactions (Scheme 7) [ 161. Following the work of Tietze [ 171, 2-silyl1,3-dithianes 42 are deprotonated with tBuLi in ether and converted into the stable lithium alkoxides 43 with enantiomerically pure epoxides. A fast 1,4-Brook rearrangement occurs only after the addition of 0.3 equivalents of hexamethylphosphoramide (HMPA) or 1,3-dimethylhexahydro-2-pyrimidone (DMPU) to the reaction mixture. A new lithiated dithiane 44 that can undergo

I

EE

OP

LE

SE

6E

9E

PE

64

A. New Methods in Stereoselective Synthesis

43

42

44

42 (2.6 eq)

47

66%

T 45

+44

46

Scheme 7. Sequential dithiane-epoxide coupling according to Smith et al. a) tBuLi, Et,O, -78 'C + -45 OC;

b) HMPA, Et,O, -78 C

48 (Scheme 8). The enantiopure 7-0x0-5-phenyldimethylsilyl-2-enimide 49 used as the chiral key intermediate is produced in a stereospecific [3.3]sigmatropic rearrangement in good yield and carries three masked hydroxy groups in the required I ,3,5 relationship. The first hydroxy group can be liberated through reagent-controlled allylboration of the aldehyde moiety of 49, which leads to either stereoisomer depending on the borane reagent used. The second hydroxy group is introduced into the molecule via the conjugate addition of a silyl cuprate reagent to the conjugated double bond. This Michael-type reaction proceeds with high stereocontrol to deliver the addition products 51 with a 3,5-syn-stereochemistry in the case of the imide 50 (auxiliary control) and 54 with a 3,5-unti-stereochemistry when using the

ester 52 (substrate control). Finally, oxidative desilylation of the phenyldimethylsilyl groups furnishes the second and third hydroxy groups which are protected as their acetonides, in one step. The terminal double bond of the protected triols may be selectively oxidized to a methyl ketone or an aldehyde - two subunits which can easily be joined in aldol reaction to get access to larger polyol chains. Although the absolute configuration has only been established for a few polyene macrolide antibiotics, the search for new, efficient, and selective strategies for the synthesis oftheir polyol structures is in full swing. A number of the synthetic procedures presented here will certainly be used in future syntheses of this class of natural products [ 191.

4

-25 "C.

New Polyol Syntheses

TMSO 0 P h M e 2 S i y A $ u 0 48

65

- ~u ' 66 SiMe,Ph

0

0

tBu

a) 65-75%

0

49

b,c)

52%

86%

SiMqPh

BnO

0

0 -/ Me 52

OMe

OMe 54

53 h-i)

BnO

1

OxO

72%

h-i)

1

70%

0

OMe 55

OMe 56

Scheme 8. General, asymmetric synthesis of 1,3,5triols according to Schneider et al. a) toluene, 170°C; b) ally1 (2-iCar),borane, Et,O, -78 "C; c) CI,CC( = NH)OBn, TfOH, CH,CI,, rt; d) PhMe,SiLi, CuI, Me,AICI, T H E -78'C; e) MgCIOMe, CH,CI,,

0 C: f) MgCIOMe, CH,CI,, 40 C; g) PhMe,SiLi, CUCN, BF,.OEt,, THF, -78 "C: h) BF,.(AcOH),, CH,CI,, rt, then mCPBA, KF, DMF, 0°C; I ) Me,C(OMe),, PPTS, rt.

Reference

161 D. A. Evans, P. J . Coleman, B. Cote, J. Org. Chem. 1997, 62, 788-789. 171 I. Paterson, K. R. Gibson, R . M. Oballa, Tetruhedrvn Lett. 1996, 37, 8585-8588. [8] D. A. Evans, J. L. Duffy, M. J. Dart, Tetruhedron Lett. 1994, 3.5, 8537-8540. 191 K. Narasaka, F.-C. Pai, Trtruhrdron 1984, 40, 2233-2238: K.-M. Chen, G. E. Hardtmann, K. Prasad, 0. Repic, M. J. Shapiro, Tetrahedron Lett. 1987, 28, 155- 158. (101 S. Kiyooka, H.Kuroda, Y. Shimasaki, Tetruhedrvn Lett. 1986, 27, 3009-3012. 11 I ] D. A.Evans, K. T.Chapman, E. M. Carreira, J. Am. Chrni. Soc. 1988, 110, 3560-3578.

[ 1 ] S. Omura, Mucrvlide Antibiotics: Chemistry B i d ogy, Practice, Academic Press, New York, 1984: S.

D. Rychnovsky, Chern. Rev. 1995, Y5,202 1-2040. 121 S. D. Rychnovsky, R. C. Hoye, J. Ant. Cliem. Soc. 1994, 116, 1753-1765. 131 S. D. Rychnovsky, U. R. Khire, G. Yang, J. Am. Cheni. Soc. 1997, 119, 2058-2059. 141 T. I. Richardson, S. D. Rychnovsky, J , Am. Chem. Svc. 1997, 119, 12360-12361. [ S ] S. D. Rychnovsky, N. A. Powell, 1. Org. Chern. 1997, 62, 6460-6461.

66

A. New Methods in Stereoselective Synthesis

[I21 D. A. Evans, A. H. Hoveyda, J. Am. Ckem. Soc. 1990, 112, 6447-6449. [ 131 J. Kruger, E. M. Carreira, Tetrahedron Lett. 1998, 39, 7013-7016. [I41 B. Pagenkopf, J . Kruger, A. Stojanovic, E. M. Carreira, Angew. Ckem. 1998, 110, 3312-3314; Angew. Ckem. Int. Ed. 1998, 37, 3122-3124. [ 151 S. Weigand, R. Bruckner, Liebigs Ann./Recuei/ 1997, 1657- 1666.

[I61 A. B. Smith, A. M. Boldi, J . Am. Ckem. SOC.1997, 119, 6925-6926. [17] L. F. Tietze, H. Geissler, J. A. Gewert, U. Jakobi, S.ynlett 1994, 5 I 1-5 12. [ 181 C. Schneider, M. Rehfeuter, Tetrahedron Lett. 1998, 39, 9-12; C. Schneider, M. Rehfeuter, Ckem. EUK J . 1999, 5, 2850-2858. [ 191 For a comprehensive review of polyol synthesis up to 1990 see: T. Oishi, T. Nakata, Synthesis 1990, 635 - 645.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Stereoselection at the Steady State: The Design of New Asymmetric Reactions Thomas Wirth, Institut fur Organische Chemie, Universitat Basel, Switzerland

A reaction leading to an optically pure product in quantitative yield is the dream of every chemist working in the field of asymmetric synthesis. If only catalytic amounts of a chiral compound are needed to achieve this goal, then it is like paradise. But only very few asymmetric reactions have been developed thus far. Compounds with asymmetric centers can be obtained from prochiral starting molecules by either face-selective reactions [ 11 (stereoheterotopic facial addition) or group-selective reactions (stereoheterotopic ligand substitution). The transition states of these selective stereodivergent reactions must be diastereomeric, and the kinetics are the same as those of parallel reactions with different products (enantiomers or diastereomers). The selectivity in the stereoselective event leading to the different transition states can never be exceeded by the final yield of the major stereoisomer. In two recent publications Curran et al. described the theoretical as well as the mathematical background of stereoconvergent reactions [2]. They give further evidence for their analysis by providing some examples from the field of radical chemistry to demonstrate this strategy called complex stereoselection. The process of stereoconver-

/

a<’

XG’

-

gent synthesis was proposed by Fischli et al. in 1975 [3]. The first step in this process is the nonselective monoprotection of a reactive group (X in 1) by a chiral agent (G*, Scheme I). After separation of the diastereomers 2a and 2b, the still reactive groups are converted into “c” and “d”. These derivatives generate 3 with a theoretical enantiomeric excess of 100 % and without destroying any material. The ratio 2a:2b has no influence on the outcome of the reaction. Although the subsequent discussion describes the stereoselection at the steady state through the example of radical reactions, the analysis and principles are general for any reaction profile that fits into the scheme of complex stereoselective reactions. In the process proposed and analyzed by Curran et al., the activation of compounds of type 1 is done, for example, by radical formation. The group selectivity in this first step has again no effect on the stereomeric nature of the product. To obtain a stereoconvergent process it is crucial, however, that the reaction is operating at the steady state. This means that the concentrations of the radial intermediates (compounds in brackets in Scheme 2) is low and stationary, while their absolute concentrations are determined by the different rates of reaction.

a b
2a

3

1

2b

Scheme I

68

A. New Methods in Stereoselective Synthesis

6

ent-4

Scheme 2

0

cause of the reaction rates. Furthermore, it is necessary for the stereoconvergence at the stcady state that at least one of these processes (reaction with either c or d) is stereoselective. The mathematical description of this and related reaction schemes are complex and will not be discussed here. To verify the analysis of the stereoselection at the steady state experimentally, diastereoselective radical cyclization reactions were selected. Although face-selective radical cyclizations are much more common than the group-selective counterparts [4], several model compounds were suggested by Curran et a1 [ 2 ] . Molecules which have two radical precursors and one radical acceptor group such as 9 were selected to provide experimental verification

The radicals 4 and ent-4 formed in the first reaction must have competing reaction rates for c and d: the second process must have a reaction rate in competition with the two rates of the first process (k, iaht > k, > k, \,ow). This means that radical 4 reacts much faster with c than with d yielding product 5. Radical ent-4, however, will react faster with d than with c, and 6 will be produced. Compounds 5 and 6 are then activated again by conversion into 7 and 8. Radical 7 is mismatched for the reaction with c (k, ,,ow < k,), and reaction with d provides product 3. Radical 8 is converted also into 3 as shown in Scheme 2. The achiral products (disubstitution of X with either c or d) result from a leakage out of one convergence and are only minor products be-

m1 C02Me

9

1 5 0 %

C02Me

0”rl c

50%/

C02Me

m.

,d\ I

1Oa

10b

kH

Ila

1

llb

c

kH

14exo

J

1

kH

14-endo

I

Scheme 3

69

Stereoselection at the Steady Stute: The Design of New Asymmetric Reactions

r

O.'

0.5

14-exo 0.6 13

0.4 0.2

14-endo

0.1 0.0

0.5

1 .o [Ph,Sfi]

1.5

2.0

Figure I . The effect of the tin hydride concentration on the formation of 13, 14-ex0, and 14-endo (selectivity

approximately five). The experimental results (*)are compared with the calculated ones (lines) [6].

(Scheme 3). This choice also seems wise from a different point of view: because the intermediates are radicals, the two competing reactions are an intramolecular cyclization and an intermolecular hydrogen transfer reaction. The latter is dependent upon the tin hydride concentration. In other words, by varying the tin hydride concentration it is possible to influence the sterochemical outcome of the reaction. At low tin hydride concentrations the product ratio of 14-exo:14-endo is approximately 1 : 1 ; this ratio confirms that there is no selectivity in the first abstraction of iodine by the tin radical. The radicals 10a and 10b are formed in equal amounts. Product 13 is not detected. The rate for the subsequent cyclization reaction is, however, different for 10a and lob. Cyclization of radical 10a to the exo-derivative l l a is faster than the generation of the endu-derivative l l b from lob. With increasing tin hydride concentration the competing hydrogen transfer reaction is opening new paths on the reaction topography. If the faster cyclizing radical 10a is reduced to 12a before cyclization occurs, most of the product 12a will end up at the doubly reduced compound 13. When the slower cyclizing radical 10b is reduced, however, most of the resulting product 12b follows the pathway to the major product 14CXO. The yield of 14-exn is, therefore, both eroded (12a + 13) and supplemented (12b + 14-exo). However, because the concentration of the slower cyclizing radical lob always exceeds

o'2 0.0

exo

\

k\

reduced endo

increasing [Ph3SnH]

Figure 2. Calculated curves showing the effect of the tin hydride concentration on the formation of 13, 14-em, and 14-endo when a selectivity of 500 is as-

sumed.

the concentration of the faster cyclizing radical lOa, the yield of 14-ex0 is supplemented faster than it is eroded (Scheme 3) IS]. This situation is additionally visualized in Fig. 1. The data fits nicely into a klhS,:kslowratio of about five. With this selectivity between the major and the minor stereoconvergence, the maximum yield of 14-ex0 is about 60 %. The importance of this concept, however, becomes appearent when a selectivity of 500 is assumed. Figure 2 shows the calculated curves for this scenario, whereby an increase in the tin hydride concentration leads to a large exo:endn ratio. The reaction of 9 to products 14 is one simple example for a complex stereoselective reaction. Other reactions based on radical chemistry are suggested by Curran et al., but these reactions with a stereoselection at the steady state are by no means restricted to radical chemistry. Organometallic reactions can also involve transient intermediates which may fulfill the crucial need for competing reactions with different rates, with the rate of the nonselective reaction lying between the rates of the two selective ones. In this context catalytic enantioselective reactions are especially challenging and could have a high preparative value. The stage is now set for the discovery of new stereoconvergent reactions orchestrated by stereoselection at the steady state.

70

A . N e w Meth0d.v in Stereoselective Synthesis

References [ I ] The dependence of reaction conditions on the facial diastereoselectivity of nucleophilic addition was reported recently: G. Cainelli, D. Giacomini, P. Galletti, Chenz. Commun. 1999, 567-572. [2] a) N. C. DeMello, D. P. Curran, J . Am. Chem. SOC. 1998, 120,329-341. b) D. P. Curran, C.-H. Lin, N. DeMello, J. Junggebauer, J. Am. Chem. Soc. 1998, 120, 342-351. [3] A. Fischli, M. Klaus, H. Mcyer, P. Schonholzcr, R. Riiegg, Helv. Chinz. Acru 1975, 58, 564-584.

[4] a) D. P. Curran, S. J. Geib, C. H. Lin, Tetruhedron: Asymmetry 1994, 5 , 199-202. b) D. P. Curran, W. Shen, J. Zhang, S. J. Gieb, C.-H. Lin, Heterocycles 1994, 37, 1773-1788. [ S ] The pairs of fast and slow rate constants are assumed to be equal to simplify the theoretical analysis. 161 The following rate constants have been used for the calculation: kf,5t = 4.6 x lo7 s-I; k,,,, = 1.0 107 s-l; k, = 2.0 107 s-~.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

B. Transition Metal Organometallic Methods Photolysis of Fischer Carbene Complexes Oliver Kiehl and Hans-Giinther Schmalz Institut f i r Orgunische Chemie, Universitat Koln, Gernzuny

Introduction Heteroatom-stabilized carbene complexes of type 1, first discovered by E.O. Fischer in 1964 [I], nowadays belong to the best investigated classes of transition metal compounds. Such complexes are coordinatively saturated, intensely co= ,, 350-400 nm), which exhibit lored solids (i, a sufficient stability for normal preparative use. Especially chromium carbene complexes (2) enjoy increasing importance in organic synthesis, and it must be added that thermal reactions such as benzannulations (i.e. the Dotz reaction), cyclopropanations and additions to a,B-unsaturated complexes clearly predominate [2].

Meerweins salt [ lb]. Alternatively, the anionic intermediates 3 can be generated by reaction of acid chlorides with Na2[Cr(CO),] (Scheme I ) [3]. Besides the thermal reactions of Fischer carbenes, photochemical transformations of such complexes also deserve attention. Since the discovery of McGuire and Hegedus [4] in the early 1980s that irradiation of chromium carbene complexes (4) with visible light in the presence of N-substituted benzaldimines (5) leads to (racemic) p-lactams of type 6, photolytic reactions of Fischer carbene complexes have been intensively investigated by L.S. Hegedus and his group in Fort Collins, Colorado [ 5 ] .

5

4

The synthetic utility of these compounds is based on their easy accessibility from commercially available (Cr(CO),] by treatment with an organolithium compound and subsequently with

6

Nowadays, it is an accepted mechanistic model

[5, 61 that the photolysis step (which proceeds

under thermo-reversible CO insertion) leads to species best described as chromium ketene complexes of type 7 (Scheme 2). Indeed, these intermediates exhibit a ketene-like reactivity: they undergo [2 21 cycloaddition reactions with olefins, imines and enol ethers, whereas reaction with nucleophiles leads to carboxylic acid derivatives.

+

3 Na2Cr(CO)5

2

t RCOCl

Scheme 1

Scheme 2

7

72

B. Trunsition Metal Orgunometullic Methods

Thus, the photolysis of Fischer carbenes opens up, under extremely mild (neutral) conditions, a synthetic access to electron-rich alkoxy- or amino ketenes which are difficult or impossible to synthesize through other means. These ketene intermediates are generated as metal-bound species in low stationary concentrations (less side reactions!), but can be further reacted in a variety of synthetically useful ways. In recent years, several synthetic methods exploiting this chemistry have been developed to a remarkable level of maturity. This article wants to briefly highlight this chemistry by discussing a few selected applications.

Synthesis of P-Lactams As mentioned above, the irradiation of Fischer carbenes in the presence of imines offers access to p-lactams [4-8]. The preparation of compound 8 is a prominent example [6b] which also demonstrates that it is possible to achieve high diastereoselectivities if chiral imines are employed as starting materials (Scheme 3 ) . It should be mentioned that [Cr(CO),] can be recovered if the photolysis is carried out under C O pressure. The most biologically active p-lactams are namino substituted derivatives (9), which according to Hegedus retrosynthetically derive from amino carbene complexes of type 10 and cyclic imines (11) (Scheme 4).

8 (= 100 % de)

Scheme 3

10

9 Scheme 4

For complexes of type 10 (with a hydrogen at the carbene carbon) a synthesis was worked out in which a formamide is first reacted with K,[Cr(CO), I followed by reaction with TMSCl [7]. This way, the non-racemic formamide 12 leads to the chirally modified amino carbene complex 13, which serves as starting material for the diastereoselective synthesis of various optically active p-lactams [S]. An example is the (formal) total synthesis of 1-carbacephalothin 16, a carbon analog of the cephalosporins (Scheme 5) [Sb]. In this case, the complex 13 is irradiated in the presence of in situ prepared imine 14 to afford the ,!-lactam with high diastereoselectivity but only in modest yield. The product (15) could (in principle) be converted in to the target compound 16. Me

b TMSCI

93 %

32 %

12

-

13

I H

COzBn

COzBn

14

11

16 (+)-1-carbacephalothin

Scheme 5. Formal total synthesis of (+)-I -carbacephalothin according to L. S. Hegedus.

73

Photolysis of Fischer Carbene Complexes

Synthesis of Cyclobutanones Similar to the thermal reaction of ketenes with alkenes, the photolysis of alkoxycarbenes 18 in the presence of (electron-rich) olefins 19 leads to cyclobutanones (Scheme 6) [9]. In these reactions the sterically more strained [2 21 cycloadducts of type ruc-17 are generally formed with good regio- and diastereoselectivity. Starting from complexes of type 21, the intramolecular version of this reaction affords bicyclic products of type ruc-20 (Scheme 7) [9].

+

17

19

18

The efficiency of this method was demonstrated in a total synthesis of the antibiotic (+)-tetrahydrocerulenin 28 (Scheme 8) and (+)-cerulenin [ 1 I]. Irradiation of complex 22 in the presence of the chiral N-vinyl-oxazolidinone 24, which is easily prepared from the amino carbene complex 23 [12], leads to the cyclobutanone 25 with high diastercoselectivity. Regioselective Baeyer-Villiger oxidation followed by baseinduced elimination of the chiral carbamate yields the butenolidc 26 in high enantiomeric purity. This is finally converted, using Nozoe's protocol [13], to the target molecule 28 by diastereoselective epoxidation (+ 27) and subsequent amino1ysis. In an analogous fashion (using substrates with modified alkyl chains), the total synthesis of the structurally related butenolides 29 and 30 was

Scheme 6

29

U

21

20

Scheme 7

If suitable chiral alkenes are employed it is additionally possible to control the absolute configuration of the newly formed chiral centers [ 101.

Cr(CO)6

a. nC8H17Li b. Me30BF, 90 %

Cr

(")5

h.v, pyrex CO (ca. 5 atrn)

MeOKCeH1,

22 a. 2 NaH

H

OH

MeoFHN)(o 'h

2. TBAF 1.mCPBA

83 %

0

84 %

'h Me

30 achieved [ 1 la]. These compounds are metabolites of the marine sponge Plakortis lita. In these cases, the chiral olefin ent-24 was used in the photolytic step. Again, the target molecules were obtained in high enantiomeric purity (>95 5% ee) with impressively high overall yields of 48 % and 38 %, respectively, based on chromium hexacarbonyl.

0

25

70%

24

23

0ec"17 - 0vc8H17 -

NaOCl DMF, Et20

OMe

26 (> 95 % ee)

30 %

OMe

0

NH3, Et20

H

~

99 %

N

~

C

0

27

28 (+)-tetrahydrocerulenin

Scheme 8. Total synthesis of (+)-tetrahydrocerulenin according to L. S. Hegedus.

B

H

~

~

14

B. Transition Metal Organometallic Methods

Synthesis of Amino Acid Derivatives The photolysis of chiral amino carbene complexes of type 31 [ 141 in the presence of alcohols leads diastereoselectively to products of type 32 and thus opens an efficient access to a wide range of natural and non-natural amino acid derivatives in optically active form [ 151. These reactions proceed via the intermediates 33 and 34, the products being formed by highly diastereoselective protonation of 34 (Scheme 9). As an example, the reaction of complex 13 with MeOD gives compound 35 in excellent yield which can easily be converted to optically active [2-2H,]glycine (Scheme 10) [16]. A special highlight of this chemistry is the possibility to construct compounds with two adjacent 13C-labeledcarbon atoms [ 171, which are of great interest for the investigation of biological systems by means of 'H NMR spectroscopic methods. For this purpose, the starting complexes (i.e. 36) are prepared from "C-labelled chromium hexacarbonyl (Scheme 11). Photolysis of 36 in the presence of the carbonyl-protected alanine derivative 37 allows the diastereoselective assembly of the dipeptide 38 in a one pot synthesis [13]. This process is remarkable for several reasons: on the one hand the peptide bond and one new stereogenic center are established in a single preparative step; on the

32

t

Scheme 9

33

34

35

13

(> 97 % D; 86 % de)

Scheme 10

other hand visible light serves as the coupling reagent. This opens up a possibility for the direct incorporation of various (even very unusual) amino acids into peptides without the requirement to synthesize the amino acid separately.

a. MeCOBr b. Ph

36

0

H Me ph

0

* 70 %

0

B " b % ' P N j MeH 0 & ,O Me Me

38

(88 % de)

37 Scheme 11. Preparation of a double I3C labelled dipeptide according to L. S. Hegedus.

Photolysis of Fischer Carbene Complexes

75

Synthesis of ortho-Substituted Phenol Derivatives In recent years the group of C. A. Merlic has reported photochemically induced cyclizations of dienyl carbene complexes of type 39 to produce phenol derivatives 40 [ 191. In these very intelligently designed reactions, which are related to the Dotz reaction, the primary, photochemically generated intermediates of type 41 undergo a (formal) electrocyclic ring-closure to form linear, conjugated cyclohexadienones 42, which then tautomerize to the phenols (Scheme 12).

-

47

48

Scheme 14

Finally, it should be mentioned that the reaction of complexes of type 39 with isonitriles leads under mild thermal conditions to aromatic amines (i.e. 47 3 48) [20]. The comparably easy formation of the intermediate ketimines (due to the nucleophilicity of the isonitrile) even permits reactions without photochemical activation (Scheme 14).

h,v.CO

- Cr(CO)6

40

t ___)

42

Using this principle, especially benzannulations can be accomplished in high yields, for instance the reactions of 43 to 44 and of 45 to 46, respectively (Scheme 13).As demonstrated by the second example, it is possible to get high regioselectivities (>25 : 1 ) in cases of substrates with unsymmetrically substituted aromatic rings [ 19bl.

43

MeO*OMe

Scheme 13

44

MeO*OMe

Outlook This brief article, which because of its limited size does not refer to all the work which has been done in the field, is intended to convince the reader that the photolytic generation of electron-rich ketene equivalents from Fischer carbene complexes represents quite a general and highly valuable synthetic methodology. One should expect that there will be a lot of interesting and useful applications arising from this chemistry in the future.

References ( I 1 a) E. 0. Fischer, A. Maasbdl, Angew. Chem., 1964, 76,645; Angew. Chem. Int. Ed. EngI. 1964,3,580; b) R . Aumann, E. 0. Fischer, Chem. BeK, 1968, 101, 954. [2] For selected reviews, see: a) K. H. Diitz, Angew. Chenz., 1984, 96, 573; Angew. Chem. Int. Ed. Engl. 1984, 23, 587; b) K. H. Ddtz in Orgunometullics in Orgutzic Synthesis (Eds: A. de Meijere, H. tom Dieck), Springer, Berlin, 1988, p. 85; c) W. D. Wulff, Advutices in Metul-Organic Chemistry, 1989, I , 209; d) W. D. Wulff in Comprehensive Organic Synthesis, Vol. 5 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 1065; W. D. Wulff in Comprehensive Organometallic Chemistr?, 11, Vol. 12 (Eds.: E.W. Abel, F.G.A. Stone, G. Wilkinson), Pergamon, Oxford, 1995, p. 470. [3] M. F. Semmelhack, G. R. Lee, Organometallics 1987, 6, 1839. [4] a) M. A. McGuire, L. S. Hegedus, J . Am. Chem. Soc. 1982, 104, 5538; b) L. S. Hegedus, Pure Appl. Chem. 1983, 55, 1745; c) L. S. Hegedus,

76

B. Transition Metal Orgunornetallic Methods

M. A. McGuire, L. M. Schultze, C. Yijun, 0. P. Anderson, J . Am. Clzem. Sac. 1984, 106, 2680; c) L. S. Hegedus, M. A. McGuire, L. M. Schultze, Org. Synthesis 1987, 65, 140. [5] For an excellen1 review, see: a) L. S. Hegedus, Tetrahedron 1997, 53, 4105. [61 a) L. S. Hegedus, G. deWeck, S. DAndrea, J. Am. Chem. Soc. 1988, 110, 2122; b) L. S. Hegedus, Phil. Trans. R. Soc. Land. A. 1988, 326, 505. [7] a) R. Imwinkelried, L. S. Hegedus, Organometallics 1988, 7,702; b) M. A. Schwindt, T. Lejon, L. S. Hegedus, Orgarzometallics 1990, Y, 28 14. [81 a) L. S. Hegedus, R. Imwinkelried, M. Alarid-Sargent, D. Dvorak, Y. Satoh, J . Am. Chem. Soc. 1990, 112, 1109; b) Y. Narukawa, K. N. Juneau, D. Snustad, D. B. Miller, L. S. Hegedus, J . Org. Chem. 1992, 57, 5453; c) B. Roman, L. S. Hegedus, Terrcrhedron 1993, 49, 5549; d) P.-C. Colson, L. S. Hegedus, J. Org.Chem. 1993, 58, 5918. [9] a) B. C. Soderbcrg, L. S. Hegedus, M. Sierra, J. Am. Clieni. Soc. 1990, 112,4364: b) A. G. Riches, L. A. Wernersbach, L. S. Hegedus, J . Org. Chem. 1998, 63, 469 I . [ 101 L. S. Hegedus, R. W. Bates, B. C. Soderberg, J. Am. Chem. Soc. 1991, 113, 923; [ 1 I] a) M. Miller, L. S. Hegedus, J . Org. Chem. 1993, 58, 6779: b) T. E. Kedar, M. W. Miller, L. S. Hegedus, J. Org. Clieni. 1996, 61, 6121.

[12J J. Montgomery. G. M. Wieber, L. S. Hegedus, J . Am. Chem. Soc. 1990, 112, 6255. [ 131 T. Ohta, H. Tsuchiyama, S. Nozoe, Heterocycles 1986, 24, 1137. [ 14) For a brief (limited) review on the use of aminocarbene complexes, see: M. A. Schwindt, J. R. Miller, L. S. Hegedus, J.Organomet. Chem. 1991, 413, 143. [IS] a) L. S. Hegedus, M. A. Schwindt, S. DeLombaert, R. Imwinkelried, J . Am. Chem. Soc. 1990, 112, 2264; b) J. M. Vernier, L. S. Hegedus, D. B. Miller, J. Org.Chem. 1992, 57, 6914. [ 161 L. S. Hegedus, E. Lastra, Y. Narukawa, D. C. Snustad, J. A m . Chem. Sac. 1992, 114, 2991. [ 171 E. Lastra, L. S. Hegedus, J. Am. Chern. Sac. 1993, 115, 87. [ 181 J. R. Miller, S. R. Pulley, L. S. Hegedus, S . DeLombaert, J. Am. Chem. Soc. 1992, 114, 5602; b) S. R. Pulley, L. S. Hegedus, J. Am. Chem. Soc. 1993, 115, 9037. [I91 a) C. A. Merlic, D. Xu, J. Am. Chem. Sac. 1991, 113, 7418; b) C. A. Merlic, W. M. Roberts, Tetrahedron Lett. 1993,34,7379;c ) C. A. Merlic, D. Xu, B. G. Gladstone, J. Org. Chem. 1993, 58, 538. 1201 a) C. A. Merlic, E. E. Burns, D. Xu, S. Y. Chen, J. Am. Clwm. Soc. 1992, 114, 8722; b) C. A. Merlic, E. E. Burns, Tetrahedron Lett. 1993, 34, 5401.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Zr-Catalyzed Carbomagnesation of Alkenes Florian Blume and Hans-Giinther Schrnalz Institut ,fur Osganische Chemie, Univessitat Kiiln, Germany

Carbometallations, i.e. reactions in which a new metallo-organic species 3 is formed by (formal) 1,2-addition of a metallo-organic species 1 along a multiple C-C bond 2, exhibit a great synthetic potential [ I ] . After all, not only is a new C-C bond formed during the course of the reaction, but also a carbon-metal bond that is directly available for further synthetic exploitation. R-M

1

+

C=C

-

R-C-C-M

2

3

While organo-magnesium species (Grignard reagents) can be counted amongst the most utilized organometallic reagents due to their facile availability [2], carbomagnesations of non-activated alkenes have not received very much attention in the past. The reason can be attributed to the fact that such reactions usually only proceed, if at all, under rather drastic conditions [3]. Exceptions are allylmagnesium halides 4, which react with olefins under comparatively mild conditions via an ene-type mechanism to yield (intermediatc) products of type 5. Intramolecular versions of such “magnesium-enc reactions” often proceed with high regio- and diastereoselectivity. They have been employed by Oppolzer and co-workers with tremendous success as key steps in natural product syntheses [4].

4

5

A few years ago, Dzhemilev and co-workers reported that the ethyl-magnesation of terminal (non-activated) alkenes (6) takes place under relatively mild conditions if catalytic amounts of zirconocene dichloride (Cp,ZrCl,) are present [ 5 , 61. These reactions lead with high regioselectivity to (racemic) products of type 7.Best results are achieved with diethylmagnesium: other ethylmagnesium derivates (e.g. EtMgX) react more slowly, and longer-chain dialkylmagnesium compounds give rise to undesired dimerization and elimination products. The high tolerance of the Zr-catalyzed reactions towards other functionalities, such as trimethylsilyl, dialkylamino, ketal (e.g. 8 + 9), alkoxy, and even hydroxy groups in the substrates is remarkable.

Et20.4 h

Me

a

b

0 M

e

9

w

M g Et

E

t

Zr-catalyzed carbomagnesation has gained much importance since 1991 as a consequence of the work of Hoveyda and co-workers [7, 81. These researchers discovered that reactions of terminal alkenes (10) with an excess of the simple Grignard reagent EtMgCl proceeded with practically complete regioselectivity (>99 : 1).

78

B. Transition Metal Organometallic Methods

Also, they demonstrated that the Grignard intermediates 11 could easily be further converted to a series of valuable functionalized products.

14 (transmetallation). After P-H elimination to give 15, the product 11 is released by reductive elimination while the active catalyst 12 is regenerated. A mechanistically related reaction that is worth mentioning is the cyclomagnesation of dienes [9]. In this case, treatment of a,w-dienes of type 17 with 2 equivalents of butylmagnesium chloride in the presence of catalytic amounts of Cp,ZrC12 gives cyclized products (1,4-bisGrignard-reagents) of type 18. 2 eq. BuMgCl cat. Cp2ZrC12

* 55 - 65 %

In a simplified picture, the mechanism of the Zr-catalyzed ethylmagnesation can be rationalized as shown in Scheme 1 181. At first, the zirconocene-ethene complex 12 is generated from the catalyst precursor Cp,ZrCI,. Complex 12 can also be regarded as a metallacyclopropane 16. After coordination and insertion of the alkene 10, a metalla-cyclopentane 13 is formed, which subsequently reacts with the Grignard reagent regioselectivcly to the open-chain intermediate

a::: 18

17

From the mechanism sketched in Scheme 1 one can conclude that carbomagnesation is unsuitable for a methyl group transfer. Homologous Grignard reagents, as seen in the transformation 19 to 20, however, can be used successfully in some cases. This example directs attention to a further aspect of this chemistry, i.e. the high stereoselectivity of many Zr-catalyzed carbomagnesations.

Cp2ZrCI2 2 Et-MgCI MgCl

2 MgClz t Et-H

w

14

R

Scheme 1. Mechanism of the Zr-catalyzed ethylmagnesation of alkenes (simplified).

79

Zr-Catalyzed Carbomagnesation of Alkenes

,&

25 to 26 demonstrates that other ethers, such as

4 eq. BuMgCl

~

*~

~ 86-88 O h

RO

&Me ~

methoxyethoxymethyl (MEM), are also suitable.

~

~

n

$

20

(R = H, MEM)

~

c

~

MEMO

cat. CpzZrC12

b: B(OMe),, Hz02,

(>99%de)

+

Po"

a. EtMgCI, THF

RO

19

~

55 %

Mei

25

26

Diastereoselective Reactions

(>99%de)

An important contribution from Hoveyda is the realization that carbomagnesations only occur smoothly and, more importantly, diastereoselectively, when the substrate provides a Lewis base functionality in the proximity of the double bond. Especially allylic and homoallylic alcohols and the corresponding ethers can be transformed with high diastereoselectivity [7]. Remarkably, the Zr-catalyzed addition of ethyl magnesium chloride to secondary allylic alcohols of type 21 gives mainly syn-configured products, while methyl ethers (23) lead predominantly to the anti-configured products. The formed Gngnard derivatives can be subsequently oxidized, for instance, to 1,3-diol derivatives of type 22 or 24 (Scheme 2). The stereochemistry of the products can be controlled by optional protection of the OH moiety. The highly selective transformation of

The relative reactivity of ally1 ethers depends on steric factors. For instance, compound 27 reacts with virtually complete regioselectivity at the less hindered double bond, as indicated by the formation of 28.

Fs *

a. EtMgCl cat. CpzZrClp

b: B(OMe),, H202

+

I

27

OH

28 (80 % de )

Homoallylic alcohols also react with high diastereoselectivity (e.g. 29+30), and their ethers give products with the same configuration (albeit with slightly lower selectivity).

OMe

R

R

OMe

yield (%) syn /anti 70 72 53

R

95: 5 95: 5 8 5 : 15

yield (%) syn /anti

n-CgHI9 c-hexyl benzyl

a: b:

I

Me0

n-CgHqg ehex-CH2 benzvl

anti

I

70 %

OMe

OH

23

TBDMSO

24

3 eq. EtMgCI, EtzO,5-10 rnol % CpzZrC12,25"C, 8 - 12 h B(OMe)3. H202,-78 "C

Scheme 2. Diastereoselective ethylmagnesation according to A. H. Hoveyda.

80 90 90

11 :89

4:96 12:88

80

B. Transition Metal Organonzetallic Methods

'A

Enantioselective Reactions

a. EtMgCl cat. CpnZrCIz

R

b: B(OMe)3,H 2 0 2 ,

OH

-

-

\ Me

OH

75 %

U

30

29 ,(

BrMg toluene, reflux 60 h 21 %

Br

oh

de

Because of the availability of the chiral catalyst 31, it was obvious to investigate the enantioselective carbomagnesation of prochiral substrates. Hoveyda and co-workers demonstrated that asymmetric carbomagnesations of cyclic allylic 1 . n-BuLi, THF then ZrC14, 24 h, 25°C 2. H2 (100 bar), cat. Pt02, CH2CIL

H

dH

rac-31

23 Yo

32 1. R*OH, NEt3, toluene 2. separation of diastereomers (cryst.)

2. 1 . MeMgCI, HCI, EtpO, THF 0C ",

39 Yo

GCl \zr\,I..cI

52 Yo

33

31

Scheme 3. Synthesis of the chiral zirconocene catalyst 31 according to H.-H. Brintzinger.

The diastereoselectivities that can be achieved in the transformations of chiral, non-racemic substrates can be improved in certain cases by use of a chiral catalyst [lo]. Because of the effect of double diastereoselection the correct absolute configuration of the catalyst is important. Hoveyda et al. chose the chiral unsa-zirconocene derivative 31, which can be synthesized according to a method described by Brintzinger (Scheme 3) [ l l l . At first, reaction of 1,2-dibromethane with an excess of indcnyl magnesium bromide leads to the ethano-bridged bis-tetrahydroindenyl ligand 32 (mixture of isomers), from which the racemic complex (rac-31) is obtained. The separation of the enantiomcrs is finally achieved by fractionated crystallization of the derivativc 33 (R4'OH = (R)-0-acetylmandelic acid).

ethers (or allylic amines) can be achieved with high enantioselectivities (Scheme 4) [ 121. In this manner several synthetically valuable compounds, such as those of type 34 have been synthesized from precursors of type 35. Me

H I

HO

+ EtMgCl

34

35

The fact that these reactions proceed under ring opening can easily be understood. For instance, the dihydrofuran 36 initially gives rise to 38 (via the intermediate 37), which easily fragments. Concomitant with the regeneration of the catalyst, the magnesium salt of the isolated product (39) is formed.

Zr-Catalyzed Curbomugnesution of Alkenes

J-=( 0

&

- - - - - -.-w

0.

36

MgCl

39

81

The examples listed in scheme 4 illustrate the reliability of this remarkable new methodology for catalytic enantioselective C-C bond formation. It should be mentioned that isopropylated products are generated when n-propyl magnesium chloride is employed - with good selectivity, as the transformation 40 to 41 indicated.

C I

\ /

LO

40

41

38

98 % ee

In more recent work, Hoveyda et al. go a step further and utilize the enantioselective carbomagnesation (catalyzed by 31) for the kinetic resolution of racemic dihydropyrans of type ruc-42, ruc-43, or rac-44.

a

65 %

b

-

+.'

Me 42

75 Yo

NHc9H19

> 95 Yo ee

a 73 Yo

43

44

When these reactions are stopped at about 60 % conversion, it is possible in most cases to isolate the unreacted dihydropyrans (e.g. 45) with enantiomeric purities of >99 96 ee. Interestingly, these selectivities can only be achieved at elevated temperatures (70 "C).

95 YOee

5 eq. EtMgCI, THF 10 mol % (31)

rac45

70°C, 30 min

40 %

a ____)

75 % OH

92 Yo ee a: 10 mol % 31, 5 eq. EtMgCI. THF, 25 "C, 6-12 h

b: 10 mol % 31, 5 eq. EtMgCI, THF, 4 "C, 12 h

45 >99%ee

The chiral product (39) obtained from the asymmetric ethylmagnesation of dihydrofuran

82

B. Transition Metal Organomerallic Methods

Outlook The work discussed in this brief article demonstrates that the Zr-catalyzed carbomagnesation of alkenes has developed over the last few years into a powerful synthetic methodology, allowing the synthesis of valuable products with high regio-, diastereo- and enantioselectivities. So far, carbomagnesations have been studied predominantly. Therefore, it will be an interesting task in the future to expand the method for higher alkyl Grignard substrates also. Moreover, the combination of the kinetic resolution methodology with subsequent ring-closing metathesic reactions opens up new powerful strategies for the construction of complex carbocycles [ 1 3 ~ 1 .

References [ 11 Review: P. Knochel in Comprehensive Organic

Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 865. [2] Grignard compounds are produced on an industrial scale and marketed e.g. by Chemetall GmbH, Frankfurt am Main. [3\ H. Lehmkuhl, Bull. Soc. Chirn. F L , Part 2, 1981, 87. [4] see, for instance: W. Oppolzer in Selecriviry - A Goal for Synthetic Efficiency (Eds.: W. Bartmann, B. M. Trost), Verlag Chemie, Weinheim, 1984, p. 137. [ S ] a) U. M. Dzhemilev, 0. S. Vostrikova, J. Organomet. Chem. 1985,285,43; h) U. M. Dzhemilev, 0. S. Vostrikova, G. A. Tolstikov, J. Organomer. Chern. 1986, 304, 17, and refs. cited therein. [6] For a review on newer developments in the field of Zr-mediated C-C coupling, see: M. E. Maier, NachL Chem. Tech. Lub. 1993, 41, 811. [7] a) A. H. Hoveyda, Z. Xu, J. Am. Chern. Soc. 1991, 113, 5079; h)A. H. Hoveyda, Z. Xu, J. P. Morken, A. F. Houri, J. Am. Chem. Soc. 1991, 113, 8950; c) A. F. Houri, M. T. Didiuk, Z. Xu, N. R. Horan, A. H. Hoveyda, J. Am. Chem. Soc. 1993, 115, 6614.

[XI A. H. Hoveyda, J. P. Morken, A. F. Houri, Z. Xu, J . Am. Chern. Soc. 1992, 114, 6692. [Y] a) T. Takahashi, T. Seki, Y. Nitto, M. Saburi, C. J. Rousset, E.-i. Negishi, J. Am. Chem. Soc. 1991, 113, 6266; h) K. S. Knight, R. M. Waymouth, 1. Am. Chem. Soc. 1991, 113, 6268; c) U. Wischmeyer, K. S. Knight, R. M. Waymouth, Tetrahedron Lett. 1992, 33, 7735; d) K. S. Knight, D. Wang, R. M. Waymouth, J. Ziller, J. Am. Chern. Soc. 1994, 116, 1845. [lo] A. H. Hoveyda, J . P. Morken, J . O r , . Chem. 1993, 58, 4237. [ l l ] a) F. R. W. P. Wild, L. Zsolnai, G. Huttner, H.-H. Brintzinger, J. Organomet. Chem. 1982, 232, 233; h) F. R. W. P. Wild, M. Wasiucionek, G. Huttner, H.-H. Brintzinger, J. Orgunomet. Chem. 1985, 288,63; c) A. Schifer, E. Karl, L. Zsolnai, G. Huttner, H.-H. Brintzinger, J. Organornet. Chem. 1987, 328, 87; for an overview on applications of 31 in organic synthesis, see: d) A. H. Hoveyda, J. P. Morken,Angew. Chem. 1996,108, 1378;Angew. Chem. In?. Ed. Engl. 1996, 35, 1262. [I21 a) J. P. Morken, M. T. Didiuk, A. H. Hoveyda, J . Am. Chem. Soc. 1993, 115, 6997; b) M. T. Didiuk, C. W. Johannes, J. P. Morken, A. H. Hoveyda, J . Am. Chem. Soc. 1995, 117, 7097; c) M. S. Visser, N. M. Heron, M. T. Didiuk, J. F. Sagal, A. H. Hoveyda, J. Ant Chem. Soc. 1996, I1 7,429 I ; for a brief review, see: d) A. H. Hoveyda in: Transition Metal.s,forOrganic Synrhesis, Vol. 1, (Eds.: M. Beller, C. Bolm), Wiley-VCH, 1998, p. 195. [I31 a) J. P. Morken, M. T. Didiuk, M . S. Visser, A. H. Hoveyda, J. Am. Chem. Soc. 1994,116,3 123;b) M. S. Visser, A. H. Hoveyda, Tetrahedron 1995,4383; c) N. M. Heron, J. A. Adams, A. H. Hoveyda, J . Am. Chem. Soc. 1997, 119, 6205; d) J. A. Adams, J. G . Ford, P. J. Stamatos, A. H. Hoveyda, J. Org. Chem. 1999, 64, 969 1. [ 141 a) A. F. Houri, Z. Xu, D. A. Cogan, A. H. Hoveyda, J. Am. Chem. Soc. 1995, 117, 10926; b) Z. Xu, C. W. Johannes, A. F. Houri, D. S. La, D. A. Cogan, G. E. Hofilena, A. H. Hoveyda, J. Am. Chem. Soc. 1997, 117, 10302.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Intramolecular Alkoxypalladation Oliver Geis and Hans-Giinther Sclzmalz Institut ,fur Organische Chemie, Universitat Kiiln, Germuny

Ever since the initial discovery of the Wacker process [ 11, i.e. the Pd/Cu-catalyzed oxidation of ethylene to acetaldehyde (1) in water, methods for the palladium (11) - mediated oxidative functionalization of alkenes have found widespread application in the synthesis of complex molecules [2].

HzC=CH2

+ 1/20?

cat PdCI2 cat CuClp Hz0

-

0

MeK~ 1

The basic principle of this chemistry is that q2alkene-Pd(I1) complexes, usually generated in situ, are easily attacked by nucleophiles to form a-alkyl-Pd species, which in turn are able to react further in a variety of ways. In general, several kinds of nucleophiles (e.g. alcohols, amines and enolethers) are able to attack the alkene complex intermediates in an intra- or intermolecular fashion. This article, however, focusses exclusively on intramolecular alkoxypalladations, i.e. transformations of the type 2 + 3, which are of particular synthetic relevance.

several synthetic applications had demonstrated the value of this methodology.

AlkoxypalladatiodCarbonylation After James and Stille had shown the general possibility to link (intermolecular) alkoxypalladation and carbonylation processes [ 41, Semmelhack et al. were the first to achieve Pd-catalyzed intramolecular alkoxycarbonylation reactions and to apply them in the synthesis of specific target molccules [5]. In a typical reaction, the substrate is stirred at room temperature in methanol under an atmosphere of CO ( 1.1 atm) in the presence of 5-10 mol% of PdCl, and an excess ( 3 eq.) of CuCI,. As the conversion of the simple model compound 4 to the products 5 and 6 implies, such reactions often proceed in good yields but not necessariliy with high diastereoselectivies (5 : 6 = 3 : 1). Me 1

5 mol % PdC12

OH

ROH.2h

Me

4

2

3

The first example of such a reaction was reported by Hosokawa et al. in 1973 [3]. Since then, many further examples have appeared in the literature [2]. In recent years, this chemistry has received increasing recognition after reliable experimental procedures had been developed and

6

COPR

The presumed reaction mechanism is shown in Scheme 1. First, the in situ generated v2-alkenePd(1I) complex 2 is intramolecularly attacked by the nucleophile to form an alkoxypalladated species 3. In the presence of carbon monoxide this intermediate rapidly undergoes migratory inser-

84

B. Trurzsition Metul Organometallic Methods

8

L CkPdX

co

HX

3 Scheme 1. Mechanism of the Pd-catalyzed alkoxycarbonylation of alkenes.

tion, usually faster than the competing P-hydride elimination. The resulting acylpalladium derivative 8 is finally trapped by a second nucleophile (usually the alcoholic solvent) to give the product 9. To close the catalytic cycle, the released Pd(0) must be converted back to Pd(l1). This is usually achieved by the addition of stoichiometric amounts of CuCI,. In principle, oxygen can be used as stoichiometric oxidant as in the Wacker oxidation; however, this seems to be efficient only in certain cases. First applications of this chemistry were reported by Semmelhack et al., who synthesized the (racemic) naphthoquinone antibiotics nanaomycin A (roc-10, R = Me) and desoxyfrenolicin (ruc-10, R = propyl). These target molecules are retrosynthetically traced back to a precursor of type 11 1.51. In these cases, the Pd-catalyzed cyclizations proceeded only with low diastereoselectivity; the desired truns-stereochemistry, however, can be set up by subsequent equilibration.

c3 0

C02H

10

0

11

If other hydroxy functionalities are appropriately placed in the substrate, the Pd-acyl intermediates are intramolecularly trapped to form lactones [.5c]. In a remarkably short enantioselective total synthesis of frenolicin B (17) (Scheme 2) Kraus et al. successfully exploited Semmelhack’s tandem methodology for the construction of rings C and D [6a]. Starting from the (prochiral) ketone 12, the alcohol 13 is generated by enantioselective reduction with (+)-diisopinocampheylchloroborane [(+)-IPC,BCl)]. This reaction represents the chirogenic step of the synthesis. The alcohol 13 is then converted with n-butyllithium into a dianion, which in turn reacts with acrolein to give a 1 : 1.5-mixture of two diastereomeric diols. The desired major product 14 can be purified by flash chromatography. The Pd-catalyzed cyclization of 14 leads diastereoselectively to lactone 15, which is first oxidized to the corresponding quinone before the missing ring is attached by a regioselective (!) Diels-Alder reaction. In the final step, the Diels-Alder product 16 is converted to the natural product 17 by Jones oxidation. It should be mentioned that Kraus et al. succeeded in controlling the regioselectivity of a Diels-Alder reaction (with the help of strategically placed substituents) also in a synthesis of hingconine [6b].

Intramolecular Alkoxypulladation

OMe OH

OMe

13

14

93 % ee

4H

85

i

cat Pd(OAc)2.CO

CuCI,

,

THF. 23°C

Me

65 %

Me

Jones ox

c _ _

0

0

90 %

85 %

0

16

17

15

Scheme 2. Synthesis of frenolicin B according to G. A. Kraus.

Based on the results of mechanistic studies on the stereochemical course of the Wacker reaction and related processes [7], one would expect the alkoxypalladation of alkenes to proceed stereospecifically as a trans-addition. Indeed, this was confirmed in the highly diastereoselective formation of compound rac-18 from 20 and of rac-19 from 21.

0 1 eq PdCI, 3 e a CuCI, CO M e O i 25 "C. 17 h a4

H '

CO.Me

22

23

Even the preparation of 2,3,5-trisubstituted tetrahydrofurans is possible in good yield as the transformations 24 to 25 and 26 to 27 exemplify [8b, 91.

Med: cat. PdCI,(MeCN), 2.2 eq. CUCI, CO. MeOH. 23 'C 100%

K

O

H

M~. . -A\,.

cat PdCI? CUCI, CO.MeOH

---a4 ah

20 kat PdCI, CUCI, CO. MeOH

-

*

24

25

rac-18 > 96 % de

cat PdCI2 3 eq CuCI, CO, MeOH 84 %

-

MeL

lac-19

(80Oh)

Me

Ph

> 98 % de

21

Purely aliphatic systems also react with good diastereoselectivity, but only if remote substituents cause an energetic differentiation of the competing transition states [S, 91. For instance, Z-configurated substrates of type 22 are suitable starting materials for the construction of 2,6-disubstituted tetrahydropyrans of type 23 @a].

M

e C02Me

26

27

As Jaeger and co-workers demonstrated, the Pd-catalyzed alkoxycarbonylation of unsaturated polyols is also useful for the w-homologization of aldoses. In general, cis-fused bicyclic lactones are obtained with high selectivities [lo]. As an example, the 0-gluco-configurated product 29 is generated in high yield starting from the D-lyxose derivative 28.

86

B. Transition Metal Organometallic Methods 10 mol % PdCI2, CO 3 eq. CuCI, . NaOAc HOAc, 23"C,41h Ho

Ho*

HO

63 %

OH

-

Y

ti

H

H6J

28

H2

O

29

This chemistry was applied in a synthesis of (-)-goniofufuron (35), the unnatural enantiomer of a cytotoxic compound isolated from the bark of

the Thai tree goniothalamus gigunteus [ 1Ob]. Starting from the D-glUCOSe derivative 30, the synthesis (scheme 3) leads, via the hexenose derivatives 31 and 32, to the epimeric mixture 33, which is converted in excellent yield to the bicyclic lactones 34 (mixture of diastereomers) by means of Pd-catalyzed alkoxycarbonylation. Finally, the desired epimer 35 is separated by flash chromatography.

OH

30

32

31

Xnflash

H 0. L V

HO

35

33

34

Scheme 3. Synthesis of (-)-goniofufurone according to V. Jager

If the alkoxypalladations are conducted in the absence of carbon monoxide, the primarily generated a-alkyl species often react to olefins by phydride elimination [2b]. Based on this fact, a novel method for the synthesis of 2-alkenyl-tetrahydropyrans 36 starting from hydroxyalkenes of type 37 was developed [ 111.

36

37

In these reactions, a remarkable solvent effect became apparent: while in DMF, THF and acetonitrile only low yields and a high proportion of isomerized products are observed, in DMSO, however, the reactions proceed very smoothly. Obviously, in this solvent the p-hydride elimination proceeds in a very controlled manner to se-

lectively give the E-configurated alkenes. Usually, Z-configurated substrates of type 38 give the best results, leading to products of type 39. By comparing the two competing chair-like transition states 41 and 43 (both having two equatorial substituents), it seems that 41 is preferred because of an unfavorable 1,5interaction in 43. Indeed, the configuration of the major product (39) corresponds to a transition state of type 41 and a resulting intermediate of type 42. A certain disadvantage of this method is that stoichiometric amounts of the palladium "catalyst" have to be employed. While it is possible to reoxidize the in situ generated Pd(0) in the above-mentioned alkoxycarbonylations, the development of efficient catalytic procedures for the alkoxypalladationlp-hydride elimination reactions still represents an unsolved problem. However, first successes [12] in special systems suggest that this problem should not be insoluble.

87

Intramolecular Alkoxypalladation

R2kMe OH

~1"'

'

1 t?q Pd(0AC)Z. DMSO 24 "C. 18 - 24 h

90 - 96 Yo

pounds for the trial of new methods for the stereoselective construction of oxygen heterocycles.

-

Me..,,

Me OMe

OH

45

PdX

PdX2

41

42

43

44

Synthesis of Tetronomycin Ionophores (polyether antibiotics) [13] such as tetronomycin (45) are challenging target molecules for organic synthesis and ideal test com-

In a synthesis of tetronomycin (45) published in 1994 [14], Semmelhack et al. probe the scope of intramolecular alkoxypalladations. The retrosynthetic analysis (Scheme 4) shows that the chosen strategy exploits such Pd-catalyzed transformations even twice. The pre-target structure 46 is formally derived from 47 by Pd-mediated cyclization. Compound 47 can be traced back via 48 to the tetrahydrofuran derivative 49, which in turn should be available by alkoxycarbonylation from a precursor of type 50. In the following, the realization of this concept will be briefly described. The synthesis of the tetronomycin building block 55 (Scheme 5 ) starts from the chiral aldehyde 51, which is easily accessed from D-arabinose. Reaction with vinyllithium leads to a 1 : 1 mixture of the epimeric alcohols 52a and 52b, which are separated by HPLC. Interestingly, both diastereomers can be converted (on separate routes) into the building block 55. Both the Pd-catalyzed key steps (53 + 54 and 56 + 57) proceed with high diastereoselectivity.

45

50

49

48

Scheme 4. Retrosynthesis of tetronomycin according to M. E Semmelhack

88

B. Transition Metal Organometullic Methods OH

PMBO

52b

Me0

52

51 OTBDPS

OH 1. TBDPSCI

TBDPSO

Pd(OAc),. CO

4 steps

OMe

OMe

52a

OMe

53 HO

55

aMe '=Xm3 %z 1 . TEDMSOTf

OH

PH

cat. PdCI,, CO CuCI,, NaOAc

2. DDQ

OMe

0

OMe

> 98 % de

O H

5 steps 51%

OMe

52b

56

57

Scheme 5. Synthesis of the tetronomycin building block 55 according to M. F. Semmelhack.

equivalents of acetic acid) then occurs with controlled P-H elimination to diastereoselectively afford compound 60. After protection of the primary hydroxy function, cleavage of the silyl group and Swern oxidation give the advanced tetronomycin precursor 61. Although the final preparation of the target molecule was not reported, the synthesis of 61 represents a convincing demonstration of the value of intramolecular alkoxypalladation techniques.

For the assembly of the tetronornycin skeleton (Scheme 6), the dilithiated species prepared from 58 with butyllithium is reacted with the aldehyde 48 to give a mixture of diastereomers ( I : 2), from which the desired isomer 59 can be separated by chromatography. The undesired epimer is converted into 59 through protection of the primary OH function, Swern oxidation and diastereoselective reduction. The crucial Pd(I1)-mediated cyclization of 59 in DMSO (in the presence of 8- 10

OTBDPS ,,.Me

Me

2 chromatogr

OH 59 Pd(0Ac)Z. DMSO

OH

58

23 "C. 36 h

OTBDPS

Me..,, OH

60 1. pMeO-C6H4CH2Br,NaH 2 TBAF

61

1

3 Swernox

Scheme 6. Synthesis of the advanced tetronomycin intermediate 61 according to M. F. Semmelhack.

Intrarnoleculur A lkoxypalladution

89

Enantioselective Reactions

Conclusion

Although diastereoselective intramolecular alkoxypalladations have been investigated intensively and have found application in synthesis (see above), there are few examples of enantioselective alkoxypalladations [2b]. For instance, Hosokawa et al. were able to cyclize unsaturated phenol derivatives of type 62 in the presence of chiral ($-allyl-PdOAc complexes, i.e. 63), but only with modest enantioselectivities. Under the same conditions the conversion of the phenol 65 to chroman 66 (a compound related to vitamin E) proceeded in acceptable yields, but with only low asymmetric induction. Newer results by Uozumi et al., for instance the Pd-catalyzed cyclization of 67 to 68 in the presence of a chiral bis-oxazolin ligand [ 151, show that much higher enantioselectivities can be achieved, at least for certain substrates.

The intramolecular alkoxypalladation has been developed into a remarkable (catalytic) methodology which exhibits a great synthetic potential, especially in combination with carbonylation. This is reflected by convincing applications in natural product syntheses. This chemistry opens reliable and highly diastereoselective approaches to several hydropyran and hydrofuran systems. The development of efficient enantioselective protocols for the various chirogenic transformations is still a challenging goal for the future.

62

64 1 - 26 % ee

Me

65

Me

Me

66 10 % el?

67

68 97 % ee

References [ I ] J. Smidt, W. Hafner, R. Jim, R. Sieber, J. Sedlmeier, A. Sabel, Angew. Chem. 1959, 71> 176; Angew. Chem. 1962, 74, 93. [2] Reviews: a) L. S. Hegedus, Tetrahedron 1984, 40, 241 5; b) T. Hosokawa, S.-I. Murahashi, Ace. Chem. Res. 1990,23,49;c ) L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic Molecules (2nded.), University Science Books, Sausalito, CA, 1999, p. 192; d) B. L. Feringa in: Transition Metalsfor Organic Synthesis, Vo1.2 (M. Beller, C. Bolm; eds.), Wiley-VCH, Weinheim 1998, chapter 2.8. 131 T. Hosokawa, K. Maeda, K. Koga, I. Moritani, Tetrahedron Lett. 1973, 739. 141 D. E. James, J. K. Stille, J. Am. Chem. Soc. 1976, 98, 1810. [5] a) M. F. Semmelhack, J. J. Bozell, T. Sato, W. Wulff, E. Spiess, A. Zdsk, J. Am. Cliem. SOC. 1982, 104, 5850; b) M. F. Semmelhack, A. Zask, J. Am. Chem. SOC.1983, 105, 2034; c) M. F. Semmelhack, C. Bodurow, M. Baum, Tetrahedron Left 1984, 25, 3 I7 1. 161 a) G. A. Kraus, J. Li, M. S. Gordon, J. H. Jensen, J , Am. Chem. SOC.1993, 115, 5859; b) G. A. Kraus, J. Li, M. S. Gordon, J. H. Jensen, J . Org. Chem. 1994, 59, 22 19. [71 a) J. K. Stille, D. E. James, L. F. Hines, J. Am. Clzem. Soc. 1973, 95, 5062; b) J. K. Stille, R. Divakaruni, J. Am.oChem. SOC.1978, 100, 1303; c ) J. E. Backvall, B. Akermark, S. 0. Ljunggren, J. Am. Chenz. Soc. 1979, 101, 241 1. 181 a) M. F. Semmelhack, C. Bodurow, J . Am. Chem. Soc. 1984, 106, 1496; b) M. F. Semmelhack, N. Zhang, J . Oix. Chem. 1989, 54, 4483. 191 a) M. McCormick, R. Monahan 111, J. Soria, D. Goldsmith, D. Liotta, J. Org. Chem. 1989, 54, 4485; b) C. P. Holmes, P. A. Bartlett, J. Org. Chem. 1989, 54, 98.

90

B. Transition Metal Organometallic Methods

[ 101 a) T. Gracza, T. Hasenohrl, U. Stahl, V. Jager, Synthesis, 1991, 1108; b) T. Gracza, V. Jager, SynLett 1992, 191. [ 111 M. F. Semmelhack, C.R. Kim, W. Dobler, M.

Meier, Tetrahedron Lett. 1989, 30, 4925. 1121 S. Saito, T. Hara, N. Takahashi, M. Hirai, T. Moriwake, Synlett 1992, 237.

[ 131 J. W. Westley, Polyether Antibiotics: Naturally Oc-

curing Acid Ionophores, Marcel Dekker, New York, 1991. 1141 M. F. Semmelhack, W. R. Epa, A. W.-H. Cheung, Y. Gu, C. Kim, N. Zhang, W. Lew, J. Am. Chem. SOC. 1994, 116, 7455. [ 151 Y. Uozumi, K. Kato, T. Hayashi, J . Am. Chrm. SOC. 1997, 119, 5063; J. Org. Chem. 1998, 63, 5071.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Ring-closing Olefin Metathesis Michael Karle and Ulrich Koert Institut f u r Chemie, Humholdt- Universitat, Berlin, Germany

Olefin metathesis is the transformation of two olefins 1 and 2 into two new olefins 3 and 4. Formally, the reaction represents a mutual exchange of alkylidene groups [Eq. (l)]. The reaction is catalyzed by various transition metal complexes. A

B

w

'

catalyst

A

3

CmD

4

2

The reaction is applied in industrial processes (Phillips triolefin process, Shell higher olefin process) and has importance in ring opening-metathesis polymerization (ROMP) in polymer chemistry [ I ] . In the past, olefin metathesis was not commonly applied in organic synthesis 121 because of the reversibility of the reaction, leading to olefin mixtures. In contrast, industrial processes often handle product mixtures easily. In ROMP, highly strained cyclic olefins allow the equilibrium of the reaction to be shifted towards the product side. Attention paid to olefin metathesis in organic synthesis has increased over recent years because of the progress in ring-closing metathesis 131. This metathesis variation consists of the cyclization of an acyclic ( a , w)-diene 5 and formation of

5

X = C. N. 0

6

7

cyclic olefin 6 and ethylene 7 under metathesis conditions [Eq. (2)]. In this cyclization, the equilibrium of the reaction is shifted towards the product side for entropic reasons, and removal of the volatile ethylene moves the equilibrium further in the same direction. Several catalysts for ring-closing metathesis are now known. Prominent examples are shown in Scheme 1: the molybdenum carbene complex 8, introduced by Schrock et al. 141, methyltrioxorhenium 9, discovered by Herrmann et al. 1.51 and the ruthenium carbene complex 10, developed by Grubbs et al. [6] Recently, chiral molybdenum catalysts such as 11 have been synthesized, giving access to asymmetric ring-closing metathesis 171. Water-soluble variations of catalyst 10, like catalyst 12, perform metathesis in water or methanol 181, extending the scope of the reaction to substrates which are poorly soluble in organic solvents. Currently the most promising catalyst is 10. Its synthesis was first described by Grubbs et al. [6] Recently, Furstner et al. reported a simple method for in situ preparation of a catalyst for ring-closing metathesis reactions by heating a solution of the diene with catalytic amounts of commercially available [(p-cymene)RuCI,], and P(cy), in CH,CI, under neon light [9]. The same group also reported ring-closing metathesis at ambient temperatures promoted by conveniently accessible coordinatively unsaturated allenylidene Rucomplexes [9]. Scheme 2 shows a simplified description of the ring-closing metathesis mechanism [3]. In the first step, one double bond of starting diene 13 forms with the catalyst 20 via the z-complex

92

B. Transition Metal Organometallic Methods

MeReO3

a

9

10 R = Cyclohexyl

+ @

R, RI +N(MeQCl P

Me

t-Bu 11

+

14 the metallacyclobutane 15. (2 2)-Cycloreversion of 15 leads to carbene complex 17. Here the by product ethylene 7 is formed. The n-complex 16, first postulated as an intermediate by Grubbs, was meanwhile confirmed by X-ray structural analysis [lo]. Intramolecular (2+2)-cycloaddition of 17 leads to the intermediate 18. Upon the release of the product 19, the catalytic

13

18

17

a

Y=

Ic:

Scheme 1. Catalysts for ring-closing metathesis.

R = Cyclohexyl

12

cycle is closed. Scheme 2 shows only the catalytic cycles pathway leading to product 19. In regard to the reversibility of the single steps, there is another catalytic cycle, which is not shown, describing the reactions pathway in the other direction. Catalyst 10 allows the production of cyclopentene (21 --t 22) and cyclohexene derivatives (23 24) in high yields [ 111 (Scheme 3). The tolerance of many different functional groups is remarkable. For example, dienes of the type 23, possessing an unprotected carboxylic acid, aldehyde, or alcohol function, can be used in ringclosing metathesis, employing catalyst 10. The application of the reaction is not limited to carbocycles. 0- and N-heterocycles are acces--f

<2 4 rnol Yo catalyst 10 C6H6,20 OC,2h

J

TBDMSO

T B D M S O G

85%

15

--

zz

21

2 rnol % catalyst 10 20 'C, 1h

Rc-

t

23

16

Scheme 2. Mechanism of ring-closing metathesis

R=C02H R=CHO R=CH20H

Scheme 3. Formation of cycloalkenes.

87% 82% 88%

24a 24b 24c

-2-4 mol % catalyst 10 C&i6,20 O C , 2h

Ph

Ph

0

84%

26

25

Ph

-

# Bn-N

2-4 mol % catalyst 10 C&. 20 OC. 8h 72%

Ph 28

21

2-4 mol % catalyst 1 0

30

29

4 mol %

catalyst 1 0

CH~CIZ, 20 'C, 36h 79%

0 c' Bn'"'N@

31

+I

NaOH

32

Scheme 4. Formation of 0- and N-heterocycles.

sible in a facile way too [ l l ] (Scheme 4). Thus, the cyclization of the bisallyl ether 25 to the dihydrofuran derivative 26 succeeds with a yield of 84 %. Even the synthesis of oxepines (27 i 28) is possible. There are limitations with N-heterocycles. Amines are not compatible with the catalyst. Thus, the cyclization of bisallylamine 29 to dihydropyrrole 30 is not possible. Since the amine nitrogen is too basic, it blocks the coordination sites at the transition-metal of the catalyst. This can be avoided by protonation. For this, the amine 29 is converted into the corre-

*

0

-

5 mol % catalyst 8 C6H6. 20 OC, 15min

93

Ring-closing Olefin Metathesis

sponding hydrochloride 31, which can be cyclized to the protonated dihydropyrrole 32. In this case, a longer reaction time is required. In the previous examples, disubstituted double bonds have been synthesized via ring-closing metathesis. As shown in Scheme 5, it is possible to extend the method to tri- or tetrasubstituted double bonds. Thus, bisallylic ether 33 leads to the trisubstituted olefin 34 and compound 35 gives the tetrasubstituted olefin 36 [3]. Here, the additional substituents are simple methyl groups, but silyl groups for example, can be introduced too. The volatile byproducts in these cases are not ethylene but butene or propene. Because of the excellent performance of the new catalysts, many research groups use ringclosing metathesis as the key step in natural product synthesis [ 121- [ IS]. Scheme 6 shows some examples. Via ring-closing metathesis of the olefin 37 to the hydroazulene 38, Blechert et a]. 1121 succeeded in synthesizing a cyclic system which is part of many sesquiterpenes. Cyclooctane derivatives, whose synthesis is the main problem in taxol synthesis, can be obtained in good yields (39 + 40), as demonstrated by Grubbs et al. [ 131. a mol % catalyst 10 on Si021A1203 reflux, CHZC12, 1.1.2-trichlorotrifluoroethane 80%

38

31

&5 mol % catalyst 25'C,4h 10

75%

Ph

39

40

41

42

0%

92%

33

34

35'

36

Scheme 5. Formation of tri- and tetrasubstituted olefins.

Scheme 6. Examples of synthetic applications.

94

B. Transition Metal Organornetallic Methods

"COOMe

CbZYN*

43

-

H

-

___)

44 O 'H

1. 0 3 , CHzCIz. -78°C 2. LiAIH4, THF. r. t., 19 h

3. Boc~O,DMAP,

10 mol %cat. 10

CHZCIz, r. t. 6 h

r.aa t.,yo 2d

Tfa"?

-

\

45

I.

Os04,Me,NO, PY, t-BuOH, H20

2. HCI, CH,OH, r.' .1 Boc'

46

OTBS

OH

;

%TBS

*

42 %

kOH HN

53 %

47

With catalyst 10, the bisallyl dipeptide 41 can be converted into the conformationally constrained but not fully rigid dipeptide 42 [13]. Artificial dipeptides of type 42 are discussed as enzyme inhibitors. The double bonds formed in ring-closing metathesis reactions can be the basis for various further transformations (e.g. epoxidation, bis-hydroxylation). One example of further functionalization of the metathesis product is the synthesis of azasugars of type 48 by Blechert et al. [I41 (Scheme 7). The starting point for the synthesis of 48 is vinylglycine methyl ester hydrochloride 43, which is converted into the Cbz-protected amino alcohol 44. Within three steps, employing standard reactions, the Tfa-protected bisallylamine 45 is synthesized. Ring-closing metathesis with catalyst 10 leads to compound 46. Regioselective ozonolysis of 46, followed by reductive work up with lithium aluminium hydride and introduction of a Boc group gave the protected diol 47. Catalytic dihydroxylation of 47 with osmium tetroxide and subsequent removal of the protecting groups with HCI resulted in the desired azasugar 48. Ring-closing metathesis is now applied as the key step in many natural product syntheses. Prominent examples are the syntheses of manzamine A [ 15,171 and epothilone A [ 181 (Scheme 8).

Scheme 7. Synthesis of azasugars.

@

N\

Manzamine A

Epothilone A

Manzamine A and epothilone A are two natural products with promising antitumor activities. Manzamine A is isolated from marine sponges, whereas epothilone A is isolated from myxobacteria. For manzamine A, Martin et al. developed a strategy for the construction of the eightmembered ring E [15], Pandit et al. succeeded in the formation of the 13-membered ring D [ 181. The efforts culminated recently in the total synthesis of manzamine A and related manzamine alkaloids, employing the ring-closing metathesis reaction as a key step [16]. Thus, 49 is converted into 50 with a yield of 67 % (Scheme 8). For epothilone A, among other compounds [ 171, Nicolaou et al. developed a ring-closing me. of diene 51 tathesis approach [ 1 7 ~ 1Cyclization gave product 52 with an overall yield of 85 %.

Ring-closing Olefin Metathesis ,OTBDPS

95

,OTBDPS

catalyst 10, 13 mol %

50

49

HO

Neat. 1 0 , 15 mol% CH2CI2 (0.006M)

,,.

r. t. a h 50 % (E-isomer) 35 % (Z-lsomerj

ER 0

0

51

52

Scheme 8. Ring-closing metathesis as the key step in the synthesis of manzamine A and epothilone A.

lone synthesis (51 + 52), a higher Z selectivity would be desirable. Here, help may come from ring-closure metathesis of alkynes, leading to cyclic alkynes, which can be reduced selectively to Z-olefins. Ring-closing metathesis has been used successfully in asymmetric synthesis (Scheme 10). Chiral catalysts such as 11 can be employed for the kinetic resolution of racemates 1211 (58 + 59 + 60). Scheme 10 demonstrates the formation of only one enantiomer 59 with a high level of optical purity. Enantiomer 60 does not undergo

Indeed, ring-closing metathesis has become an interesting alternative in the formation of many different macrocyclic structures, such as catenanes [ 191. Ring-closing metathesis is not limited to olefins. Catalysts promoting ring closure of alkynes [20] have also been developed (Scheme 9). Alkyne 56 can easily be converted into cyclic alkyne 57 with a yield of 73 %. For this purpose, a tungsten catalyst has been used. Looking at the EIZ ratio in the formation of macrocyclic structures, for example in the epothi-

/

R1

X

-\ 53

-

R1

cat.

(t-BUO)sWIC-t-Bu

c

X

S

l

+

111 R2

R2

X=C, N . 0

Scheme 9. Ring-closing alkyne metathesis.

54

55

96

B. Transition Metal Orgunometallic Methods

I1 58

61

93 % ee

II

59

60

I62 99 % ee

Scheme 10. Asymmetric ring-closing metathesis

cyclization and can be isolated with a high optical purity. Another interesting approach in asymmetric ring-closing metathesis is the catalytic enantioselective desymmetrization of achiral starting materials [2 I ] (61 + 62). Starting with achiral material 61, the use of chiral catalyst 11 leads selectively to the enantiomer 62. In summary, the development of new powerful catalysts has made ring-closing metathesis a very valuable method for the formation of common, medium-sized and macrocyclic rings. Remarkable features of the reaction are the compatibility of many different functional groups and the good yields, even in synthesis of macrocyclics. For this reason, ring-closing metathesis plays an important role in organic synthesis nowadays, and will contribute substantially in the future.

References 11 1 a) K. J. Ivin, Olefin Metuthesis, Academic Press, London, 1983; b) V. Dragutan, A T. Balaban, M. Dimonie, Olyfin 1l4etuthi~si.stmd Ring Opening Polynzerizutiorz cf’ Cyclo-Olefins,2 nd, Ed., Wiley Interscience, New York, 1985; c ) R. H. Grubbs, W. Tumas, Science 1989, 243, 907; R. H. Schrock, Acc. Chem. Kes. 1990, 23, 158. [2] R . H. Grubbs. S. H. Pine in Coniprehensive Orgarric Sytzthesis (Ed. B. M. Trost), Pergamon, New York, 1991, Vol 5, Chapter 9.3. 131 G. C . Fu, R. H. Grubbs, J. Am. Chem. SOC. 1992, 114, 5426. For reviews see: R. H. Grubbs, S . Chang, Tetruhedron 1998, 54, 4413; M. Schus-

ter, s. Blechert, Angew. Chem. 1997, 109, 2124; M. Schuster, S. Blechert, Angew. Chem. Int. Ed. Engl. 1997, 36, 2036; H.-G. Schmalz, Angerv. Chem. 1995, 107, 1981; H.-G. Schmalz, Angew. Chem. Int. Ed. EngI. 1995, 34, 1833. [4] G. C . Bazan, J. H. Oskam, H.-N. Cho,L. Y. Park, R. R. Schrock. J . Am. Chem. Soc. 1991, 113, 6899. [5] W. A. Herrmann, F. E. Kiihn, R. W. Fischer, W. R. Thiel, C. C. Romao, Inorganic Chenz. 1992, 31, 443 1. [ 6 ] S. T. Nguyen, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1993, 115, 9858. [7] J. B. Alexander, D. S. La, I>. R. Cefalo, A. H. Hoveyda, R . R. Schrock, J.Am. Chem. Soc. 1998.120, 4041, [8] T. A. Kirkland, D. M. Lynn, R. H. Grubbs, J. Org. Chem. 1998, 63, 9904. [9] a) A. Furstner, L. Ackermann, Chern. Cornmun. 1999, 95; b) A. Fiirstner, A. EHill, M. Liebl, J.

D. E. 7: Wilton-Ely, Chem. Commun. 1999, 601.

[ 10) C. Hinderling, C. Adlhart, P. Chen, Angew. Chem. 1998, 110, 2831; C. Hinderling, C. Adlhart, P.

Chen, Angew. Clzem. Int. Ed. Engl. 1998,37,2685.

[ I 1 ] G. C. Fu, S. T. Nguyen, R. H. Grubbs, J . Am. Chern.

Soc. 1993, 115, 9856.

[ 121 S. T. Nguyen, L. K. Johnson, R. H. Grubbs, J . Am.

Chem. Soc. 1992, 114, 3974.

[ 131 C. M. Huwe, S. Blechert, Tetrtihedron Lett. 1995.

36, 1621. [I41 C. M. Huwe, S. Blechert, Synthesis 1997, 61. [15] S. F. Martin, Y. Liao, H.-J. Chen, M. Pitzel, M. N. Rarnser, Tetruhedron. Lett. 1994, 35, 6005. [ 161 S. F. Martin, J. M. Humphrey, A. Ah, M. C. Hillier, J. Am. Chem. SOC.1999, 21, 866. 1171 a) D. Schinzer, A. Limberg, A. Bauer, 0. M. Bohrn. M. Cordes, Angew. Chem. Int. Ed. EngI. 1997, 38, 523; D. Schinzer, A. Limberg, A. Bauer, 0. M. Bohrn, M. Cordes, Angew. Chem. 1997, 109, 543; b) D. Meng, D . 3 . Su, A. Balog, P. Bertinato, E. J. Sorenson, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. Horwitz, J. h 7 . Chcm. Soc. 1997, 119. 2733; c) Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Arigew. Chem. Irrt. Ed. Engl. 1997, 36, 166; Z . Yang, Y. He, D. Vourlournis, H. Vallberg, K. C. Nicolaou, Angew. Chem. 1997, 109, 170. 1181 S. E Martin, Y. Liao, Y. Wong, T. Rein, Tetrahedron Lett. 1993, 34, 69 1. [I91 D. G. Hamilton, N. Feeder, S. J. Teat, J. K. M. Sanders, New J. Chem. 1998, 1019. I201 A. Fiirstner, G. Seidel, Angewf. Chem. 1998, 110, 1758; A. Furstner, G. Seidel, Angew: Chem. Int. Ed. Engl. 1998, 37, 1734. [211 D. S. La, J. B. Alexander, D. R. Cefalo, D. D. Graf, A. H. Hoveyda, R. R. Schrock, J. Am. Chern. Soc 1998, 120, 9720.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Metal-Catalyzed Hydroformylations Oliver Reiser

Hydrocarbonylations of C-C multiple bonds belong to the most attractive metal-catalyzed reactions. Inexpensive starting materials can be converted into useful intermediates without generating toxic by-products. Concurrent with the formation of a new C-C bond a versatile and further transformable carboxyl, carbonyl or alcohol functionality is introduced into the substrate. With the development of extremely efficient heterogeneous or homogeneous catalysts, which excel in high turnover numbers and turnover rates, hydrocarbonylations are especially attractive for industrial applications. The drawback of such reactions - the possible formation of several isomeric products can be minimized in technical processes through effective separation of the products, which are in general all useful as intermediates. To arrive at only one hydrocarbonylation product a selective reaction process is of course necessary. In this article the scope and limitation of hydroformylations and related reactions will be discussed.

generally more reactive and selective and are mainly described in this article. The processes as well as the potential problems of hydroformylations are depicted in Scheme 1 . Catalytically active is the 16-electron complex 4, which, after coordination of the olefin 1 to the n-complex 5, forms in a stereospecific syn addition the a-complex 8. Subsequently, coordination and insertion of C O gives rise to the acyl complex 9. After addition of H, to the Rh(II1) complex 7, a reductive elimination to

Hydroformylations of C-C Double Bonds

R

As early as 1938, Roelen discovered the cobaltcatalyzed hydroformylation of olefins, then known as the 0x0 reaction, which allowed the synthesis of aldehydes by addition of carbon monoxide and hydrogen to alkenes. Not long after this discovery it was found that cobalt, rhodium, ruthenium and platinum are also suitable as catalysts. However, because of the considerable price advantage for large scale applications in industry, cobalt catalysts are mostly used. Rhodium complexes, however, are

1

3

2

H Rh(C0)Lz 4

/+

11 -co

HRh(C0)Lz

H

H- Rh(CO)L,

Hkto

HRh(C0)ZLz

R

6

H

7

5

11

syn-Addition

-

HHRh(CO)L2

1) CO

R

2) Insertion

H

-

R

'H

9

8

+ regioisomer

Hdo

-

3

Scheme 1. Mechanism of rhodium-catalyzed hydroformy lation.

98

B. Transition Metal Organometallic Methods

the linear product 2 occurs concurrent with the regeneration of the catalytically active species 4. Instead of the addition of the rhodium fragment in 5 onto the less-substituted end of the double bond to 8, the addition can also occur in the opposite way, which overall results in the formation of the branched product 3. In this case a chiral product is formed, which opens the possibility for an asymmetric reaction process. Further problems can arise from the fact that the combination of H,/Rh(I) is also a good hydrogenation reagent, which can effect the reduction of the alkene to the corresponding alkane or the reduction of the generated aldehyde to the corresponding alcohol. Since all reaction steps are reversible, migration of double bonds in alkylsubstitued alkenes resulting in even more regioisomeric products, is possible. Only recently has it been possible to develop catalysts through which high regiocontrol (and for branched products high enantiocontrol) has been achieved. The product distribution in hydroformylations is also dependent on the applied pressure, on the CO/H, ratio, and on the temperature, but the discussion of these parameters is beyond the scope of this article [ 11.

G-

Rh(CO),acac / 10

Linear or Branched? Rhodium catalysts that bear phosphorus ligands give rise preferentially to linear hydroformylation products. This can be explained by the greater steric bulk of the catalyst, forcing, in the addition step 5 + 8, the metal to the less-substituted side of the double bond. According to this simple picture (a more sophisticated analysis is possible by taking different P-Rh-P angles in rhodium phosphine catalysts into account), it can be understood that a rhodium(1)-catalyst developed by Union Carbide [2], which is formed in situ from the readily available ligand biphephos (lo), and rhodium(CO),(acac) yields with excellent regioselectivity linear hydroformylation products 131. An interesting application was recently demonstrated by Buchwald with the synthesis of the basic structure of pyrrolizidine alkaloids: starting from the proline derivative 11 one can obtain the linear aldehyde 12 which could be cyclized to 13 upon treatment with HCN (Scheme 2) [4]. The synthesis of pipecolic acid derivatives was accomplished by Ojima by hydroformylation of allylglycine 14 in a single step. Notably, a pressure of only 60 psi was sufficient to achieve

-

5atmCO/Hp(l:l)

I

Boc

77%

Boc

11

OMe

OMe

(6

BU'

NC

13

Biphephos 10

99% (GC)

C0,Me

Scheme 2. Regioselective hydrolhrmylation 14

15

by a Rh(1)-Biphephos catalyst.

Metal-Catalyzed Hydroformylations

L

16

17

99

J

18

94% ee = 88-12]

(IS0 /I?

20

21

(S.RI-BINAPHOS

0 22 Ibuprofen

23

24

Ketoprofen

Naxoprofen

Rh(li / 19

P

x

25

26

27

28

X = OAc

86 (92%ee)

14

X = NPht

89 (85xee)

I1

high turnover rates and yields [ S ] . The primarily formed aldehyde cyclized and subsequently dehydrated spontaneously under the reaction conditions applied. Multiatomic 161 as well as cationic [7] rhodium catalysts also display a high preference for linear hydroformylation products. However, a catalyst system which generally yields branched hydroformylation products has not yet been found. Vinylarenes, such as styrene (16), form preferentially the iso-aldehyde 20 and not the n-aldehydes. The possibility to form a relatively stable Rh-nally1 complex 18 is most likely the decisive factor for this result [8]. Subsequent oxidation of 20 leads to 2-arylpropionic acids 21, of which some derivatives like 22-24 are of great importance as non-steroidal inflammatory drugs (NSID) (Scheme 3 ) 191. For their synthesis by the hydroformylation of styrenes, not only a regioselective but also an enantioselective reaction process is

Scheme 3. Enantioselective hydroformylation by a Rh(1)-BINAPHOS catalyst.

necessary. Despite many attempts [lo], only in recent times have catalysts been developed which are sufficiently selective for this process. The breakthrough was accomplished by developing mixed phosphine/phosphite-ligands,and the best results so far have been achieved with 19 and its enantiomer [ 111. Also, heterosubstituted alkenes 25 lead preferentially to the branched hydroformylation products 27, which are interesting building blocks for the synthesis of amino acids. An explanation put forward for the observed regiochemistry has been the coordination of rhodium onto the alkene to give 26. Because of the electron-withdrawing substituent X, the Rh-Crr bond is stronger than the Rh-CP bond; therefore, hydride insertion takes place into the Rh-Cp bond [ Ic]. An interesting step forward in asymmetric hydroformylation is the development of chiral catalysts on a platinudtin basis [ 121, which surpass

100

B. Transition Metal Organornrtallic Methods

via a five-membered ring instead of a six-membered ring. An intriguing strategy for regioand diastereoselective hydroformylations of methallylic alcohols 36 was developed by Breit et al. using ortho-diphenylphosphinyl benzoate as a removable catalysts-directing group [ 151. Polypropionate subunits with syn stereochemistry are available in selectivites of up to 96:4, which are central building blocks in polyketide natural products. The directing ability of amide groups (Scheme 5 ) seems to be preparatively useful. Starting from 38, formation of 40 is accomplished via 39 (six-membered ring chelate instead of seven-membered ring chelate) [ 161, and starting from 41 the aldehyde 42 is preferentially formed rather than 43 (five-membered ring chelate instead of six-membered ring chelate) 11 71. Amines also act as directing groups, however, the amino group coordinates with rhodium so strongly that in such cases stoichiometric amounts of the catalysts have to be used [ 181.

the previously introduced rhodium catalysts, in part in their enantioselectivity. However, with Pt-Sn systems, more side reactions such as hydrogenation generally occur, and also, with regard to regioselectivity, these catalysts cannot so far compete with the rhodium-phosphine-phosphite systems.

Directed Hydroformylations The concept of controlling a reaction by intramolecularly directing a metal by a functional group in the substrate 1131 has also been successfully applied to hydroformylations in some cases. It is not surprising that phosphine and phosphite groups can exhibit a directing function in a molecule (Scheme 4) [ 141. Starting from the cyclohexene derivatives 29 or 30, the aldehyde 32 is obtained with high regio- and diastereoselectivity via the five-membered ring chelate 31. The example of the hydroformylation of 33 shows in particular that chelation occurs preferentially

29 X = OP(OEt)Z

31

32

30 X = PPh2

regio- and diastereoselectivity > 20:i

Regioselectivity > 20: 1

33

34

35

up to 96:4

36

syn-37

anti-37

Scheme 4. Substrate directed rhodium-catalyzed hydroformylations

-

phosphorus groups.

Metal-Catalyzed Hydruformylations

101

regioselectivity > 2o:i

30

39

40

0

MeKW?

*

H,/CO

OYCH3

0

Co2Rhz(COh2

0

M e A N T c H o

18

82 41

42

43

Hydro- and Silylformylation of C-C Triple Bonds

Scheme 5. Substrate directed rhodiumcatalyied hydrofortnylations - nitrogen groups.

to &unsaturated aldehydes 48, which was accompanied by reduction products only in minor amounts [20]. Again, the ligand 10 was the best choice; however, it was particularly important to lower the H,/CO-pressure to 15 psi and to stop the reaction at the appropriate time. This method can so far be only applied to symmetrically substituted alkynes; with unsymmetrical substrates one always obtains the two possible regioisomeric products with not very high selectivity. With excellent chemo- and regioselectivity, alkynes and especially terminal alkynes 49 undergo silylformylations (Scheme 7) [21]. Instead of hydrogen, phenyldimethylsilane is used, which adds, after activation of the Si-H bond by the metal catalyst, exclusively via the silicon-metal and not via the hydrogen-metal bond onto the al-

Alkynes can also be hydroformylated. but hydrogenations of the starting materials or of the resulting olefinic products can not usually be suppressed. If one succeeds, however, to trap the primarily formed a,P-unsaturated aldehydes intramolecularly, preparatively useful transformations can be achieved: for example, from p-alkynyl amines 44 one can obtain pyrroles 46 in good yields [19]. It is questionable whether the intcrmediate 45 is formed, since usually hydroformylation is a stereospecific cis addition (cf. Scheme I ) , so that in this case an isomerization has to have taken place (Scheme 6). Recently, the hydroformylation of non-terminal alkynes 47 was achieved for the first time in good yields leading R

R’ NH?

Rhp(OAc), i PPh, COIH~(l:lilOObar)t

H

50-96%

R = Ar, Bu; R’ = H,Me, Ph 44

45

Rh(CO),acac i 10

R-R

*

1 barCO/H2(1,1) R = Alkyl. Ph

47

46

R

56-90%

40

R

Scheme 6. Rhodium-catalyLed hydroformylations of alkynes.

102

B. Transition Metal Organometullir Methods

49

50

t

(R3Si)-[M]-H

H 51

52

54

53

I

Scheme 7. Silylformylations of 55

56

Domino Processes

kyne to give 51. The bulky silyl residue orients itself to the less-substituted side of the triple bond. After insertion of CO into the metal-vinyl bond to 52, a reductive elimination occurs to yield the final silylformylation product 50. This reaction can also be carried out in an intramolecular fashion, in which the exo-dig ring closure products 54 are always formed from the precursors 53 [22]. As demonstrated in the example of 49, silylformylations do not occur with C-C double bonds. However, C - 0 double bonds do react, e.g. aldehydes 55 can be transformed to u-siloxyaldehydes 56.

The aldehydes 58 which are obtained in hydroformylations can also be directly converted to further products in the course of the reaction. For example, in the presence of a secondary amine, a reductive amination to 59 can be added onto the hydroformylation reaction (aminomethylation, Scheme 8) [23]. Especially elegant seems the possibility to add onto the hydroformylation another carbonylation reaction. If dicobalt octacarbonyl is used as the catalyst and the aldehyde 58 is trapped with a primary amide to give 60, a second carbonylation occurs, resulting in a

4

60

58

61

alkynes and aldehydes.

62

Scheme 8. Domino-carbonylation reactions.

Metal-Catalyzed Hydroformylutions

carboxylic acid 61 and not in an aldehyde because of the N-acyl group [24]. With this sequence it is therefore possible to transform an alkene into a glycine unit in a single step. There are many more fascinating aspects and possibilities of carbonylation reactions, which could not be covered within this article. As a result of the continuous discovery of new catalysts, the great synthetic potential of these processes will certainly be further explored.

References [ 1] a) B. Cornils, W. A. Herrmann, R. W. Eckl, J . Mol.

Catal. A - Chemical 1997, 116, 27-33. b) M. Beller, B. Cornils, C. D. Frohning, C. W. Kohlpaintner, J. Mol. Catul. Chem 1995, 104, 17. c) J. K. Stille in Comprehen.yive Orgunic Synthesis Vol. 4; B. M. Trost, I. Fleming: Ed.; Pergamon Press: Oxford, 1991; pp. 913. d) I. Ojirna, Chem. Rev. 1988, 88, 1011. [2] Union Carbide Corporation (E. Billig, A. G. Abatjoglou, D. R. Byant), Chem. Ahstr: 1987, 107, 7392. [3] G. D. Cuny, S. L. Buchwald, J . Atn. Chem. Soc. 1993, 115, 2066. [4] G. D. Cuny, S. L. Buchwald, S.ynletf 1995, 519. [ S ] I. Ojima, M. Trarnarioudaki, M. Eguchi, 1. Org. Cliem. 1995, 60, 7078. [6] a) G. G. Stanley, in M. P. Doyle (Ed.): Advances in Catalytic Processes, Vol. 2, Jai Press Inc., 55 Old Post Road/ No 2IGreenwichlCT 06836 1997, pp. 221 -243. b) G. Suss-Fink, Angew. Chern. 1994, 106, 71. 171 C. W. Lee, H. Alper, J. Org. Chem. 1995, 60,499.

103

[81 A. van Rooy, E. N. Orij, P. C. J. Kamer, P. W. N. M.

van Leeuwen, Organometallics 1995, 14, 34. [9] C. Botteghi, S. Paganelli, A. Schionato, M. Marchetti, Chiralioi 1991, 3, 355. [ 101 F. Agbossou, J. F. Carpentier, A. Mortreaux, Chem. Rev. 1995, 95, 2485. [II] a) N. Sakai, K. Nozaki, H. Takaya, J. Cheni. Soc. Chem. Commun. 1994, 395. b) N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115, 7033. 1121 S. Gladiali, D. Fabbri, L. Kollar, J . Organomeral. Chem. 1995, 491, 91. [I31 A. Hoveyda, D. A. Evans, G. C. Fu, Chem. Rev. 1993, 93, 1307. [I41 R. W. Jackson, P. Perlrnutter, E. E. Tasdelen, Aust. J. Chem. 1991, 44, 95 I . 1151 (a) B. Breit, M. Dauber, K. Harms, Chem. Eus J. 1999, 5, 2819-2827. (b) B. Breit, Eus J. Org. Chem. 1998, 1 123 - 1 134. [I61 1. Ojima, A. Korda, W. R. Shay, J. Org. Chem. 1991, 56,2024. 1171 I. Ojima, Z. Zhang, J. Org. Chem. 1988, 53, 4422. [ I S ] M. E. Krafft, X . Y. Yu, S. E. Milczanowski, K. D. Donnelli, J. Am. Chem. Soc. 1992, 114, 9215. [ 191 E. M. Campi, W. R. Jackson, Y. Nilsson, Tetrahedron Lett. 1991, 32, 1093. [20] J. R. Johnson, G . D. Cuny, S. L. Buchwald,Angew. Chern. 1995, 107, 1877. [21] a) 1. Matsuda, A. Ogiso, S. Sato, Y. Izurni, J . Am. Chern. Soc. 1989, 111, 2332. b) I. Ojima, R. J. Donovan, M. Eguchi, W.R. Shay,P. Ingallina, A. Korda, Q. Zeng, Tetrcrhedron 1993, 49, 5431. [22] F. Monteil, 1. Matsuda, H. Alper, J. Am. Chem. Soc. 1995, 117, 4419. 1231 T. Baig, J. Molinier, P. Kalck, J . Orgunornet. Chem. 1993, 455, 219. [24] I. Ojima, K. Hirai, M. Fujita, T. Fuchikami, J. Orgariomet. Chem. 1985, 279, 203.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Rare Earth Metal Catalysts Patrick Amrhein and Karola Ruck-Braun Institut fiiv Organische Chemie, Universitat Mainz, Germany

The growing demand for efficient chemical transformations and catalysts has inspired a few research groups in recent years to develop rare earth metal catalysts for organic synthesis [ I , 21. Triflates of rare earth metals are strong Lewis acids, which are stable in aqueous solution. Rare earth metal alkoxides on the other hand are of interest as Lewis bases, e.g. in the catalysis of carbonyl reactions, because of the low ionization potentials (5.4-6.4 eV) and electronegativities (1.1 -1.3) of the 17 rare earth elements. Rare earth metal-alkali metal complexes in contrast show both Br~nsted-basicand Lewis-acidic properties. Impressive applications of such catalysts are presented and discussed here.

Reactions in Aqueous Media Traditional Lewis acids such as AICI, or BF, . OEt, catalyze key steps in many reactions involving carbonyl compounds, leading to carbon-carbon bond formation. Because of their reactivity and instability these catalysts cannot be used in aqueous solution. For this area of application, rare earth metal catalysts open up new perspectives. For example, aldol reactions of silyl enolates with aldehydes in the presence of Sc(OTf), (Tf = OSO,CF,) or the rare earth metal triflates Ln(OTf), (Ln = Yb, Gd, Lu) proceed smoothly in both organic solvents and aqueous solution under mild reaction conditions in high yields [ I , 31. Not only are these triflates highly stable in aqueous media, but in some cases reactions proceed many times faster in the presence of water. Furthermore, these Lewis acids can be recovered

easily and completely. In toluene-ethanol-water mixtures, Cu(OTf), as well as Sc(OTf), and Sm(OTf), are effective catalysts, e.g. in catalytic aldol reactions or allylation reactions of aldehydes [4]. Recently, it was found that Sc(OTf), catalyzes allylation reactions of aldehydes with tetraallyltin (2) solely in water, with sodium dodecyl sulfate (SDS) as an additive, to afford homoallylic alcohols in high yields [S].For example, 0.2.5 equiv. of 2 and 2-desoxyribose 1 in the presence of 0.1 equiv. of Sc(OTf), and 0.2 equiv. sodium dodecylsulfate at room temperature gave the addition product in 99 % yield within 48 h (Scheme I). Based on this and earlier work, Kobayashi et al. in 1998 reported initial investigations of threecomponent reactions of aldehydes, anilines and allyltributylstannane to give homoallylic amines 4 [6]. With the catalyst Sc(OTf), in the presence of sodium dodecyl sulfate for building a micellar system, yields in the range 66-90 % were obtained (Scheme I). The stability of the catalyst towards oxygen is noteworthy. Rare earth metal-catalyzed Michael additions of a-nitro esters or P-keto esters with a,P-unsaturated carbonyl compounds were investigated by Feringa and co-workers [7]. According to these authors, the use of Yb(OTf), enables addition products 5 to be isolated in higher yields and greater purities than those obtained in organic solvents (Scheme 1). Until now, the regioselective addition of enolates to imines in the presence of an aldehyde functionality could not be realized with stoichiometric amounts of traditional Lewis acids such as SnCI,, TiCI, or BF, . OEt,. Recently, Kobayashi and coworkers reported that, in the presence of

Rare Earth Metal Catalysts 1 SC(OTf),, SDS H20, RT.--* 48 h

' O W O H +

I

105

OAc OAc

(CH,=CH-CH,),Sn

OH

2. A 4 0 , pyridine

2

1

OAc

3

Scheme I

0

OSiMe

R'

Yb(OTf)3 (0.2 equiv.)

*

CHBCN,-23°C

6:2%

7 : 92%

catalytic amounts of Yb(OTf), this type of reaction takes place at low temperature (Scheme 2) [8]. NMR studies prove that the Lewis acid activates the imine functionality and not the aldehyde group by highly selective complex formation. Kobayashi et al. also published experiments in which they applied polymcr-bound rare earth metal triflates [9]. The performance of Lewis acid-catalyzed imino-aldol reactions at the solid phase was realized by linking the silyl enolethers tc6-(4' -chloromethylphenyl)pentylpolystyrenef101.

Friedel-Crafts Catalysts By use of the catalyst system Ln(OTf),-LiCIO, and Sc(OTf),-LiCIO,, respectively, Friedel-

Scheme 2

Crafts acylations are performed in high yields (Scheme 3) [ 1I]. In the absence of LiCIO,, the acylations proceed only sluggishly. However, a homogenous solution is obtained and the start of the reaction is observed only after the addition of the above mentioned triflate to a suspension of LiCIO,, acetic anhydride and the aromatic compound. Thus, the highly reactive cationic acylation reagent is formed from acetic anhydride and LiC10, only after the addition of the triflate M(OTf), (M = Yb, SC). Advantageously, catalytic amounts of rare earth metal triflates are used instead of stoichiometric amounts of aluminum trichloride in catalytic Fries rearrangements of carboxylic acid aryl esters furnishing keto building blocks, e.g. 10

106

B. Transition Metal Orgunametullic Methods

[ 121. The rearrangement of naphthol derivatives is best carried out with 5 mol 96 of Sc(OTf), in

toluene at 100°C (Scheme 3). Sc(OTf), is also the catalyst of choice for the direct synthesis of the ketones 10 from naphthol and acid chlorides in toluenehitromethane (yield > 90 %).

Multi-Component Couplings Multi-component couplings open up an economic and straightforward route to very different compound libraries. For example, 1,3-dipolar cycloaddition reactions of nitrones with alkenes furnish isoxazolines, which can be transformed reductively to hydroxyketones or P-amino alcohols. In 1997, two groups reported on the synthesis of isoxazolines by rare earth metal-catalyzed [3 21 cycloadditions (Scheme 4) 113, 141. Reactions catalyzed by Yb(OTf), proceed much more slowly than those catalyzed by Sc(OTf), in the presence of molecular sieve (4 A), but with better endolexo selectivity [ 141. According to Kobayashi et al. the products 13 are obtained smoothly with high endo-selectivity in 3 1 - 82 % yield by three-component coupling of aldehydes, hydroxylamines and alkenes catalyzed with Yb(OTf), [ 13). Enantioselective reaction procedures were carried out with (+)-BINOL (BINOL = 2,2'-dihydroxy-l, 1'-binaphthyl) and PyBOX 14 as chiral ligands by Jargensen et al. for the first time. While Yb(OTf), H,O and (+)-BINOL furnished endo-13b as a racemic mixture, the use of the ligand 14 (PyBOX) enabled enantioselectivities in the range 67-73 % ee to be realized. However, for the enantioselective synthesis of endo-13a [72 %, endo:exo >90 : I ,

+

78 % eel starting from l l a and 12, (+)-BINOL in combination with I ,2,6-trimethylpiperidine should be used as catalysts according to Kobayashi et al. Lewis acid-catalyzed tandem Michael iminoaldol reactions enable the one-pot synthesis of y-acyl-b-lactams from a, ,!-unsaturated thioesters, silyl enolates and imines [15]. For the initial Michael addition, the combination of SbCI, with Sn(OTf), ( 5 mol %) proved to be efficient. However, after the addition of the imino compound the iminoaldol product was isolated in moderate yield. For the enhancement of turnover and yield, Sc(OTf),, once again proved to be the Lewis acid of choice (Scheme 4, 15:16=81:19,94%). Likewise, four-component reactions (silyl enolates, a, b-unsaturated thio esters, amines and aldehydes) proceed at low temperatures in high yields (65-97 %) with Sc(OTf),, as catalyst when aromatic aldehydes and aniline building blocks are employed. With catalytic amounts of rare earth metal triflates, heterocarbonyl compounds, e.g. acylhydrazones, are also successfully activated. From the latter and silyl enolates (Scheme 4), the coupling products are obtained directly or in a one-pot synthesis in the presence of 5 mol% of Sc(OTf), or Yb(OTf), in 45-96 % yield. For example, compound 17 was isolated in 92 % yield and was subsequently cyclized with base to the corresponding pyrazolone (Scheme 4) [16]. In comparison with typical Lewis acids, such as SnCl,, (10 % yield) and boron trifluoride etherate (42 % yield), Sc(OTf), proved to be superior.

LiCIO,, MeNO,, 5OoC,1h

8

0.05 equiv. Sc(OTf), LiC104, M e N 0 2

9

78-89%

10

Scheme 3

Rare Earth Metal Catalysts

lla: R = Ph, R' = Bn

12

107

13

11 b: R = R '= Ph 11~R : = Ph, R' = P C ~ H ~ C H ~

OSi'BuMe2 O H C, , - , L , ,

+

H2NNHCOPh

+

Yb(OTf)3

*OMe

OM^

CH&N

. H

,NHCOPh

NaOMe

MeOH, 70°C-

17

Asymmetric Two-Center Catalysis During the last decade Shibasaki and co-workers focussed on the application of rare earth metal catalysts with special properties [2]. More recently, impressive studies by this group revealed the broad applicability of chiral heterobimetallic catalysts based on rare earth metal alkoxide complexes in asymmetric catalysis. Whereas initial

Scheme 4

investigations concentrated on catalytic and asymmetric nitroaldol reactions with nitromethane, hydrophosphonylations of imines [ I 71 and Michael additions [2], more recently the direct catalytic aldol reaction of aldehydes with non-modified ketones [IS] and the epoxidation of a$-unsaturated ketones were reported [ 191. By use of the rare earth metal-alkali metal complex LaNa,-tris[(R)-(binaphthoxide)] (10 mol %),

108

B. Trunsition Metal Orgunoinetallic Methods

the reaction of 18 (Scheme 5 ) with rert-butyl hydroperoxide (TBHP) afforded 21 in 92 % yield with 82 % ee. With the La-BINOL catalysts 19a and 19b and the Yb-BINOL catalysts 20a and 20b, products with higher optical purity can generally be obtained. Interestingly, the alkali metal-free BINOL complexes 19b and 20b (Ln = La, Yb, R = CH,OH) were found to be the most efficient catalysts. By the latter, epoxidations of differently substituted enones with cumol hydroperoxide (CMHP) or TBHP are catalyzed, providing high enantiofacial selectivity (83 -94 % ee). These La-BINOL complexes are of oligomeric structure, and the asymmetric catalysis is attributed to the positive interaction of two rare earth

(R)-Ln-BINOL

-

metal centers. One metal center, therefore, appears to act as a Lewis acid, activating the enone and controlling the orientation of the carbonyl function. In contrast, a second metal alkoxide unit seems to activate the hydroperoxide because of its BrBnsted-basic properties. For catalytic asymmetric aldol-type reactions, the transformation of the methylene compounds to a silyl enolate or a silyl ketene acetal was at one time necessary. Recently, the aldol reaction of aldehydes with non-modified ketones was realized by use of the lanthanum-Li,-tris[(R)-binaphthoxide] catalyst 22 1181. According to the proposed catalytic cycle, after abstraction of an a-proton from the ketone, the reaction between the lithium-enolate complex and the aldehyde

Ph-.&'yPh

Phqph 0

MS 4A, ROOH

0

21

18

19a: Ln = La, R = H 19b: Ln = La, R = CH20H 20a:Ln =Yb, R = H 20b:Ln =Yb, R = CH20H

20 mol% (RJ-LLB THF, -20°C

R'

23

\

/

22

Scheme 5

Rare Earth Metal Catalysts

coordinated to the lanthanum center takes place. From the p-keto metal alcoholate obtained by proton exchange, the catalyst is regenerated, and simultaneously the optically active aldol adduct 23 is liberated. The products are obtained in 2890 % yield with an enantiomeric excess in the range of 44 to 94 %. Self-condensation of the aldehydes applied was only observed with dihydrocinnamic aldehyde. Only recently, Shibasaki et al. reported on the application of a Sm-Na-(R)-BINOL-complex as catalyst in a reaction cascade consisting of an asymmetric Michael addition of thiols to a, B-unsaturated carbonyl compounds followed by an asymmetric enolate protonation [20]. The development and application of these rare earth catalysts excellently demonstrate the fruitful combination of the empirical with the rational approach [2]. In the near future, additional applications of these and other rare earth metal complexes in various enantioselective reactions are expected.

References 111 Review: S. Kobayashi, Synlett 1994, 689 and lit-

erature cited therein. [2] Review: M. Shibasaki, H. Sasai, T. Arai, Angew. Chem. 1997, 109, 1290 and literature cited therein. [3] S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oyamada, Tetrahedron Lett. 1997, 38, 4559 and literature cited therein.

109

[41 S. Kobayashi, S. Nagayama, T. Busujima, Chem. Lett. 1997, 959. 151 S. Kobayashi, T. Wdkabayashi, H. Oyamada, Chem. Lett. 1997, 83 1 . (61 S. Kobayashi, T. Busujima, S. Nagayama, J . Chem. Soc. Chem. Commun. 1998, 19. [71 a) E. Keller, B. L. Feringa, Synlett 1997,842; b) E. Keller, B. L. Feringa. Tetrahedron Lett. 1996, 37, 1879. [8] S. Kobayashi, T. Busujiama, S. Nagayama, J. Org. Chenz. 1997, 62, 232. [Y] a) S. Kobayashi, S. Nagayama, Synlett 1997, 653 and literature cited therein; b) L. Yu, D. Chen, J. Li, P. G. Wang, J. Org. Cliem. 1997, 62, 3575. [lo] S. Kobayashi, M. Moriwdki, Tetrahedron Lett. 1997, 38, 425 1. [ 1 I ] A. Kawada, S.Mitamura, S. Kobayashi, J. Chem. Soc. Comm. 1996, 183. 1121 S. Kobayashi, M. Moriwaki, I . Hachiya, Anll. Chem. Soc. Jpn. 1997, 70, 261. [ 131 S. Kobayashi, R. Akiyama, M. Kawamura, H. Ishitani, Chern. Lett. 1997, 1039. [I41 A. I. Sanchez-Blanco, K. V. Gothelf, K. A. Jqjrgensen, Tetruhedron Lett. 1997, 38, 7923. [IS] S . Kobayashi, R. Akiyama, M. Moriwaki, Tetruhedron Lett. 1997, 38, 48 19. [161 H. Oyamada, S. Kobayashi, Synlett 1998, 249. [I71 H. Grbger, Y. Saida, H. Sasai, K. Yamaguchi, J. Martens, M. Shibasaki, J. Am. Chem. Soc. 1998, 120, 3 189. [ IS] Y. M. A. Yamada, N. Yoshikawa, H. Sasai. M. Shibasaki, AngrM: Cheni. 1997, 109, 1942. [ 191 M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am. Clzent. Soc. 1997, 119, 2329. [20] E. Emori, T. Arai, H. Sasai, M. Shibasaki, J . Am. Chern. Soc. 1998, 120, 4043.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Dithioacetals as an Entry to TitaniumAlkylidene Chemistry: New and Efficient Carbonyl Olefination Bernhard Breit Organisrh-Chemisches Institut der Ruprecht-Karls-UniversitatHeidelherg, Germany

Reactions in which two halves of a complex molecule are linked by means of a convergent synthetic strategy belong to the most valuable framework-building reactions in organic synthesis. Especially successful are those reactions in which C-C double bonds are formed, such as the Wittig reaction and its variants according to Horner, Wadsworth, and Emmons (referred to here as Wittig-type reactions) [ I ] . Decisive for the effectiveness of these methods is the simple preparative access to the two individual components - a carbonyl compound: and a Wittigtype reagent, which can be obtained, for instance, by the reaction of an alkyl halide with phosphanes or phosphites followed by deprotonation (Scheme I). Only such a simple and general approach enables the synthetic chemist to convert any two complex building blocks into carbonyl and Wit-

I

1) PPh3 P(OR)3

tig-reagent components in a late step of the synthetic sequence. The components can be subsequently coupled by either an inter- or intramolecular olefination reaction. However, Wittigtype reactions are also subject to certain limitations. One example is the cis selectivity upon use of nonstabilized ylides under salt-free reaction conditions. Fortunately, the Wittig-type reactions can be supplemented by the Julia-Lythgoe olefination (Scheme 2 ) , which is a general method for preparing trans-disubstituted olefins [ 2 , 31. The components required for the Julia-Lythgoe olefination - the carbonyl and sulfone components - also meet the criterion of being readily available, and allow the corresponding functionalization in a late synthetic step. Another disadvantage of Wittig-type reactions is their limitation to aldehydes and ketones as the carbonyl component; carboxylic acid derivates

0

+ Y =-PPh3 + Y=-PO(OR)p

2) Base

‘Cd LG

Scheme 1. Schematic representation of the Wittig and Horner-Wadsworth-Emmons reactions. LG = leaving group.

-

1) Base

2) R’CHO

R’CH2S02Ph

NdHg h

3) AcpO

OAc

Scheme 2. Stereoselective synthesis of disubstituted trans-olefins according to Julia and Lythgoe

Dithioacetals as an Entry to Titanium-Alkylidene Chemistry Tebbe

Grubbs

Petasis

2

Me CpPTi< Me 3

Cp2Ti$VMe2 CI 1

Cp2Ti=CH2

I

111

4

Y = H, R, OR, NR2. SR, SiR3 etc.

Scheme 3. Carbonyl methylenation with the titanium-methylene species 4 prepared from the Tebbe, Grubbs, or Petasis reagents (1 - 3).

are generally inert in this respect. Furthermore, Wittig-type reactions and Julia-Lythgoe olefinations both require a more or less basic reaction medium. Especially in the case of easily enolizable carbonyl compounds, this can lead to undesired side reactions such as elimination and racemization of adjacent stereocenters. The olefination of sterically demanding carbonyl substrates also clearly demonstrates the limitations of the Wittig reaction. For this reason, considerable efforts have been devoted to finding improved olefination reagents that can overcome these shortcomings of both the Wittig-type reactions and Julia-Lythgoe olefinations. A milestone was reached in 1978 by Tebbe, who recognized the usefulness of the titanium-aluminum complex 1for carbonyl methylenations [4]. In addition to the Tebbe reagent 1, the titanacyclobutane 2 reported by Grubbs [ 5 ] and the Petasis reagent 3 [6]. are available for efficient methylenation of carbonyl compounds (Scheme 3). These reagents are reactive under neutral to slightly Lewis acidic conditions, which allows easily enolizable carbonyl compounds to be used in methylenation reactions without competing side reactions. Another advantage is the clean methylenation of carboxylic acid derivatives with formation of, for example, preparatively valuable enol ethers and enamines [7].

A plausible intermediate of this olefination is the titanium-methylene species 4, which is formed from 1 by removal of AlMe,CI with a Lewis base, from 2 by fragmentation with elimination of isobutene, and from 3 by a-elimination and release of methane. However, none of these three routes to titanium-carbene complexes of type 4 proved to be generally applicable. Consequently, the use of these reagents in synthesis is essentially limited to the transfer of a methylene unit 181. From a synthetic viewpoint, a general and easy route to substituted titanium-alkylidene species and their use in carbonyl olefinations would be more desirable. The first progress was made by Takai and Lombardo, who developed an in situ entry to titaniumalkylidene chemistry starting from the reagent combinations 5 and 6 [Scheme 4) [9]. These reactions proceed via a gem-dizinc compound 7 [its formation is catalyzed by traces of lead or lead(I1) salts), which is subsequently transmetalated with TiCI, to the titanium-alkylidene species 8, the actual olefination reagent. To date, 8 has not been characterized in detail [lo]. These in situ reagents exhibit chemoselectivities similar to those of the structurally defined methylenation reagents 1-3. The advantage of the Takai-Lombard0 reagents is the possibility of transferring substituted alky-

112

8. Transition Metal Organometallic Methods Zn - RCHX2- Tic14 - TMEDA

Zn - CH2X2 - Tic14 X = Br, I

5

CH,X,

Zn

6

Zn

XCH2-ZnX

XZn,

~

cat. Pb(O)/Pb(ll)

C

,ZnX

H2

7

TiCI4

9

fiH2 /c-y

+

*

[

/c-y

Y = H, R,OR, NR2

8

lidene units in addition to methylene units. The use of the olefination reagent 6 allows the general alkylidenation of carboxylic esters [ I I]. In this transformation, the (a-enol ethers 9 are obtained with high stereoselectivity (Scheme 5 ) . ~

0

L,~,=~H2

R’

6 (X = Br) 70-90%

9 ZEEL9.1

R’CHI~ 10 E Z t 7:l

Scheme 5. General alkylidenation of esters to enol ethers 9 and synthesis of disubstituted (E)-alkenes 10 from aldehydes and chromium(I1) reagents according to Takai and Utimoto.

Scheme 4. Takai-Lombardo reagents; TMEDA= N. N. N’. N’-tetramethylethy lenediamine.

A variation of this reaction was developed in 1986 by Takai and Utimoto, in which geminal dihaloalkanes were added to aldehydes in a reaction mediated by chromium dichloride. This led to the stereoselective formation of the corresponding trans-olefins 10 [12]. The major drawback of this method is the rather cumbersome access to the corresponding substituted dihalomethane compounds, which prevents a broad application of this reaction for synthesis. The solution to the above problem was recently found by Takeda et al., who reported on the desulfurization of dithioacetals as a general and easy entry to titanium-alkylidene chemistry [ 131. Dithioacetals, which are easily accessible from carbonyl compounds, are treated with the (ll), titanocene source [Cp,Ti [ P(OMe),],] which was specifically developed for this purpose; the respective titanium-alkylidene species 12 is formed, presumably by desulfurization (Scheme 6). The most important subsequent reac-

.--.

12 R’, R’ = H, alkyl, alkenyl, alyl R3, R4 = H, alkyl, awl, Oalkyl

Scheme 6. Carbonyl olefination with titanium-alkylidene species 12 prepared from dithioacetals according to Takeda et al.

Dithioacetals as an Entry to Titanium-Alkylidene Chemistry

PhS

SPh

11

PhXH

Ph3

H

P

Ph

52%

h

113

+

EtOL

-

56:44 (EZ)

11

P

h

75%

P

h

T

P

h

OEt 86:14

(z:E)

Scheme 7. Stereoselectivity of the Takeda olefination.

tion of this species is carbonyl olefination, which proceeds smoothly with aldehydes, ketones, and esters. The intermediates formed in these reactions exhibit a chemoselectivity spectrum similar to that of the titanium reagents 1-3,5, and 6. No limitations have yet been observed with respect to the structure of the dithioacetals; that is, even 1substituted dithioacetals with @-hydrogen atoms can be converted. It is still unclear as to which functional groups can be tolerated in this reaction. A clear disadvantage is the unsatisfactory stereoselectivity observed for the olefination of aldehydes so far. However, one can easily envision that modifying the microenvironment of the reactive titanium center will bring about improvements. Better selectivities have been obtained in the olefination of carboxylic esters (Scheme 7). The good accessibility of dithioacetals offers the possibility, e.g. by Wittig-type reactions, to I

convert any two complex fragments into an olefin using the titanium reagent 11 in a late step of the synthetic sequence. This olefination is therefore as valuable as the Wittig-type reactions. Moreover, this reaction offers all the advantages of the titanium-mediated reactions that proceed in Lewis acidic media. Interestingly, the subsequent reactions of the titanium-alkylidene species 12 obtained from dithioacetals are not limited to carbonyl olefinations. When the carbene complex is prepared in the presence of olefins, the latter are smoothly cyclopropanated (Scheme 8; 13) [ 141. Furthermore. the reaction of symmetrically disubstituted acetylenes with dithioacetals containing a methylene unit provides the corresponding trisubstituted 1.3-dienes 14 in a stereoselective fashion

IW.

Interestingly, if an alkene functionality is available intramolecularly (15), a ring closing meta-

_--. .

13 (57-72%)

14

E:Z2 98:2 (50-80%)

Scheme 8. Reactions of the titanium-alkylidene \pecies 12, prepared from dithioacetals, with olefins and acetylenes.

114

B. Transition Metal Organometallic Methods

- Cp2Ti(SPh)2 R 15

II TiCp,

Scheme 9. Titanocene(I1)-promoted ring-closing metathesis of unsaturated thioacetals.

thesis towards five-, six-, seven- and eight-membered carbo- and heterocylic ring systems may be realized (Scheme 9; 16) [16]. Dithioacetals have already proven to be very useful in organic synthesis. For instance, they function as carbonyl protecting groups that can be used orthogonal to 0,O-acetals [ 171. The introduction of a dithioacetal leads to a polarity reversal of the carbonyl group (dithiane method according to Seebach) [18]. As a result, any complex dithioacetal can be obtained by a deprotonation-alkylation sequence. This remarkable multifunctionality of the dithioacetal unit has now been expanded by the work of Takeda et al. with respect to the specific formation of titanium-alkylidene species. Although the subsequent chemistry of this species needs to be established in detail, the intermolecular carbonyl olefination as well as the intramolecular ring-closing metathesis have given a glimpse of the synthetic scope of this reaction strategy. In addition to the Wittigtype reaction and the Julia-Lythgoe olefination, the Takeda olefination has the potential of becoming another general olefination reaction which proceeds under Lewis acidic conditions.

16

References [ I ] a) A. Maercker, Org. React. 1965, 14,270-490; b) M. Schlosser, Top. Strreachem. 1970, 5, 1-30: c) W. S. Wadsworth, J K , Org. React. 1977, 25, 13253: d) B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863-927; for the use of the Wittig reaction in the synthesis of complex natural products, see e) H. J. Bestmann, 0. Vostrowsky, Top. CurI: Chem. 1983, 109, 85- 163: f) K. C. Nicolaou, M. W. Harter, J. L. Gunzner, A. Nadin, Liebigs Ann. 1997, 1283-1301. [2] S. E. Kelly in Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 792 ff. 131 Although the Schlosser modification of the Wittig reaction provides access to trans-olefins from nonstabilized ylides, the Julia-Lythgoe olefination has proven to be the method of choice for solving this synthetic problem today. a) M. Schlosser, K.-F. Christmann, Justu.s Liebigs Ann. Chem. 1967, 708, 1-35; b) M. Schlosser, K.-F. Christmann, A. Piskala. Chem. Brr 1970, 103, 2814-2820. [4] a) F. N. Tebbe, G. W. Parshall, G . S. Reddy, J. Am. Chem. Soc. 1978, 100, 361 1-3613: b) S. H. Pine, R. Zahler, D. A. Evans,R. H. Grubbs, J. Am. Chem. Sac. 1980, 102. 3270-3272; c) S. H. Pine, R. J. Pettit, G . D. Geib, S. G . Cruz, C. H. Gallego, T. Tijerina, R. D. Pine, J. Org. Chem. 1985, 50, 1212- 1216. 151 a) T. R. Howard, J. B. Lee, R. H. Grubbs, J. Am. Chrm. Soc. 1980, 102, 6876-6878; b) K. A. Brown-Wensley, S. L. Buchwald, L. Cannizzo, L. Clawson, S. Ho, D. Meinhardt, J. R. Stille, D. Straus, R. H. Grubbs, Pure Appl. Chern. 1983, 55, 1733-1744. 161 N. A. Petasis, S.-P. Lu, E. I. Bzowe,j, D.-K. Fu, J. P. Staszewski, I. Akritopoulou-Zanze, M. A. Patane, Y.-H. Hu, Pure Appl. Chem. 1996, 68, 667-670. 171 Review: S. H. Pine, Org. React. 1993, 43, 1-91.

Dithioacetals as an Entry to Titanium-Alkyliderze Chemistry

181 Reports have appeared on the olefination of carbonyl compounds with the use of dibenzyl-, bis[(trimethylsilyl)methyl]-, and dicyclo- propyltitanocenes: a) N. A. Petasis, E. 1. Bzowej, J. Org. Chem. 1992, 57, 1327-1330; b) N. A. Petasis, I. Akritopoulou, Synletr 1992,665-667; c) N. A. Petasis, E. I. Bzowej, Tetrahedron Lett. 1993, 34, 943-946; d) N. A. Petasis, J. P. Staszewski, D.-K. Fu, ibid. 1995, 36, 3619-3622. 191 a) K. Takai, Y. Hotta, K. Oshima, H. Nozaki, Tetruhedron Lett. 1978, 2417-2420; b) L. Lombardo, ibid. 1982, 23, 4293-4296; c) Org. Synth. 1987, 65, 81 -87; J. Hibino, T. Okazoe, K. Takai, H. Nozaki, Tetrahedron Lett. 1985,26,5579-5580; e ) T. Okazoe, J. Hibino, K. Takai, H. Nozaki, ibid. 1985, 26, 5581 -5584; f ) K. Takai, 0. Fujimura, Y. Kataoka, K. Utimoto, ibid. 1989, 30, 21 1-214. [lo] K. Takai, T. Kakiuchi, Y.Kataoka, K. Utimoto, J. Org. Chem. 1994, 59, 2668-2670. [ I l l a ) T. Okazoe, K. Takai, K.Oshima, K. Utimoto, J. Org. Chem. 1987,52,4410-4412; b) K. Takai, Y. Kataoka, T. Okazoe, K. Utimoto, Tetrahedron Lett. 1988, 29, 1065- 1068.

115

1121 a) T. Okazoe. K. Takai, K. Utimoto, J. Am. Chem. Soc. 1987,109,951-953; b) K. Takai, K. Nitta, K. Utimoto, ihid. 1986, 108,7408-7410; c) K. Takai, Y. Kataoka, T. Okazoe, K. Utimoto, Tetrahedron Lett. 1987, 28, 1443-1446. [ 131 Y. Horikawa, M. Watanabe, T. Fujiwara, T. Takeda, J. Am. Chem. SOC. 1997, 119, 1127-1128. [I41 Y. Horikawa, T. Nomura, M. Watanabe, T. Fujiwara, T. Takeda, J. Org. Chenz. 1997, 62, 36783682. [ 1 51 T. Takeda, H. Shimokawa, Y. Miyachi, T. Fujiwara, Chern. Cornrnun. 1997, 1055- 1056. [I61 T. Fujiwara, T. Takeda, Synlett 1999, 354-356. [ 171 P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 1994, p. 171 - 178. [ 181 a) D. Seebach, Angew. Chem. 1969, 81, 690-700; Angew Chem. Int. Ed. Eizgl. 1969, 8, 639-649; b) B. T. GrSbel, D. Seebach, Synthesis 1977, 357-402; c) D. Seebach, Angew. Chem. 1979, 91, 259-278; Angew. Chem. Inf. Ed. Engl. 1979, 18, 239-258; d) P. C. Bulman-Page, M. B. van Niel, J. C. Prodger, Tetrahedron 1989, 45, 7643-7677.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

New Developments in the Pauson-Khand Reaction Oliver Geis and Hans-Giinther Schmalz Institiit fiir Organische Chemie, Universitat Koln, Germany

Introduction

Improved Reaction Conditions

Metal mediated and catalyzed reactions have made significant contributions to organic synthesis over the past two decades [I]. One of the earliest and most useful of these is the PausonKhand carbon-carbon coupling reaction [2] first reported in 197I . In this reaction, a cyclopentenone is formed from an alkyne and an alkene in the presence of [Co,(CO),] with insertion of carbon monoxide in a formal [2+2+I 1-cycloaddition. The exceptional potential of this reaction has been demonstrated in many (mostly intramolecular) syntheses (Scheme 1 ) [3].

Once the high synthetic value of the PausonKhand reaction was recognized, considerable efforts were made by several groups in the early 1990s to optimize the reaction conditions. An important improvement came with the use of tertiary amine N-oxides that generate free coordination sites at cobalt by oxidative removal of C O ligands. These reactions proceed rapidly at room temperature, often in high yields [4]. A very promising procedure for the stoichiometric Pauson-Khand reaction was recently described by Sugihara et al. [ 5 ] , who discovered that the use of primary amines as solvent leads to a dramatic increase in reaction rates. Excellent yields are obtained within few minutes with only 3.5 equivalents of cyclohexylamine when the reactions are run in dichloromethane at 83 "C under argon. Alternatively, the reactions can be performed in a 1 : 3 mixture of 1,4-dioxane and 2 M aqueous ammonia at 100°C (Scheme 2).

cR CO,(CO)B A

Scheme I . The general pattern of the Pauson-Khand reaction.

Although a catalytic approach was discussed in the initial publication [2b], stoichiotnetric amounts of the metal were usually required to achieve acceptable yields. In most cases, the readily prepared and air-stable alkyne-Co2(CO), complexes (1) were heated (60- 120 'C) with the alkene (occasionally under C O atmosphere), but long reaction times (often several days) were needed and the yields were frequently unsatisfactory. R2, -

R2

4R' co2(co)6

1

c-c'

R'

\A'/CO(CO)3

(OC)&o-

Catalytic Variants Only catalytic Pauson-Khand reactions fulfill the criterion of atom economy [6], and the use of stoichiometrical amounts of the transition metal is not acceptable commercially. It is not surprising, therefore, that several research groups have focused more recently on the development of catalytic variants. Based on the work of Pauson and Billington [2,7], Rautenstrauch et al. showed in their 1990's synthesis of the dihydrojasmonate precursor 2 (Scheme 3) that catalytic Pauson-Khand

New Developtnents in the Pauson-Khand Reaction

117

92-94%

Scheme 2. Stoichiometric Pauson-Khand reactions according to T. Sugihara. a) 3.5 equiv. cyclohexylamine, 1,2dichloromethane, 8 3 T ; b) 1,4-dioxan/2N NH,(aq) (1 : 3 ) , 100 C.

*&

ethylene/CO (310-360 bar) 0.22 mol% C O ~ ( C O ) ~ 150°C. 16 h

-

=C5H11

48 Yo

C5Hll

2

Scheme 3. Catalytic Pauson-Khand reactions according to Rautenstrauch.

h.v,latmCO 5 mol % Co2(C0)* DME,50-55”C, 12h

-

91 Yo

Scheme 4. Photochemically induced, catalytic PausonKhand reactions according to Livinghouse.

reactions are possible if high C O pressure and high temperature are used [S]. Korean laboratories have since found that more efficient transformations can be achieved with modified cobalt catalysts such as [Co,(CO),/P(OPh),], [(indenyl)Co(cod)] or [C~(acac)~/NaBH,] under C O pressure or with Co,(CO), in supercritical fluids [9]. A seemingly practicable procedure was published in 1996 by Pagenkopf and Livinghouse, who obtained high yields with photoactivation of [Co,(CO),] and low C O pressures (Scheme 4) [ 101.

Although a whole series of carbonyl complexes of other transition metals (Fe, Mo, W, Ni) could only be used in stoichiometric Pauson-Khand reactions [ 1 11, two Japanese laboratories have since independently reported efficient ruthenium-catalyzed (intramolecular) reactions. The desired cyclopentenones are formed in good to excellent yields in dimethylacetamide [ 121 or dioxane 1131 in the presence of 2 mol% of [Ru,(CO),,] at 140- 160°C and 10- 15 atm C O pressure.

Pauson-Khand Type Reactions with Metallocenes Negishi et al. have demonstrated that alkynes react with “zirconocene” generated in situ to give metallacyclopentene species of type 3, which when treated with carbon monoxide afford typical Pauson-Khand products (Scheme 5 ) 1141. Tamao et al. have also shown that enynes react with isocyanides to form iminocyclopentenones in the presence of stoichiometric amounts of [Ni(cod),/n-Bu3P] [ 151. More recently, Buchwald and co-workers have developed a titanocene-based method in which the intermediate titanacyclopentenes are initially captured by isocyanides and the resulting imines are subsequently hydrolyzed to the cyclopentenones 1161. They have also succeeded in performing

118

B. Transition Metal Organometullic Methods

X

3

M = Zr, Ti Scheme 5. Metallocene-mediated Pauson-Khand type reactions.

cat.

CO, toluene

-

12-16 h , 90°C

H 85-94% 74-96 %e.e .

Scheme 6. Catalytic enantioselective bicyclizations according to Buchwald.

Ti(CO),] as chiral catalyst [20] the desired cyclopentenones are obtained in high enantiomeric purity (Scheme 6) [21].

the reactions catalytically with trialkylsilylcyanides as the isocyanide source and catalytic amounts of [Cp,Ti(PMe,),] or, alternatively, a catalyst which is generated in situ from [Cp,TiCI,] by addition of two equivalents of n-BuLi or EtMgBr [17]. An Ni-based catalyst system ([Ni(cod),]/BDPEDA) has also proved to be efficient [18]. Recently, Buchwald and co-workers devised an outstanding procedure for the direct, titanocenecatalyzed cyclocarbonylation of enynes [ 191. This catalytic method has a number of advantages: it occurs at low CO pressure, tolerates a variety of functional groups including disubstituted alkenes, and gives the cyclopentenones in high yields (>85 %). This industrially attractive process was later modified to proceed enantioselectively. With 5 -20 % of [(S,S)-(EBTHI)

+02& SMe 4

Asymmetric Pauson-Khand Reactions Considerable efforts have been made to develop asymmetrical variants of the classical PausonKhand reaction. Initial investigations have shown that compounds derived from cobalt complexes of type 1, in which a carbonyl ligand is replaced by a chiral phosphane (glyphos), react with high enantioselectivity [22]. However, the procedure is too complex to be of preparative value. The concept of Kerr et al., who achieved significant enantioselectivities (max. 44 % e e ) in intermolecular Pauson-Khand reactions by

a. 1.1 eq. C O ~ ( C O ) ~ b. 9 eq. NMO, r.t.

0

63 %

OR* 5

(d.s.:89 : 11) Scheme 7. A diastereoselective Pauson-Khand reaction using a chiral-modified substrate according to M. A. Pericis.

New Developments in the Pauson-Khand Reaction

119

@

CZ~RI R

a. b. co2(co)8 6eq. NMO * THF-CH2C12 -78 2O”C, 3 h

-

q

R

o

+

R

Scheme 8. Pauson-Khand reactions with allenes.

R“

employing chiral amine oxides as promoters, appears more elegant [23]. A different approach was used by Pericas, Moyano, Riera and Greene, who observed high levels of asymmetric induction in Pauson-Khand reactions when chirally modified substrates were used [24]. The potential of this method was demonstrated in total syntheses of hirsutene [25], brefeldin A [26], and P-cuparenone [27]. The same concept was applied successfully in a recently published synthesis of ( + ) - I 5 nor-pentalenene, wherein the key step is conversion of enyne 4 into the tricyclic product 5 (Scheme 7) [28]. As the preparation of chirally modified substrates always requires considerable effort, the attractiveness of the above-mentioned catalytic enantioselective method is obvious, and it would be interesting to test the Buchwald procedure with the achiral analogs of Pericas’ substrates.

R

lecular conversions of allenes with enynes are also possible (Scheme 8) [30]. In these reactions, however, the formation of P-methylenecyclopentenones is favoured and di- or trisubstituted allenes must be employed in intramolecular reactions, because less substituted allenes tend to polymerize in the presence of [Co,(CO),].

“Hetero-Pauson-Khand Reactions”: Synthesis of y-Butyrolactones Buchwald and his group have also synthesized y-butyrolactones successfully by a metallocene mediated cyclization of enones (and ynones) with carbon monoxide in a formal [2+2+1]-addition, and have thus achieved the first “heteroPauson-Khand reaction” [3I]. The reactions can be conducted in high yields with either stoichiometrical or catalytical amounts of [Cp,Ti(PMe,),] as the example in Scheme 9 shows.

Pauson-Khand Reactions with Allenes Several authors have demonstrated that a PausonKhand type formation of methylenecyclopentenones from enynes, allenes and carbon monoxide occurs with stoichiometric ammounts of [Fe,(CO),] or [Mo(CO),], and catalytically with [Cp,Ti(CO),] [19, 291. Cazes et al. recently reported that cobalt-mediated inter- and intramo-

“Interrupted” Pauson-KhandReactions Krafft et al. have found that in the conversions of enyne-Co,(CO), complexes significant amounts of monocyclic by-products are obtained in addition to the desired cyclopentenones (via oxidation

cat. Cp2Ti(PMe& I .2 atm. CO, toluene 105”C, 15-18 h

98 %

Me

*

Xo

Scheme 9. An example of a “hetero-Pauson-Khand

reaction” according to Buchwald.

Scheme 10. The “interrupted Pauson-Khand reaction”

according to Krafft.

120

B. Transition Metal Organometallic Methods

-

@ ' Me

Me

0

Me

H 6

7

0 \SiMe3 9

8

Scheme 11. Strategy of the Schreiber synthesis of (+)-epoxydictymenein a retrosynthetic representation.

0

0

OMe

10 (90% ee)

11

Scheme 12. Combined arene-Cr(C0)3and Pauson-Khand chemistry according to Kundig.

of the primary enyne cyclization product) [32]. In fact, the conventional Pauson-Khand reaction can be almost totally suppressed if it is conducted in air. An example of an "interrupted Pauson-Khand reaction" is illustrated in Scheme 10.

New Synthetic Applications of the Pauson-Khand Reaction The high value of the Pauson-Khand reaction in the synthesis of natural products and other complex compounds has been frequently demonstrated [3]. One of the most impressive examples is the synthesis of the marine natural product (+)-epoxydictymene by Schreiber and co-workers [33]. The synthetic strategy (Scheme 1 I ) uses an intermolecular Nicholas reaction [34]

(the Lewis acid mediated conversion of the C O ~ ( C Ocomplex )~ derived from 1)) for the preparation of the actual Pauson-Khand substrate 9, which is then converted to the epoxydictymene precursor 7. A reaction sequence published recently by Kundig and co-workers also deserves notice [35]: in a one-pot reaction the planar chiral arene-Cr(CO), complex 10 is first converted (with chirality transfer) to the enyne 11, which then affords the tricyclic Pauson-Khand product 12 in high yield and completely diastereoselectively (Scheme 12). Finally, sequential Pauson-Khand reactions (domino reactions) are possible [36, 371. A particular fascinating application of this concept is the synthesis of a fenestrane by Keese and coworkers (Scheme 13) [36].

New Developments in the Pauson-Khand Reaction

OSiMe,

121

$OH OSiMe,

Scheme 13. Synthesis of a fenestrane by domino Pauson-Khand reaction according to Keese.

Conclusions The Pauson-Khand reaction (together with related metallocene-catalyzed transformations) has established a prominent place in the repertoire of synthetic organic chemists. Its use enables the construction of complex molecules in a convergent and atom economic way starting from structurally simple precursors. High levels of enantioselectivity can be achieved. It is therefore not surprising that an increasing number of research groups is focussing on the further development of this reaction. In the era of combinatorial chemistry the conversion of solid-supported substrates is just one possibility [38].

References [ I ] a) L. S. Hegedus, Transition Metal Organometal1ic.s in the Synthesis of Complex Molecules, 2nd Edn., University Science Books, Sausalito, CA, 1999; b) M. Beller, C. Bolm (eds.), Transition Metals for Organic, Synthesi.s, Wiley-VCH, Weinheim. 1998; c) R. Noyori, Asymmetric Catalysis in Organic S,vnthesis, Wiley, New York, 1994. [ 2 ]a) I. U. Khand. G. R. Knox, P. I,. Pauson, W. E. Watts, J. Chem. Soc. Chem. Commun. 1971, 36; b) I. U. Khand, G. R. Knox, P. L. Pauson, W. E. Watts, M. 1. Foreman, J . Chem. Soc., Perkin Trans. I 1973, 977; c ) P. L. Pauson, I. U. Khand, Ann. N . K Acad. Sci. 1977, 295, 2. [3] For reviews on the Pauson-Khand reaction, see: a) P. L. Pauson, Tetrahedron 1985, 41, 5855; b) P. L. Pauson in 0r~anometallic.sin Organic Svnrkesis, A. de Meijere, H. tom Dieck (eds.), Springer-Verlag, Berlin 1987, p. 233; c) N. E. Schore, Org. Reuct. 1991,40, 1 ; d) N. E. Schore in Comprekensive Organic Synthesis, Vol5; B. M. Trost (ed.), Pergamon, Oxford, 1991, p. 1037; e) N. E. Schore in Comprehensive Organometallic Chemistry 11, Wd. 12, E. W. Abel, F. G. A. Stone, G. Wilkinson (eds.), Pergamon, Oxford, 1995, p. 703; f) N. Jeong in: Trunsition Metals for Organic Synthesis. Vol. I , M. Beller, C. Bolm (eds.), Wiley-VCH, Weinheirn,

1998, p. 56 1 ;for a recent review on metal mediated cycloadditions in general, see: g) H.-W. Fruhauf, Ckem. Rev. 1997. 97, 523. [4) a) S. Shambayati, W. E. Crowe, S. L. Schreiber, Tetrahedron Lett. 1990, 31, 5289; b) N. Jeong, Y. K. Chung, B. Y. Lee, S. H. Lee, S.-E. Yoo, Synleft 1991,204; c) A. R. Gordon, c . Johnstone, W. J. Ken; Synlett 1996, 1083. [S] T. Sugihara, M. Yamada, H. Ban, M. Yamaguchi, C. Kaneko, Angew. Ckem. 1997,109,2884; Angew. Chem. Int. Ed. Engl. 1997, 36, 2801; (for a related paper which also describes a method for the in situ complexation of alkynes with CoBr,, Zn and CO, see: T. Rajesh, M. Periasarny, Tetrahedron Lett. 1998, 39, 117). 161 a) B. M. Trost, Science 1991, 254, 1471; b) B. M. Trost, Angew. Chem. 1995, 107, 285; Angew. Chem. Int. Ed. Engl. 1995, 34, 259. [7] D. C. Billington, W. J. Ken; P. L. Pauson, C. F. Farnocchi, J. Organornet. Ckem. 1988, 356, 213. IS] V. Rautenstrauch, P. MCgard, J. Conesa, W. Kiister, Angew. Chem. 1990,102, 1441; Angew. Chem. Int. Ed. Engl. 1990, 29, 1413. 191 a) N. Jeong, S. H. Hwang, Y. Lee, Y. K. Chung, J. Am. Chem. Soc. 1994,116,3159; b) B. Y. Lee, Y. K. Chung, N. Jeong, Y. Lee, S. H. Hwang, J. Am. Chem. Soc. 1994, 116, 8793; c) N. Y. Lee, Y. K. Chung, Tetrahedron Lett. 1996, 37, 3145; d) N. Jeong, S. H. Hwang, Y. W. Lee, Y. S. Lim, J. Am. Chem. Suc. 1997, 119, 10549. [lo] a) B. L. Pagenkopf, T. Livinghouse, J. Am. Ckem. Soc. 1996, 118, 2285; for newer work on catalytic Pauson-Khand reactions, see: b) M. Hayashi, Y. Hashimoto, Y. Yamamoto, J. Usuki, K. Saigo, Angew. Chem. 2000, 112,645; Angew. Chem. Int. Ed. Engl. 2000, 39, 631; and refs. cited therein. [ 11 I a) A. J. Pearson, R. A. Duhbert, J. Chem. Soc., Chem. Commun. 1991, 202; b) A. J. Pearson, R. A. Dubbert, Oi-jianometa1lic.s 1994, 13, 1656; c) T. R. Hoye, J. A. Suriano, Organometallics 1992, 11, 2044; d) T. R. Hoye, J. A. Suriano, J. Am. Chem. Soc. 1993, 115, 1154; e) C. Mukai, M. Uchiyama, M. Hanaoka, J. Chem. Soc. Chem. Commun. 1992, 1014; f) N. Jeong, S. J. Lee, Tetrahedron Lett. 1993, 34, 4021; g) L. Pagks, A. Llebaria, F. Camps, E. Molins, C . Miravitlles, J. M. Moret6, J . Am. Ckem. Suc. 1992, 114, 10449.

122

B. Transition Metal Ovganometallic Methods

1121 T. Kondo, N. Suzuki, T. Okada, T.-a. Mitsudo, J . Am. Chem. Soc. 1997, 119, 6187. I131 T. Morimoto, N. Chatani, Y. Fukumoto, s. Murai, J. Org. Chem. 1997, 62, 3762. [I41 a) E.-i. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, J . Am. Chem. Soc. 1985, 107, 2568; b) E.-i. Negishi, F. E. Cederbaum, T. Takahashi, Tetrahedron Lett. 1986, 27, 2829; C) E.-i. Negishi, S. J. Holmes, J. M. Tour, J. A. Miller, F. E. Cederbaum, D. R. Swanson, T. Takahashi, 1. Am. Chem. Soc. 1989, 11, 3336. [ I S J a) K. Tamao, K. Kobayashi, Y. Ito, J. Am. Chem. SOC.1988, 110, 1286; b) K. Tamdo, K. Kobayashi, Y. Ito, Synlett 1992, 539. [ 161 R. B. Grossmann, S . L. Buchwald, J. Org. Chem. 1992,57, 5803. 1171 a) S. C . Berk, R. B. Grossmann, S. L. Buchwald, J . Am. Chem. Soc. 1993, 115,4912; b) S. C. Berk, R. B. Grossmann, S. L. Buchwald, J. Am. Chem. Soc. 1994, 116, 8593; c) F. A. Hicks, S. C. Berk, S. L. Buchwald, J . Org. Chem. 1996, 61, 2713. [ 181 M. Zhang, S. L. Buchwald, J. Org. Chem. 1996,61, 4498; BDPEDA = N,N’-bis(diphenylmethy1ene) ethylenediamin. [19] a) F. A. Hicks, N. M. Kablaoui, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118,9450; b) F, A. Hicks, N. M. Kablaoui, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 5881. [20) For the use of EBTHI complexes in enantioselective synthesis, see: A. H. Hoveyda, J. P. Morken, Angew. Chem. 1996, 108, 1378; Angew. Chem. Int. Ed. Engl. 1996, 35, 1262. [21] F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 11688. (221 a) P. Bladon, P. L. Pauson, H. Brunner, R. Eder, J. Organornet. Chem. 1988,355,449;b) H. Brunner, A. Niederhuber, TetrahedronAsym. 1990, I , 7 1 1 ; c) A. M. Hay, W. J. Kerr, G. G. Kirk, D. Middlemiss, Orgunometallics 1995, 14, 4986. 1231 a) W. J. Kerr, G. G. Kirk, D. Middlemiss, Synlett 1995, 1085; b) W. J. Ken, D. M. Lindsay, J. S. Scott, S. Watson, OMCOS 9 Corzference, Gottingen 1997 (Poster Nr.3 18). [24] a) J. Castro, A. Moyano, M. A. Perichs, A. Riera, A. E. Greene, Tetrahedrori Asym. 1994, 5, 307; b) V. Bernardes, X. Verdaguer, N. Kardos, A. Riera, A. Moyano, M. A. Pericis, A. E. Greene, Tetrahedron Lerf. 1994, 35, 575; c) X. Verdaguer, A. Moyano, M. A. Pericas, A. Riera, V. Bernardes, A. E. Greene, A. Alvarez-Larena, J. F. Piniella, J. Am.

Chem. SOC. 1994, 116, 2153; d) S. Fonquerna, A. Moyano, M. A. Pericas, A. Riera, Tetrahedron 1995,51,4239;e) S. Fonquerna, A. Moyano, M. A. Pericis, A. Riera, 1. Am. Chem. Soc. 1997, 119, 10225; f) E. Montenegro, M. Poch, A. Moyano, M. A. Perichs, A. Riera, Tetrahedron Lett. 1998, 39, 335; g) S. Fonquerna, R. Rios, A. Moyano, M. A. Perichs, A. Riera, Eur: J. Org. Chern. 1999, 3459. [25] J . Castro, H. Sorensen, A. Riera, C. Morin, A. Moyano, M. A. Pericis, A. E. Greene, J. Am. Chern. Soc. 1990, 112, 9388. [26] V. Bernardes, N. Kann, A. Riera, A. Moyano, M. A. Pericas, A. E. Greene, J. Org. Chem. 1995, 60, 6670. [27] J. Castro, A. Moyano, M. A. Perichs, A. Riera, A. E. Greene, A. Alvarez-Larena, J. F, Piniella, J. Org. Chem. 1996, 6 1 , 9016. [28] J. Tormo, A. Moyano, M. A. Pericas, A. Riera, J. Org. Chem. 1997, 62, 4851. [29] a) R. Aumann, H.-J. Weidenhaupt, Chem. Be% 1987, 120,23; b) J. L. Kent, H. Wan, K. M. Brummond, Tetrahedron Lett. 1995, 36, 2407. [30] a) M. Ahmar, F. Antras, B. Cazes, Tetrahedron Lett. 1995,36,4417; b) M. Ahmar, 0. Chabanis, J. Gauthier, B. Cazes, Tetrahedron Lett. 1997, 38, 5277; c) M. Ahmar, C. Locatelli, D. Colombier, B. Cazes, Tetrahedron Lett. 1997, 38, 528 1 . [31] a) N. M. Kablaoui, F. A. Hicks, S. L. Buchwald, J. Am. Chenz. Soc. 1996, 118, 5818; b) N. M. Kablaoui, F. A. Hicks, S. L. Buchwald, J . Am. Chem. Soc. 1997, 119, 4424. 1321 M. E. Krafft, A. M. Wilson, 0. A. Dasse, B. Shao, Y. Y. Chung, Z. Fu, L. V. R. Bonaga, M. K. Mollmann, J. Am. Chem. Soc. 1996, 118, 6080. [331 a) T. F. Jamison, S. Shambayati, W. E. Crowe, S. L. Schreiber, J. Am. Chem. Soc. 1994,116,5505;b) T. F. Jamison, S. Shambayati, W. E. Crowe, S. L. Schreiber, J. Am. Chem. Soc. 1997, 119, 4353. [34] K. M. Nicholas, Acc. Chem. Res. 1987, 20, 207. [351 A. Quattropani, G. Anderson, G. Bernardinelli, E. P. Kundig, J. Am. Chem. Soc. 1997, 119, 4773. [361 M. Thommen, R. Keese, Synlett 1997, 23 I . 1371 S. G. Van Ornum, J. M. Cook, Tetrahedron Left. 1997, 38, 3657. [381 a) G. I,. Bolton, Tetrahedron Lett. 1996, 37, 3433; b) J. L. Spitzer, M J. Kurth, N. E. Shore, S. D. Najdi, Tetrahedron 1997, 53, 6791; c) G. L. Bolton, J. C. Hodges, J. R. Rubin, Tetrahedron 1997, 53, 6611.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Multicomponent Catalysis for Reductive Bond Formations Alois Fiirstner Max-Planck-Ii~stitut,fur Kohlenforschung, MuiheindRuhr, Germany

Catalysis in general and asymmetric catalysis in particular are at the forefront of chemical research [ I]. Their impact on industrial production can hardly be overestimated and is likely to increase further [2]. However, the high degree of sophistication reached in many respects may hide the simple notion that there still remain fairly large domains in preparative organic chemistry in which no catalytic alternatives to well-established stoichiometric transformations yet exist. The following account is intended to put into perspective some pioneering studies which address this problem and try to develop new concepts for metal-catalyzed reductive bond formations [ 31.

Catalytic Processes Mediated by Chlorosilanes Titanium. The high reducing ability and the pronounced oxophilicity of early transition metals in low oxidation states act jointly as a formidable driving force in many transformations. However, such processes are usually hampered by the fact that the metal oxides or alkoxides formed as the inorganic by-products usually resist attempted re-reductions to the active species and thus render catalysis a difficult task.

Rho -<"F! R II

..

I

--___.___.--I'

RI I

9 ,

'.--.'

-

A prototype example is the famous McMurry coupling of carbonyl compounds to alkenes (Scheme 1) [4]. The very high stability of the accumulating titanium oxides constitutes the thermodynamic sink which drives the conversion but demands the use of stoichiometric or excess amounts of the low-valent titanium reagent [Ti]. Only recently has it been possible to elaborate a procedure that for the first time enables us to perform intramolecular carbonyl coupling reactions catalyzed by titanium species [5]. This development was triggered by some earlier insights into the essentials of this transformation: it has been shown that a large number of lowvalent titanium species, [Ti], differing in their formal oxidation states, ligand spheres and solubilities promote carbonyl coupling processes with comparable ease. Because this fact refutes previous assumptions that metallic titanium was essential, the strong and aggressive reducing agents required for its preparation can be avoided. As a consequence it was possible to develop a particularly convenient - but still stoichiometric - "instant method" for performing carbonyl coupling reactions based on the formation of [Ti] from TiCI, and Zn in the presence of the substrate [6]. Since the latter feature meets a fundamental requirement for catalysis, this set-up paved the

RHR R I1

+ nTixOy

9 '.---' I

Scheme 1. The McMurry coupling of carbonyl compounds to alkenes.

124

€2.

Transition Metal Organometallic Methods

V 2 Tic13

2 R3SiOSiR3

\

2

[“,:I

Scheme 2. Catalytic cycle for McMurry-type couplings.

R1

4 R3SiCI

way for a truly catalytic process. However, Zn dust cannot re-reduce the titanium oxides or oxychlorides initially formed into any active low-valent [Ti] species. Therefore an indirect way to complete a catalytic cycle was devised which relies on a ligand exchange between the titanium oxides or oxychlorides and a chlorosilane (Scheme 2 ) . In fact, a multicomponent redox system consisting of TiCl, cat., Zn and a chloro-

silane accounts for the first titanium-catalyzed carbonyl coupling reactions. The efficiency of this method can be tuned to some extent by choosing the R,SiCI additive. The examples compiled in Table 1 show that this new catalytic procedure compares favorably with the existing stoichiometric precedent in terms of yields and reaction rates. These studies have been carried out using 0x0-amide derivatives as substrates, which ex-

Table 1. Titanium-induced indole syntheses: comparison of the catalytic with the stoichiometric “instant” procedure.

Product

mrh

Catalytic procedure TiCI, cat., Zn, TMSCI, 0.5 h

“Instant method” TiCI, (2-4 equiv), Zn, 1-4 h

SO %

98 7 G

79 %

81 %

82 % [a]

I6

88 %

82 9%

61 p/o

YO lo

H

[a] Using CIMe,Si(CH,),CN as additive instead of TMSCI.

7G

Multicomponent Catalysis for Reductive Bond Formations hibit a pronounced tendency to cyclize to indole derivatives on treatment with [Ti] [5-7]. It was clear at the outset that the basic principle of this catalytic scenario may apply to other transformations as well. An obvious extension concerns the pinacol coupling since any McMurry reaction probably passes through the 1,2-diolate stage (cf. Scheme 1) 141. In fact, several titanium-catalyzed procedures have been reported which rely on chlorosilane additives for the liberation of the product and the simultaneous regeneration of the TiC1, salt. They involve either [Cp,TiCI,] cat., Zn, chlorosilane [8], or [Cp,TiCl,] cat., Mn, chlorosilane [9], or [TiCI,(THF),] cat., Zn, TMSCI, t-BuOH [ 101, or [Cp,Ti(Ph)Cl] cat., Zn, chlorosilane 11I]. The use of Cp,TiCI, in this context deserves particular emphasis, because titanium sources of this type open up new vistas for stereocontrol if ansa-titanocene derivatives are used to transfer chiral information from the ligand to the diol [ 121. Chromium. Similar chlorosilane-mediated catalytic processes can be envisaged with many other early transition metals. The development of the first Nozaki-Hiyama-Kishi reactions catalyzed by chromium species 1131 illustrates how to avoid the use of an excess of a physiologically suspect and rather expensive salt without compromising the efficiency, practicality and scope of the reaction. The tentative catalytic cycle is depicted in Scheme 3.

2 CrX2

MnX2

12s

In this case, the silylation of the metal alkoxide initially formed represents the key step of the overall process which releases the chromium salt from the organic product. The other crucial parameter is the use of the stoichiometric reducing agent for the regeneration of the active Cr" species. Commercial Mn turned out to be particularly well suited, as it is very cheap, its salts are essentially non-toxic and rather weak Lewis acids, and the electrochemical data suggest that it will form an efficient redox couple with Cr"'. Moreover, the very low propensity of commercial Mn to insert on its own into organic halides guarantees that the system does not deviate from the desired chemo- and diastereoselective chromium path. Thus, a mixture of CrX, ( n = 2, 3) cat., TMSCI and Mn accounts for the first Nozaki reactions catalytic in chromium [ 131. This method applies to aryl, alkenyl, ally1 and alkynyl halides as well as to alkenyl triflates and exhibits the same selectivity profile as its stoichiometric precedent (Scheme 4). Moreover, it does not matter if the catalytic cycle is started at the Cr" or Cr'" stage as implied by Scheme 3. Therefore it is possible to substitute cheap and stable CrCI, for the expensive and air-sensitive CrCI, previously used for Nozaki reactions. In some cases other chromium templates such as [Cp,Cr] or [CpCrCI,] can be employed, improving the total turnover number of this transformation even further [13, 141.

CrX3 CrX3

Mn OSiMe3 I

Scheme 3. Proposed catalytic cycle for the first Nozaki-HiyamaKishi reactions catalyzed by chromium species.

126

B. Trunsition Metal Orgunornetullic Methods

80%

66%

83% (aiititsyri = 92 : 8)

57% ‘

72%

79%

/

Scheme 4. The scope of Nozaki reactions catalyzed by chromium resembles that of the stoichiometric version.

Electrochemically driven Nozaki-HiyamaKishi reactions constitute an attractive modification of this basic concept (Scheme 5 ) [15]. Although the current density turned out to be a critical parameter and must be carefully controlled, the authors show that in this case the LiClO, used as supporting electrolyte also acts as the oxophilic mediator instead of TMSCI. They also used a palladium cocatalyst in order to form more highly nucleophilic “chromium ate” complexes as the actual intermediates. Encouraged by this precedent, further studies using electrons as the ultimate reducing agent are likely to appear in the near future. Other Transition Metals. The rather general validity of the chlorosilane-based catalysis concept is further substantiated by some recent examples of pinacol coupling processes catalyzed either by low-valent vanadium ([CpV(CO),] cat., Zn, chlorosilane) [ 161 or low-valent samarium (SmI, cat., Mg, chlorosilane) [ 171. Likewise,

a report from Coreys group on samarium iodide catalyzed additions of carbonyl compounds to acrylates deserves mention; these follow essentially the same rationale (SmI, cat., Zn(Hg), TMSOTf, LiI) [18]. In view of the extensive use of SmI, in stoichiometric transformations, the possible impact of catalytic alternatives is easy to imagine.

Catalytic Processes Based on Other Mediators Although chlorosilanes are an obvious choice as mediators for catalysis on account of their high affinity for oxygen, low price and lack of toxicity, several other additives can also be envisaged. The recent publication on the electrochemical version of the Nozaki reaction mentioned above simply employs the Li cations of the supporting electrolyte for this very purpose [ 1.51, whereas another titanium-catalyzed pinacol

CrC12 (10 mol%)

Pd(0Ac)Z (0.1 mol%), PPh3 (0.4 rnol%) 0.1 M LiC104 in DMF

constant current (40 rnAcm-2)

Scheme 5. An electrochemically driven Nozaki-Hiyama-Kishi

reaction.

Multicomponent Catalysis for Reductive Bond Formations

COOEt

Cp2TiC12 cat., Mn collidine.HCI 1,4-~yclohexadiene

COOEt

@+

(COOMe

78%

HO

127

COOEt COOEt

CpnTiCI2 cat., Zn collidine.HCI 1,4-~yclohexadiene 77%

Scheme 6. Inter- and intramolecular C-C coupling reactions by the method of Gansauer et al.

coupling reaction [TiCI, cat., Li(Hg), AICI,] is based on the oxophilicity of Al“’ [ 191. An even more interesting development concerns the use of protons. Thus, Gansauer et al. were able to achieve epoxide ring-openings and pinacol coupling reactions with catalytic amounts of Cp,TiCI,, simply by using pyridinium hydrochlorides as scavengers for the product and Zn or, preferably, Mn as the stoichiometric reducing agent [20, 211. The pK, of the pyridinium salt is properly adjusted, and the protic medium does not interfere with the radical intermediates prior to product formation. This method applies to inter- and intramolecular C-C coupling reactions (Scheme 6) as well as to simple reductions and turned out to be compatible with various sensitive functional groups in the oxirane substrates. Another approach to multicomponent redox catalysis employs silanes (R,SiH) as the addi-

tives. This allows the stoichiometric reducing agent and the oxophilic reaction partner to be merged into a single component. Two independent reports from Buchwald [22] and Crowe [23] on the cyclization of unsaturated carbonyl compounds based on the turnover of a “Cp,Ti” template rely on this principle (Scheme 7) [24]. A similar idea allows the well-known BartonMcCombie deoxygenation of alcohols to proceed for the first time with catalytic rather than stoichiometric or excess amounts of tributylstannane (Scheme 8) [25]. As shown in the proposed catalytic cycle, this exceptionally versatile but highly toxic reagent is regenerated from the otherwise accumulating “dead-end’ product Bu,Sn(OPh) by means of polymethylhydrosiloxane (PMHS). Once again it is the affinity for oxygen in combination with the reducing ability of this inexpensive, non-toxic and easily handled silicon hydride which qualifies PMHS as an an-

R

R

Si(0Et)s

I

eCH3 U

H

/‘TiCp2

H

Scheme 7. The cyclization of unsaturated carbonyl compounds based on the turnover of a CpzTi template with a silane as the additive.

128

B. Transition Metal Organornetallic Methods S OAOPh

-4

BugSn’

f

[Sij-OPh

start Itere

BugSnH

\

/

\

BugSnOPh

[Sil-H

+

RIA@

[Si)-H = MegSiO-(SiHMeO)n-SiMes

s=c=o

cillary component for catalysis. The authors show that the addition of n-BuOH facilitates the regeneration of the tin hydride, improves the key step of the catalytic process and makes the reaction as efficient as the stoichiometric version (Table 2). These and related examples rival - and may well replace - their stoichiometric counterparts. Although none of them is “atom economical”

8. The Barton-McCombie deoxygenation of alcohols with catalytic rather than stoichiometric amounts of tributylstannane.

[26] in the pure sense, they do at least permit economy in the key component. If the latter is expensive, difficult to handle and/or of physiological concern, such multicomponent catalyst systems up-grade established transformations to a significant extent, quite apart from the heuristic lessons in and the stimulus for catalysis research which they provide [27].

TabZe 2. Barton-McCombie deoxygenation of phenyl thionocarbonate esters: comparison of the catalytic with the stoichiometric reaction 1251. Substrate

Product

=: phiiz;oyoph phq Ph

Ph

Catalytic

Stoichiometric

66 %

68 %

70 c/c

65 %

S

72 9%

68 %

61 5%

Multicornponent Catalysis .for Reductive Bond Formations

References [ 11 a) R. Noyori, Asymmetric Catulvsis in Organic

Synthesis, Wiley, New York, 1994; b) I. Ojima (Ed.), Catalytic Asymmetric Synthesis, VCH, New York, 1993 and ref. cited. [21 For a leading reference see: B. Cornils, W. A. Herrmann, Applied Homogeneous Catalysis with Organometallic Compounds, VCH, Weinheim, 1996. [31 a) This article is an up-dated version of the following account: A. Fiirstner, Chem. EUI:J . 1998, 4, 567570. b) See also: A. Furstner, Pure Appl. Chem. 1998, 70, 1071-1076. [41 a) For a recent review see: A. Furstner, B. Bogdanovic, Angew. Chem. 1996, 108, 2583-2609; Angew. Chem. Int. Ed. Engl. 1996, 35, 2442-2469; b) J. E. McMurry, Chem. Rev. 1989, 89, 1513-1524. c) A. Fiirstner in Transition Metals f o r Organic Synthesis (M. Beller, C. Bolm, Eds.), Wiley-VCH. Weinheim. 1998, Vol. I , 381-401. [5] A. Furstner, A. Hupperts, J. Am. Chem. Soc. 1995, 117, 4468-4475. [6] A. Furstner, A. Hupperts, A. Ptock, E. Janssen, J. Org. Chem. 1994, 59, 5215-5229. [7] For applications see: a) A. Fiirstner, A. Ptock, H. Weintritt, R. Goddard, C. Kriiger, Angew. Clzern. 1995, 107, 725-728; Angew. Chern. Int. Ed. Engl. 1995, 34, 678-681; b) A. Furstner, A. Ernst, Teiriihedron 1995,51,773-786; c) A. Furstner, A. Ernst, H. Krause, A. Ptock, Tetrahedron 1996, 52, 73297344; d) A. Furstner, D. N. Jumbam, G. Seidel, Chern. Rer. 1994, 127, 1125- 1130; e) A. Fiirstner, A. Hupperts, G. Seidel, Org. Synth. 1998, 76, 142-150 and ref. cited. [S] a) A. Gansauer, ,I. Clzern. Soc. Chem. Conimun. 1997, 457-458; b) A. Gansauer, M. Moschioni, D. Bauer, Eur: J. Org, Chem. 1998, 1923- 1927; c) T. Hirao, B. Hatano, M. Asahara, Y. Muguruma, A. Ogawa, Tutrahedron Lett. 1998, 39, 5247-5248. 191 M. S. Dunlap, K. M. Nicholas, Synth. Cornmun. 1999, 29, 1097- 1106. 1101 T. A. Lipski, M. A. Hilfiker, S. G. Nelson, J. Org. Clzem. 1997, 62, 4566-4567. [ 11 1 Y. Yamamoto, R. Hattori, K. Itoh, Chem. Commun. 1999, 825- 826. [ 121 a) A. Gansauer, Synlett 1997, 363-364; b) For a recent complementary approach towards diastereoselective pinacol coupling using Schiff bases as ligands to TiCIJTHF), cat. in combination with Mn and TMSCI see: M. Bandini, P. G. Cozzi, S. Morganti, A. Umani-Ronchi, Tetrahedron Lett. 1999,40, 1997 2000. [ 131 a) A. Furstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 2533-2534; b) A. Fiirstner, N. Shi, J. Am. Cheni. Soc. 1996, 118, 12349- 12357;c) For a recent comprehensive review on stoichiometric and catalytic Nozaki-Hiyama-Kishi reactions see: A. Furstner, Chem. Rev. 1999, 99, 991 - 1045. -

129

I141 For recent applications of this multicomponent system to other Nozaki-Hiyama-Kishi reactions catalytic in chromium see: a) With acrolein acetals: R. K. Boeckman, R. A. Hudack, J. Org. Chem. 1998, 63, 3524-3525; b) With trichloroethane: J. R. Falck, D. K. Barma, C. Mioskowski, T. Schlama, Terruhedron Lett. 1999, 40, 2091 -2094; c) CrCI, cat., TMSCI, NiCI, cat., Al-powder: M. Kuroboshi, M. Tanaka, S. Kishimoto, K. Goto, H. Tanaka, S. Torii, Tetrahedron Lett. 1999,40, 2785-2788. [I51 R. Grigg, B. Putnikovic, C. J. Urch, Tetrahedron Lett. 1997, 38, 6307-6308. [I61 a) T. Hirao, T. Hasegawa, Y. Mugumura, I. Ikeda, J. Org. Chem. 1996,61,366-367; b) T. Hirao, M. Asahara, Y. Muguruma, A. Ogawa, J. Org. Chem. 1998, 63, 2812-2813; c) For an application of the same multicomponent system to the reductive dimerization of aldimines see: B. Hatano, A. Ogawa, T. Hirao, J. Org. Chem. 1998, 63, 9421 -9424. [I71 R. Nomura, T. Matsuno, T. Endo, J. Am. Client. Soc.

1996, 118, 1 1666- I 1667. [ 181 E. J. Corey, G. Z. Zheng, Tetrahedron Lett. 1997,38,

2045 -2048. [I91 0. Maury, C. Villiers, M. Ephritikhine, New. J . Chem. 1997, 21, 137- 139. [20] Epoxide openings: a) A. Gansauer, M. Pierobon, H. Bluhm, A n p w Chern. 1998,110, 107- 109; Angew. Chem. Inr. Ed. Engl. 1998,37, 101 103; b) A. Gansauer, H. Bluhm, Chem. Commun. 1998, 21432144; c) A. Gansauer, H. Bluhm, M. Pierobon, J. Am. Chem. Soc. 1998, 120, 12849-12859. [21] Pinacol couplings by Cp,TiCI, cat. and Mn under buffered protic conditions: a) A. Gansauer, D. Bauer, J. Org. Chem. 1998, 63, 2070-2071; b) A. Gansauer, D. Bauer, EUI: J . Org. Chem. 1998, 2673-2676. [22] a) N. M. Kablaoui, S. L. Buchwald, .I. Am. Chem. SOC.1995, 117, 6785-6786; b) N. M. Kablaoui, S. L. Buchwald, J . Am. Chetn. Soc. 1996, 118, 3182-3191; c) See also: N. M. Kablaoui, F. A. Hicks, S. L. Buchwald, J. Am. Chem. Soc. 1996, 118, 5818-5819. [23] W. E. Crowe, M. J. Rachita, J. Am. Ckem. SOC.1995, 117, 6787-6788. [24] Closely related are reports from the same authors in which isocyanates or CO insert into titanaoxacycles in order to release the catalytically active “Cp,Ti” species, cf: a) F. A. Hicks. S. C. Berk, S. L. Buchwald,J. Org. Chem. 1996,61, 2713-2718; b) W. E. Crowe, A. T. Vu, J . Am. Clzem. SOC. 1996, 118, 1557- 1558 and ref. cited. [25] R. M. Lopez, D. S. Hays, G. C. Fu, J . Am. Chern. Soc. 1997, 119, 6949-6950. 1261 B. M. Trost, Angew Chem. 1995, 107, 285-307; Angew. Chem. Int. Ed. Engl. 1995, 34, 259. (271 For recent accounts on similar topics see also: a) T. Hirao, Synletr 1999, 175- 18 I . b) A. Gansauer, S.yviileft 1998, 801 -809. -

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Natural Product Synthesis by Rh-mediated Intramolecular C-H Insertion Douglass E Taber Department of Chemistry and Biochemistry, University of Delaware, USA

Salah-E. Stiriba Department

of

Chemistry, Texas A & M Univer.yity, USA We summarize here the applications to natural product synthesis of this method for ring construction. Although most of the work with Rh-mediated intramolecular C - H insertion has focussed on five-membered ring construction, the first application to natural product synthesis, by Cane, involved establishment of a six-membered ring. Thus, on exposure to Rh2(0Ac),, diazoketone 2 was cyclized to the tricyclic lactone 3 121. This product had previously been transformed by Paquette into pentalenolactone E (4) [3].

Since the observation that Rh(I1) carboxylates are superior catalysts for the generation of transient electrophilic metal carbenoids from a-diazocarbonyls compounds, intramolecular carbenoid insertion reactions have assumed strategic importance for C - C bond construction in organic synthesis [ I ] . Rhodium(I1) compounds catalyze the remote functionalization of carbon-hydrogen bonds to form carbon-carbon bonds with good yield and selectivity. These reactions have been particularly useful in the intramolecular sense to produce preferentially five-membered rings.

mo

4 steps

25%

-

1

2 07 0&N2

9 steps

Q3C02Me

A0;

12%

0

Scheme 1

0

3

b5

Scheme 2

4 Pentalenolactone E methyl ester

Rh;?(OAc)4 CH2C12

58%

~

% h% Se02

\

/

6

tBu0H.A

/ 7 Bullatenone

Natural Product Synthesis by Rh-mediated Intramolecular C-H Insertion

2 steps

Me0

i

0

131

Me0

78%

OH 8

-

HO

8 steps 3%

Me0

1

HO 11 (+)-morphine

Scheme 3

10

12

14

MOM

13

15 Pentalenolactone E methyl ester

Scheme 4

The utility ofthis approach to five-membered hetrrocycles is illustrated by the synthesis of bullatenone (7) by A d a m . Rhodium acetatemediated insertion is especially preferred adjacent to ether oxygen, as illustrated by the cyclization of 5 to 6 [4].Oxidation of furanone (6) with SeOz according to the procedure of Smith provided bullatenone (7) [ S ] .

Rh-mediated C-H insertion is also useful for carbocyclic construction, as illustrated by the new asymmetric route to (+)-morphine (11) recently reported by White [6]. Cyclopentane formation is used to fashion a pentacyclic skeleton (10) from which the piperidine ring of 11 is evolved at a later stage.

132

B. Transition Metal Organornetallic Methods

Rh octanoate L

89%

CH,O& 3steps

-

I

1

17

56%

3 steps

p

66%

19 Akaloid251F

OBn

h0*

18 Scheme 5

Md3

90%

20

23 (-)-cembranolide

Intramolecular C -H insertion is, essentially, a method for the specific remote functionalization of hydrocarbons. An important implication of this for synthetic strategy is that the C-H insertion process can dissolve symmetry, thus leading from a simple precursor to a much more complex product. An alternative route to pentalenolactone E (15) takes advantage of this idea [7]. In the key step, p-keto ester 13, which has a single stereogenic center, is transformed into the tricycle 14, which has four stereogenic centers.

Scheme 6

A simple route to the Dendrobatid alkaloid 251F (19) nicely illustrates the synthetic utility of Rh-mediated C - H insertion [S]. The excellent diastereoselectivity observed in the cyclization of 16 to 17 was in fact predicted computationally [9]. A single stereogenic center on the bridge between the target C-H bond and the diazocarbonyl can be sufficient to induce high diastereoselectivity. This is illustrated [lo] by the cyclization of 21, prepared from farnesol(20), which has two enantiotropic H atoms on the alcohol methy-

Natural Product Synthesis by Rh-mediated IntrumoleculLir C-H Insertion

133

0 Rhz(oAC)4_

@0$H3

TBDMSO

TBDMSO

75%

TBDMSO

4: 1

26

25

9

five steps ___)

4 -+'

HQa*

CiZzY

&OH

37%

z

HO

RC4

OH

21

ul

Scheme 7

PGF,,

*q#& t$,@ 0

C02Me U2(OAC)4 67%

0

3 4 steps 6%

31 (+)-a-Cuparenone

30

29

Scheme 8

k-1-naphthyl

32

33

CQMe

5 41%

92%

-

&

34 8%

Me0 Me0

35

36 (+)- Estrone methyl ether

Scheme 9

lene. Rh-mediated insertion occurred with high selectivity for Ha to give 22. Ester 22 was carried on over several steps to the marine natural product (-)-cembranolide (23). A single stereogenic center can also induce substantial diastereoselectivity in the course of Rh-mediated carbocyclization. Diazo ester 24, for instance [ 1 I], cyclized with a 4 : 1 preference for 25. Ester 25 was carried on to the Corey lac-

tone (27), the starting point for the total synthesis of the prostaglandins, exemplified by PGF,, (28). A key feature of intramolecular C-H insertion is the inherent ability to transform an acyclic tertiary stereogenic center into a cyclic quaternary stereogenic center, with retention of absolute configuration 1121. This was first demonstrated by rhodium-mediated cyclization of 29 to 30, leading to (+)-a-cuparenone (31) [ 131.

134

B. Transition Metal Organornetallic Methods 0

I 40 (-)- hinokinin

Scheme 10

k

l-R 41

42

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14]. In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C - H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclopentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether

(36).

CH,CI, 62%

The high point in the development to date of Rh-mediated C -H insertion has been the design by Doyle of enantiomerically pure Rh(I1) complexes that direct the absolute sense of the cyclization of a-diazo acetates. The applicability of such cyclizations to natural product synthesis has been demonstrated by Doyle with the con-

Scheme 11

struction of chiral lignane lactones such as (-)-hinokinin (40) [ 151. The a-diazocarbonyl derivatives used in these studies are easily prepared, and the rhodium-mediated cyclizations proceed rapidly, with high catalyst turnover (ca. 100- 1000). The catalysts are stable at room temperature for years, and are not air sensitive. The reactions work best in inert solvents such as dichloromethane or benzene, and the solvent must be dry. Slow addition of the diazocarbonyl compound to the catalyst is not usually necessary. There are many aspects of these Rh-mediated cyclizations that are yet to be explored. What factors, for instance, govern the ratio of 25 to 26 (Scheme 7)? Would an Rh catalyst that was more readily polarizable and so more sensitive to electronic effects give a higher proportion of 25? The enantioselective lactone cyclizations of Doyle [ 151 are particularly intriguing. Attempts toward enantioselective carbocyclization using a chiral rhodium catalyst have to date [I61 not

Natural Product Synthesis by Rh-mediated Intramolecular C-H Insertion

yielded preparatively useful enantiomeric excess. If, for instance, a generally useful catalyst for the selective transformation of 41 specifically to 42 or to 43 could be developed, it would have widespread utility. As the factors governing regio-, chemo-, diastereo- and enantioselectivity come to be better understood, the Rh-mediated cyclization of an a-diazocarbonyl derivative will come to be a powerful tool for natural product synthesis.

References [l] Reviews: a) For an excellent recent overview of stereoselection in metal-mediated intramolecular C-H insertion, see G.A. Sulikowski, K.L.Cha, M.M. Sulikowski, Tetrahedron: Asymm. 1998, 9, 3145. For other reviews, see b) A. Padwa, D. J. Austin, Angew. Chem. Int. Ed. Engl. 1994, 106, 1881-1899; c) M. A. McKervey, T. Ye, Chem. Rev. 1994, 94, 1091 - 1160; M. A. McKervey, M. P. Doyle, J. Chern. Soc. Chenz. Comm~in.1997, 983- 1072. d) M. P. Doyle, In Homogeneous Trarzsition Metal Catulyxts in Organic Synthesis; (Eds.: Moser, W. R., Slocum, D. W.), ACS Advanced Chemistry Series 230; American Chemical Society, Washington, DC, 1992; Chapter 30. e) D. F. Taber in Comprehensive Organic Synthesis, Vol. 3, (Ed.: B.M. Trost), Pergamon Press, Oxford, 1991, p. 1045. f) M. P. Doyle, A. B. Dyatkin, G. H. P. Roos, F. Ganas, D. A. Pierson, A. van Basten, P. Muller, P. Polleux, J . Am. Chem. Soc. 1994, 116, 4507. g) P. Wang, J. Adams, J. Am. Chem. Soc. 1994, 116, 3296. h) D. F. Taber

135

in Methods of Orgunic Chemistry, (HoubenWryl) Wil. E 2 I ; (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), George Thieme Verlag, Stuttgart, 1995, p. 1127.i) For a recent review of intramolecular C-H insertion by alkenylidenes, see W. Kirmse, Angew. Chem. Int. Ed. Engl. 1997, 36, 1164. [2] D. E. Cane, P. J. Thomas, J. Am. Chem. Soc. 1984, 106, 5295. 131 L. A. Paquette, G. D. Annis, H. Schostarez, J. F. Blount, J. Org. Chem. 1981, 46, 3768. [4] J. Adams, M.-A. Poupart, L. G. Chris, Tefruhedron Lett. 1989, 30, 1749-1752. [ S ) A. B. Smith 111, P. Jerris, Syn. Commun. 1978, 8, 421. [6] J. D. White, P. Hrnciar, E Stappenbeck, J. Org. Chem. 1997, 62, 5250-525 1. [7] D. F. Taber, J. L. Schuchardt, J . Am. Chem. SOC. 1985, 107, 5289. [8] D. E Taber, K. K. You, J. Am. Chern. Soc. 1995, 117, 5757. 191 D. F. Taber, K. K. You, A. L. Rheingold, J. Am. Chem. Soc. 1996, 11 8, 547. [ 101 D.F. Taber, D.F.; Y. Song, J. Org. Chenz. 1997, 62, 6603. [ 11 I Y. Takayuki, S. Yamada, M. Azuma, A. Ueki, M. Ikeda Synthesis 1998, 973. I121 J. C. Gilbert, D. H. Giamalva, M. E. Baze, J. Or,. Chem. 1985. 50, 2557. 11 31 D. F. Taber, E. M. Petty, K. Raman, J . Am. Chem. Soc. 1985, 107, 196. 1141 D. F. Taber, K. Raman, M. D. Gaul, J. O r , . Chrm. 1987, 52, 28. [151 J. W. Bode, M. P. Doyle, M. N. Protopopova, Q.-L. Zhou, J. Org. Chem. 1996, 61, 9146. [I61 S.-I. Hashimoto. N. Wdtanabe, T. Sato, M. Shiro, S. Ikegami, T'truhedrorz Lett. 1993, 33, 5 109.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

C. Enantioselective Catalysis Enantioselective Heck Reactions Murkus Juchmann and Hans-Gunther Schmalz Institut .fur Organische Chemie, Universitat Koln, Germany

Chirogenic reactions, i.e. reactions which lead from achiral starting materials to chiral products [l], deserve particular attention, as only such transformations offer the possibility to be enantioselectively catalyzed. Among the non-enzymatic, catalytic-asymmetric reactions, homogeneous transition metal catalyzed processes play a predominant role [2]. This is mainly due to the fact that by means of chiral ligands it is comparatively facile to transfer absolute stereochemical information to a catalytically active metal center. However, the success of some of these reactions (e.g. the Sharpless asymmetric epoxidation or the Noyori hydrogenation) must not hide the fact that the number of powerful transition metal-catalyzed C- C coupling reactions, which proceed reliably with high enantioselectivity, is still rather small. The Heck reaction, i.e. the palladium(0) catalyzed vinylation of aryl- or vinylhalides (or the corresponding triflates), belongs undoubtedly to the most important metal-catalyzed C-C coupling reactions [3, 41. Accordingly, it enjoys increasing application as a key reaction in total synthesis [ 5 ] . The basic pattern of the Heck reaction in its classical form is depicted in Scheme 1 . It involves, for instance, the reaction of an aryl halide (1) with an olefin in the presence of a base and a catalytic amount of a palladium complex to give a styrene derivative (2) under elimination of HX.

Mechanistically, the Heck reaction can be rationalized as follows (Scheme 2): First, a Pd(I1) complex of type 3 is formed by oxidative addition of the halide 1 to a L,Pd(O) species. Complex 3 then reacts with an olefin via the 71-complex 4 to give the /I-insertion product, i.e. the alkyl complex 5. After p-H elimination, the product 2 is released and the active catalyst is regenerated by base-assisted reductive elimination of HX. The Heck reaction in its original form is not a chirogenic reaction. However, the situation changes if cyclic alkenes are employed as a coupling component, as was initially shown by Larock et al. [6]. In such cases, non-conjugated, chiral products of type 6 are formed because only one syn-H atom is available for p-H elimination in the intermediates of type 7 (Scheme 3). While racemic mixtures are obtained with achiral catalysts, such transformations of course afford the possibility of achieving enantioselective Heck reactions.

X

LpPd:

X H

L*pd% 3 .

base

1

Scheme I

2

Scheme 2 Mechanism of the Heck reaction

137

ArOTf

3 mol % Pd(OAc), 6 mOl % (R)-BINAP proton sponge benzene. 40 "C, 2-9d +

42 - 66 %

8

9

*

A

r

Q

10 (87- >96 % ee)

7

Scheme 3 I

Intermolecular Reactions While several groups had been working on asymmetric intermolecular Heck reactions [7], Hayashi and Ozawa et al. were the first to report synthetically useful selectivities [S, 91. The reaction of various aryl triflates 8 with 2,3-dihydrofuran (9) proceeds under optimized conditions [9d] with high enantioselectivity (>96 % ee) and leads to (R)-2-aryl-2,3-dihydrofurans 10 with acceptable yields (Scheme 4). As catalyst, an in situ generated Pd-(R)-BINAP complex is used in combination with 1,8-bis-(dimethylamino)-naphthalene (proton sponge), which has been established as the base of choice. The (S)configured regioisomers 11 are often observed as by-products. They can be separated by chromatographic methods and exhibit significantly lower enantiomeric purity than the major products 10 (6-53 % ee). Obviously, the isomerization of the double bond under the reaction conditions (via P-H-insertionlp-H elimination) is accompanied by an additional kinetic resolution.

proton sponge

(R)-BINAP

Scheme 4 a.

4. CH2C12,

0

MeOH, -70"C OMe

94 %

12

13

Scheme 5

The enolethers of type 10 represent useful intermediates for further synthetic use. For example, Reiser and co-workers showed a way to transform the c h i d 2,3 -dihydrofuranderivative 12 by ozonolysis directly to the synthetically valuable P-hydroxyester 13 (Scheme 5) [lo]. The power of their methodology was demonstrated by Hayashi and Ozawa in a remarkably short synthesis of 18, an antagonist of the plate-

3 mol % Pd(OAc), proton sponge benzene, 40 "C

9

Me0

15

14

Meoflm 36 % ab 14

H,,PtO,

c _ _

Me0

100%

18

Meo# Me0

17

Scheme 6 Total synthesis of a PAF inhibitor according to T. Hayashi.

138

C. Enantioselective Cutulysis

Q OWOMe

19

1 I

Et0,C. T f 0 - A

3 mol % Pd(0Ac)Z 6 mol % (R)-BINAP proton sponge benzene. 60 "C. 20 h

K2COJ,Toluol. 60"C,27h 60 %

OTf

95 %

H

26

25

(91 % ee)

_I

21 TBDMSO,

10 mol % PdCI,-(R)-BINAP

PTSDMS

20

Scheme 7

let-activating factors (Scheme 6). Initially, the 2,3-dihydrofuran 9 is reacted under the established conditions with the /I-naphthyl triflate 14 to give 15, which is not isolated but directly reacted in a second Heck reaction with triflate 16 at elevated reaction temperatures. Finally, the double arylated product 17 is hydrogenated to afford the target molecule 18. The method of Hayashi and Ozawa is neither restricted to aryl triflates nor to 2,3-dihydrofuranes. Vinyl triflates can also be employed, and N-(methoxycarbony1)-pyrroline 19 as the olefin component gives even better results. Thus, the reaction of 19 with the enol triflate 20 results in the formation of 21 with excellent yield and almost complete enantioselectivity (Scheme 7) [gel.

Intramolecular Reactions The enantioselective cyclization of prochiral substrates of type 22 to bicyclic products 23 was examined by Shibasaki and co-workers [ 11 - 141. In the presence of BINAP as a chirdl ligand the two enantiotopic double bonds of 22 are differen-

[

H

:-----

2:

...

GPd@

24

Scheme 8

28 (87 % ee)

&

10 mol % PdCI,-(R)-BINAP NMP, 6WC.23-49h

73 - 78 %

29

30 (80 - 86 % ee)

R = COOMe

CH,OAc CH,OTBDMS CH,OPiv

Scheme 9

tiated, and two new chiral centers are generated simultaneously in a single step (Scheme 8). In order to obtain high enantioselectivities it seems to be important that the reactions proceed via cationic intermediates (e.g. 24) to disfavor the partial dissociation of the chiral ligand. For this reason, silver salts are added to reactions of vinyliodides. These reactions are best performed in N-methylpyrrolidone (NMP) as a solvent. As the examples shown in Scheme 9 demonstrate, both cis-decalin [ 121 and cis-hydrindane [ 131 derivatives can be obtained in useful yields and enantiomeric purities. In their search for suitable synthetic applications of their methodology, Shibasaki and coworkers spared no efforts and carried out an 18-step synthesis of lactone 35, which represents an early intermediate of Danichefsky's synthesis of (+)-vernolepin (Scheme 10) [ 141. First, the ester 31 is transformed via 32 into the allylic alcohol 33, which is then cyclized with good enantioselectivities to yield the enone 34 (which is initiallv formed as an en01 bv 8-H-elimination).

a,,,. 1 Pd(O)L,*

22

27

i

l

139

aCozMe m m ,OPiv

1 Cr03 2 NaBH,,CeCI,

5 steps 40 %

HO "'

TfO

31

OPiv /-

32 0 0 -\ 9SteDS

11 mol % (R)-BINAP (CHzC1)z. t-BuOH KzCO,, 60"C, 42 h

76 %

TfO

-

33

,OPiv

m

9 mOl % Pd(0)

=-

34

-

..

35

'0

36

(86 % ee)

(+)-vernolepin

Scheme 10 Formal total synthesis of (+)-vernolepine according to M. Shibasaki.

This (formal) total synthesis of vernolepin deserves attention because of the elegance of the key step, which generates 34 in non-racemic form. However, the long and inefficient overall sequence impairs the competitiveness of the synthesis. Three new chirality centers are formed with high enantio- and complete diastereoselectivity in the course of the reaction of the enol triflate 37 to the bicyclo [3.3.0]octane derivative 38 (Scheme I I ) [15]. In this transformation, the intermediate 39, formed by oxidative addition, leads to the cationic palladium-n-ally1 complex 40, which is finally converted to the isolated product 38 by regio- and diastereoselective nucleophilic addition of an acetate anion. The bicyclic product 38 is of interest as a building block for the synthesis of capnellene sesquiterpenes.

1 7 mol % Pd(OAc& 2 1 mol % (3-BINAP Bu,NOAc. DMSO, 20%;$h *

B

Me

O

A

By converting the enol triflate 41 to the spirotricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantioselective formation of quaternary chiral carbon centers can be carried out through an intramolecular Heck reaction. While the enantioselectivities were only moderate at the beginning [ 161,the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclization of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. Subsequently, Overman and co-workers reported an application of their method in an enantioselective total synthesis of the alkaloid (-)-physostigmine (50), which as an effective acetylcholine esterase inhibitor is of interest for

'

42

41

(45 % ee)

Me

38

37

10 mol % Pd(O)-(Fi-BINAP

4 @OAc

1

60.80 ' C

0 Me

.._..._._.._ t

44

39

Scheme I1

(80% ee)

40

Scheme 12

140

C. Enuntioselective Cutulysis 1 Pd(O)-(s)-BlNAP

CHO

PMP. DMAC. 100°C

45 67 %

Me

48 ( 95 % ee)

46

1

ee)

(>99

Me

cryst 80

Y Me"yo

1 MeNH,-HCI Et3N 2 LiAIH4.THF

'

363 steps %

88 %

S

N

.F M !H e Me

Me

50

49

(-)-physostigrnine

Scheme 13 Total synthesis of (-)-physostigmin according to L. E. Overman.

the treatment of glaucoma, myastenia gravis and Alzheimers desease [ 181. The synthesis (Scheme 13) starts with the coupling of the two readily accessible components 45 and 46 to give the amide 47. The enantioselective Heck cyclization of 47 was then performed using a Pd(0)-(S)BINAP catalyst in the presence of the bulky base 1,2,2,6,6-pentamethylpiperidine(PMP) in dimethylacetamide (DMAC) as solvent. After acidic hydrolysis of the initially formed enol ether to the corresponding aldehyde 48, the enantioselection was completed by a single recrystallization. The conversion of 48 [via (-)-esermethol 491 into the target molecule 50 was accomplished in only a few steps. All in all, the synthesis is remarkably short and efficient, and impressively demonstrates the power of the asymmetric Heck cyclization. It should be pointed out that only the Z-configured

9 Me."

substrates of type 51 react with good selectivities (80 to 90 % ee), while the E-isomers 52 lead to products of much lower enantiomeric purity (< 45 % ee).

Me

Me

Me

Me

51

a;+R

52

As Shibasaki and co-workers demonstrated, tetralin derivatives of type 55 (with a quaternary benzylic carbon center) can also be enantioselectively prepared by an intramolecular Heck reaction (Scheme 14) 1191. Again, the geometry of the double bond proved to be of central importance: while only moderate selectivities were obtained with E-configured SubStrdteS 54, Pd(0)-BINAP-catalyzed reactions of the Z-configured substrates 53 provided the

_ _ - J

? 54

Scheme 14

RO

55

OR

ROAH

56

141

aMe 10 mol % Pd(OAc),

1 TBAF 2. MeNH,. H,, Pto,

(R)-BINAP KzCO,. THF. 60 fC

Me0

OTBDMS 55%

Me0

TBDPSOJ

57

58

%OTBDPS

59 (93% ee)

1. Cr03, AcOH

0

62 (-)-eptazocine

Scheme 15 Total synthesis of (-)-eptazocine according to M. Shibasaki.

products 55 with good yield (79 % to 85 %) and enantioselectivity (87 9%to 91 %). In these reactions, a quaternary chirality center is generated in the insertion step. As a consequence, the P-H elimination of the intermediate 56 can only proceed to one side. This avoids the formation of any undesirable regioisomers. The methodology discussed above was applied by Shibasaki in an efficient total synthesis of (-)-eptazocine, an analgetic compound which contains (like other analgesics such as morphine) a 1,1 -disubstituted tetralin as a substructure (Scheme 15) 1191. Starting from the trisubstituted benzene derivative 57, the prochiral cyclization precursor 58 is prepared in only five steps. In the chirogenic key reaction, 58 is then cyclized to 59 with high enantioselectivity by treatment with a catalyst formed in situ from Pd(OAc), and (R)BINAP. After cleavage of the enol ether, reductive amination and N-acetylation, the resulting intermediate 60 is converted to the tricyclic pre-target compound 61 by benzylic oxidation, amide hydrolysis and Mannich cyclization. The above discussed early work of Overman and Shihasaki had shown that products of type

64 with a quaternary carbon atom in the benzylic position (R' # H) can be prepared by Pd-BINAPcatalyzed Heck cyclization with high enantioselectivity (Scheme 16). It is important to keep in mind that the configuration of the double bond in the starting material 63 severely influences the selectivity of the reaction and that the absolute configuration of the products has to be established in all individual cases. An important further development came from the group of Tietze, who introduced the concept of silyl termination in order to control the regioselectivity of the final P-H elimation step in the case of substrates (63) with R' = H [20]. An example is the transformation shown in Scheme 17, a key step in an enantioselective synthesis of a cytostatic nor-sesquiterpene [20c].

Meoy Pd2(dba)3CHCI~.

Ag3P04, DMF, 48 h.

Me

Me

91% 66 92% ee

Scheme 17

Pdz(dba)3.(R)-BINAP toluene, PMP. 110°C

0 67

Scheme 16

Scheme 18

83%

0 60

90% ee

142

C. Enantioselective Catalysis

Another field was opened by Keay et al., who reported interesting enantioselective tandem cyclizations of polyenes, for instance, the reaction shown in Scheme 18. This chemistry was successfully employed in a total synthesis of (+)-xestoquinone [21]. While BINAP had been used as the sole ligand of choice in the early days of asymmetric Heck chemistry, the introduction of the chiral P,N-Iigand 69 by Pfaltz and co-workes has led to another great improvement of the general methodology [221.

% J

Ph,P

N

. i-Bu

69

The few selected examples shown in Scheme 19 impressively demonstrate the efficiency of the catalyst system derived from 69 and a (halogen-free ! !) Pd source. Interestingly, the reactions employing the Pfaltz catalyst proceed in most cases without concomitant double bond migration.

Conclusion The enantioselective Heck reaction has matured into a powerful method for asymmetric C-C bond formation and has proven its value in several total syntheses. One can expect that it will find many more applications in the future, even in industry. There is still an extensive space for chemists to design new suitable substrates and to search for new effective chiral ligands [23].

3 moi% [cat], (1-Pr),NEt

THF. 70°C. 4 d 87%

(3+Tfon{J'%,o -% 9 3 mol% THF,70"C,7d [cat], (CPr),NEt

*

92% ee

70%

[Pd(dba)~I. CsH,. 80% 69. (cPr)zNEt 5d

/

R

85%ee

R

88% R = COzCH,

&

OTf

H A 0

Pd(OAc),. 69, (i-Pr),NEt toluene, 110°C. 48 h 71%

*%+-&I

2%

HA0 6 1

[cat] = [Pd,(dba), dball69

Scheme 19

87% ee

>99% ee

143

References 11I S. Drenkard, J. Ferris, A. Eschenmoser, Hehi Chim. Actu 1990, 1373. [21 See, for instance: a) I. Ojima (Ed.) Catalytic Asymmetric Synthesis, VCH, New York, 1993; b) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994; c) L. S. Hegedus, Trunsition Metuls in the Synthesis of Complex Organic Molecules (2nded.), University Science Books, Sausalito, 1999. L31 Reviews: a) R. F. Heck, Orgunic Reucrions, 1982, 27, 345; b) R. F. Heck in Comprehensive Organic Synthesis, (Eds.: B. M. Trost, 1. Fleming) Pergamon, Oxford, 1991; Vol. 4, chapter 4.3., p. 833; c) A. de Meijere, F. Meyer, Angew. Chem. 1994, 106, 2437; Angew Chem. Int. Ed. Engl. 1994, 33, 2379; d) M. Beller, T. H. Riermeier, G. Stark in: Transition Metals f o r Organic Synthesis, Mil. I (M. Beller, C. Bolm; eds.), Wiley-VCH, Weinheim 1998, chapter 2.13; and refs. cited therein. [4] K. Ritter, Synthesis 1993, 735. [5] Selected work: a) C. Y. Hong, N. Kado, L. E. Overman, J. Am. Clzem. Soc. 1993, 115, 11028; b) J. J. Masters, D. K. Jung, W. G. Bornmann, S. J. Danishefsky, Tetruhedron Lett. 1993, 34, 7253; c) D. J. Kucera, S. J. OConnor, L. E. Overman, J . Org. Chem. 1993, 58, 5304; d) A.O. King, E. G. Corley, R. K. Anderson, R. D. Larsen, T. R. Verhoeven, P. J. Reider, Y. B. Xiang. M. Belley, Y. Leblanc, M. Labelle, P. Prasit, R. J. Zamboni, J. Org. Chem. 1993, 58, 3731. [ 61 R. C. Larock, W. H. Gong, J. Org. Chem. 1989,54, 2047; and refs. cited therein. [7] a) H. Brunner, K. Krdmler, Synthesis 1991, 1121; b)T. Sakamoto. Y. Kondo, H. Yamanaka, Tetrahedron Lett. 1992, 33, 6845. [S] Review: T. Hayashi, A. Kubo, F. Ozawa, Pure. Appl. Chem. 1992, 64, 42 1. 191 a) F. Ozawa, A. Kubo, T. Hayashi, J. Am. Chenz. Soc. 1991, 113, 1417; b) F. Ozawa, T. Hayashi, J. Organomet. Chem. 1992, 428, 267; c ) F. Ozawa, A. Kubo. T. Hayashi, Chem. Lett. 1992, 2177; d) F. Ozawa, A. Kubo, T. Hayashi, Tetrahedron Lett. 1992, 33, 1485; e) F. Ozawa, Y. Kobatake, T. Hayashi, Tetrahedron Lett. 1993,34,2505. [lo] S. Hillers, A. Niklaus, 0. Reiser, J . Org. Cheni. 1993, 58, 3169. [Ill Overviews: a) M. Shibasaki, C. D. J. Boden, A. Kojima, Tetrahedron 1997, 53, 7371; b) M. Shibasaki, E. M. Vogl, J , Organomet. Chem. 1999, 576, 1 . [I21 a) Y. Sato, M. Sodeoka, M. Shibasaki, 1. Org. Chem. 1989, 54, 4738; b) Y. Sato, M. Sodeoka, M. Shibasaki. Chem. Lett. 1990, 1953; c) Y. Sato, S. Watanabe, M. Shibasaki, Tetrahedron Lett. 1992, 33, 2589.

[ 131 Y. Sato, T. Honda, M. Shibasaki, Tetrahedron Lett.

1992, 33, 2593. 1141 a) K. Kondo, M. Sodeoka, M. Mori, M. Shibasaki, Synthesis 1993,920; b) K. Kondo, M. Sodeoka, M. Mori, M. Shibasaki, Tetrahedron Lett. 1993, 34, 4219; c) K. Ohrai, K. Kondo, M. Sodeoka, M. Shibasaki, J. Am. Chem. Soc. 1994, 116, 11737. I151 a) K. Kagechika, M. Shibasaki, J . Org. Chem. 1991, 56, 4093; b) T. Ohshima, K. Kagechika, M. Adachi, M. Sodeoka, M. Shibasaki, J. Am. Cheni. Soc. 1996, 118, 7108. [I61 N. E. Carpenter, D. J. Kucera, I,. E. Overman, J , Org. Chem. 1989, 54, 5846. II71 a) A. Ashimori, L. E. Overman, D. J. Poon, J. Org. Chem. 1992, 57, 4571; b) A. Ashimori, B. Bachand, L. E. Overman, D. J. Poon, J. Am. Chem. SOC. 1998, 120, 6477; c) A. Ashimori, B. Bachand, M. A. Calter, S. P. Govek, L. E. Overman, D. J. Poon, J. Am. Chern. Soc. 1998, 120, 6488. [I81 a) A. Ashimori, T.Matsuura, L. E. Overman, D. J. Poon, J. Org. Chem. 1993,58,6949; b) L. E. Overman, Pure Appl. Chem. 1994.66, 1423; c) T. Matsuura, L. E. Overman, D. J. Poon, J . Am. Chem. Soc. 1998, 120, 6500. 1191 T. Takemoto, M. Sodeoka, H. Sasai, M. Shibasaki, J. Am. Clzem. Soc. 1993, 115, 8477. [20] a) L. F, Tietze, R. Schimpf, Angew. Chenz. 1994, 106, 1138; Angew. Chem. Int. Ed. Etzgl. 1994, 33, 1089; b) L. F, Tietze, T. Raschke, Synlett 1995, 597; c ) L. F. Tietze, T. Raschke, Liehigs. Ann. 1996, I98 I . [21] a) B. A. Keay, S. P. Maddaford, W. A. Cristofoli, N. G. Andersen, M. S. Passafaro, N. S. Wilson, J. A. Nieman, Can. J . Chem. 1997, 75, 1163; b) S. Y. W. Lau, B. A. Keay, Synlett 1999, 605. 1221 a) 0. Loiseleur, P. Meier, A. Pfaltz, Angew. Chem. 1996, 108, 2 18; Angew Chem. Int. Ed. Engl. 1996, 35, 200; b) 0. Loiseleur, M. Hayashi, N. Schmees, A. Pfaltz, Synthesis 1997, 1338; c) 0.Loiseleur, M. Hayashi, M. Keenan, N. Schmees, A. Pfaltz, J . Organoniet. Chem. 1999,576, 16; see also: d) L. Ripa, A. Hallberg, J. Org. Chern. 1997, 62, 595. [23] a) M. Shibasaki, C. D. J. Boden, A. Kojima, Tetruhedron 1997, 53, 7371; b) F. Miyazaki, K. Uotsu, M. Shibasaki, Tetrahedron Left. 1997, 38, 3459; c) S. Y. Cho, M. Shibasaki, Tetrahedron Lett. 1998, 39, 1773; d) L. F. Tietze, K. Thede, F. Sannicolo, Clzem. Commun. 1999, 181 I ; e) M. Tschoerner, P. S. Pregosin, A. Albinati, Orgunometullics 1999, 18, 670.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Catalytic Asymmetric Aldol Reactions Rolf Kruuss and Ulrich Koert Institut fur Chemie, Humboldt- Universitat, Germany

Carbon-carbon coupling reactions belong to the most important and often hardest steps in organic synthesis. Nowadays, stereoselective C - C bond formations using covalently bound chiral auxiliaries are well known and established [ I ] . Because of economical and ecological requirements, the use of chiral catalysts rather than covalently bound auxiliaries is an urgent necessity [2a]. Apart from oxidation reactions (SharplessJacobsen epoxidation, Sharpless dihydroxylation [2b-d]) and reductions (CBS reduction, catalytic hydrogenation [2e-fl), the number of truly useful and widely applicable enantioselective catalysts is still limited [3]. Therefore asymmetric catalysis for C-C linkage will be important in the future. Especially in the case of the aldol reaction important progress has been made recently [4].

Catalytic asymmetric aldol additions can at present be divided into - the Mukaiyama-type reactions, which can be catalyzed by Lewis acids and Lewis bases, and - the direct methods, where no preconversion of the ketone moiety into a more reactive species is necessary (Scheme 1 ) . In the Mukaiyama aldol reaction an aldehyde (1) reacts with a silyl enol ether (3) under Lewis-acid catalysis to yield the aldol adduct (4). The use of a chiral Lewis acid (L*) offers the opportunity to perform the reaction in an asymmetric manner (Scheme 1) [ 5 ] . If the right reaction conditions are chosen, only a small amount of catalyst is needed. The catalytic cycle is demonstrated in Scheme 2. The aldehyde 1 is activated by coordination of the Lewis acid

a) Mukaiyama-type reactions Lewis acid catalyzed reactions

I

Lewis base promoted reactions chiral phosphoramides

6

R'CHO

*

'R mR2

5

1

A

b) Direct reactions

chiral catalyst A 7 R 2 -

1

L' = chiral Lewis acid

'

Scheme I Different types of catalytic asymmetric aldol reactions.

H30'

O r F

Catalytic Asymmetric Aldol Reuctions

145

1Oa

R2

Scheme 2. Mechanism of the Lewis acid-catalyzed Mukaiyama aldol reaction.

10b

L*forming intermediate 8. Trapping 8 with a silyl enol ether 9 leads to the aldol addition product 5. The open-chain structure 1Oa and the cyclic structure 10b are discussed as transition states in the literature. Release of the Lewis acid L* is the final step of the catalytic cycle.

As one of the first groups, Reetz et al. (61 reported a catalytic Mukaiyama aldol reaction (Scheme 3a) with the chiral aluminum complex 13. However, low yields and a low level of enantioselectivity made this reaction not generally applicable.

toluene - 78 -> 20 O C , 10h H JJ

OMe

4-

yield: 15% 11

12

ee 66%

+oMe %

14

Sn(0Tf)~.EtCN SEt yield: 71%

15

16

syn/anti= 100/0

ee > 98%

18

Scheme 3. Catalytic asymmetric aldol reaction with aluminum- and tin-containing chiral Lewis acids: a) Reetz and b) Mukaiyama.

146

C. Enantioselective Catalysis

1. THF. - 78 OC

,pH FLU

2. n-BudNF. THF Ph

+

vield: 77 %

19

20

22

anti / syn = 94 / 6

anti

ee 82%

20 rnol % Ts

25

Bu

I

& +.^o -+% H

OTMS

1. EtCN, - 78 OC,14h

2. H30'

23

yield: 100 %

24

/

\

26

ee 92%

20 mol %

28 1. EtCN. 0 OC. 4h 2. H30+ ___)

yield: 97 %

19

27

P

syn I anti: 93 I 7 ee 94 %

A chiral Lewis acid derived from Sn(OTf), and the proline derivative 17 has proven to catalyze the aldol reaction effectively. As Mukaiyama et al. [7J demonstrated, a high degree of enantioselectivity was achieved (Scheme 3b). Boron compounds formed the next generation of chiral catalysts (Scheme 4). Masamune [S] was able to use a thioketeneacetal (20) and the chiral boron-based Lewis acid 21 in the stereoselective formation of the anti aldol product 22. Unfortunately, the demand for 20 mol ?hcatalyst was still very high. Corey's group [ 91 reported the successful use of the tryptophane-derived catalyst 25 in an

h

29 syn

v

Scheme 4. Catalytic, asymmetric aldol reaction with boron-containing Lewis acids: a) Masamune, b) Corey and c) Yamamoto.

asymmetric Mukaiyama aldol reaction (23 + 24 26). Tartaric acid is the starting point of the synthesis of acyloxyborane complex 28, introduced by Yamamoto et al. [ 101. With this catalyst the silyl enol ether 27 was converted to syn-umethyl-b-hydroxyketone 29 with high enantioand diastereoselectivities (Scheme 4c). Worth mentioning is the practicable reaction temperature (0 "C) in Yamamoto's example. Chiral titanium Lewis acids belong today to a very promising class of catalysts. In contrast to boron(III), titanium(1V) has the advantageous ability to expand its coordination sphere from tet+

Catalytic Asymmetric Aldol Reactions

-

147

32

0

OTMS -t A S E t

BnoaH

35

OTMS

0

,,,C6AH 15

+

AoMe 34

TMSQ B n O d S E f

ee 94%

31

30

toluene, 0 OC.2h

33

.BUG 1. Et20 kBU - 10 OC.4h 2. B u ~ N FTHF , ___)

moMe

Scheme 5. Catalytic, asymmetric aldol

yield: 72-98% ee 95%

rahedral to trigonal-bipyramidal or even octahedral (Scheme 5). The amount of catalyst can be reduced to 5 mol % using the binaphthyl-derived Ti-complex 32 [ 1 I]. Only 2 mol% of Carreira's [ 121 catalyst 35 is necessary to obtain good yields and high ee values. However, the chiral binaphthyl ligand for 35 is not commercially available. Lewis acid catalysts activate the aldehyde by coordination to the carbonyl oxygen. Shibasaki et al. [ 131 were able to demonstrate that the activation of the enol ether is possible too. The reaction of the aldehyde 37 with the silyl enol ether 38 in the presence of the catalyst 39 proceeds with good, but still not excellent enantioselectivity to yield the aldol adduct 40. Only 5 mol % of the chiral palladium(I1) complex 39 was used (Scheme 6a). Activation of the Pd(I1)-BINAP complex 39 by AgOTf is necessary. Therefore, addition of a small amount of water is important. Better results were achieved by the cationic palladium(I1) complex 41 (Scheme 6b) [ 141. The reaction was performed at 0 "C in 1,1,3,3-

36

reaction with titanium containing chiral Lewis acids: a) Mikami and b) Carreira.

tetramethylurea without any activation of the palladium(I1) complex. NMR-spectroscopic analysis led to the postulation of a mechanism [13] (Scheme 7) involving the formation of a palladium enolate. The neutral palladium(I1) compound 43 is transformed by addition of AgOTf into the cationic complex 44. In the presence of water an exchange of the triflate anion to hydroxide occurs (44 + 45). Finally, the palladium enolate 46 is formed from the palladium complex and the silyl enol ether. C,-Symmetric tridentate bis(oxazoliny1)pyridine-Cu(1l) complexes, introduced by Evans et al., can function as effective chiral Lewis acid catalysts in the Diels-Alder reaction [ 15a]. When applied to catalytic asymmetric aldol reactions [ 1.51, remarkable results were achieved (Scheme 8) [ISa]. Only 0.5 mol % of catalyst 48 was needed for the reaction of 30 with the silylketene thioacetal 47 to yield after deprotection 49 in 99 % chemical yield. The ee values were determined to be 99 %. Today, catalysts

148

C. Enantioselective Catalysis

a)

1. AgOTf, H20, DMF

molecular sieves 4 A

23 OC, 37h

OTMS PhA H + A P h

38

37

2.H30'

OH Ph

Ph

40

ee 73%

1. TMU (1,1,3.3-tetramethylurea) 0°C 2. H ~ O + QH

+

HP 'h

19

Ph

24

0

ee 89%

of type 48 rank in the top position for asymmetric aldol reactions. Compared to the great variety of Lewis acid catalysts for the catalytic asymmetric aldol reaction the field of nucleophilic (Lewis base) catalysts is less explored. This strategy involves the transient activation of the latent enolate equivalent via Lewis base coordination to the silyl enol ether (Scheme 9) [3]. For instance the trichlorosilyl enol ether 50 is able to expand its valency at the silicon atom from four to five and six. It reacts with an aldehyde (51), proceeding through a closed Zimmerman-Traxler-like transition state (54), to give 53 after quenching with saturated aqueous NaHCO, [ 161. A useful synthetic alternative to the Mukaiyama aldol addition is the carbonyl-ene reaction [17]. This reaction of an aldehyde 51 with an enol ether 55, bearing at least one hydrogen atom in the allylic position, under Lewis-acid catalysis, yields a a-hydroxy-enol ether of type 56 (Scheme 10). By use of a chiral Lewis acid (L*) enantioselectivity can be achieved. For the

0

Scheme 6. Palladium-catalyzed

Ph

Mukaiyama aldol reactions according to Shibasaki.

42

carbonyl-ene reaction a cyclic transition state 57 is postulated [ 181. The primary product 56 may be further transformed either into the ketone 58, under acidic conditions, or oxidized to the ester 59 by ozone. The compounds 58 and 59 are the aldol products of the aldehyde 51 with acetone or

+ AgOTf

5

(>p
P

DMF

[(y 1'

OTf-

DMF

43

44

46

45

Scheme 7. Mechanism of the palladium-catalyzed Mukaiyama aldol reaction.

Catalytic Asymmetric Aldol Reactions

-78°C. CH2C12, 12-24h OTMS

2. TBAFnHF

OH

0

BnOU ,,l.

+

B n o d H

S'BU

yield: 99% ee 99%

30

47

49

Scheme 8. Copper(I1)-catalyzed aldol reaction according to Evans.

1 Me

OSiC13

6

CH2C1210.1M l-78'C

+

2. sat. aq. NaHC03

*

51

50

53

R = phenyl: yield 95%; anti/syn, 6511; ee 93% R = (E)-cinnamyl: yield 94%; antikyn, >99/1; ee 88%

O=P(NR2)3 54

Scheme 9. Lewis base-promoted catalytic asymmetric aldol reaction according to Denmark

L'

R I H Yx +'&H

51

55

56

57

2 N HCI Et20

- 5 6

R

58

59

Scheme 10. The carbonyl-ene-reaction: a synthetic alternative to the Mukaiyama aldol reaction.

149

C. Enantioselective Catalysis

150 a)

n

0~~

1.2mol% 35 2.6-Di-tert-butyl-4-rnethylpyridine 0°C.22 h 2.2N HCI I Et20

QH

=

0

II

as solvent

5 mol% 32

hi -I

0

oTMs

CH2C12 0 "C, 30 min

-

QH

-62

27

synlanti = 9 9 / 1 ee 99%

methyl acetate respectively, illustrating the similarity of the Mukaiyama aldol and the carbonylene reactions. In 1995 Carreira et al. [ 191 reported a catalytic variant of the asymmetric carbonyl-ene reaction (Scheme Ila). By treatment of the aldehyde 60 with 2 mol % of titanium catalyst 35, already used in the Mukaiyama aldol reaction, the P-hydroxyketone 61 is formed in quantitative yield and with an excellent re value. Here, the enecompound, 2-methoxypropene, is used simultaneously as solvent in a large excess. The high enantioselectivity is still limited to aldehydes similar to 60; benzaldehyde for instance is converted with an ee of only 66 %. Mikami et al. [18] demonstrated that under Lewis acid catalysis silyl enol ethers, bearing at least one hydrogen atom in the allylic position, form carbonyl-ene products. They succeeded in using the titanium catalyst 32 for the asymmetric catalysis of this reaction (Scheme 11b). If the aldehyde contains an activating substituent, as in the case of the glyoxolate 62, an excess of the enecompound is not necessary. For example, the reaction of 62 with the silyl enol ether 27 to the carbonyl-ene adduct 63 still proceedes with good stereoselectivity, but yields drop to a moderate -value. Besides the Mukaiyama aldol and the carbonylene reactions another successful application of asymmetric catalysis is the nitro-aldol reaction

63

QTMS

carbonyl-ene reaction with titaniumcontaining chiral Lewis acids: a) Carreira and b) Mikami.

(Scheme 12) [20a]. Shibasaki et al. [20b] used a chiral in situ generated lanthanide complex (64) as catalyst. The optically active lanthanide complex 66 is postulated as the basic intermediate, activating the nitromethane as shown in 67. However, in the case of the Mukaiyama aldol addition, lanthanide Lewis acids still give moderate ee values. Worth mentioning are chiral gold complexes [20d, e] as well as chirdl quaternary ammonium fluorides [21], which are used successfully as catalysts in the asymmetric aldol reaction.

Direct Catalytic Aldol Reactions Recent success was achieved in carrying out direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones [22]. No preconversion of the ketone moiety to a more reactive species such as an enol silyl ether or enol methyl ether is necessary. As Scheme 13 shows, reaction of the tertiary aldehyde 68 with methyl-phenyl ketone 69 under catalysis by the barium complex 70 gave compound 71 in a smooth reaction and in quantitative yield [23]. Only 5 mol % of catalyst and 2.0 eq. of the ketone are needed. However, the ee value of 70 % is only moderate. Scheme 14 gives a mechanistic rationale for the role of the barium complex 70. After substitution

Catalytic Asymmetric Aldol Reactions

151

10 rnol %

64

L LaS(O'Bu)g, LiCI. H20 THF, -42OC, 18h -F

H~C-NOP yield: 91%

ee 90%

$"--.

15

65

Scheme 12. Chiral lanthanum complex as catalyst in the asymmetric nitro-aldol 66

(1

reaction according to Shibasaki.

67

( =binaphthyl

5 mol%

X = BINOL-Me andlor DME

70

DME, -20°C

P

A

68

69

+

20h

Ph

yield: 99%

Scheme 13. Barium-catalyzed direct

ee 70%

of X by the aldehyde 51, complex 72 is formed. Here, the barium center acts as a Lewis acid and activates the aldehyde. In the following, the addition of the ketone 69 occurs and 73 is generated. The coordination sphere of the barium atom is expanded from six to seven. Then a Bransted base unit of 73 deprotonates an a-proton of methyl phenyl ketone to yield the intermediate 74. Now the reaction of the aldehyde and the barium enolate takes place in a chelation controlled manner to deliver the aldol product 75. Inspired by enzyme chemistry, Shibasaki et al. [ 241 developed several heterobimetallic asymmetric catalysts [25], displaying both Lewis acidity and Br@nstedbasicity. Best results so far were

71

asymmetric aldol reaction.

achieved with a chiral lanthanum-lithium binaphthoxide complex 78 [24]. Reaction of 76 with ethyl methyl ketone (77) under catalysis by 20 mol % 78 gave 79 with an ee value of 94 % and in 71 % chemical yield. The mechanism is similar to that of the bariumcatalyzed direct aldol reaction (Scheme 16). The reaction commences with deprotonation of the ketone (2) by the Bransted base unit of the catalyst under generation of the enolate 81. After addition of the aldehyde 1 the Lewis acid-base adduct 82 is formed. Then the reaction of the aldehyde and the enolate occurs (82 -+ 83). After release of the aldol product 5 the catalyst 80 is recovered ready for the next cycle.

152

L.

C. Enantioselective Cutalysis

( =binaphthyl X = BINOL-Me andlor DME

X

69

R

74

Scheme 14. Mechanism of the barium-catalyzed direct aldol reaction.

GH +

THF, -20°C.185h

*

Ph

%

76

77

yield: 71% ee 94%

P h + %

79

Scheme 15. Heterobimetallic-catalyzed direct asymmelric aldol reaction.

Catalytic Asymmetric Aldol Reactions

153

R2

H

0-M 80

H

R2

/

82

LA: Lewisacid

M : Metal of Bmnsted

base

R' 0- LA'

5

: chiral ligand

83

Direct methods mentioned above are generally only practicable with tertiary aldehydes. In the case of secondary and primary aldehydes ee values achieved are still too low. Nevertheless, direct methods are important supplementary alternatives to the Mukaiyama-type reactions. Last but not least, the synthetic power of enzymes in this field is noteworthy [26]. Aldolases are c h i d catalysts optimized during evolution, and are able to work in aqueous systems. Only a minimum amount of catalyst is necessary. One example is [26c] the reaction of 29 and 84

Scheme 16. Catalytic cycle of the direct heterobimetallic asymmetric aldol reaction.

with D-fructose- 1,6-bisphosphate aldolase 85 as catalyst with formation of 86 (Scheme 17). Compared to nonbiological catalysts, enzymes often provide products of higher enantiomeric purity. The required amount of catalyst is much lower. Synthetic catalysts however, are often much more widely applicable; their substrate specifity is not as limited as those of their biological counterparts. With regard to their use in complex syntheses, both synthetic and biological catalysts will be indispensable in the future.

OH

84

29

1. fructose-I ,Ci-bisphosphat=e-

yield: 75%

aldolase 85

syn I anti > 99%

(RAMA. EC 4.1.2.13) ee > 99%

16 U aldolase for 13 rnrnol aldehyde 2. phosphatase

OH 86

Scheme 17. Aldol reaction catalyzed by fructose-l,6-hisphosphatealdolase.

154

C. Enantioselective Catalysis

References [I] Methods of Organic Cliemistty, (Houben-Weyl) Additional and Suppl. Vol. of the 4th Edn., Vol E 21b, Stereoselective Synthesis (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Stuttgart, 1995. [2] a) Catalytic Asymmetric Synthesis (Ed.: 1. Ojima), VCH, Weinheim, 1993; b) R. A. Johnson, K. B. Sharpless in a) P. 103; c) E. N. Jacobsen in a) p. 159; d) R. A. Johnson, K. B. Sharpless in a) p. 227; e) E. J. Corey, R. K. Bakshi, B. Shibata, J . Org. Chem. 1988, 53, 2861; f) H. Takaya, T. Ohta, R. Noyori in a) p. I . [3] a) M. Sawamura, Y.Ito in 2a) p. 367; b) K. Maruoka, H. Yamamoto in 2a) p. 413; c) P. Knochel, R. D. Singer, Chem. Rev. 1993, 93, 21 17; d) T. Hayashi in 2a) . 325. 141 For a comprehensive review of catalytic enantioselective aldol reactions: S. G Nelson, Tetrahedron: Asymmetry 1998, 9, 357. [S] a) C. H. Heathcock in Modern Synthetic Methods 1992 (Ed.: R. Scheffold) VHCA, Basel, 1992, p. I . b) K. Narasaka, Synthesis 1991, 1; c) T. Bach, Angew. Chem. 1994,106,433; Angew. Chem. Int. Ed. Engl. 1994, 33, 417; d) T. K. Hollis, B. Bosnich, J . Am. Chem. Soc. 1995, 117, 4570. [6] M. T. Reetz, S.-H. Kyung, C. Bolm, T. Zierke, Cheni. Ind. 1986, 824. [7] S. Kobayashi, Y. Fujishita, T. Mukaiyama, Chem. Lett. 1990, 1455. [8] E. R. Parmee, Y. Hong, 0. Tempkin, S. Masamune, Tetrahedron Lett. 1992,33, 1729; E. R. Parmee, 0. Tempkin, S. Masamune, A. Abiko, J. Am. Chem Soc. 1991, 113, 9365. [9] E. J. Corey, C. L. Cywin, T. D. Roper, Tetrahedron Lett. 1992, 33, 6907. [I01 a) K. Furuta, T. Maruyama, H. Yamamoto, J. Am. Chem. Soc. 1991, 113, 1041; b) K. Furuta, T. Maruyama, H. Yamamoto, Synlett 1991, 439. [ I l l a) K. Mikami, S. Matsukawa, J. Am. Chem. Soc. 1994, 116, 4077. b) G. E. Keck, D. Krishnamurthy, J. Am. Chem. Soc. 1995, 117, 2363. [ 121 E. M. Carreira, R. A. Singer, W. Lee, J. Am. Cheni. Soc. 1994, 116, 8837. [ 131 M. Sodeoka, K. Ohrai, M. Shibasaki, J. Org. Chem. 1995, 60, 2648. 1141 M. Sodeoka and M. Shibasaki, Pure App/. Chem. 1998, 70, 41 I . [ 151 a) D. A. Evans, , J. A. Murry, C. S. Burgey, K. R. Campos, B. T. Connell, and R. J. Staples, J. Am. Chem. Soc. 1999, 121, 669; b) D. A. Evans, C. S. Burgey. M. C. Kozlowski, and S. T. Tregay, J. Am. Chern. Soc. 1999, 121, 686; c) D. A. Evans, T. Rovis, M. C. Kozlowski, and J. S. Tedrow, J. Am. Chem. Soc. 1999, 121, 1994; d) D. A. Evans, D. W. C. MacMillan, and K. R. Campos, J. Am. Chem. Soc. 1997, 119, 10859; e) D. A.

Evans, M. C. Kozlowski, C. S. Burgey, and D. W. C. MacMillan, J. Am. Chem. Soc. 1997, 119,7893; t)D. A. Evans, J. A. Murry, and M. C. Kozlowski, J. Am. Chem. SOC. 1996, 118,5814 and references therein. [I61 S. E. Denmark, S. B. D. Winter, X. Su, and K:T. Wong, J. Am. Chem. Soc. 1996, 118, 7404. [17] D. J. Berrisford, C. Bolm, Angew. Chem. 1995, 107, 1862; Angew. Chem. lnt. Ed. Engl. 1995, 34, 1717. 1181 K. Mikami, S. Matsukawa, J. Am. Chem. Soc. 1993, 115, 7039. [I91 E. M. Carreira, W. Lee, R. A. Singer, J. Am. Chem. Soc. 1995, 117, 3649. [20] a) For a review, see: M. Shibasaki, H. Sasai, T. Arai, Angew. Chern. 1997, 109, 1290; Angew. Chem. Int. Ed. Engl. 1997, 36, 1236; b) H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki, J. Am. Chem.Soc. 1992, 114, 4418; c) K. Uotsu, H. Sasai, M. Shibasaki, Tetrahedron: Asymnzetq 1995, 6 , 71; d) Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108, 6405; e) A. Togni, S. D. Pastor, J. Org. Chem. 1990, 5.5, 1649. [21] T. Shioiri, A. Bohsako, and A. Ando, Heterocycles 1996, 42, 93. (221 For a review on new catalytic concepts for the asymmetric aldol reaction, see: H. Groger, E. M. Vogl, and M. Shibasaki, Chem. Eur: J. 1998, 4, 1137. [23] Y. M. A. Yamada, and M. Shibasaki, Tetruhedron Let. 1998, 39, 5561 [24] N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, and M. Shibasaki, J. Am. Chem. Soc. 1999, 121, 4168 and references therein. [25] For reviews on heterobimetallic catalysts, see: a) Shibasaki et al. in footnote 20a; b) H. Steinhagen, G. Helmchen, Angew. Chem. 1996, 108, 2489; Angew. Chem. Int. Ed. Erigl. 1996, 35, 2339; c) M. Shibasaki, T. Iida, Y. M. A. Yamada, J . Synth. Org. Chem. Jpn. 1998, 56, 344. [26] a) W.-D. Fessner in I ) Chapter 1.3.4.6, p. 1736; b) H. Waldmann, Nuchrichten Chem. Echn. Luh. 1991, 1408; c) M. D. Bednarski, E. S. Simon, N. Bischofierger, W.-D. Fessner, M.J. Kim, W. Lees, T. Saito, H. Waldmann, G. M. Whitesides, J . Am. Chern. Soc. 1989, 111, 627; d) W.-D. Fessner, A. Schneider, H. Held, G. Sinerius, C. Walter, M. Hixon, J. V. Schloss, Angew. Chem. 1996, 108, 2366; Angew. Chem. Int. Ed. Engl. 1996,35,2219; e) G . Zhong, D. Shabad, B. List, J. Anderson, S. C. Sinha, R. A. Lerner, C. F. Barbas 111, Angew. Chem. 1998, 110, 2609; Angew. Chem. Int. Ed. Engl. 1998, 37, 2481.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Binaphthyls: Universal Ligands for Catalysis Tobias Wubnitz and Oliver Reiser Institut ,fur Orgunische Chemie, Universitat Regensburg, Germany

In stereoselective synthesis, the use of chiral catalysts -consisting of metals and chiral ligands - is of central significance. While the periodic table imposes natural boundaries upon the number of available metals, the structural variety of the ligands is only limited by the fantasy of the research scientist. Thus, in 1992 there were already known more than 2000 different chiral ligands [ 11, and their number has been constantly growing ever since. Why does a need for so many different ligands exist? Given a certain metal-catalyzed reaction, in general there exists only one suitable metal, and only in a limited number of cases a number of metals can be used as catalysts. Normally, the catalyst found works about equally well with the whole range of substrates of the reaction concerned. However, within a class of reactions brought about by the chiral ligands, the induced diastereo- or enantioselectivity is found to vary considerably with minor structural alterations of the substrates. Especially research groups that resort to asymmetric catalysis only occasionally and just as a means to an end have to limit their pool to a few chiral ligands, particularly since the latter

(R)-la:X =OH (R)-lb: X = PPh2

(R)-lc:X = OPPh2 X

Figure I

(R)-ld: X = P(O)Ph*

(R)-1h: X = AsPh2

need to be synthesized or acquired for non-negligible amounts of money. It would be required of an ,,ideal" chiral ligand to form chiral catalysts with as many metals as possible, which in turn are able to catalyze a great number of reactions and allow of broad substrate variability without loss of selectivity. There are no such universal ligands yet, but binaphthyls 1 come close to this ideal. The C, axially-symmetric biaryl frame is an excellent transmitter of chiral information, and the possibility of varying the coordination sites X (e. g. la-h) 121 enables the use of a wide range of metals.

Synthesis and Structure of Binaphthyl Compounds The most frequently applied ligands are 2,2'binaphthol (BINOL la) and 2,2'-bis(diphenylphosphino)binaphthyl (BINAP lb). Both antipodes of these compounds are commercially available in enantiopure form, though not at little cost [3]. It is rewarding, therefore, to become acquainted with the syntheses of these compounds, which have been described in detail [4] and have been simplified substantially on the basis of recent publications [ 5 ] . The iron(lI1)-catalyzed dimerization of 2-naphthol (2) to give racemic BINOL (rue)-la succeeds smoothly and on a large scale (Scheme 1). Its resolution can be achieved easily with N-benzylcinchoidinium chloride (3) and yields both (R)- and (S)-la in high enantiomeric excesses. After conversion into the ditriflate 4, enantiopure l a can be coupled with diphenylphosphine (or, in lower yield, with cheaper chlorodiphenylphosphine) in a nickel-catalyzed

156

C. Enantioselective Catalysis

/

2

/

1) MeOH

(lac)-la

2) HCI

t (R)-1a > 99.8%

ee

3

PhpPH

*

NiClpdppe

(/?)-la

Tf20, Pyridin

m

75%

Ph2PCI NiClpdppe / Zn

Scheme 1

-

(R)-1b

52%

reaction which directly affords lb. Hence both the formerly necessary, difficult bromination of (ruc)-la and the costly optical resolution at a later stage of the previously employed synthetic procedure [4] can be dispensed with. What is the distinction of the binaphthyls l a and l b as outstanding ligands for catalysis? On the basis of their pliant structure due to the possibility of rotation about the biaryl axis, a great number of differently sized metal ions can coordinate without significant increase in torsional strain of the resulting complexes. The oxophilic early main-group (e. g. B, Al, Sn) and early transition metals (e. g. Ti, Zr) as well as the lanthanoids (e.g. La, Yb) are especially suited to coordinate BINOL la, whereas l b is generally used to complex transition metals of the Group VIII (e.g. Pd, Rh, Ru). Binaphthyl complexes can normally be prepared by simply mixing the ligand and a metal salt. However, it is not easy to understand the principles upon which these complexes perform as such excellent chiral multiplicators. Difficulties arise since the exact structures of the catalytically active species are unknown in most cases and the depiction of the complexes as [metal-ligand] monomers often represents an unrealistic simplification.

In every case the coordination of a binaphthyltype ligand by a metal atom results in the formation of a seven-membered chelate ring. Due to its backbone of sp2-hybridized carbon atoms, this ring is rigid in conformation and skewed in an unambiguous way, as determined by the chiral binaphthyl unit. In these complexes, the ligand transfers its chirality effectively to the central metal and to other ligands or substrates coordinated by the same center. For example octahedral complexes containing two additional bidentate ligands as in ( S ) - 5 always form only one diastereomer, which exhibits A-configuration.

R

Figure 2

(59-5

Binaphthyls: Universal Ligunds f o r Catalysis

BINAP Catalysts The Ru(I1) complex 5 has proved to be an extremely versatile catalyst in asymmetric reductions of C-C and C - 0 double-bonds (Scheme 2) 161. Suitable substrates generally seem to be those containing a hetero atom for coordination, thus a chelate ring accommodating the ruthenium atom and the moiety that is to be reduced y-uncan be formed. The reduction of a,P- and 8, saturated carboxylic acids to their saturated, optically active analog can be achieved in this way. Especially amino acids can be prepared in high optical purities, e. g. the reduction of 9 affords the phenylalanine derivative 6 with a selectivity of up to 92 % ee. The hydrogenation of geraniol (11) with (R)-5 distinctly demonstrates the necessity of pre-coordination via two functional groups of the substrate: the exclusive product citronellol (8) is obtained in excellent enantiomeric excess and the double bond between C 6 and C 7 remains completely intact. Allyl- and homoallyl alcohols generally can be reduced using (R)-5, but if another methylene group is inserted, the distance

’’

(92% ee)

6

7

between the double bond and the hydroxyl group becomes too large and no hydrogenation occurs. The reduction ofg-ketoesters to aldols is one of the most important applications of Ru(I1)-BINAP catalysts [7]. As a special bonus, the chirally labile C2 stereogenic center can be exploited in a dynamic kinetic resolution such that racemic reactants yield only one of the four conceivable stereoisomers in high diastereomeric and enantiomeric excess. This strategy has been extended to the reduction of 8-ketophosphonates 10. The 3hydroxyphosphonic acids 7 which are accessible by this route constitute promising starting materials for the synthesis of peptide analog and antibiotics 181. Whereas 5 only reacts with bifunctional substrates, a new modification enables the catalytic hydrogenation of simple ketones 13. The ternary catalyst consisting of [Ru(II)-BINAP] and a chiral 1,2-diamine in an alcoholic solution of KOH exhibits an activity more than 1000 times that of (Ru(I1)-BINAP] alone. The products have been obtained with optical purities greater than 99 % ee by choosing a suitable chiral diamine

(94-98% ee)

(96-99% ee)

8

OH 1

up to > 99% ee 14

157

up to > 99% ee

15

Scheme 2

158

C. Enantioselective Cuta1ysi.s CI

CI

(S,S)-DPEN

(S,S)-DPEN

16

18

p-p = (6')or (S)-TolBINAP; S = Solvent, X = CI, H

17

19

in order to increase the enantioselectivity in a "mutched case" situation. Probably the most exciting recent discovery has been that as well as hydrogen, isopropanol can be used as the reducing agent [9]. The concept of asymmetric activation [ 101 has been transferred successfully to [Ru(II)-BINAP] catalysts and chiral diamine auxiliaries (Scheme 3). a$-Unsaturated ketones such as 19 have been hydrogenated in 100 9% yield and 95 % r e using Ru(I1) complexes comprising optically pure (S,S)-diphenylethylenediamineand racemic BINAP analog s [ 1 I]. This surprising result can be explained by the formation of diustereorneric complexes [Ru(BINAP)(diamine)j 16 and 17 exhibiting WS,S- or S/S,S-configuration with re-

20

Scheme 3

spect to the BINAP and diaminc ligand. Under the hydrogenation conditions employed, only one of these coexisting catalysts was significantly activated by the diamine; hence high selectivities are attainable. A highly interesting variation of this concept is the application of achiral, conformatively flexible 2,2- bis(diphenylphosphino)biphenyI-type ligands (BIPHEP) instead of BINAP. Here, the configuration of BIPHEP only becomes fixed when the ligand is incorporated into [Ru(BIPHEP) (diamine)] complexes 21 or 22. In the reduction of 1-acetonaphthone, selectivities up to 92 % ee have been attained exploiting the different catalytic activities of the coexisting diastereomeric complexes thus formed [12].

Binaphthyls: Universal Ligands for Catalysis

3

1

21

22

Scheme 4

Chirality Transfer in Metal-BINAP Complexes The high asymmetric inductions that can be attained in these reductions are above all to be attributed to steric interactions of the substrate with the phosphorus-bound phenyl groups of the [Ru(R)-BINAP] complex (R)-5 (Scheme 5 ) . It can be assumed that hydride, being the smallest ligand, coordinates cis to both phosphine ligands. The P-bound phenyl groups occupy equatorial (parallel to the substrate coordination plane) and axial positions (perpendicular to the substrate coordination plane) with respect to the metal-ligand cycle. The skewed BINAP skeleton requires the equatorial phenyl substituents to protrude directly into two of four coordination quadrants that are accessible to the substrate. The complexation of the substrate occurs in the way that entails the minimal steric interactions with these occupied quadrants. Compared to other C,-symmetric biphosphines, the differentia-

1

tion of the four quadrants is particularly distinct with BINAP due to the bond angles and the rigidity of the composite system. Therefore, a high chiral recognition of prochiral substrates can be achieved (Fig. 3). blocked quadrants

(9-BINAP

(Fn-BINAP

Figure 3

Apart from a few exceptions [ 131, the quadrant model can be employed to predict the asymmetric induction of BINAP complexes. For example, the model can be referred to when considering the reduction ofp-dicarbonyl compounds (Scheme 5 ) . In 24, repulsion between the equatorial phenyl moiety and R' occurs when the substrate adapts the orientation where the keto function is complexed coparallel to the Ru-H bond, which is

1

disfavored

favored

OH 0

UR1

RO

RJ'JOR 25

159

26

Scheme 5

160

C. Enantioselective Catalysis

[Rh(S)-BINAP]C104

acetone 25°C

27

Akl,

28

A\k,,k,

Ph: 60 - 81%ee

4-Me-C6H4: 44% ee 4-OMe-C6H4: 25%ee

Alktert,RCO, SiR3: 87 - > 99% ee

Ph

necessary for the transfer of hydrogen. On the other hand, the coordination of the ester group in 23 is realized via a lone electron pair of the carbonyl group so that the substituent OR does not experience steric hindrance by the phenyl moiety of the BINAP ligand. If the priority is defined as 0 > large substituent (corresponds to R' in this case) > small substituent, the carbonyl group is always attacked from the re face when using (R)-5. The relative stereochemistry between C-2 and C-3 is determined by the structure of a substituent attached to C-2. It can be memorized as a rule of thumb that acyclic P-ketoesters are reduced to syn-aldols and cyclic P-ketoesters are reduced to anti-aldols. This model can also be employed successfully for explaining why the double reduction of 1,3-diketones 12 with 5 affords anti-configured 1,3-diols in high diastereomeric and enantiomeric excess [14]. The quadrant model which has been described for [Ru-BINAP] can normally be applied analogously with [Pd-BINAP] [ 151 and [Rh-BINAP] complexes. A new example for the latter is the hydroacylation of 4-substituted 4-pentenal 27 to 3-substituted cyclopentenones 28 using the [Rh-BINAPICIO, catalyst (Scheme 6). However, the strong dependence of the selectivity upon the nature of the substituents R suggests that stereoelectronic factors have to be taken into account as well [ 161.

Scheme 6

Binaphthyls in Cyclic Transition States Many reactions for forming C-C bonds such as the aldol reaction, the carbonyl-ene reaction or the allylation of aldehydes require the participation of a Lewis acid and proceed through a chair-like transition state in accordance with the Zimmermann-Traxler model. This model can explain the relative configuration of newly formed stereogenic centers, but in the absence of chiral information there can always exist two enantiomeric chair-like structures which govern the absolute product configuration. These transition state structures can be differentiated effectively if binaphthol l a participates in the reaction, e.g. via complexation of a Lewis acid such as titanium, aluminum or boron which coordinates the ligand tetrahedrally. The following model can be used for predicting the asymmetric induction if the metal is fitted directly into the chair-like transition state. If analyzing the metal atom that bears the (S)-la ligand from its front face, it can be seen that both the axial and the equatorial position of the neighboring atom on the left-hand side experience strong steric interactions by the binaphthyl skeleton. Less strong, but nevertheless perceptible, steric hindrance is experienced by the equatorial position of the neighboring atom on the right-hand side. The axial position of the latter atom is the least hindered site, but it is subjected, of course, to the 1,3-diaxial interactions of the chair configuration. The reduction of ketones 29, where S signifies small substituent and L signifies large substituent, by stoichiometric amounts of (S)-BINAL-H 30

Binaphthyls: Universal Ligands for Catalysis (S)-BINAL-H

OH

30 *

S A L

31

29

32

Figure 4

demonstrates that this model can be referred to successfully for prediction of the asymmetric induction [ 171. In the complex 32, the small substituent H is oriented towards the left, and the larger OR appendage to the right of the AI atom. The small and the large substituents of the ketone are positioned axially and equatorially, respectively. It must be noted that the definition of small and large cannot be based solely on steric arguments. On the contrary, the arrangement is dominated by electronic effects because of n-n-interactions between the axial 0 - A l and the substituents of the ketone. Repulsive interactions that occur with n-systems of unsaturated groups such as phenyl, alkenyl or alkynyl make these groups large

'""0

"Bu-

7 1%

100% ee

33

Scheme 7

ee

34

(S)-BINAL 30

161

substituents. The presence of electronic effects becomes obvious with the formation of 34 and 36. Only in the case of very strong n-acceptors such as 4-cyclopent-1 -ene-3-one the repulsive (nn) interaction is surpassed by the attractive (nn*) interaction. Hence the formation of 37 occurs with the opposite absolute configuration to that of 33-36 (Scheme 7). If the metal-binaphthyl complex is not fitted directly into the cyclic transition state, it becomes difficult to explain the asymmetric inductions observed. The following rule seems to be generally valid for both BINOL and BINAP complexes: The complexation of carbonyl or imine moieties by (R)-binaphthyl-metal complexes results in a shielding of the si ,face, the reaction proceeds from the re face. Correspondingly, the opposite principle applies when (S)-binaphthyl complexes are used. All aldol reactions and carbonyl-ene reactions which are catalyzed by binaphthyl complexes abide by this rule [18], and the scheme can also be applied to the addition of ketene-silyl-acetals to imines with boron-BINOL catalysts [ 191. Diels-Alder reactions have been very successfully subjected to asymmetric catalysis by binaphthyl complexes. Accordingly, the synthesis of tetrahydropyranes 41 and 42 can be realized by reaction of glyoxylic esters 39 with methoxydienes 38 (Scheme 8) [20]. Some of these reactions take place with excellent endo-control and

162

C. Enantioselective Catalysis OMe

R' R3

71 bis > 95% ee

E = C02Me

38

39

(R)-40

43

-

41

44

ee

78122to 42 41

L' = (R)-BINOL

z 90%

>98:<2

-

42

45

-

41

up to 99.6 : 0.4 up to 94% ee

46

47

48

enantioselectivity. In complete analogy to the aldo1 and ene reactions mentioned earlier, catalysis with (R)-40 yields both the endo-product 41 via 43 and the em-product 42 via 44, in each case the aldehyde 39 is attacked from the re face. In addition to its ability of shielding the si face of the carbonyl group, the (R)-BINOL complex (R)-40 is also capable of shielding a vicinal double bond from the .same face. Methacrolein 47 is expected to adapt s-truns-configuration and anticomplexation by the titanium catalyst before reacting with the diene 46. In fact, the cyclohexene 48 is obtained with high selectivity. This can be explained on the basis o f t h e transition state 45. The selectivities of the cyloadditions between cyclopentadiene and 2 - bromoacrolein with boronBINOL complexes as catalysts, which have been described by Yamamoto, can also be understood using this model [21].

Scheme 8

Further Applications of Binaphthyls in Homogenous Catalysis The new binaphthyl ligands 49 [22] and 50 [23] have led to a breakthrough in the copper catalyzed 1,4-addition of organozinc reagents to u,p-unsaturated ketones, a reaction which has proved to be difficult if carried out enantioselectively. Selectivities up to 96 % ee have been reached with cyclic substrates, while acyclic substrates still leave room for further improvement. 50 has also been successfully employed in palladium-catalyzed alkylations of ally1 acetates [24]. Finally, a fascinating development in the field of lanthanum-BINOL complexes remains to be mentioned [25]. These compounds so far have proved to catalyze enantioselectively hydrophosphonylations of imines 1261, nitroaldol reactions [27], Michael additions [28] and cpoxidations of

Binuphthyls: Universal Ligands for Cutalysis

163

Ph

BU‘

49

50

Scheme 9

enones [29]. In every case, the direction of asymmetric induction is identical to the titanium-catalyzed aldol and Diels-Alder reactions: if (R)-BINOL is used as ligand, the addition to the imine, to the aldehyde or to the &unsaturated carbonyl compound always occurs from the re face. The hypothesis that the structure of these catalysts is not always in accordance with a monomeric structure has been expressed for both the titanium-BINOL complexes [30] and the corresponding lanthanum species. In the latter case, this hypothesis has been corroborated impres-

sively. The complexes, which are prepared in situ from alkali-BINOL compounds and lanthanum alkoxides, are in fact bimetallic compounds of thc type La-(alkali)3[BINOL],. The complexation of the lanthanum atom by the three BINOL ligands leads exclusively to the formation of the A-diastereomer. Every pair of BINOL ligands is linked via a bridging alkali metal atom, which coordinates the BINOL oxygen atoms. The alkali atoms play an important role in catalytic activity and selectivity. For example, it is assumed that in Michael addition the sodium atom coordinates the

up to 92% ee 42

44

Scheme 10

164

C. Enuntioselective Cutalysis

nucleophile and the central lanthanum atom coordinates the Michael acceptor (Scheme 10). The positions of both substrates are unambiguously determined by the screw-like structure of the complex; therefore, the reactions can proceed with high selectivity. A marvelous, multicolored graphical illustration of these facts can be seen in the original paper 1281. These complexes are the first examples of multifunctional catalysts and demonstrate impressively the opportunities that can reside with the as yet hardly investigated bimetallic catalysis. The concept described here is not limited to lanthanides but has been further extended to main group metals such as gallium [31] or aluminum [32]. In addition, this work should be an incentive for the investigation of other metalbinaphthyl complexes to find out whether polynuclear species play a role in catalytic processes there as well. For example, the preparation of titanium-BINOL complexes takes place in the presence of alkali metals [molecular sieve (!)I. A leading contribution in this direction has been made by Kaufmann et al. as early as 1990 [33]. It was proven that the reaction of (S)-la with monobromoborane dimethyl sulfide leads exclusively to a binuclear, propeller-like borate compound. This compound was found to catalyze the Diels-Alder reaction of cyclopentadiene and methacrolein with excellent em-stereoselectivity and enantioselectivity in accordance with the empirical rule for carbonyl compounds which has been presented earlier. Acknowledgement: The authors would like to acknowledge support from the Fonds der Chernischen Industrie and the Studienstiftung des Deutschen Volkes (fellowship T.W.)

References [ I J H. Brunner, W. Zettlmeier, Hundhook of Enrintioselective Catalysis with Transition metal cornpounds - Ligand.r - References, VCH, Weinheim, 1993, 359. [21 Recent developments: la: E-Y. Zhang, C.-C. Pai, A. S. C. Chan, J . Anz. Chem. Soc. 1998, 120, 5808. lb: H. Suga, T. Fudo, T. Ibata, Synlett 1998, 933. lc: A. Kojima, C. D. J. Boden, M. Shibasaki, Tetrahedron Lett. 1997, 38, 3459.

[3] Approx. prices per mmol - BINOL: 35 Euro, B1NAP: 300 Euro. [4] a) J. Jaques, C. Fouquey in Organic Synthwis (ed.: B . E . Smart), Organic Synthesis, Inc., 1988, 67, I ; b) H. Takaya, S. Akutagawa. R. Noyori, ;hid 1988, 67, 20; c) L. K. Truesdale, ihid. 1988, 67, 13. [S] a) D. Cai, B. L. Huges, T. R. Verhoeven, P. J . Reider, Tetrahedron Lett. 1995, 44, 7991; b) D. Cai, J . F. Payack, D. R. Bender, D. L. Hughes, T. R. Verhoeven, P. J. Reider, J. Orx. Clzem 1994, 59, 7180; c) D. J. Ager, M. B. East, M. Eisenstadt. S. A . Laneman, Chern. Commun. 1997, 2359. [6] R. Noyori, H. Takaya, Acc. Clzenz. Res. 1990,23, 345. [7] R. Noyori, M. Tokunaga, M . Kitamura, Bull. Clzenz. SOL:Jpn. 1995, 68, 36. [ X I K. M. Tokunaga, R. Noyori, J . Am. Chem. Soc. 1995, 117, 2675. [Y] a) T. Ohkuma, H. Ooka, S. Hashigushi, T. Ikariya, R. Noyori, J . Am. Clzem. Soc. 1995,117, 2675; b) T. Ohkuma, H. Ooka, M. Yamakawa, T. Ikariya, R . Noyori, J . Org. Chem. 1996, 61, 4872; c) K.-J. k, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. Int. Ed. 1997, 36, 285; d ) T. Okuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Kunihiko, Y. Eijii, T. Ikariya, R. Noyori, 1.Anz. Chem. SOC.1998, 120, 13529. [ 101 a) J . W. Faller, J . Parr, J. Am. Chem. Soc. 1993,115, 804; b) K. Mikami, S. Matukawa, Nature 1997, 385, 613. [ I l l T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M. Terada, R. Noyori, J . Am. Chem. Soc. 1998, 120, 1086. [I21 K. Mikami, T. Korenaga, M. Terada, T. Ohkuma, T. Pham, R. Noyori, Arzgew. Chem. Inr. Ed. 1999,38, 495. 131 A. Miyshita, A. Yasuda, T. Souchi, R . Noyori, Tetrahedron 1984, 117, 2931. 141 M. Kitamura, T. Ohkurna, S. Inoue, N. Sayo, H. Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya, R. Noyori, J. Am. Chem. SOC.1988,110,629. 151 a) T. Hayashi in Organic Synthesis in Japan - Past, Present, and Future (ed.: R. Noyori), Tokyo Kagak u Dozin, Tokyo, 1992, 105; b) K. Ohrai, K. Kondo, M. Sodeoka, M. Shibasaki, J . Am. Clzem. Soc. 1994, 116, 11737. [I61 R. W. Barnhart, X. Wang, P. Noheda, S. H. Bergens, J. Whelan, B. Bosnich, J. Am. Chenz. Soc. 1994, 116, 1821. [I71 a) R. Noyori, 1. Tomino, M. Yamada, M. Nishizawa, J. Am. Chem. Soc. 1984, 106, 6709; b) R. Noyori, 1. Tomino, M. Yamada, M. Nishizawa, ihid. 1984, 106, 6717. [181 U. Koert, Nuchr: Chem. Ech. Lah. 1995,43, 1068. [I91 K. Ishihara, Y. Kuroki, H. Yamamoto, Synlrrr 1995, 41.

Binuphthyls: Universal Ligunds for Catalysis 1201 K. Mikami, Y. Motoyama, M. Terada, J. Am. Chem. Soc. 1994, 116, 2812. [21] K. Ishihara, H. Yamamoto, J. Am. Chenz. Soc. 1994, 116, 1561. 122) B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos, A. H. M. de Vries, Angew. Chem. lnt. Ed. 1997,36, 2620. 1231 A. K. H. Knobel, I. H. Escher, A. Pfaltz, Svnlett 1997, 1429. [24] R . Pretot, A. Pfaltz, Angew. Chem. Int. Ed. 1998, 37, 323. [25] M. Shibasaki, H. Sasai, T. Arai. Angew. Chem. fnt. Ed. 1997, 36, 1237. [ 261 H. Sasai, S. Arai, Y. Tahara, M. Shibasaki. J. Org. Chern. 1995, 60, 6656. 1271 a) H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, J. Org. Chem. 1995, 60,

165

7388; b) H. Sasai, T. Suzuki, S. Arai, M. Shibasaki, J. Am. Chem. Soc. 1992, 114, 4418. [28] a) H. Sasai, T. Arai, Y. Satow, K. N. Houk, M. Shibasaki, J. Am. Chenz. Soc. 1995, 117, 6194; b) M. Shibasaki, H. Sasai, T. Arai, T. Iida, Pure Appl. Chcm. 1998, 70, 1027. 1291 M. Bougachi, S. Watanabe, T. Arai, H: Sasai, M. Shibasaki, J . A m Chem. Soc. 1997, 119, 2329. 1301 G. E. Keck, D. Krishnamurthy, J. Am. Chem. SOC. 1995, 117, 2363. [31] a) E. M. Vogl, S. Matsunaga, M. Kanai, T. Iida, M. Shibasaki, Tetrahedron Lett. 1998, 39, 7917. b) T. Iida, N. Yamarnoto, S. Matsunaga, H.-G. Woo, M. Shibasaki, Angew, Chem. Int. Ed. 1998, 37, 2223. [32] a) T. Arai, H. Sasai. K. Yamaguchi, M. Shibasaki, J. Am. Chern. SOC. 1998, 120, 441; b) S. Yamasaki, T. Iida, M. Shibasaki, Tetrahedron Lett. 1999, 40, 307.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Fluorotitanium Compounds - Novel Catalysts for the Addition of Nucleophiles to Aldehydes Rudolf 0. Duthaler Pharma Research, Novartis Pharma AG, Basel Switzedand

Andreas Hafner Consumer Care Division CIBA SPECIALTY CHEMICALS, Basel, Switzerland Transformations involving chiral catalysts most efficiently lead to optically active products. The degree of enantioselectivity rather than the efficiency of the catalytic cycle has up to now been in the center of interest. Compared to hydrogenations, catalytic oxidations or C-C bond formations are much more complex processes and still under development. In the case of catalytic additions of dialkyl zinc compounds[ I], allylstannanes [2], allyl silanes 131, and silyl enolethers [4] to aldehydes, the degree of asymmetric induction is less of a problem than the turnover number and substrate tolerance. Chiral Lewis acids for the enantioselective Mukaiyama reaction have been known for some time [4a - 4c], and recently the binaphthol-titanium complexes 1 [2c - 2e, 2jl and 2 [2b, 2i] have been found to catalyze the addition of allyl stannanes to aldehydes quite efficiently. It has been reported recently that a more active catalyst results upon addition of Me,SiS(i-Pr) [2k] or Et,BS(i-Pr) [21, 2m] to binaphthol-Ti(1V) preparations. Most desirable, however, would be chiral catalysts for the addition of the more readily available and less toxic allyl silanes, but so far the efforts towards an enantioselective variant of the Sakurai-Hosomi reaction have been less successful. Some time ago Ketter and Herrmann [3a] obtained 24 % ee for the addition of ally1 silane to aldehydes catalyzed by the dichlorotitanate 1. r 1

X = ,-Pro

2

x=cI

3

X =F

TI-O-TI bridged oligomer

TI-F-TI brajged oligomer’

Better results (80 % ee) have been reported by Mikami, Nakai and co-workers [3c] for the addition of crotyl silane also catalyzed by complex 1. Yamamoto and co-workers [3b] used chiral acyloxy boranes to catalyze the Sakurai-Hosomi-reaction. While an excellent 96 9% ee was obtained for the addition of 2,3-disubstituted allyl groups, the conversion with parent allyl silane was low (46 %) and the asymmetric induction mediocre (55 % ee). Gauthier and Carreira [5] then made a big leap forward by using the difluorotitanium-binaphthol complex 3. The catalyst 3 is prepared in situ via the TiF,-binaphthol adduct 4 and formal H F elimination mediated by ally1 silane 5 . The addition of 5 to aldehydes 6 (-+ 7) catalyzed by 10 % of 3 proceeds with 61 -94 % ee and good yields (69-93 %), the best results being observed for aldehydes with tertiary alkyl residues (Scheme 1). The prerequisites for enantioselective catalysis of the Mukaiyama reaction with chiral metal complexes have been thoroughly analyzed by Hollis and Bosnich [4a] (see also [4b,c]). They are depicted in Scheme 2 for the Sakurai-Hosomi reaction with a titanium catalyst: ( I ) the Lewis acid should form a complex 8 with the aldehyde, rather than being transformed to an allyltitanium compound by reaction with allyl silane 5. (2) The T i - 0 bond of intermediate 9 should be comparatively weak, thus enabling direct conversion to the 0-silylated adduct 7 with regeneration of catalyst 10 according to the variant “A”. In the case of pathway “B” a titanated product 11 is formed together with Me,SiX 12. For X = CF,SO, 12 is an excellent catalyst for the allylsilylation, proceeding to racemic product 7. In most cases catalysis by 12 is indeed much faster than the me-

Fluorotitunium Compounds - Novel Cutulysts for the Addition of Nucleophiles to Aldehydes

1

H'R

+

10% 3

167

OSiMe,

______r_

CYCI,/CH,CN

%SiMe3

\

R-

0 oc

5

7 R=Ph 80%ee R = t-Bu 94% ee R = Ph(Cfi~h61% ee

L

2 Propene

J 4

tathesis of 11 and 12 to product 7 and chiral catalyst 10. We have been able to document such a metathesis by treating the primary product 13 of the allyltitanation of benzaldehyde by 14 either with Me3SiBr or Me,SiI in toluene, whereby the silylether 15 and the titanium halogenide 16 are formed. In a stepwise manner 16 (or chloride 17) can be converted back to the allyltitanium reagent 14 by reaction with allyl-Grignard, allowing the one-pot conversion of a further batch of benzaldehyde [6]. Interesting in this context are recent reports on the Mukaiyama reaction catalyzed by copper complexes. By working in hydroxylic solvents the achiral pathway can be suppressed, as any trimethylsilyl triflate is hydrolyzed [4d]. Carreira and co-workers, on the other hand, postulate formation of a Cu enolate in a copper-catalyzed addition of a silyl dienolate. The catalytic cycle would have to include silylation of the Cu-aldolate by the silylenol ether, thereby regenerating the Cu-enolate [4e, 4fl. As put forward by Gauthier and Carreira [ 5 ] , the special nature of the titanium fluoride bond is decisive for the catalytic properties of complex 3. Because of the extreme electronegativity of fluorine the Ti-F bond is highly polar and, hence, also very strong. A characteristic feature

Scheme I

of fluoride ligands, as opposed to chloride and oxido substituents, is the high tendency to bridge metal centers. This has been well documented by Roesky, Noltemeyer, and co-workers [7] with numerous crystal structures. Quite analogous to the allylstannane addition catalyzed by alkoxide 1 [2c - 2e, 2j], the asymmetric induction observed with complex 3 exceeds the optical purity of the binaphthol ligand [ 5 ] . This is explained by aggregate formation (see also [2d, 2iJ) and the crystal structure of 1, which reveals oligomer formation by Ti-0-Ti bridging [81. Based on the many structures of titanium fluorides [7] it would, on the contrary, be astonishing if the fluoride 3 was not aggregating via Ti-F-Ti bridging. One could therefore envisage, that, starting from dimer 18, a ternary transition state 19 is responsible for the catalytic Sakurai-Hosomi reaction, whereby the electrophilic titanium center activates the aldehyde, while at the same time the nucleophilic fluoride bridges to silicon and thereby increases the reactivity of the allylsilane. It is known that pentacoordinated, negatively charged ally1 siliconates add without Lewis acid to aldehydes [9]. The adduct 20 as the primary product could then fragment to the silyl ether 7, and catalyst 18 would be regenerated. Direct catalysis by

168

C. Enantioselective Cutalysis

7

11

I Toluene

PhW

f 17

X=CI

16

X=Er,I

13

15

dimer 18 or higher oligomers is also possible (cf discussion in [2d, 2il). We speculated earlier whether a fluoride ligand could add catalytic properties to our chiral dialkoxy cyclopentadienyltitanium complexes. Chlorotitanium-TADDOLate 17 - an excellent template for controlling the stereochemistry of stoichiometric additions also to chiral aldehydes [ 101 - could easily be transformed to the comparably inert methyltitanium derivative 21, isopropoxide 22, and trifluoromethylsulfonate 23. However, the preparation of fluoride 24 turned out to be rather tricky [ 1 I]. We finally succeeded when a new method developed by Roesky and coworkers [7a,b] appeared, allowing a clean conversion of chloride 17 to 24 with Me,SnF (Scheme 4) [ 111. An X-ray analysis revealed that the fluoride 24 is monomeric in the crystal and also nearly congruent with chloride 17, except for the

Scheme 2

Ti-F bond [182.5(5) pm], which as expected is shorter than the Ti-CI bond of 17 [228.4(3) pm] [ 121. We were of course interested in the catalytic properties of 24 in comparison with triflate 23. In the presence of 23, allylsilane 5 adds smoothly to benzaldehyde; the product is, however, racemic. Most probably the catalyst is trimethylsilyl triflate, which is formed according to pathway "B" (Scheme 2, c j [4a]). On the contrary, no reaction between benzaldehyde and ally1 silane 5 is observed in the presence of fluoride 24. As we observed earlier, all cyclopentadienyltitanium TADDOLates studied catalyzed the conversion of benzaldehyde 25 with salt-free (i-PrO),TiCH, 26 to 2-phenylethanol 27 [ 1 I]. In this case the titanium fluoride effect was indeed very pronounced, as at -78°C 0,s % of 24 afforded 60 % of product 27 in 17 h with 78 % ee; with 2 % of 24 the induction is 93 % ee.

Fluorotitunium Compounds - Novel Cutul.ysts for the Addition of Nucleophiles to Aldehydes

I69

r-7 RUH

-SiMe,

+

J

L

18 (dirner of 3)

2

OSiMe,

\

-R

\

R 7

20

Scheme 3

Q

Me,SnFIToluene

I

TI

GP

Ph

I

TI 17 X = C I

21 X=CH, Ph P h % L

22

X =t-PrO

24

,

I

0 PhKH 25

I

o-&

Ph

23

-

(i-PrO),TiCy (i-PrO),TCy (26) CH,CI,

I

9 H OH PhA%

I

I I

AoA L O A T \

2 0 mol% 24

93% ee(77%) 27

0 5 mol% 24

70% ee (60%)

@ ' >

Ph Ph

I

r

28

OH R*CH,

30 (54 - 85% ee) 27 (R = Ph) 80 % ee

Fluoride 24 thus by far outperforms the analogous complexes, as 27 of only 40-60 % ee is obtained in the presence of 10 % of 17, and also 21-23 [ 111. The reaction of 26 with aldehydes can also be catalyzed by titanate 28 lacking the cyclopentadienyl ligand. In this case, how-

Scheme 4

ever, 20 % or even stoichiometric amounts of catalyst were used [13]. For comparison we have tested complex 28 under comparable conditions. With 0.5 % of 28 only 6 % of benzaldehyde 25 was converted to product 27 [ 1 1 1. Originally we hoped for high versatility and substrate toler-

170

C. Enantioselective Catalysis

ance of fluoride 24. However, with complex aldehydes such as glyceraldehyde acetonide no conversion with (i-PrO),TiCH, was observed. Recently Pagenkopf and Carreira reported that the addition of trimethyl aluminum to aldehydes can be catalyzed by the putative difluorotitaniumTADDOLate 29, giving secondary alcohols 30 of moderate enantiomerical purity (Scheme 4) [ 141. In accordance with structural studies by Roesky, Noltemeyer, and co-workers [ 151 a fluoride bridging titanium and aluminum is postulated for the transition state. As exemplified by the reactions of Schemes 1 and 4, fluorotitanium compounds could open new possibilities for metal-catalyzed processes. Their fascinating structural diversity [7] as well as further catalytic possibilities in the field of olefin polymerizations [7i, 161 have been put forward by the pioneering work of Roesky, Noltemeyer and co-workers. Similar properties were also exhibited by the analogous zirconium and hafnium compounds [7b,i]. A Zr binaphtholate has already been successfully applied for the enantioselective allylstannylation of aldehydes [2fl. Buchwald and co-workers successfully used a chiral titanocene difluoride as precursor for the corresponding Ti(II1) hydride, a very efficient catalyst for the enantioselective hydrosilylation of imines [171.

References: [ I 1 K. Soai, S. Niwa, Chem. Rev. 1992, 92, 833-856.

121 a) J.A. Marshall, Y. Tang, Synlett 1992, 653 - 6.54; h) A.L. Costa, M.G. Piazza, E. Tagliavini, C. Trombini, A. Umani-Ronchi, J . Am. Chenz. Soc. 1993, 115, 7001 - 7002; c) G.E. Keck, K.H. Tarbet, L.S. Geraci, ihid. 1993, 115, 8467 - 8468; d) J.W. Faller, D.W.I. Sams, X. Liu, ibid. 1996, 118, 1217 - 1218; e) R. Briickner, St. Wcigand, Chemistry, A European Journul 1996, 2, 1077 1084: t) P. Bedeschi, S. Casoiari, A.1,. Costa, E. Tagliavini, A. Umani-Ronchi, Tetmhedron Lett. 1995, 36, 7897 - 7900. g) A. Yanagisawa, H. Nakashima, A. Ishiba, H. Yamamoto, J. Am. C/iern. Soc. 1996, 118, 4723 - 4724. h) A. Yanagisawa, A. Ishiba, H. Nakashima, H. Yamamoto, S?.nlett 1997, 88 90. i) P.G. Cozzi, E. Tagliavini, A. Umani-Ronchi, Gozz. Chim. I m l . 1997, 127, 247 - 254. j ) G.E. Keck. T. Yu, Org. Lett. 1999, I , 289 - 291. k) Ch.-M. Yu, H . 4 . Choi, W.-H. Jung, S.-S. Lee, Tetrulzedron Lett. 1996, -

37, 7095 - 7098. 1) Ch.-M. Yu, H.-S. Choi, W.H. Jung, H.-J. Kim, J. Shin, Chem. ~ o m m u n . 1997, 761 - 762. m) Ch.-M. Yu, S.-K. Yoon, H.S. Choi, K. Baek, ibid., 763 - 764. [3] a) A. Ketter, R. Herrmann, Z. Nariirforsch B, Chern. Sci. 1990, 45, 1684-1688; b) K. Ishihara, M. Mouri, Q. Gao, T. Maruyama, K. Furuta, H. Yamamoto, J . Am. Chem. Soc. 1993,115, 11490 - 1149.5: c) S. Aoki, K. Mikami, M. Terada, T. Nakai, E t r a hedron 1993,49, 1783 - 1792. 141 a) The most important catalysts for the Mukaiycrma-reaction are cited in: T.K. Hollis, B. Bosnich, J. Am. Chem. SOC. 1995, 117, 4570 - 4581; h) E.M. Carreira, R.A. Singer, Tetrahedron Lett. 1994, 35, 4323 - 4326; c) S.E. Denmark, Ch.-T. Chen, ibid. 1994,35, 4327 - 4330. d) Sh. Kobayashi, S. Nagayama, T. Busujima, Tetmhedron 1999, 55, 8739 - 8746. e) J. Kriiger, E.M. Carreira, J. Amer: Chem. SOC. 1998, 120, 837 838. f] B.L. Pagenkopf, J. Kriiger, A. Stojanovich, E.M. Carreira, Angew. Chem. 1998, 110, 3312 - 3314; Angew. Chem., Int. Ed. Engl. 37, 3124. [ S ) D.R. Gauthier, Jr., E.M. Carreira, Angew. Chern. 1996, 108, 2521 -2523: Angew. Clzem., lnt. Ed. Engl. 1996, 35, 2363-2365. [6] A. Hafner, unpublished results. [7] a) A. Herzog, E-Q. Liu, H.W. Roesky, A. Demsar, K. Keller, M. Noltemeyer, F. Pauer, Orgcmometczll i c . ~1994, 13, 125 1 - 1256: h) E.F. Murphy, P. Yu, St. Dietrich, H.W. Roesky, E. Parisini, M. Noltemeyer, .I. Chem. soc., Dalton Trans 1996, 1983 1987; c) H.W. Roesky, M. Satoodeh, M. Noltemeyer, Angew. Chem. 1992, 104, 869 - 870; Angew. Chem., lnt. Ed. Engl. 1992, 31, 864 - 866; d) E-Q. Liu, H. Gornitzka, D. Stalke, H.W. Roesky, ibid. 1993, 105,441 - 448; lnt. Ed. Engl. 1993, 32, 442 - 444; e) H.W. Roesky, I. Leichtweis, M. Noltemeyer, Inorg. Chem. 1993, 32, 5102 5104; f) F.-Q. Liu, A. Kuhn, R. Herhst-lrmer, D. Stalke, H.W. Roesky, Angew. Clzem. 1994, 106, 577 - 578; Angew. Chern., Int. Ed. Engl. 1994, 33, 555 - 556; g) E-Q. Liu, D. Stalke, H.W. Roesky, ihid. 1995, 107, 2004 - 2006; hit. Ed. Engl. 1995, 34, 1872 - 1874; h) A. Kunzel, H.W. Roesky, M. Noltemeyer, H.-G. Schmidt, J. Chem. Soc., Chem. Cotnnzun. 1995, 2145-2146: i ) S.A.A. Shah, H. Dorn, A. Voigt, H.W. Roesky, E. Parisini, H.-G. Schmidt, M. Noltemeyer, Orgnnonzetallies 1996, 15, 3 176 - 3 I8 1. j) E.F. Murphy, R. Murugavel, H.W. Roesky Clieni. Rev. 1997,97,3425 3468. k) H.W. Roesky, I. Haiduc J. Chem. Soc., Dulton Trans. 1999, 2249 - 2264. 181 a) C.A. Martin, Ph.D. Thesis, Massachusctts Institute ofTechnology, 1988; h) R.O. Duthaler, A. Hafner. Chcm Rev. 1992, 92, 807 - 832 (Chart 11). 191 a) T. Hayashi, Y. Matsumoto, T. Kiyoi, Y. Ito, Sh. Kohra, Y. Tominaga, A. Hosomi, Tetmhedron Lett. 1988, 29, 5667-5670; b) M. Kira, K. Sato, H. Sa-

Fluorotitanium Compounds

-

Novel Catalysts for the Addition of Nucleophiles to Aldehydes

kurai, J . Am. Chem. Soc. 1990, 112, 257 - 260; c) M. Kira, K. Sato, H. Sakurai, M. Hada, M. Izawa, J. Ushio, Chenz. Lett. 1991, 387 - 390. [lo] R.O. Duthaler, A. Hafner, P.L. Alsters, P. RotheStreit, G. Rihs, Pure Appl. Chem. 1992, 64, 1897- 1910. [ I l l R.O. Duthaler, A. Hafner, P.L. Alsters, M. Tinkl, unpublished results, partially presented e.g. at the Seventh IUPAC Symposium on Organo-Metallie Chemistry directed towards Organic Synthesis, Sept. 19 - 23, 1993, Kobe (Japan). [I21 G. Rihs, unpublished results. 1131 a) D. Seebach, D.A. Plattner, A.K. Beck, Y.M. Wang, P. Hunaiker, W. Petter, Helv. Chim. Actu 1992, 75, 2171 - 2209 (Scheme 3); b) B. Weber, D. Seebach, Tetrahedron 1994, 50, 7473 - 7484; c) Y.N. Ito, X. Ariza, A.K. Beck, A. Bohac, C. Ganter, R.E. Gawley, F.N.M. Kuhnle, J. Tuleja, Y.M. Wang, D. Seebach, Helv. Chim. Actu 1994, 77, 2071 - 2110 (Scheme 7 4 .

171

[ 14) B.L. Pagenkopf, E.M. Carreira Tetrahedron Lett.

1998, 3Y, 9593 - 9596. 1151 a) P. Yu, H.W. Roesky, A. Demsar, Th. Albers, H.G. Schmidt, M. Noltemeyer, Angew. Chem 1997, 109, 1846 - 1847; Arzgew Chem., Int. Ed. Engl. 36, 1766. b) H. Wessel, M.L. Montero, C. Rennekamp, H.W. Roesky, P. Yu, I. Us6n Angew. Chem. 1998, 110,862 - 864; Angew. Chem., Int. Ed. Engl. 37, 843. [I61 a) W. Kaminsky, S. Lenk, V. Scholz, H.W. Roesky, A. Herzog, Mucrornolecules 1997, 30, 7647 7650. b) P. Yu, P. Muller, M.A. Said, H.W. Roesky, I. Uson, G. Bai, M. Noltemeyer, Organornetullies 1999, 18, 1669 - 1674. 1171 X. Verdaguer, U.E.W. Lange, M.T. Reding. 3 . L . Buchwald, J. Amel: Chem. SOC. 1996, 118, 6784 - 6785.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Enzymes and Transition Metal Complexes in Tandem - a New Concept for Dynamic Kinetic Resolution Rainer Stiirmer BASFAG, Ludwigshafen, Germany

The resolution of racemic compounds mediated by enzymes has become a valuable tool for the synthesis of chiral intermediates. In most cases, however, only one enantiomer of the intermediate is required for the next step in the synthesis; thus, the unwanted isomer must be either discarded or racemized for reuse in the enzymatic resolution process. Dynamic kinetic resolution is one way of avoiding this problem: the unwanted enantiomer is racemized during the selective enzymatic process and serves as fresh starting material in the resolution.

-

This concept has been known for a long time in pure enzymatic synthesis, e.g. amino acid synthesis via hydantoins [ I ] or oxazolidinones (21. Cyanohydrins [3] and lactols [4] are prone to in situ racemization as well and may serve as substrates in kinetic resolutions. Dynamic kinetic resolution is well known in pure chemical synthesis, as illustrated by work by Noyori et al. on the asymmetric hydrogenation of a-substituted P-ketoesters. Noyori et al. [ 5 ] , Ward [6] and Caddick et al. [7] have reviewed the chemical syntheses, and biocatalytic routes have been discussed by Faber et al. [S].

enzyme

OAc

R’?R1

OH

TI

Pd-catalyzed racemisation

\

R-’

R’*

R’

OAc

R’ OH

Scheme 1. Pd-catalyzed racemization of an allylic acetate [8]. 0

racernate

catalyst

Scheme 2. Racemization of a secondary alcohol 191.

Enzymes arid Trcrnsition Metal Complexes in Tundem - a New Concept f . r Dynamic

6-

5mol% PdCI,(MeCN), _______)

0. I M phosphate buffer Lipase from Pseudomonos Fliiorescens

8 I % , 96 % ee

Williams et al. have now demonstrated the compatibility of enzyme and transition metal complexes in one reaction vessel. Two examples illustrate the concept: first a palladium-catalyzed racemization 191 of an allylic acetate in the presence of a hydrolase (Scheme I), and second the racemization of a secondary alcohol [ l o ] through Oppenauer oxidation I Meerwein-Ponndorf-Verley reduction with concomitant acylation of one enantiomer with a lipase from Pseudomonas fluorescens (Scheme 2). To utilize these reactions, a few conditions must be met. A selective enzyme is crucial and the metal-organic catalyst must facilitate a fast racemization of the substrate. Last but not least the catalyst should not influence the enzyme in terms of selectivity and reactivity. In the ideal case the enzyme hydrolyzes one enantiomer of the allylic acetate, giving rise to the allylic alcohol, which itself is not susceptible to Pd-catalyzed racemization. Scheme 3 provides a specific example of the enzymatic hydrolysis outlined in Scheme 1. The substituted allylic acetate is hydrolyzed with a lipase from Pseudomonas Juorescens in a phosphate buffer in the presence of 5 mol% palladium complex. After 19 days the conversion is 96 % (yield is 8 I %), and the enantiomeric excess reaches 96 %. The rate-determining step is most likely the slow Pd-catalyzed step, since SO % conversion is achieved after only two days. A more active vinylacetate. lipase lroiii Pveu~Ior,,~ionu.s flitnre.sceii,s

173

Scheme 3. Specific example of the racemization shown in Scheme I ,

metal complex has yet to be identified for a more practical reaction. The reaction time in the second example (Scheme 4) is rather long as well; the rate-determining step is again the metal-catalyzed racemization. After 6 days the conversion is 76 % with 3 mol % [Rh(COD)CI], and the enantiomeric excess reaches 80 %. Theoretically, in a simple kinetic resolution the ee value should not exceed 32 % at this specific conversion. In addition to the rhodium complex, this reaction requires acetophenone as stoichiometric hydride acceptor, phenanthroline as coligand and potassium hydroxide as base. An ee value of 98 % at 60 % conversion (theoretical value 67 %)is achieved with [Rh,(OAc),] without an added base after 3 days. Surprisingly, the enzyme tolerates potassium hydroxide in amounts up to 20 mol% at elevated temperatures; however, the enantiomeric excesses are somewhat lower than those obtained in an ordinary kinetic resolution. Unselective, base- or metal-catalyzed acylation might be the reason for the somewhat lower ee value. BLckvall et al. [lo] have recently reported substantial improvements in the described process. A rangc of 1 -phenylethanol derivatives can be synthesized from the racemates in excellent yields and >99 % ee by using a binuclear ruthenium complex combined with an immobilized lipasc and a specifically designed acyl donor (4-C1-PhOAc). Even aliphatic alcohols and diols OAc

acetophenone, KOH

3 mol% [Rh(COD)]?

2 niol'h Rh,(OAc),

76 5% conversion, 80 % ee

Scheme 4. Spccific example of the

60 % conversion. 98 % ee racemization shown in Scheme 2,

174

C. Enantioselective Cuta/ysis Br

Br

+

Lipase. water ____L

f'hXC02Me

polymer bound bromide source

Br

Ph A CO,H

Scheme 5. Resolution of a bromo-ester [ 131.

78 'lo, 79 yo ee

can be used in this optimized protocol. Furthermore, no additional base is necessary and the reaction is considerably faster. This concept was also recently extended by Reetz et al. to the resolution of phenylethylamine [ 121. In this case, an immobilised lipase and ethyl acetate as acyl donor are used; the non-acylated (S)-enantiomer of the amine is racemized in situ by palladium on charcoal. After 8 days the metal catalyzed racemization is again likely to be the rate-determining step - (R)-N-acetylphenylethylamine is isolated in 64 % yield and 99 (7~enantiomeric excess. Williams et a1.[13] used a combination of a polymer-bound phosphonium bromide and a cross-linked lipase from Cundidu vugosn for a resolution process of an a-bromo ester (Scheme 5). The corresponding acid was obtained in 79 % enantiomeric excess and in 78 5% yield. In summary, a new concept for dynamic kinetic resolution has been demonstrated. It is still a long way to practical systems, but the first steps to team up enzymes with classical metal-organic catalysts have been successfully achieved.

References: [ I ] S.Takahashi in Progress in fndustriril Microbiology vOl.24 (Eds. K. Aida, I. Chibata, K. Nakayama, T. Takanarni and H. Yamada). Elsevier, Amsterdam, 1986, S. 269-279. [2] C.J. Sih et al. in Stereocontrolled Organic Synrhe.sis, (Ed. B.M. Trost). Blackwell Scientific Publications. Oxford, 1994, PP. 40 I -404. [3] H. v.d. Deen, A.D. Cuiper, R.P. Hof, A. v. Oeveren, B.L. Feringa, R.M. Kellog, J. Am. Chem. Soc. 1996, 118, 3801 -3803. [4] M. Inagaki, J. Hiratake, T. Nishioka, J. Oda, J. Org. Chem. 1992, 57, 5643-5649. [S] a) R. Noyori, Science 1990,248, 1194- 1199; b) R. Noyori, H. Takaya, Acc. Chern. Rex 1990, 23, 345 - 350. [6] R.S. Ward, TetrLihedron:Asymmrtry 1995, 6 , 1475- 1490. [7] S. Caddick, K. Jenkins, Chem.Soc.Rev. 1996, 25, 447 -456. 181 a) H. Stecher, K. Faber Synthesis 1997, I - 17; b) U.T. Strauss, U. Felfer, K. Faber, Tetruhedroii;Asymmetry 1999, 10, I07 - I 17. [XI P.M. Dinh, J.A. Howarth, A.R. Hudnott, J.M.J. Williams, W. Harris, Terrcihedrori Lett. 1996, 37, 7623-7626. [lo] J.V. Allen, J.M.J. Williams Terrcihedon Left. 1996, 37, 1859- 1862. 11 I ] a) A.L.E. Larsson, B.A. P e r s o n , J.-E. Backvall, Angew. Chem. 1997. 109, 1256- 1258; Angebv. Clzenz. h t . Ed. Engl. 1997, 36, 12 I I- 1212 b) B.A. Person. A.L.E. Larsson, M. Le Ray, J.-E. Backvall, J. Ani. Chem. Soc. 1999, 121, 16451650. [I21 M.T. Reetz, K. Schimossek, Chiniia 1996, 50, 668 669 1131 M.M. Jones, J.M.J. Williams, Cl7em. C o r n m ~ n ~ . 1998, 25 I9 - 2520. -

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Non-Enzymatic Kinetic Resolution of Secondary Alcohols Peter Somfai Organic Chemistry, Royal Institute of Technology, Stockholm, Sweden

Secondary alcohols represent an important class of readily derivatizable compounds that can be incorporated into a variety of synthetic strategies. The kinetic resolution of these compounds, or more often of their corresponding acetates, has traditionally been done by using esterases and often with excellent results [I]. Recent developments of this approach, which use metal catalysts in order to racemize the substrate in combination with appropriate enzymes, have resulted in efficient dynamic kinetic resolutions [2]. However, the non-enzymatic kinetic resolution of racemic alcohols has proven to be more difficult, the only prominent example being the Sharpless resolution of allylic alcohols 131, but recently several impressive results have been documented. In principle, four conceptually different strategies have been pursued with varying degrees of success. In the most straightforward one, a preformed enantiomerically pure acylating agent, e.g. an acyl halide 141 or N-benzoyl oxazolidinone 1 1.51, is reacted with a racemic secondary alcohol (2) to give the corresponding acylated product (3) and recovered starting mate-

1 (1 eq.)

rial (Scheme 1). The inherent drawbacks with this method are that a stoichiometric amount of the chiral reagent is required and, in the former case, that the acylated product will be formed as a mixture of diastereomers unless the resolution proceeds with complete selectivity. Alternatively, advantage can be taken of the fact that the acylation of secondary alcohols is subjected to nucleophilic catalysis. In a pioneering study more than 60 years ago Wegler investigated the acylation of several different racemic secondary alcohols mediated by brucine and strychnine 161. For example, when racemic 2a was reacted with acetic anhydride in the presence of stoichiometric amounts of brucine, (S)-amethylbenzyl acetate [(S)-41 was formed, although its optical purity cannot be ascertained from the data given. More recently the efficiency of other tertiary amines as acylation promoters has been investigated, the best result for the acylation of 2a being obtained with amine 5 (2a:AcCI:5 = 2 : 1 : 1) yielding (S)-4 with an optical purity of 68 % ee 171.

2 (10 eq.) a R=Ph, R'=Me b R=Ph, R k P r c R, R'=cC6HI1, Me

Scheme 1. Kinetic resolution of 2 using oxazolidinone 1 151.

3a ee=95% b ee=65% c ee=5%

176

C. Enantioselective Catalysis

CI

8 Ar=3,5-di(tBu)Ph

7

The first example of a chiral nucleophilic promoter that is also capable of catalytic turnover was described by Vedejs et a1.[8], who showed that acylation of 2 a with Ac,O in the presence of the C,-symmetric phospholane 6 (2a:Ac20:6= 1 : 2.5 : 0.16) gave 4 with ee = 34 % (44 % conversion, s = 2.7, s = kf,,t/k+,,), while racemic 1 -phenyl-2,2-dimethylpropanol was acylated with m-chlorobenzoic anhydride under the same reaction conditions to yield the corresponding ester 7 with ee = 81 % (25 % conversion, s = 12- 15). In a continuation of these studies the bicyclic phosphine 8 was prepared and evaluated (Scheme 2) [9]. It was found that 8 is an efficient catalyst for the resolution

of several secondary aryl-alkyl carbinols, resulting in unprecedentedly high s-values. The choice of anhydride is important for obtaining optimal selectivity, with isobutyric anhydride performing well for a variety of alcohols, and the resolutions using 8 can be conducted at low temperatures, with concomitant improvements in selectivity due to the its favorable activity. In a parallel investigation the enantiomerically pure DMAP-analog 10 (ee>998)was prepared by the same group and converted into the pyridinium salt 11(Scheme 3), which, for steric reasons, is not sufficiently reactive to promote acyl transfers to alcohol 2 by itself [lo]. However, in the presence of Lewis acids (ZnBr, or MgBr,) and Et,N, neither of which can be omitted, a slow acylation ensues to give the mixed carbonates 12 in high ee and with good s values. The inherent problem with these resolutions is that there is a continuous enrichment of the slower reacting isomer of the starting material as the reaction proceeds, thus requiring exceptional rate differences between the enantiomers in order to obtain high ee of the product as well as the recovered starting material and high conversion (e. g. at SO % conversion s = 200, ee = 96 %; s = 500, ee = 98 %). In an attempt to overcome this an ingenious protocol was developed by Vedejs and Chen in which two competing processes, with

8 (2.5-12.1 mol-Yo) R

OH

*

heptane (PhMe for 2e)

2a R=Ph d R=2-Me-C,H4 e R=mesityl

2a conv.=29.2%, ee=38.4%, -20 'C a conv.=42.4%, ee=61.9%, rt d conv.= 50.1%, ee=95.3%, -4O'C e conv.=44.4%, ee=78.8%, -4O'C

9a ee=93.3Y0, s=42 a ee=84.0%, s=22 d ee=94.9%, S=145 Scheme 2. ~ i resolution ~ e ee=98.7%9 ~ ~ 3 6 9 using phosphjne 8 191,

~ 2

~

i

Non-Enzymatic Kinetic Resolution of Secondary Alcohols

177

+

BU OMe

10

2a R=Ph f R=l-naphthyl

g R=2-naphthyl

ZnBr, (2 eq.) Et3N (3 eq.) *

10

RAO ( S)

12a ee=93%, conv.=25%, s=38 f ee=94%, conv.=28%, s=44 g ee=94%, conv.=24%, s=45 Scheme 3. Kinetic resolution of 2 using pyridinium salt 9 [lo]. NMe2

I

11 (0.56eq.)

x

+

R

OH

f enchylO

13 (0.56 eq.)

2 (1 eq.1 f R=l -naphthyl g R=2-naphthyl d R=2-Me-C6H4

MgBr, (2.25 eq.) Et3N (3 eq.)

CCI,

( S) 12f 46%, ee=88% g 49%, ee=86% d 46%, ee=83%

+

R

Ofenchyl

(R) 14f 46%, ee=88% g 49%, ee=86% d 46%, ee=83%

Scheme 4. Parallel kinetic resolution of 2 [ l I ] .

similar rates and selectivities but for opposite enantiomers, are run in parallel (parallel kinetic resolution, PKR), the advantage being that the optimal 1 : 1 ratio between the stereoisomers is maintained throughout the experiment [ 1 1 1. The

advantages can be appreciated by considering a PKR experiment involving two simultaneous reactions with selectivities for opposite isomers, each reaction with s = 49 (100 % conversion) and which, ideally, would give both products in

178

C. Enuntioselective Cutalysis

R

15a R=Me, R'=H b %Me, R'=Me, SiMe3 c R=Ph, R'=H

ee = 96 %. In comparison, a simple kinetic resolution would need to have s = 200 (SO % conversion) in order to equal the former result. Reagents 11 and 13 were selected with the expectation that they would behave as quasi-enantiomers and acylate opposite enantiomers of racemic secondary alcohols to give products that could be readily separated. In the event, when 11 and 13 were reacted with three different aromatic secondary alcohols the corresponding carbonates were formed in high yield and ee, clearly demonstrating the potential of the method (Scheme 4). Two other groups have described useful nucleophilic catalysts for the kinetic resolution of secondary alcohols. Fu and coworkers have pre-

A

R

pared a family of novel chiral 7r-complexes of heterocycles with iron, e. g. 15, and showed them to be potent nucleophilic catalysts for a variety of transformations [ 121. This design allows for an asymmetric environment close to the planar sp'-hybridized nitrogen atom that is quite different from that found in 10. Kinetic resolution of 2a using catalyst 15a resulted in only a low enantioselection, and introduction of a methyl or TMS group in the 7 position (15b) did not improve the situation. Instead, replacing the $C,Mes group in 15a with a ys-CsPhs moiety gave derivatives 15c, which have been shown to be excellent catalysts for the kinetic resolution of secondary aryl-alkyl and alkynyl-alkyl carbinols (Schemes S and 6). Several aspects of these resolutions are noteworthy. It was shown that the enantioselective acylation of racemic 1 -phenylethanol using 1% and acetic anhydride was dependent on the choice of solvent, the best result being obtained in tert-amyl alcohol, which itself apparently is not acetylated under the reaction conditions. Under the optimized reaction conditions, exceptional levels of resolution can be obtained using only 1 mol% of 1% at O"C, and the reaction is not sensitive to small amounts of oxygen, moisture or adventitious impurities [ 1 2 ~ 1In . the kinetic resolution of propargylic alcohols, it

15c (1 mob%), Et3N

OH

+

Ac20

*

R'

+

R

R n O H

t-amyl alcohol, 0 'C

(S) 2a R=Ph, R'=CH3 d R=2-Me-CsH4,R'=CH3 h R=Ph, R'=tBu

1 OAc

(R)

2a conv.=55%, ee=99%, s=43 15a ee=79% d conv.= 5370, ee=99%, s=71 d ee=87% h conv.=51%, ee=96%, s=95 h ee=92%

Scheme 5. Kinetic resolution of 2 using 15c [12c].

15c (1 rnol-Yo)

+ Ac~O

f-amyl alcohol, 0 'C

+

R

16a R=Ph b R=4-MeO-C&l4 Scheme 6. Kinetic resolution of 16 using 15c [12d].

R

16a conv.=58%, ee=96%, s=20 b conv.= 60%, ee=94%, s=14

17a ee=69% b ee=63%

Non-Enzymatic Kinetic Resolution of Secondary Alcohols

179

* OH

18 (0.05 eq.)

(0.7 eq.)

19 (1 ea.1

19a conv.=73%, ee=54%, s=2.4 b conv.=71%, ee=81%, sz4.5 c conv.=70%, ee=>85%, ~ ~ 5 . 3 d conv.=72%, ee=>99%, s>lO.1

was found that external bases resulted in a decreased enantioselectivity, optimal results being obtained by simply omitting the addition of a base (Scheme 6) [ 12dI. These workers also succeeded in isolating the acetylated form of 1% (lScAc+.SbFi), which is the actual acylating species, and to confirm the structure by X-ray crystallography [ 12dI. In this acetylpyridinium ion, the NMe, moiety, the pyridine ring and the acetyl group reside in a common plane, consistent with an extended delocalization of the positive charge, while the two cyclopentadienyl rings deviate from coplanarity by about 8”. The last observation might be due to steric interactions between the $-C,Ph, moiety and the pyridine ring and also results in an efficient blocking of one face of the acetylpyridinium complex. In an interesting extension of this study, Fu and co-workers prepared the ruthenium analog of 1 5 ; its catalytic activity in the acetylation of I -phenylethanol was slightly higher than that of 15, while its enantioselectivity in the kinetic resolution of the same substrate was markedly lower [ 131.

Scheme 7. Kinetic resolution of 19 using pyridine derivative 18 1141.

A completely different approach was pursued by Fuji and coworkers [14]. The enantiomerically pure pyridine derivative 18 was prepared, the rationale being that the reduced steric hindrance in the proximity of the nitrogen nucleus should result in efficient catalytic turnover and that chiral recognition might be possible by remote asymmetric induction in a process similar to the “induced fit” mechanism in enzymes. When 18 was reacted with racemic 19b and isobutyric anhydride (1R,2S)-19b was recovered with ee = 81 % (71 % conversion, s = 4.5, Scheme 7). Interestingly, the optical purity of the recovered alcohol is dependent on the electron donating ability of the aromatic nuclei in the substrate, possibly indicating that n - z stacking plays a pivotal role in the enantiodifferentiating event. It was also shown that the pyridinium ion derived from 18 and isobutyric anhydride adopts a “closed conformation”, in contrast to 18, in which the naphthyl moiety is situated over the pyridine ring, thus shielding the si face of the carbonyl group and supporting the “induced fit” concept.

180

C. Enuntioselective Cutulysis

% 20 (0.33e.)%

OH

1) SnBr, (0.3 eq.),

MS 4A, c

+

('I-U

'

P

h

CH2C12,-78'C 2) PhCOBr (1 eq.)

21 (1 eq.) a b n=l n=2

(1R 2 R )

22a n=l; 44%, ~ ~ 8 6 21a % 46%, ee=86%, s=27 b 49%. ee=84%, s>100 b n=2: 44%. ee=97% The kinetic resolution of secondary alcohols is also subjected to asymmetric Lewis acid catalysis, as described in a recent elegant study by Oriyama et al [ 151. It was shown by these authors that the complex formed by mixing SnBr, and amine 20, derived from proline, in the presence of molecular sieves was able to catalyze the benzoylation of racemic 21 to give benzoate 22 along with recovered (IR,2R)-21 in exceptional yields and selectivities (Scheme 8). Several other alcohols were also investigated, the cyclic species generally performing better than the acyclic ones. Finally, Noyori and coworkers have shown that chiral Ru"-diamine complexes are efficient catalysts for the enantioselective transfer hydrogenation of several prochiral ketones, using 2 -propano1 as the hydrogen source, to give the corresponding alcohols in high ee [ 16aI. The reaction

Scheme 8. Lewis acid catalyzed kinetic resolution of 21 [15].

is microscopically reversible and the more rapidly formed stereoisomer of the product is also the one that is more readily oxidized in the reverse process. Consequently, secondary alcohols with a high reduction potential should be eligible for kinetic resolution by using these types of catalysts [ 16a,b]. That this is indeed the case was elegantly demonstrated using the Ru" complex 23a or the corresponding mesitylene derivative 23b (Scheme 9). Several alkyl-aryl carbinols could be successfully resolved by using 23, with excellent recovery of the unreacted substrate in high ee. Two cyclic allylic alcohols, 2-cyclohexen- 1-01 and 3-methyl-2-cyclohexen-l-ol, were also shown to be suitable substrates in this resolution, both of which are particularly valuable substrates in organic synthesis. Although this transformation superficially bears a resemblance

23

+

R

(R)

2 a 50%, ee=92%, s>80 i 47%, ee=92%, s>30 j 44%, ee=98%, s>30

Ph

23a arene=pcymene b arene=mesitylene

Scheme 9. Ru"-Catalyzed kinetic resolution [16b].

Non-En7ymatic Kinetic Resolution of Secondary Alcohols

to the Oppenauer oxidation, it has been unequivocally shown that the Ru"-catalyzed kinetic resolution proceeds by an 1&electron metal hydride species and not by a metal alkoxide intermediate, as is the case for the latter transformation [ 1 6 ~ 1 . In summary, scalemic secondary alcohols can be obtained by non-enzymatic kinetic resolution and in some cases with excellent selectivities. Although these results in general fall short when compared with those obtained with the esterase-promoted resolutions, it is expected that a more thorough understanding of the enantiodiscriminating event in these processes will result in the development of even more efficient catalysts.

References [ I ] For some recent reviews on esterase-promoted rcsolutions, see: a) C. J. Sih, S.-H. Wu, Top. Stereochem. 1989, / Y , 63; b) C . 4 . Chen, C. J. Sih, Angew. Chem. 1989, 101,7 1 I ; Angew. Chem. Int. Ed. Engl. 1989,28,695; c) A. M. Klibanov, Acc. Chem. Kes. 1990,23, 1 14;d) S. C. Ward, Chern. Rev. 1990, 90, I ; e) D. G. Drueckhammer, W. J. Hennen, R. L. Pederson, C. F. Barbas 111, C. M. Gautheron, T. Krach, C.-H. Wong, Synthesis 1991, 499; f) S . M. Roberts, Chiinin 1993, 47, 85; for the use of' designed peptides, see: g) S . J. Miller, G. T. Copeland, N. Papaioannou, T. E. Horstmann, E. M. Ruel, J. Am. Chern. Soc. 1998, 120, 1629; h) G. T. Copeland, E. R. Jarvo, S. J. Miller, J. Org. Chem. 1998, 63, 6784. [21 R. Sturmer, Angew. Chem. 1997, 109, 1221; Angew. Chem. Int. Ed. Engl. 1997, 36, 1173. [ 3 ] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. KO, H. Masamune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109. 5765.

181

[4] A. Mazbn, C. Nijem, M. Yus, A. Heumann, Tetrahedron: Asymmetry 1992, 3, 1455; K. Ishihara, M. Kubota, H. Yamamoto, Synlett 1994, 61 1. [5] D. A. Evans, J. C. Anderson, M. K. Taylor, TerrnIiedron Lett. 1993, 34, 5563. [6] R. Wegler, Liebigs Ann. Chem. 1932, 498, 62; R. Wegler, ibid. 1933, 506, 77; R. Wegler, ibid. 1934, 510, 72. 171 P. J. Weidert, E. Geyer, L. Horner, Liehigs Ann. Chem. 1989, 533. IS] E. Vedejs. 0. Daugulis, S. T. Diver, J . Org. Chern. 1996, 61, 430. 191 E. Vedejs, 0. Daugulis, J. Am. Chem. Soc. 1999, 121, 5813. [ l o ] E. Vedejs, X. Chen, J. Am. Chem. Soc. 1996, 118, 1 809. [ l l ] E. Vedejs, X. Chen, J . Am. Chem. Soc. 1997, 119, 2584. [I21 a) J. C. Ruble, G. C. Fu, J . Org. Chem. 1996, 61, 7230; b) J. C. Ruble, H. A. Latham, G. C. Fu, J . Am. Chem. Soc. 1997, 119, 1492; c) J. C. Ruble, J. Tweddell, G. C. Fu, J. Org. Chem. 1998, 63, 2794; d) B. Tao, J. C. Ruble, D. A. Hoic, G. C. Fu, J , Am. Chem. Soc. 1999, 121, 5091. [I31 C. E. Garrett, G. C. Fu, J. Am. Chem. Soc. 1998, 120, 7479. [14J T. Kawabata, M. Nagoto, K. Takasu, K. Fuji, J. Am. Chem. Soc. 1997, 119, 3169. [I51 T. Oriyama, Y. Hori, K. Imai, R. Sasaki, Tetrahedron Lett. 1996, 37, 8543. [ 161 a) R. Noyori, S . Hashiguchi, Ace. Chem Res. 1997, 30, 97; b) S. Hashiguchi, A. Fujii, K.-J. Haack, K. Matsumura, T. Ikariya, R. Noyori, Angew. Chem. 1997, 109, 300; Angew. Chem. Int. Ed. Engl. 1997, 36, 288; c ) K.-J. Haack, S. Hashiguchi, A. Fujii, T. Ikariya, R. Noyori, Angew. Chem. 1997, 109, 297; Angew. Chem. Int. Ed. Engl. 1997, 36, 285.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Copper-Catalyzed Enantioselective Michael Additions: Recent Progress with New Phosphorus Ligands Norbert Krause Lehrstuhl .fur Organische Chemie I/, Universitiit Dortmund, Germany

The enantioselective Michael addition of a chiral organometallic reagent to a prochiral substrate is an attractive method for creating a center of chirality in an organic molecule [ I ] . For this purpose, chirally modified organocopper compounds of the composition RCu(L*)Li can be used; the chiral nontransferable ligand L* controls the stereochemical course of the transfer of the group R to the substrate 1. By using stoichiometric amounts of these “chiral cuprates”, the research groups of Bertz, Corey, Dieter, Rossiter and Tanaka obtained the 1,4-adducts 2 with good enantioselectivities (over 90 % ee in some cases). Naturally occurring alcohols and amines were used as chiral ligand L* (e.g., ephedrine and proline derivatives) [ I]. However, these investigations also revealed two fundamental problems of enantioselective Michael additions: 1. In solution, organocopper compounds show a dynamic behavior, with equilibria between several species. If this leads to the formation of achiral, but more reactive cuprates, a loss of enantioselectivity is unavoidable. Therefore, it is crucial to develop chiral reagents which react so rapidly with the substrate that undesired competing reactions are suppressed. 2. Many chiral organocopper reagents exhibit a high substrate specificity; that is, they give good stereoselectivities with only one or very few Michael acceptors.

Both problems may be solved by taking advantage of the concept of ligand-accelerated catalysis [ 2 ] ,which involves catalytic reactions characterized by dynamic ligand exchange processes. The presence of a suitable ligand can lead to the formation of a highly reactive and selective catalyst by self-assembly. If a chiral ligand is used, a stereoselective reaction may be favored over a nonselective one. Other advantages of catalytic transformations compared to their stoichiometric counterparts are the more efficient use of the metal and the chiral ligand, as well as the minimization of waste production. Michael additions of organolithium, Grignard, and diorganozinc reagents to enones and other n,a-unsaturated carbonyl compounds are catalyzed inter alia by copper, nickel and cobalt salts. The best results are obtained with copper(1) catalysts, especially those in which copper is bound to a “soft”, readily polarizable center (sulfur or phosphorus). The first reaction of this type was reported by Lippard et al. in 1988: the reaction of 2-cyclohexenone (3) with Grignard reagents in the presence of the chiral aminotroponeimine copper complex 5 as catalyst gave the 1,4-adducts 4 with 4- 14 % ee [3a]. The selectivity was increased to 74 % ee by addition of hexamethylphosphoric triamide (HMPA) and silyl halides

13~.

RCu(L*)Li

or R-M / CuX (cat.) / L* (cat.) 1

*

6

R 2

Formula 1

Copper-Catalyzed Enantioselective Michael Additions . . .

RMgX or RzZn

u

Cat" U

3

Cat* =

183

R 4

PhYMe SCu Ph2PCH2CHzPPh2 6 (rnax. 60% eelB)

5 (4.14% ee r3a1)

(max. 74% ee; + iBupPhSiCl / HMPA13b1)

Ph x > P l ~ * ~ N M e/ Cul z

Me Pr

\

IPr

8 (32% eel6])

7 (60-72%ee; + HMPAI'])

&PPhZ

/ Cul

A0

Me2N

9 (67-90% eelq) 10 (63% ee''])

Spescha et al. (41 used the copper complex 6, which was obtained from a thioglucofuranose derivative, as catalyst for 1,4-additions of Grignard reagents to 3, and observed enantioselectivities of up to 6 0 % ee. The dihydrooxazolylthiophenolato copper complex 7 was employed by Pfaltz et al. [ 5 ] for the enantioselective catalysis of' Michael additions to cyclic enones; the best results were obtained with tetrahydrofuran as solvent and HMPA as additive. There was a pronounced dependence of the stereoselectivity on the ring size of the substrate: 16-37 % ee for 2-cyclopentenone, 60-72 % ee for 3, and 83-87 % ee for 2-cycloheptenone. Alexakis et al. [6] used the heterocycle 8, which is readily accessible from

Formula 2

ephedrine, as chiral ligand for the copper(1)-catalyzed addition of diethylzinc to 3, and obtained ketone 4 (R = Et) with 32 9k ee. Another neutral phosphorus ligand is the proline derivative 9, with which Kanai and Tomioka [7] obtained 67-90 % ee in the Cu(1)-catalyzed 1,4-addition of Grignard reagents to 2-cyclohexenone (3). Recently, Feringa et al. [S] reported the use of phosphorus amidites of type 10 in Michael additions of diethylzinc to enones. These reactions are catalyzed by copper(1) salts and by copper(I1) triflate; when 3 was used as substrate, stereoselectivities of 60 % ee (with CuOTf) and 63 % ee [with Cu(OTf),] were obtained (a much higher value of 81 % ee resulted with 4,4-dimethyl-2-

184

C. Enuntioselective Cutalysis

R2MgX or R22Zn Ph

Cat*

* Ph

11

12

Pr -N

13 (R’ = R2 = Me: 76% eeL5])

\

/Cu(OTf)z Pr

10 (R’ = Ph, R2 = Et: 87% eel*])

cyclohexenone in the presence of 10 and Cu(OTf),). Even when Cu(OTf), is employed, the actual chiral catalyst is probably a copper(1) species which is formed by in situ reduction of the copper(I1) complex. In all these cases, the regioselectivities (1,4-vs 1,2-addition) and chemical yields are acceptable or good. As these examples show, cyclic enones are normally used as substrates for copper-catalyzed enantioselective Michael additions. In some cases, however, good stereoselectivities were also attained with acyclic enones of type 11. Thus, van Klaveren, van Koten et al. 191 employed the copper arenethiolate 13 as catalyst for the 1,4-addition of methylmagnesium iodide to benzylideneacetone and obtained adduct 12 (R’ = R2 = Me) with 76 % ee. Interestingly, this catalyst is not suitable for analogous additions to cyclic enones; similarly, the structurally related copper thiolate 7 does not catalyze enantioselective Michael additions of Grignard reagents to acyclic enones of type 11. With 7 and 13, complicated nonlinear relationships between the enantiomeric excesses of the catalyst and the product were observed, indicating that the product is formed via different organocopper intermediates in several reaction pathways. Progress with regard to this undesired substrate specificity was achieved with the phosphorus amidite 10, which catalyzes not only Michael additions of organozinc reagents to cyclic enones but also to chalcone (11; R’ = Ph) and related acyclic substrates. In the case of the addition of diethylzinc to chalcone, a good enantioselectivity of 87 % ee was observed [S].

Formula 3

The last example shows that neutral binaphthol phosphorus ligands are particularly well suited for enantioselective Michael additions. On the basis of this structural feature, Feringa et al. [ l o ] achieved a breakthrough. By combining the C2-symmetrical axially chiral binaphthol with the C,-symmetrical bis( 1- phenylethy1)amine through a phosphorus center, they obtained the new ligand 15, which can be used in highly enantioselective copper-catalyzed Michael additions of diorganozinc reagents to numerous cyclic enones. Here, the steric properties of the substrate and the reagent are unimportant, since the transfer of methyl, ethyl and isopropyl groups to 2-cyclohexenone takes place with high enantioselectivities ( 2 94 % ee) and good chemical yields (72-95 %), as does the transfer of an ethyl group to 4,4-diphenyl-2-cyclohexenone.Additional functionalities can be introduced into the addition product in several ways without affecting the stereochemical course of the reaction. Thus, the addition of diethylzinc to 4,4-dimethoxy-2,5-cyclohexadienone (17), catalyzed by 15 and Cu(OTf),, gives adduct 18 with 94 % ee. The functionalized zinc reagent [AcO(CH,),],Zn, prepared by hydroboration of the corresponding alkene and transmetalation according to Knochel’s method, can be added to 2-cyclohexenone with excellent selectivity of 95 % ee. Finally, the zinc enolates formed in these transformations can also be treated with more complex electrophiles instead of protons. For example, the three-component coupling of 2-cyclohexenone, diethylzinc and benzaldehyde in the presence of 15 and Cu(OTf), fur-

Copper-Catalyzed Enantioselective Michael Additions . . .

6 R'

185

R22Zn, Cu(OTf), (cat.)

R'

14

16

15

0

bIpr 94% ee

> 98% ee

> 98% ee

Ph &Et

> 98% ee

@Ph

95% ee

95% ee

EtPZn Cu(OTf), (cat.), 15 (cat.)

ia

17

Formula 4

94% ee

b

* A

R**,Zn, Cu(OTf)2 (cat.)

3

4 "tBU

R = Me: 95% ee R = Et: 90% ee

19

nishes the expected hydroxyketone with 95 % ee; however, the diastereoselectivities of these transformations are not yet satisfactory [ 101.

Formula 5

With the combination of phosphorus amidite 15 and Cu(OTf),, a catalyst has been developed for the first time which can be applied with con-

186

C. Enantioselective Catalysis

fidence to almost any combination of Michael acceptor and organozinc reagent. This system apparently exploits the principle of ligand-accelerated catalysis. However, an important limitation has to be taken into account: only enones with six-membered rings give high stereoselectivities (the analogous reactions of diethylzinc with 2-cyclopentenone and 2-cycloheptenone gave the adducts with 10 and 53 % ee, respectively). Another recent report by Pfaltz et al. [ 1 11 underlines the fact that the bridging of binaphthol and a chiral amine through a phosphorus center is a general feature of catalysts which are suitable for highly enantioselective Michael additions. In the presence of the phosphite 19 with oxazoline structure, the 1,4-additions of dimethyl- and diethylzinc to 3 also give enantioselectivities of 95 and 90 % ee, respectively. Hopefully, this major progress will trigger further investigations leading to new chiral copper catalysts which can be applied even more generally to cyclic Michael acceptors with different ring sizes as well as to acyclic substrates [ 121.

References [I]

121 [3]

[4] (51

161 [7] 181

Reviews: a) B.E. Rossiter, N.M. Swingle, Chem. Rev. 1992, 92, 771 -806; b) N. Krause, Kontakte (Darmstudt)1993, ( I ) , 3 - 13; c) N. Krause, A. Gerold, Angew. Chem. 1997, 109, 194-213; Angew. Chem. bit. Ed. Engl. 1997, 36, 186-204. D.J. Berrisford, C. Bolm, K.B. Sharpless, Angew. Chem. 1995, 107, 1159-1171; Angew. Chem. Int. Ed. Engl. 1995, 34, 1050- 1064. a) G.M. Villacorta, C.P. Rao, S.J. Lippard. J. Am. Chem. SOC. 1988, 110, 3 175 - 3 182; b) K.H. Ahn, R.B. Klassen, S.J. Lippard, Orgunometallics 1990, 9, 3178-3181. M. Spescha, G. Rihs, Helv. Chim. Acta 1993, 76, 1219- 1230. a) Q.-L. Zhou, A. Pfaltz, Tetrahedron Lett. 1993, 34, 7725-7728; b) Q.-L. Zhou, A. Pfaltz, Tetrahedron 1994,50,4467-4478; cf.: c) Y. Takemoto, S. Kuraoka, N. Hamaue, C. Iwata, Tetruhedron: Asymmetry 1996, 7, 993-996; d) Y. Takemoto, S. Kuraoka, N. Hamaue, K. Aoe, H. Hiramatsu, C. Iwata. Tetrahedron 1996, 52, 14177- 14188. A. Alexakis, J. Frutos, P. Mangeney, Tetrahedron: Asymmetry 1993, 4, 2427-2430. M. Kanai, K. Tomioka, Tetrahedron Lett. 1995,36, 4275 -4278. A.H.M. de Vries, A. Meetsma, B.L. Feringa, Angew. Chem. 1996, 108, 2526-2528; Angew. Chem. Int. Ed. Engl. 1996, 35, 2374-2376.

[9] a) F. Lambert, D.M. Knotter, M.D. Janssen, M. van Klaveren, J. Boersman, G. van Koten, Tetrahedron: Asymmetry 1991, 2, 1097- 1100; b) G. van Koten, Pure Appl. Chem. 1994, 66, 14551462; c ) M. van Klaveren, F. Lambert, D.J.F.M. Eijkelkdmp, D.M. Grove, G. van Koten, Tetrahedron Lett. 1994, 35, 6135-6138. [ l o ] B.L. Feringa, M. Pineschi, L.A. Arnold, R. Imbos, A.H.M. de Vries, Angew. Chem. 1997,109,27332736; Angew. Chem. Int. Ed. Engl. 1997, 36, 2620 - 2623. [ 1 I ] A.K.H. Knobel, 1.H. Escher, A. Pfaltz, Svnletf 1997, 1429-1431. [ 121 Recent reports on copper-catalyzed enantioselective Michael additions: a) V. Wendisch, N. Sewald, Tetrahedron: Asymmetry 1997, 8, 12531257; b) N. Sewald, V. Wendisch, Tetrahedron: Asymmetry 1998, 9, 1341-1344; c ) A.H.M. De Vries, R.B. Hof, D. Staal, R.M. Kellogg, B.L. Feringa, Tetrahedron: Asymmetry 1997, 8, 15391543; d) E. Keller, J. Maurer, R. Naasz, T. Schader, A. Meetsma, B.L. Feringa, Tetrahedron: Asymmetry 1998, 9, 2409-2413; e) R. Naasz, L.A. Arnold, M. Pineschi, E. Keller, B.L. Feringa, J. Am. Chem. Soc. 1999, 121, 1104- 1105; f) D. Seebach, G. Jaeschke, A. Pichota, L. Audergon, Helv. Chirn. Actu 1997, 80, 25 15 -25 19; g) A. Alexakis, J. Vastra, J. Burton, P. Mangeney, Tetrahedron: Asymmetni 1997, 8, 3193-3196; h)A. Alexakis, J. Burton, J. Vastra, P. Mangeney, Tetrahedron: Asymmetry 1997, 8, 3987-3990; i) A. Alexakis, J. Vastra, J. Burton, C. Benhaim, P. Mangeney, Tetruhedron Lett. 1998, 39, 7869-7872; j ) E.L. Stangeland, T. Sammakia, Tetrahedron 1997, 53, 1650316510; k) F.-Y. Zhang, A.S.C. Chan, Tetrahedron: A.syninzetry 1998, 9, I1 79- 11 82; 1) M. Yan, L.-W. Yang, K.-Y. Wong, A.S.C. Chan, Chem. Cominun. 1999, I 1 - 12. m) T. Mori, K. Kosaka, Y. Nakagawa, Y. Nagaoka, K. Tomioka, Tetrahedron: Asymmetry 1998, 9, 3175-3178; n) Y. Nakagawa, M. Kanai, Y. Nagaoka, K. Tomioka, Tetrahedron 1998, 54, 10295- 10307; o) M. Kanai, Y. Nakagawa, K. Tomoika, Tetrahedron 1999, 55, 3843-3854; p) S.M.W. Bennett, S.M. Brown, J.P. Muxworthy, S. Woodward, Tetruhedron Lett. 1999, 40, 1767- 1770; q) A. Alexakis, C. Benhaim, X. Fournioux, A. van der Heuvel, J.-M. Leveque, S. March, S. Rosset, Syrzlett 1999, 181 1 - 1813; r) A. Alexakis, Chimu 2000, 54, 55-56; s ) 0. Pamies, G. Net, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 1999, 10, 20072014; t) M. Ydn A. S. C. Chen, Tetruhedron Lett. 1999, 40, 6645-6648; u) X. Hu, H. Chen, X. Zhang, Angew. Chem. 1999, 111, 3720-3723; Angew. Chem. In?. Ed. 1999, 38, 3518-3521; v) J. P. G. Versleijen, A. M. van Leusen, B. L. Feringa, Tetrahedron Lett. 1999,40, 5803-5806; w) R. Imbos, M. H. G. Brilman, M. Pineschi, B. L. Feringa, O r , . Lett. 1999, I , 623-625.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

C,-Symmetric Ligands for Catalysis Mark Mikulas and Karola Ruck-Braun hstitut fur Orgunische Chemie, Universitut Mainz, Germany

Metalloenzymes with copper, iron or manganese in the active center are involved in biological oxidations and oxygenations as well as in other enzymatic transformations [I]. For the better understanding of the function of these biological metal catalysts numerous model complexes with suitable ligands were synthesized and their physical and chemical properties were investigated. Tridentate amido ligands have been employed successfully for years to simulate the enzymatic processes of non-heme metalloproteins [ 1 -41. Recently, an increasing interest in such ligands and their chiral analogs has arisen in the area of catalytic asymmetric synthesis. Therefore, a series of tripodal ligands and their current applications are presented here.

Auxiliary Ligands in Bioinorganic Chemistry Nitrogen-containing, acyclic and cyclic C,-symmetric ligands, such as hydrotris(pyrazoly1) borates [ 11, tris[(2-pyridyl)methyl] amines [4] or 1,4,7-triazacycIononanes[ S ] are well established tools in bioinorganic chemistry for the preparation of biomimetic model compounds (see Schemes 1 and 2). The oxygen-carrying protein hemocyanin from mollusks (e.g. squids) and arthropods (e.g. spiders) contains in the deoxy form two neighboring Cu(1) centers [I]. Model compound 1 bearing hydrotris(pyrazoly1)borate ligands has been developed to clarify the fast and reversible dioxygen binding by this metalloenzyme. Protein crystallographic data give evidence for two Cu(I1) centers, which are bridged by the side-

H

1

2

Scheme I

188

C. Enantioselective Catalysis

ing group for the metal center, with a certain chemo- and regiospecifity [6]. Because of the importance of the controlled functionalization of nonactivated aliphatic carbon-hydrogen bonds, it is not surprising that nowadays biomimetic catalyst systems are finding increasing attention.

on coordinated peroxide ion (O:-) with p-v2:v2 bonds in oxy-hemocyanin as well as in model compound 1. Copper-dioxygen complexes display a vast variability of the C u - 0 bonding geometry. Binuclear copper(1) complexes of bis(triazacyclononane) ligands and their dioxygen adducts, e.g. 2, appropriate mononuclear compounds and iron-containing analogs are further efficient model systems for the examination of the assimilation and activation of oxygen by metalloproteins such as hemocyanin, tyrosinase, ribonucleotide reductase or methane monooxygenase [ I ] . The structure and reactivity of these catalytically active systems depends primarily on the properties of the ligands used. Significant structural differences are already caused by the presence or absence of an ethylene bridge between tridentate triazacyclononane ligands of binuclear copper complexes (see compound 2) [5]. Therefore, structure-reactivity relationships remain largely unexplained. Methane monooxygenase consists of a catalytically active diiron center. In the presence of oxygen this enzyme oxidizes methane and other hydrocarbons, i.e. molecules without any anchor-

Biomimetic Bleaching Agents and Oxidants Some of the first catalytic model systems for the simulation of the function of methane monooxygenase comprise monomeric as well as dimeric iron-containing model complexes bearing hydrotris(pyrazoly1)borate ligands 161. These complexes, e.g. 3, catalyze the oxidation of aromatic and aliphatic carbon-hydrogen bonds in the presence of oxygen ( 1 atm), acetic acid and zinc powder at room temperature (Scheme 2). The conversion of cyclohexane using this catalyst system yields cyclohexanol highly selectively, as well as cyclohexanone (22 : I ) . There is also a great interest in the design of biomimetic metal catalysts for the hydroxylation of al-

OH

I

1 equiv. 3 , CH2C12

r. t., 30h

H-

Me

3 2+

r

2PFi, L

Me 4

5

Scheme 2

Cj-Symmetric Ligands f o r Catalysis

kanes, alkenes and arenes in the presence of peroxides such as hydrogen peroxide or tert-butyl hydroperoxide. In this context the development of new bleaching agents with high activity at low temperature and good environmental compatibility is of great commercial interest, too. Recently, ecologically tolerable iron and manganese complexes have been synthesized and tested for their bleaching activity with hydrogen peroxide [7]. During these industrial studies, the binuclear manganese complex 4 (Scheme 2) proved to be an efficient catalyst (pH 9- 10). By oxidation of styrene and 4-vinylbenzoic acid with complex 4 in the presence of hydrogen peroxide in water or acetone (pH 9) at room temperature, the corresponding epoxides were successfully obtained within 5 h or 2 h, respectively. Allylic oxidation products were not observed. In this, as well as in other oxidations, achiral triple-alkylated 1,4,7triazacyclononane ljgands such as 5 have been tested successfully [7- lo]. Triazacyclononane ligands containing polyfluoroalkyl side chains at the nitrogen atom were prepared based on the fluorous biphasic catalysis concept (FBC) developed by Horvath and Ribai for catalysis in homogenous systems, and were employed in oxidations of alkanes and alkenes with tert-butyl hydroperoxide and oxygen, in order to achieve an effective separation of the mangenese catalyst from the product [S]. Recently, immobilized hgands were utilized for the manganese-mediated oxidation of alkenes

to epoxides with hydrogen peroxide [9]. The application of complex 4 (Scheme 2) for the oxidation of benzylic alcohols to benzaldehydes has been described by Feringa and co-workers [ 101. In this case, high turnover numbers in the range 280- 1000 and high selectivities were obtained. These few examples already demonstrate that polyfunctional ligands with C, symmetry permit unusual complex geometries with metals in a multitude of oxidation states. As a rule, extremely stable complexes are obtained, especially of early transition metals and metals in low oxidation states.

Enantioselective Oxidations For quite some time now, chiral, enantiomerically pure tripodal ligands bearing C , symmetry have been actively developed [ 2 ] . C,-symmetric optically active compounds are well-established ligands and auxiliaries in asymmetric synthesis. Numerous examples prove the high stereoselectivities achieved with chiral C2-symmetric ligands in transition metal-catalyzed reactions [2,3]. The efficiency of appropriate catalyst systems is explained by the reduced number of possible diastereomeric transition states. With a bidentate C,-symmetric ligand, a square-planar metal complex has two remaining identical (homotopic) coordination sites. An octahedral complex bearing a chiral bidentate C,-symmetric

8

6

40% ee

tert-butyl perbenzoate, 0%

92h

189

44%.

84% ee

Scheme 3

190

C. Enuntioselective Cutdysis

in the selectivity-dependent reaction step. Recently, chiral C,-symmetric 1,4,7- triazacyclononanes have been employed in catalytic enantioselective epoxidations for the first time [ 1 11. Oxidation of the chromene 6 with excess 30 % aqueous hydrogen peroxide was achieved in methanol using manganese(I1) acetate and ligand 7 (3 mol%, 1 : 1.5) yielding the epoxide 8 with (3R,4R)-configuration after 15 h and SO % conversion with 40 % ee (Scheme 3).

ligand offers two inequivalent (diastereotopic) coordination sites (axial and equatorial) for substrate binding. However, with C,-symmetric ligands in octahedral environment, three equivalent (homotopic) positions are obtained. Because of the three fold symmetry, an effective steric shielding should lead to high enantioselectivities in asymmetric synthesis. Thus, a precondition for the rational application of C,-symmetric ligands is precise knowledge of the complex geometry

+

NH,

MeOH

3hlR

H

O

q

2

R

10

R

(S,S,S)-lOa: R = Me (R,R,R)-lob R = Ph

+

LH,

___

Zr(O'Bu),

(L-Zr('")-O'Bu),

11

1Oa

L = N

12

w

0 ,

R' = R' = (CH2)4,86%, 93% cx R' = R' = Me, 59%, 87% ee

0 ArSCH3

+

PhMe,COOH

13 ~

CHZCI,, -20°C

O'Pt

13

-

I

O\

S Ar'

\CH:,

+

p

A/~\cH,

0-0

14

Scheme 4

C?-Symmetric Ligands for Cutalysis

From Cu(OTf), or Cu(0Tf) and the chiral C,symmetric tris(oxazo1ine) ligand 9, copper complexes are obtained that are capable of catalyzing the allylic oxidation of cyclopentene by tert-butyl perbenzoate in up to 84 % ee [ 121. Even today, for most oxidations with chiral or achiral ligand systems, the structures of the real active metal catalysts are unknown. Because of this it is difficult to give a scientific rationale for the selectivities and inductions observed. Chiral trialkanolamines 10 represent yet another class of chelating polyfunctional chiral ligands for use in asymmetric synthesis (Scheme 4) [13- 181. These tetradentate C,-symmetric ligands allow the synthesis of stable alkoxy complexes of the

early transition metals. Ligands 10 can be prepared by the reaction of ammonia with chiral epoxides in yields ranging from 40 to 97 % [ 14,171. Chiral trialkanolamine complexes with titanium(1V) as well as zirconium(1V) centers have been employed in asymmetric catalysis so far. The ring opening of meso epoxides was successfully accomplished at 0-25 "C with silyl azides in high enantiomeric excess (83-93 %), when a preprepared oligomeric complex obtained from 10a and 12 was used [13,17,18]. A two-centered zirconium(1V) complex is discussed as the catalytically active species. In contrast, titanium(1V) isopropoxide and ligand 10a form the monomeric highly reactive tiTs

I

Phl=NTs

*

H

N

5 mol % 15

40 - 90% N2CHC02Et

R2

R'

c

1 mol

15

XEt

R'

R2

30 - 51%

H

P

h

+

H~ yCo2Et N2

1 mot % 16

-

CICH2CHpC1, 24h, 0°C trans : cis = 0.6

191

d b C O Z E t P O z E t + Ph Ph 37% ee

57% ee

Scheme 5

192

C. Enantioselective Cutalysis

tanium(1V) complex 13, which has been employed successfully in the catalytic enantioselective oxidation of sulfides to sulfoxides (Scheme 4) [15- 171. On account of the distinct electrophilicity of the peroxotitanium(1V) complex, a high selectivity is achieved. Therefore, sulfones could only be detected gas-chromatographically. The best selectivities were obtained for 10b and Ar = MeC,H, (40 % ee). This stereoselection is caused by two processes. After the preferred oxidation furnishing the chiral (S)-configured sulfoxide a kinetic resolution during further oxidation to the sulfone leads to an additional accumulation of the (S)-configured product by removing more of the (R)-configured sulfoxide.

Tris(pyrazoly1) Ligands Metal catalysts with tripodal ligands are in no way restricted to oxidations in their application. For instance, the reaction of hydrotris(pyrazo1yl)borate-copper complex 15 (Scheme 5 ) with alkenes and ethyl diazoacetate results in the formation of cyclopropanes in yields in the range 63-78 % [19]. Starting from alkynes, cyclopropenes were obtained under mild reaction conditions at room temperature (30-51 %). Aziridines were isolated in 40-90 96 yield with catalyst 15 using [(p-tolylsulfonyl)imino]phenyliodinane,Phl = NTs. The first chiral tris(pyrazoly1) ligand was prepared as early as 1992 by Tolman and co-workers starting from a camphor-pyrazole derivative and H

\

POCI, 1201. With ICu(CH3CN),]BF, this compound forms the cationic monomeric copper(1) complex 16. The latter catalyzes the cyclopropanation of styrene with ethyl diazoacetate in up to 6 0 % ee. In recent years the synthesis of chiral and achira1 tripodal phosphines and their application in homogeneous catalysis has been studied in more detail [2]. Enantiomerically pure tripodal ligands were synthesized from the corresponding trichloro compounds and chiral, cyclic lithiophosphanes, e.g. 17, (Scheme 6) [21,22]. Using a rhodium(1) complex of ligand 18, an enantiomeric excess of 89 % was obtained in the asymmetric hydrogenation reaction of methyl acetamidocinnamate (19). With dimethyl itaconate (20) an enantiomeric excess of 94 % was achieved, whereas with the corresponding C,-symmetric bidentate ligand lower enantiomeric excesses were observed. However, the reactions with catalyst 18 proceed at higher temperature and also require longer reaction times [22]. Numerous achiral ligands containing C, symmetry are known today [2, 31. The application of their metal complexes in organic synthesis will undoubtedly lead to many surprises. Suitably, the first applications display biomimetic characteristics. The results obtained should lead to a more general application of achiral and chiral tripodal ligands in catalysis. C,-symmetry has the potential to be a key element in achieving high stereoselectivities in enantioselective transformations.

\

substrate:

PhA C O N(H)COMe Z M ' 19

MeO&

C02Me 20

Scheme 6

C1-Symmetric Ligands for Catalysis

References [I] Review: Y. Moro-oka, K. Fujisawa, N. Kitajima, Pure Appl. Chem. 1995, 67, 241 -248, and references cited. [2] Review: M. C. Keyes, W. B. Tolman inAdvance.7in Catalytic Processes (ed.: M. P. Doyle), JAI Press Inc., Greenwich 1997, 189, and references cited therein. [3] Review: C. Moberg, Angew Chern. 1998, 110, 260-281: Angew. Chem. Int. Ed. Engl. 1998, 37, 248-268, and references cited therein. [4] C. Kim, K. Chen, J. Kim, L. Que, J. Am. Chem. Soc. 1997, 119, 5964-5965, and references cited therein. [5] S . Mahapatra, V. G. Young, S. Kaderli, A. D. Zuberbiihler, W. B. Tolman, Angew. Chem. 1997,109, 125- 127; Angew. Chem. Int. Ed. Engl. 1997, 36, 130- 133, and references cited therein. 161 N. Kitajima, M. Ito, H. Fukui, Y. Moro-oka, J. Chem. Soc. Chem. Commun. 1991, 102-104, and references cited therein. [7] R. Hage, J. E. Iburg, J. Kerschner, J. H. Koek, E. L. M. Lempers, R. J. Martens, U. S . Racherla, S . W. Russell, T. Swarthoff, M. R. P. van Vliet, J. B. Warnaar, L. van der Wolf, B. Krijnen, Nature 1994, 369, 637 -639, and references cited therein. 181 J.-M. Vincent, A. Rabion, V. K. Yachandra, R. H. Fish, Angew. Chem. 1997, 109, 2438-2440: Angew. Chem. Int. Ed. EngI. 1997, 36, 2346-2349, and references cited therein. [9] Y. V. Subba Rao, D. E. De Vos, T. Bein, P. A. Jacobs, Chem. Commun. 1997, 355-356.

193

[ 101 C. Zondervan, R. Hage, B. L. Feringa, Chem. Com-

mun. 1997, 419-420.

[ 111 C. Bolm, D. Kadereit, M. Valacchi, Synlett 1997,

687-688.

[ 121 K. Kawasaki, S . Tsumurd, T. Katsuki, Synlett 1995,

1245-1246. [I31 W. A. Nugent,J. Am. Chenz. Soc. 1992,114,27682769. [I41 W. A. Nugent, R. L. Harlow, .I Am. . Chem. Soc. 1994, 116, 6142-6148. [IS] F. Di Furia, G, Licini, G. Modena, R. Motterle, J. Or,,. Chem. 1996, 61, 5175-5177. [I61 M. Bonchio, S . Calloni, F. Di Furia, G. Licini, G. Modena, S. Moro, W. A. Nugent, J. Am. Chem. Soc. 1997, 119, 6935-6936. 1171 Review: W. A. Nugent, G. Licini, M. Bonchio, 0. Bortolini, M. G. Finn, B. W. McCleland, Pure Appl. Chem. 1998, 70, 1041- 1046. [I81 W. A. Nugent, J.Am. Chem. Soc. 1998, 120,71397140. [19] P. J. Perez, M. Brookhart, J. L. Templeton, Organometullics 1993, 12, 261 -262. [20]a) C. J. Tokar, P. B. Kettler, W. B. Tolman, Organometallics 1992,11,2737-2739; b) M. C. Keyes, B. M. Chamberlain, S . A. Caltagirone, J. A. Halfen, W. B. Tolman, Organometallics 1998, 17, 19841992. [2 I] M. J. Burk, R. L. Harlow, Angew. Chem. 1990,102, 151 1 - 15 13; Angew. Chem. Int. Ed. Engl. 1990,29, 1467. [22] M. J. Burk, J. E. Feaster, R. L. Harlow, Tetmhedron: Asymmetry 1991, 2, 569-592.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Highly Enantioselective Catalytic Reduction of Ketones Paying Particular Attention to Aliphatic Derivatives Renat Kadyrov and Riidiger Selke Institut fur Organische Kutalyseforschung an der Universitiit Rostock, Germuny Dedicated to Professov Dr. Klaus Peseke on the occasion of his 60th birthday over 95 % ee through the hydrogenation of amino ketones. This was achieved by Hayashi et al. [3] using planar chiral ferrocenebis(ph0sphanyl)rhodium( I ) catalysts and above all by application of the control concept developed by Achiwa et al. [4] with BCPM rhodium(1) catalysts (BCPM = (2S,4S)-N-(tert-butoxycarbonyl)-

The research group of Zhang at Pennsylvania State University has climbed a mountain that had long defied all attempts - the complexcatalyzed, highly enantioselective (ee values of over 90 %) hydrogenation of purely aliphatic ketones [ I ] . Such high ee values have up till now remained the exclusive domain of enzymatic methods [2]. It has long been possible to hydrogenate a wide range of functionalized ketones asymmetrically achieving selectivities of over 90 % ee. Thus, pharmaceutically important 1,2-amino alcohol derivatives have been available since 1979 with

0 n

4-(dicyclohexyIphosphanyl)-2-(diphenylphosphanylmethy1)pyrrolidine) [4b]. Very high turnover rates (100 000) can thus be achieved. Likewise, a- and p-ketocarboxylic acid derivatives have been reduced (> 90 % ee) to the hydroxy acids or corresponding derivatives with high selectivOH

+

H2

(RuCl,((S)-SINAP)(DMF),1 2, KOH j-POH 8 atm H2, 28 "C,2 h

100 % 95 % ee

1

1

:

500

:

(S)-BINAP

RUCIZ[(S)-BINAP](DMF), 1

2 :

1

KOH :

2

(R,R)-I ,2diphenylethylenediamine

Scheme I . Regioselective hydrogenation of unsaturated ketones

Highly Enuntioselective Catulytic Reduction of Ketones Paying Particular Attention . . .

4

3

ity [4a, 5, 19al; the most impressive results were obtained with chiral. modified heterogeneous catalysts [6]. Since the pioneering studies of Noyori et al. with BINAP-ruthenium( 11) complexes [7] (BINAP = 2,2’-bis(diphenylphosphanyl)-I , 1 ’-binaphthyl, see Scheme I ) , the range of ketones which can be homogeneously hydrogenated with ee values of well over 90 % has been expanded to encompass among others y-keto esters, hydroxy ketones, u- and P-diketones, and even phenyl thioketones [7fj. Also the important regioselective hydrogenation of unsaturated, and above all cyclic, ketones such as 1 was possible with 95 % ee (Scheme 1) [7d, el. In this case, the otherwise preferred hydrogenation of the olefinic double bond [7g] is completely suppressed by the addition of a chiral diamine such as (R,R)1,2-diphenylethylenediamine (2), which serves as a selectivity-promoting modifier (Scheme 1). Moreover, Noyori et al. have recently shown that the selective power of the enantiomerically pure diamine 2 alone is sufficient for a successful reaction, as the enantioselectivity only falls from 96 to 95 % if racemic TolBINAP[7h] is used instead of (R)-TolBINAP (TolBINAP is a BINAP derivative in which the four phenyl groups attached to the phosphorus atoms are replaced by four p-tolyl groups). The transformation of unfunctionalized alkyl aryl ketones such as acetophenone and its analogs to the corresponding chiral alcohols was

5

195

6

for a long time possible only by asymmetric hydrosilylation [8] or hydroboration [9], giving enantioselectivities of around 95 %. However, in 1995 this reaction was accomplished by activation of BINAP-ruthenium catalysts with chiral diamines and KOH [lo]. In its optimized form the reaction needs less than mol % of catalyst [lob]. Similarly high selectivities were also reported for cyclic alkyl aryl ketones with BINAP-iridium catalysts [ 1 I]. Use of sodium borohydride as the reductant and the cobalt catalyst 3 with tetradentate ligands derived from Schiff bases afforded reduction of ketone 4 with 94 % ee. However, the corresponding reaction with acetophenone was unsatisfactory, leading only to 68 % ee [ 121. A successful approach in the field of transfer hydrogenation has been developed by Noyori [13a] using formic acid or isopropyl alcohol as the hydrogen source and ruthenium catalysts containing chiral N - P chelating ligands such as 5 or monosulfonated bisamines such as 6. This breakthrough is particularly significant in the case of alkyl aryl ketones or ketones with triple bonds in the c1 position [ 13b]. The excess hydrogen pressure, normally necessary for ketone hydrogenations, is avoided here by the high concentration of the hydrogen donor. Enantioselectivities of between 95 and 99 % are afforded in most cases for aryl alkanols; such values can otherwise be obtained only with microbiological processes [ 141.

196

Ph-N

C. Enuntioselective Cutalysis

,

!-Ph

Me

Me 7

The number of publications describing new ligands that allow the transfer hydrogenation of aromatic ketones with over 90 % ee has grown in leaps and bounds since 1996 [IS]. In these reactions the use of ruthenium [ 1Sa-fl and iridium [ISg] as the catalytically active metals has recently been augmented by the use of phosphorus-free ligands such as chiral diamines, amino alcohols, and bisthioureas such as 7 [ lSa,e-g]. A ruthenium-catalyzed transfer hydrogenation with 9 2 % ee has even been reported for the aliphatic ketone pinacolone (tert-butyl methyl ketone) [16]. One problem that remains unsolved is the complex-catalyzed enantioselective hydrogenation of dialkyl ketones with dihydrogen gas, as these substrates lack the aryl substituent or second functional group necessary for effective enantiofacial selective binding to the catalyst. Corey et al. nevertheless succeeded in reducing pinacolone, in which the steric requirements of the methyl and tert-butyl substituents differ quite distinctly, by the hydroboration method and obtained the product alcohol in 97 % ee [9]. By contrast, the straight-chain octan-2-one gave an ee value of only 72 % [ 171, compared to 94 % ee with an alcohol dehydrogenase [ 2 ] . A particularly successful approach to the catalytic hydrogenation of dialkyl ketones with hydrogen has been the use of the heterogeneous contact catalyst system - Raney nickel chirally modified with tartaric acid [ IS]. Here too, selectivity is enhanced by branching of the alkyl substituent in the alkyl methyl ketones (e.g., 85 % ee for the hydrogenation of isopropyl methyl ketone). With

PennPhos 8a 8b

R = Me R=iPr

DuPhos 9 (R = Me, Et, nPr, iPr)

straight-chain ketones the highest ee values were achieved for hexan-2-one and octan-2-one (80 %). Catalyst selectivity was optimized by the use of pivalic acid as a modifier, which through association clearly blocks one side of the chirality-inducing tartaric acid molecules on the surface of the nickel. Owing to the sterically demanding tert-butyl group of the pivalic acid, the range of options for coordination of the ketone to the tartaric acid in the transition state is limited. It is, of course, perfectly conceivable that this differentiation effect is particularly pronounced for alkyl methyl ketones and decreases upon replacement of the methyl group with a larger alkyl moiety. Ligands of type 8, known as PennPhos, have given new impetus to the rhodium-catalyzed homogeneous hydrogenation of prochiral ketones [ I ] . In 8 the favorable properties of the strongly basic Duphos ligands 9, developed by Burk et a/. [ 191. are cleverly enhanced by the incorporation of additional ring-forming bridges into the molecule, in accordance with the established principle of increasing the rigidity in the backbone. This at the same time increases the spatial requirements of the ligands. For the hydrogenations with 8 the enantiomeric excesses obtained are likewise optimized by the use of non-chiral modifiers such as bromides and weak bases. A remarkable feature of this reaction is that bases such as 2-methylimidazole and 2,6-lutidine, if added in substoichiometric amounts to the rhodium catalyst, achieve very similar increases in selectivity, whereas if equimolar quantities are used (basehhodium catalyst: 1/1) the results obtained differ dramatically ( 1 % ee versus 95 % ee, (S)-alcohol]. Use of triethylamine as the added base even yields the R enantiomer. The turnover rate also shows optima that are dependent on the ratio of base to the rhodium catalyst. This is viewed by the authors as an opportunity to improve the still unsatisfactory length of time required for hydrogenations with the PennPhos rhodium catalyst, which in some cases is as long as several days at 30 atm hydrogen pressure and room temperature. The influence of the alkyl substituents in the substrate on the enantioselectivity of the hydrogenation (Table 1 ) corresponds to experience from experiments with modified .Raney nickel [ 181.

Highly Enantioselective Catalytic Reduction of Ketones Puying Particular Attention . . .

Table 1. Enantioselectivities for the hydrogenation of simple ketones RCOR’. R

R’

ee (S) [%]

rBu

Me

94

Me

92

iPr

Me

84

nBu

Me

75

Ph

Me

95 (without KBr)

Ph

Et

93

Ph

iPr

72

C,H,

I

[a] With 0.5 mol % [Rh(COD)CI],, Sa, lutidine, and KBr under 30 atm H2 [ I ] .

0

According to these, for purely aliphatic ketones the highest enantioselectivities are achieved for methyl ketones with a second, branched-chained alkyl substituent (84-94% ee). The value of 75 % ee obtained with the straight-chain hexan2-one is, to the best of our knowledge, in any case better than anything achieved to date with nonenzymatic systems and homogeneous catalysis. Higher selectivities have been reported for reductions with stoichiometric amounts of chiral borohydrides (e.g. 80 % ee for the reduction of octan-2-one) [20]. For alkyl aryl ketones, the use of the novel PennPhos rhodium catalyst afforded enantioselectivities of over 90 %, such as are routinely obtained by transfer hydrogenation [ 131, but, only for alkyl groups up to C,. This is in contrast

tripenern antibiotics

_L

y

197

-

Ca channel blocker

(S)- zearalenone (rnycotoxic)

Scheme2. Optically active alcohols that can be used to synthesize biologically important chirai compounds [7c, 221.

198

C. Enantioselective Catalysis

to microbial reductions, where the selectivity rises with the number of carbon atoms in the alkyl group [ 141. A recent report describes a most spectacular inversion of selectivity for a novel ruthenium-catalyzed transfer hydrogenation of alkyl phenyl ketones with the use of the bis(thiourea) ligand 7 derived from (R,R)-I,2-diphenylethylenediamine (2 11. In this reaction the following enantioselectivities were obtained as a function of the alkyl group in the substrate molecule: Me: 89 9’0, (S); Et: 91 %, (S); iPr: 94 %, (S); rBu: 85 %, ( R ) . By ordering the substrates according to the magnitude of the selectivities obtained, other studies have likewise demonstrated a marked dependence on the structure of the catalyst [ 101. The significance for industrial processes is clear. Scheme 2 shows several examples from a survey recently published by Noyori [7c] of optically active alcohols that can be used to synthesize biologically important chiral compounds below along with some of relevance to the pharmaceutical industry [221. Pheromones constitute a particularly diverse family of chiral aliphatic alcohols [23]. Finally, the bis(trialky1phosphane) ligands 10 developed by Imamoto et u1. may, on account of their high basicity, also be suitable for the hydrogenation of ketones. Use of these ligands, which contain chiral phosphorus centers, affords enantiomeric excesses of over 99 % for the rhodium( I)-catalyzed hydrogenation of N-acyl-dehydroamino acids [24]. The tetrasubstituted substrates, which are generally difficult to hydrogenate enantioselectively, are of particular interest. The partially reversed orders of selectivity for the five ligands described leads us to suspect that high enantiomeric excesses may also be possible for the reduction of ketones. Further advances are conceivable by combining the methods developed by the research groups of Noyori and Zhang, with the use of bases as modifiers. I

10

R

The Progress of Asymmetric Reduction of Ketones since 1998 The actuality of the subject matter is underlined by the fact that since January 1998 up to the middle of May 1999 more than 140 papers were published in the field of enantioselective hydrogenation of ketones, which we will briefly discuss here only if the enantioselectivity surpasses 90 % ee. Among them, the particularly relevant manuscripts dealing with the hydrogenation of purely aliphatic ketones are in the minority. Four rapidly developing main lines can be recognized: enzymatic reduction, oxazaborolidine-catalyzed reduction by boron hydride, transition metal complex-catalyzed hydrogenation with hydrogen or transfer hydrogenation mainly with isopropanol [251.

Enzymatic Reductions Exclusively enzymatic reductions give satisfying selectivities in the region o f 9 0 to over 9 9 % ee for substrates possessing only the carbonyl as functional group [26]. Enantioselective reduction by a crude alcohol dehydrogenase from Geotrichium cundidum is effective even for alkyl-trifluoromethyl ketones (96-99 % ee) [27]. The enantiopure synthesis of 3-hydroxypiperidine-2one 12 is possible according to Scheme 3 by chemoenzymatic synthesis from 5-nitro-2-0x0-pentanoate 11, with enzymatic reduction of the carbonyl group as the key step. Nearly enantiopure a-hydroxy ketones or a-hydroxy esters are obtained using baker’s yeast reductase by reduction of the a-keto groups [28]. With D-hydroxyisocaproate dehydrogenase from genetically engineered H205Q mutants some N-protected (S)-4amino-2-hydroxy esters could be synthesized in better yield than with the wild-type lactate dehydrogenases [29]. In addition to this, that an interesting novel emulsion membrane reactor concept overcomes the difficulties of the large solvent volume otherwise required for the reduction of poorly soluble ketones [30]. 2-Octanone was reduced by a carbonyl reductase from Candida parupsilosis to (S)2-octanol with > 99.5 % ee and total turnover number of 124 -the 9-fold value of that obtained in a classical enzyme reactor.

Highly Enantioselective Catalytic Reduction of Ketones Paying Particular Attention . . .

199

___)

PtO,

H

12

Scheme 3

The main disadvantage for all enzymatic hydrogenations is the indispensability of a coenzyme such as NADH, whose regeneration needs an additional dehydrogenase system and a hydrogen source such as formic acid. This can be overcome by the use of complete cells. Choosing the appropriate microorganism, the extremely difficult enantioselective reduction of ketone functions located in the middle of carbon chains (as in 4-chloro-5-nonanone) succeeded recently with > 98 % ee [31]. A first application of baker's yeast in an industrial process for the production of trimegestone by selective monoreduction of a triketone using glucose as hydrogen source was a new highlight 1321. Success with baker's yeast cells immobilized on chrysotile fibers is reported for large-scale preparation of chiral alcohols 1331.

13

Oxazaborolidine-Catalyzed Reduction with Boron Hydride For aryl ketones the Corey-Bakshi-Shibata (CBS) reduction using oxazaborolidines as catalysts for the boron hydride mediated hydrogenation is particularly useful, with maximum selectivities up to 99 % ee (see Scheme 4) [34]. The excellent review by Corey et al. 13.51 also shows clearly the power for chemo- and enantioselective reduction of purely aliphatic cr,D-enones and -ynones only on the carbonyl group. In the re-

A

duction of enones such as 13, a bulky R group leads to an enhanced yield and selectivity: R = S i M e , (9496, 90% ee), R = H (30%, 76 % ee) 1361. 13 is a key precursor for the synthesis of atractyligenin, a naturally occurring adenosine diphosphate transport inhibitor. Recently, this method found application also for a key step in the synthesis of zaragozic acids investigated for the treatment of hypercholesterolemia [37]. Sulfur-containing phenylthioalkenones are proven to be excellent substrates for highly regio- and enantioselective reduction (89 - 98 % ee) [38]. For saturated methyl ketones with a branched alkyl group the enantioselectivities can exceed

90 % ee (see Scheme 4) [39]. This convenient method serves even for the preparation of chiral ligand precursors 15 by reduction of 1 , l ' -diacylmetallocenes 14 with over 98 % ee (Scheme 5 ) [40]. The modified catalysts 16 have been applied recently in enantioselective hydrogenation of Ij-ketoesters (91 -98 % ee) and for P-diketones, also giving excellent diastereoselectivities [4 I]. It seems important to note that unsaturated diketones 17 may be reduced selectively on

Ph P h

Me PhNEt2'BH3

*

PH

* R-CH~

R = iPr R=Bu R = Ar

91 % e e 97 % ee up to 99 % ee

Scheme 4

200

C. Enuntioselective Catalysis

$Zh

"B Me

*

20

BH3'SMe2/ THF

M = F e , R u 6H

Scheme 5

R

16

k

R 0

17

15

-

OH R?

R GH

18

Scheme 6

both carbonyl groups to unsaturated diols 18 (rneso : dl = 13 : 87; the latter with 99 % ee (see Scheme 6). The alternative use of LiH/BF,OEt, as a reducing agent for the in situ generation of borane is used to save costs [42]. Polymer-enlarged oxazaborolidines have been applied with success in a membrane reactor (431.

Hydrogenation Catalyzed by Transition Metal Complexes Impressive progress in the particularly important asymmetric hydrogenation of ketones by hydrogen using transition metal complex catalysts was demonstrated by Noyori et al. [44]. The introduction of XylBINAP with P-xylyl groups in the ruthenium chelate 19 allowed an increase in the enantioselectivity of the reduction of acetophenone to 9 9 % ee compared to 87 % ee with BINAP or TolBINAP. The fine tuning of the diamine substituents R', R2 and R' enables 19 to reach 95 to 99 % ee for the fully selective hydrogenation of a broad spectrum of olefinic or cyclopropyl ketones such as 20 without affecting the

double bond or the three-membered ring. Ru-BINAP or similar complexes derived from atropisomeric diphosphane ligands also catalyze the enantioselective reduction of 3 -oxobutanoate or P-ketoesters bearing functional groups in 95 to 9 9 % ee, and the method could be widened to P-ketophosphonates and sulfur-containing ketones [45, 461. The work of Geni3 et al. [46] is worthy of notice regarding some interesting applications for the synthesis of multifunctional bioactive compounds e.g. 2-amino-3-hydroxy acids, some heterocycles such as (-)-swainsonine or some channel blockers such as DilthiazemC9 or the side chain for Taxotere@. Ruthenium catalysts with the new ligand 21, given the abbreviation BICP, were introduced by the Zhang group and are particularly effective for the hydrogenation of thiophene containing ketones such as 22 [47]. Rhodium chelates of BICP also allow the synthesis of P-aminoalcohols in 90-99 % ee by hydrogenation of E,Z-mixtures of protected P-hydroxy enamides 23 (see Scheme 7) [48]. In principle, this is a selective reductive transformation of the carbonyl group of a-hydroxyacetophenones via the oxime to an amino group. Respectable results for the ruthenium chelatecatalyzed reduction of P-ketoesters were also obtained by Pye [49] with 2.2-PHANEPHOS (24) and Imamoto [50]with 1Oa as the ligand. An interesting stepwise reduction of 2,4-dioxovalerate (25) with BINAP-analogous ruthenium

BICP

21

22

Highly Enantioselective Catalytic Reduction of Ketones Paying Particular Attention . . . 0 L O P G

Ar

-

20 1

Fe, Ac20 __t

OPG

Ar

cat*

OPG

___)

10 atrn H2

E-23

Scheme 7

2-23

0C(0)R'

R2--LooR 27 24

0

0

H2 (cat*)

O .H 26

__t

U C O O E t "one pot"

25

84 % syn 98 % ee

Scheme 8

chelates followed by cyclization gives 84 % of the syn-a-hydroxy-y-valerolactone 26 in 98 % ee (see Scheme 8) [5 11. For the hydrogenation of a-ketoesters, -amides or -amines, a further number of highly enantioselective rhodium(1) catalysts have found application (maximum 97 - 9 9 % ee) [52, 531. Burk realized the synthesis and reduction of a-acyloxy-acrylates 27 in over 9 9 % ee by using a rhodium (S,S)-Et-DuPHOS (9) catalyst [54]. This method competes successfully with the reduction of a-keto esters and is remarkable because the high selectivities are obtained using the En-mixtures of the substrates 27. The very new highly enantioselective hydrogenation of enol acetates by a rhodium PennPhos chelate should be mentioned here [%I. Cyclic

28

29

30

enol acetates are especially suitable for this hydrogenation, yielding the products in 99 % ee. Exciting results using an iron gelatin complex supported on zeolite for heterogeneous asymmetric hydrogenation of purely aliphatic ketones under normal pressure at 20 "C have been reported recently by Ying-Yan Jiang et al. (Chinese Academy of Sciences, Peking) [66]. This procedure yields the corresponding chiral alcohols with highter than 95 % ee (polarimetric measurements).

Transfer Hydrogenantion Catalyzed by Complexes Some progress has been made, particularly with the ruthenium complex-catalyzed transfer hydrogenation [56] For tert-butyl methyl ketone as the first purely aliphatic ketone the bench mark of 90 % ee has been crossed by application of the oxazolinylferrocenylphosphine 28; the transfer hydrogenation by isopropanol under reflux in the presence of sodium hydroxide resulted in 93 % ee (S)-3,3-dimethyl-butan-2-01 [57].For alkyl aryl ketones 92-95 % ee is obtained with

202

C. Enantioxelective Cutulysis

Conclusion

31

NHMe -

Ph NHMe

32

(lS,3R,4R)-2-azanorbornylmethanol 29 [S8] and up to 98 % ee with Ph-Ambox 30 1591 as ligands free of phosphorus for ruthenium. Murata et al. worked on further optimization of the power of ruthenium chiral diamino-monotosylates 6 [60]. Other metals and amines were investigated. It seems that rhodium chelates are somewhat less active for the hydrogenation of acetophenone but more selective (up to 97 % ee for catalyst 31 with ( 1R,2R)-N-(p-toluenesulfonyl)1,2-cyclohexanediamine). With iridium as the central metal 96 o/o r e is still possible, but the activity strongly decreases. Also analogous polymer-bound catalysts of ruthenium [61] and iridium [62] give high enantioselectivities. But, the selectivity decreases when the immobilized catalyst is reused (with ruthenium: first run > 99 % ee, second run 96 % ee and third run 91 % ee in methylene chloride). With ferrocenyl diamines such as 32, the transfer hydrogenation of 1 '-acetonaphthone reached 90 % ee at -30°C with 2-propanol as the hydrogen source [63].Even amino acids have been used as ligands for ruthenium [64], but, more than 90 o/o ee results only when tetralone is the substrate. In the transfer hydrogenation of acetylacetates ephedrinium chelates of ruthenium led to 94 % ee [651.

As before, the enzymatic reduction is the method of choice for the enantioselective reduction of purely aliphatic ketones and only in the case of tert-butyl methyl ketone could the bench mark of 90 % ee be crossed by the transfer hydrogenation and both other catalytic hydrogenation methods. However, substantial success in the hydrogenation of aromatic ketones by transition metal complexes with respect to the enantioselectivity and the activity (TON) strengthens the confidence that further progress is possible, enabling us to use some advantages of these nonenzymatic processes for extended application in the near future, for example in the facilitation of product isolation.

References [ 1 ] Q. Jiang, Y. Jiang, D. Xiao, P. Cao, X. Zhang, Angew. Chern. 1998, 110, 1203-207; Angew. Chem.

Int. Ed. 1998, 37, 1100- 1103. 121 In the case of purely aliphatic ketones such as nonan-3-one, use of the alcohol dehydrogenase extracted from Gluconobucter oxidarts (ATCC 62 I ) results in enantioselectivities of up to 95 %: P. Adlercreuz, Enzyme Mikrob. Technol. 1991, 13,9- 14; see also review: R. Csuk, B. Glanzer, Chem. Rev. 1991, 91, 49-97. 131 T. Hayashi, A. Katsumura, M. Konishi, M. Kumada, TetrahedronLett. 1979, 425-428. a) T. Morimoto, H. Takayashi, K. Fujii, M. Chiba, K. Achiwa, Chem.Lett. 1986, 2061-2064; b) H. Takeda, T. Tachinami, M. Aburdtami, H. Takahashi, T. Morimoto, K. Achiwa, Tetrahedron Lett. 1989, 30. 363-366; c) K. Inoguchi, S. Sakuraba, K. Achiwa, Synlett 1992, 169- 178. A. Roucoux, M. Devocelle, J.-F. Carpentier, F. Azbossou. A. Mortreux.. Svnlett 1995. 358-360. 161 a) A. Tai, T. Kikukawa, T. Sugimura, Y. Inoue, S. Abe, T. Osawa, T. Harada, Bull. Chem. Soc. J p . 1994, 67, 2473-2417; b) H. U. Blaser, H. P. Jalett, J. Wiehl, J . Mol. Cutul. 1991, 68, 215222; c) H. U. Blaser, H. P. Jalett, F. Spindler, J. Mol. Cutul. A. 1996, 107, 85-94; d) H. U. Blaser, H. P. Jalett, M. Muller, M. Studer, Cutul. Toduy 1997, 37, 465-480. 171 a) R. Noyori, T. Ohkuma, M. Kitamurd, H. Takaya, N. Sayo, H. Kumobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109, 5856-5858; b) M. Kitamura, T. Ohkuma, S. Inoue, N. Sayo, H. Kumobayashi, S. Akutagawa, T. Ohta, H. Takaya. R. Noyori, ibid. 1988, 110, 629-631; for a review of subsequent work, see c) R. Noyori, A.symrnetricY

Highly Enantioyelective Catalytic Reduction of Ketones Paying Particular Attention Catalysisin Organic Synthe.sis, Wiley, New York, 1994, 61-82; d) T. Ohkuma, H. Ooka, T. Ikariya, R. Noyori, J . Am. Chem. Soc. 1995, 117, 10417- 10418; e) T. Ohkuma, H. Ikehira, T. Ikariya, R. Noyori, Synletr 1997, 467-468; f) J.-P. Tranchier, V. Ratovelomanana-Vidal, J.-P. Genet, S. Tony, T. Cohen, Tetrahedron Lett. 1997, 38, 295 1-2954; g) T. Ohta, T. Miyake, N. Seido, H. Kumobayashi, H. Takaya, J. Org. Chem. 1995, 60, 357-363; h) T. Ohkuma, H. Doucet, T. Pham, K. Mikami, T. Korenaga, M. Terada, R. Noyori, J. Am. Cliem. Soc. 1998. 120, 1086- 1087. [81 a) H. Brunner, Orgunometallics 1984, 3, 13541359; b) H. Nishiyama, M. Kondo, T. Nakamura, K. Itoh, ibid. 1991, 11, 500-508. c) M. B. Carter, B. Schiott, A. Gutierrez, S. L. Buchwald, J. Am. Cheni. Soc. 1994, 116, 11667- 11669. [91 E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, V. K. Singh, J. Am. Chein. Soc. 1987, 109, 79257926. [lo] a) T. Ohkuma, H. Ooka, S . Hashiguchi, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1995, 117, 26752676: b) H. Doucet, T. Ohkuma, K. Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F. England, T. Ikariya, R. Noyori, Angew. Chern. 1998, 110, 1792- 1796, Angew. Cheni. Int. Ed. 1998, 37, I703 - 1707. [ I I] X. Zhang, T. Taketomi, T. Yoshizumi, H. Kumobayashi, S. Akutagawa, K. Mashima, H. Takaya, J . Am. Cliem. Soc. 1993, 115, 3318-3319. 11 21 T. Nagata, K. Yorozu, T. Yamada, T. Mukaiyama, Angew. Chem. 1995, 107, 2309-231 I ; Angecv. Chem. In?. Ed. Engl. 1995, 34, 2145-2147. For a recent review on the asymmetric reduction of carbonyl groups with hydrides, see J. SeydenPenne, Reductions by the Alumino- and Borohydrides in Organic Sjnthesis, 2nd edn., Wiley, New York, 1997, 55-84. [13] Review: a) R. Noyori, S. Hashiguchi, A N . Chem. Res. 1997, 30, 97- 112; b) K. Matsumura, S. Hashiguchi, T. Ikariya, R. Noyori, J. A177. Cheiii. SOC.1997, 119, 8738-8739. [I41 K. Nakamura, T. Matsuda, A. Ohno, Tetrahcdro17:Asyinmetr). 1996, 7, 302 I - 3024. [IS] a) J. Takehara, S. Hashiguchi, A. Fujii, S. Inwe, T. Ikariya, R. Noyori, Chem. Connnun. 1996, 233-234; b) T. Langer, G. Helmchen, Tefnrhedror7 Left. 1996, 37, 1381 - 1384; c ) K. Piintener, L. Schwink, P. Knochel, ibid. 1996, 37, 8165-8168; d) T. Sanimakia. E. L. Stangeland, J. Org. Chem. 1997, 62, 6104-6105; e) M. Palmer, T. Walsgrove, M. Wills, ibid. 1997, 62, 5226-5228; f) F. Touchard, P. Gamez, F. Fache, M. Lemaire, TetrahedronLett. 1997, 38, 2275 2278; g) S. Inoue, K. Nomura, S. Hashiguchi, R. Noyori, Y. Izawa, Chmz.Lrtt. 1997, 957-958. [I61 Y. Jiang, Q. Jiang, G. Zhu, X. Zhang, TetrahedronLett. 1997, 38, 215-218. -

...

203

[I71 R. Berengeuer, J. Garcia, J. Villarasa, Tetruhedron:Asymmetry 1994, 5, 165- 168. 11 81 a) T. Osawa, T. Harada, A. Tai, J. Mol. Cutul. 1994, 87, 333 -342; b) T. Osawa, T. Harada, A. Tai, Cata/. Todciy 1997, 37, 465-480. [I91 a) M. J. Burk, M. F. Gross, T. G. P. Harper, C. S. Kalberg, J. R. Lee, J. P. Martinez, Pure Appl. Chem. 1996,68, 37-44; b) J. Albrecht, U. Nagel, Angew. Chem. 1996,108,444-446; Angew Chem. Int. Ed. Engl. 1996, 35, 404-407. [20] T. Imai, T. Tamura, A. Yamamuro, J. Am. Chem. Soc. 1986, 108, 7402-7404. [21 I F. Touchard, F. Fache, M. Lemaire, Tetrahedron:As,ymmetry 1997, 8, 33 19-3326. [22] R. Stiirmer (BASF AG), personal communication. [23] Review: K. Mori, Chem. Commurz. 1997, 13, 1153-1158. [24] T. Imamoto, J. Watanabe, Y. Wada, H. Masuda, H. Yamada, H. Tsuruta, S. Matsukawa, K. Yamaguchi, J. Am. Chein. Soc. 1998, 120, 1635-1636. [25] Earlier results see also the relevant chapters in: M. Beller, C. Bolm (Eds.), Transition Metals ,fiw Organic Synthesis, Wiley VCH, Weinheim, 1998. 1261 N. Itoh, N. Mizuguchi, M. Mabuchi, J. Mol. Catal. B: Enzym. 1999, 6 , 41 -50. [27] a) K. Nakamura, J. Mot. Catal. B: Enzym. 1998,5, 129- 132; K . Nakamura, T. Matsuda, M. Shimizu, T. Fujisawa, Tetrahedron 1998,54, 8393-8402, c ) K. Nakamura, T. Matsuda, J . Org. Chem. 1998,63, 8957 - 8964. [28] Y. Kawai, K. Hida, M. Tsujimoto, S. Kondo, K. Kitano, K. Nakamura, A. Ohno, Bull. Cliem. Soc. Jap. 1999, 72, 99-102. [29] A. Sutherland, C. L. Willis, 1. Org. Chem. 1998,63, 7764-7769. [30] A. Liese, T. Zelinski, M.-R. Kula, H. Kierkels, M. Karutz, U. Kragl, C. Wandrey, J . Mol. Cutul. B: Enzym. 1998, 4 , 91 -99. 1311 P. Besse, T. Sokoltchik, H. Veschambre, Tefruhedrorz: Asymmetry 1998, Y, 4441 -4457. 1321 V. Crocq, C. Masson, J. Winter, C. Richard, G. Lemaitre, L. Lenay, M. Vivat, J. Buendia, D. Prat, Org. Process Rex Dev. 1997, I , 2- 13. [33] R. Wendhausen, P. J. S. Moran, I. Joekes, J. A. R. Rodrigues, J . Mol. Caful. B: Enzynz. 1998, 5, 69-73. 1341 a) Z. X. Shen, W. Huang, J . W. Feng, Y. W. Zhang, Tetrahedron: Asynnwfry 1998, 9, 1091 1095; b) K. Manju, S. Trehan, Tetrahedron: Asymmetry 1998, 9, 3365-3369; c) R. Hett, C. H. Senanayake, S. A. Wald, Tetrahedron Lett. 1998, 39, 1705- 1708; d) M. Shimizu, K. Tsukamoto, T. Matsutani. T. Fujisawa, 7ktruhedron 1998, 54, 1026510274; e) M.P. Sibi, G. R. Cook, P. R. Liu, Tetrahedron Lett. 1999, 40, 2477-2480. 13.51 E. J . Corey, C. J. Helal, Aiigew. Chem. Int. Ed. 1998, 37, 1987-2012. -

204

C. Enantioselective Cataly.sis

[36] E. J. Corey, A. Guzmann-Perez, S. E. Lazerwith, J. Am. Chem. Soc. 1997, 119, 11769- 11776. 1371 J. Bach, M. Galobardes, J. Garcia, P. Romea, C . Tey, F. Urpi, J. Vilarrasa, Tetrrrhedron Lett. 1998, 39. 6765-6768. 1381 a) R. Berenguer, M. Cavero, J. Garcia, M. Munoz, Tetrahedron Lett. 1998, 39, 2183-2186; b) T. K. Ymg, D. S. Lee, Tetrahedron: Asymnzetry 1999, 10, 405-409. (391 A. M. Salunkhe, E. R. Burkhardt, Tetrahedron Lett. 1997, 38, 1523-1526. [40] L. Schwink, P. Knochel, Chern. ELK J. 1998, 4, 950-968. 1411 T. Ireland, G. GroBheimann, C. Wieser-Jeunesse. P. Knochel, Angew. Chern. Int. Ed. 1999, 38, 32123215. 1421 A. Ford, S. Woodward, Synth. Commuri. 1999, 29, 189-192. (431 G. Giffels, J. Beliczey, M. Felder, U. Kragl, Tetrcrhedron: Asymmetry 1998, 9, 69 I -696. [44] T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa, K. Murata, E. Katayama, T. Yokozawa, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1998, 120, 13529-13530. 1451 U. Matteoli, V. Beghetto, A. Scrivanti, J. Mol. Card. A: Chem. 1999, 140, 131 -137. 1461 Review: V. Ratovelomanana-Vidal, J.-P. Genkt, J . Organomet. Chem. 1998 567, 163-171. [47] P. Cao, X. Zhang, J. Org. Chem. 1998,64, 21272 129. 1481 G. Zhu, A. Casalnuovo, X. Zhang, J. Org. Chem. 1998, 64, 8100-8111. 1491 P. J. Pye, K. Rossen, R. A. Reamer, R. P. Volante, P. J . Reider, Tetrahedron Lett. 1998, 39, 4441 -4444. [SO] T. Yamano, N. Taya, H. Kawada, T. Huang, T. Imamoto, Tetruhedron Lerr. 1999, 40, 2577 -2580. IS11 V. Blandin, J. E Carpentier, A. Mortreux, Tetruhedron: Asymmetry 1998, 9. 2765-2768. [52] C. Pasquier, J. Eilers, 1. Reiners, J. Martens, A. Mortreux, F. Agbossou, Synlett 1998, 1162.

[53] C. Pasquier, S. Naili, L. Pelinski, J. Brocard, A. Mortreux, F. Agbossou, Tetrahedron: Asymmetry 1998, 9, 193- 196. [54] M. J. Burk, C. S. Kalberg, A. Pizzano, J. Am. Chem. Soc. 1998, 120, 4345-4353. [ 5 5 ] Q. Jiang, D. Xiao, Z. Zhang, P. Cao, X. Zhang, Angew Chem. Int. Ed. 1999, 38, 516-518. [56] a) M. J. Palmer, M. Wills, Review: Asymmetric Transfer Hydrogenation of C = O and C = N Bonds, Tetrahedron: A.symmetry 1999, 10, 2045 2061; b) J. A. Kenny, M. J. Palmer, A. R. C . Smith, T. Walsgrove, M. Wills, Synlett 1999, 1615- 1617. [57] Y. Arikawa, M. Ueoka, K. Matoba, Y. Nishibayashi, M. Hidai, S. Uemura, J. Orpnomet. Chem. 1999, 572, 163-168. [581 D. A. Alonso, D. Guijarro, P. Pinho, 0. Temme, P. G. Andersson, J. Org. Chem. 1998, 63, 2749275 1. [59] Y. Jiang, Q. Jiang, X. Zhang, J. Am. Cliem. Soc. 1998, 120, 3817-3818. [60] K. Murata, T. Ikariya, .I. Org. Cheni. 1999, 64. 2186-2 187. [61] D. J. Bayston, C. B. Travers, M. E. C. Polywka, Tetrahedron: Asyinmetry 1998, 9, 2015-2018. [62] R. ter Halle, E. Schulz, M. Lemaire, Synlerr 1997, 1257-1258. [63] L. Schwink, T. Ireland, K. Puntener, P. Knochel, Tetrcihedron: Asymmetry 1998, 9, 1143- 1163. 1641 T. Ohta, S. Nakahara, Y. Shigemura, K. Hattori, 1. Furukawa, Cliem. Lett. 1998, 491 -492. [651 K. Everare, J. F. Carpentier. A. Mortreux, M. Bulliard, Tetrahedron: Asymmetry 1998, 9, 297 l 2974. [661 X. Zhang, Y. Geng, M. Yin, M. Hang, Y. hang, J. Mol. Sci. 1999, I S , 243-244. Poster on the 1XIh International Symposium on Fine Chemistry and Functional Polymers in Haikou, P. R. China (December 1999). -

Part 11. Applications

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

A. Total Synthesis of Natural Products Total Synthesis of Ikarugamycin Oliver Schwarz and Hans-Gunther Schrnalz Institut f i r Organische Chemie, Universitat Koln. Germany

Acyclic q4-butadiene Fe(CO), complexes have repeatedly demonstrated their enormous value for organic synthesis in the last few years [ I ] . In this context, both the changed reactivity of the ligand and the steric effect(s) of the Fe(CO), fragment have been exploited for the stereocontrolled generation of new chirality centers in the neighborhood of the butadieneFe(CO), unit. It is important to note that unsymmetrically substituted complexes (e.g. of type A with R' # R2) are chiral.

This synthesis will be discussed in some detail in the following.

The Target Molecule: In 1972 Ito and Hirata reported on the isolation and structure elucidation of (+)-ikarugamycin as the first representative of a new class of macrolactam antibiotics [ 5 ] .Besides its remarkA ent-A able biological activity, ikarugamycin is of interIn order to utilize such a chiral substructure as a est because of its unusual architecture and it source of absolute stereochemical information in a represents an attractive target structure for organic synthesis [6, 7, 81. synthesis, it is necessary to employ the complexes According to R. K. Boeckmann [6], the retroA and ent-A in non-racemic form. While the enansynthetic analysis of ikarugamycin lcads (by distioselectivc preparation of such chiral complexes was achieved in the past more or less exclusively connection of the double bonds within the macrovia resolution of racemic mixtures, the diastereo- cyclic ring) to the tricyclic building block 2 which, because of its eight subsequent stereocenters, selective complexation of chirally modified liis still of considerable structural complexity gands was shown more recently to be a practical (Scheme I ) . In the synthesis of Roush discussed alternative [2]. Another possibility, the enantiosehere [4], the cis-anti-cis configured decahydrolective conversion of prochiral metal complexes by means of chiral reagents, has been achieved by W. us-indacene derivative 2 is formed by cyclization R. Roush 131. In a remarkable (formal) total syn- from the bicyclic dialdehyde 3, which in turn is the thesis of the antibiotic (+)-ikarugamycin (l), product of an intramolecular Diels-Alder reaction Roush et al. apply their method and demonstrate of the acyclic dialdehyde 4. The special feature of the Roush synthesis is the way the acyclic interin a highly convincing fashion the synthetic usefulness of acyclic butadiene-Fe(CO), complexes [4]. mediate 5 is prepared from the iron complex 6.

208

A . Total Synthesis of Nutural Products

3

0

..___

OHC

K: 8

a

MeO..(oMflii,Me

0 OHC

5

6

OHC

4

Scheme 1. Retrosynthesis of ikarugamycin according to W. R. Roush and R. K. Boeckmann.

Stereoselective Synthesis of the Acyclic Intermediate 5

from diol 7 by complexation and oxidation, with the chiral crotylboronic ester 8. After work-up, the chiral complex 9 is isolated in excellent yield as a virtually pure diastereomer in high enantiomeric purity. In this remarkable (reagentcontrollcd) reaction, two new stereocenters as

The synthesis (Scheme 2) starts with an impressive transformation, i.e. the conversion of the prochiral complex 6, which is easily prepared

7

6

9 OH

-

L 98 %

ee

H2C=CHMgBr THF, -78 + 0 “C 83 - 88 %

0

0

I

10

0

MeFMe

11

1. A@ DMAP pyridine. CH2CIP

Scheme 2. Enantioselective synthesis of the acyclic intermediate 5 according to W. R. Roush.

Total Synthesis of Ikariigamycin

209

Me

.-

L (&Et3AI

15

Figure 3

well as the chiral metal-complex substructure are generated with extremely high stereoselectivity. Practically, only one of eight possible diastereomers is formed. The formation of the two chirality centers, with the relative and absolute configuration as shown in structure 9, can be rationalized by assuming a chair-like transition state of type B (Fig. 1 ) [7]. More difficult to explain is how the reagent distinguishes between the two enantiotropic aldehyde functions in substrate 6 [3]. Condensation of complex 9 with Meldrums acid (10) gives complex 11 in good yield, which is then reacted with an excess of vinyl-MgBr to afford complex 12. The complete diastereoselectivity of the latter reaction can be explained by assuming that the substrate prefers conformation 14 shown in Fig. 2 and that the nucleophile attacks the ligand exclusively from the less hindered 7-r-face opposite to the Fe(CO),. Next, the ethyl substituent is introduced via stepwise conversion of 12 with acetic anhydride and triethyl aluminum. This results in the completely diastereoselective formation of complex 13. The fact that the substitution of the oxygen func-

oc\ 5co / 2 Fe

tie

\\

>MgBr

H&=C,

14

Figure 2

H

0

tionality occurs with complete retention of configuration can be explained as follows (Fig. 3). Supported by the iron fragment as a neighboring group, the acetoxy group leaves the molecule in an exo fashion. The resulting iron-stabilized cation 15 is then attacked by the nucleophile (Et,AI) from the ex0 side, i.e. the side from which the acetoxy group left the molecule. At this point of the synthesis the Fe(CO), fragment has done its job and is oxidatively removed. Hydrolysis, decarboxylation and re-esterification then afford the desired intermediate 5. With the aid of the small iron fragment, the synthesis of the acyclic intermediate 5 has been achieved in a short, highly selective sequence. Thus, the problem of the stereocontrolled generation of distant stereocenters ( 1,6 asymmetric induction) was solved in an elegant manner.

The Completion of the Ikarugamycin Synthesis The transformation of the acyclic intermediate 5 into the tricyclic ikarugamycin precursor 2 was achieved by Roush following the route shown in Scheme 3. At first, both terminal double bonds of 5 are hydroborated and the diol, obtained after oxidative work-up, is treated with mild acid (PPTs) resulting in the selective protection of one OH function through lactone formation. Now, the other OH group can be selectively oxidized to give the aldehyde 16, which is then converted in a Wittig reaction to the a,/l-unsaturated ester 17. The transformation of 17 to the dialdehyde

210

.

A. Totul Synthesis of Natural Products 1 . g-BBN, THF H202,NaOAc 2. PPTs 3. Swern ox.

.

57 %

fl

/Me

1 . DIBAH

2. Dess-Martin ox.

?

(Me0)2PC , 02Me

MeoYI

,.Me

LiCI, DBU

(Me

1. LiOH, then CH2N2 2. Swern ox. 3. (MeO)&H. PPTs 4

56 %from 16

Me02C

Me02C

0

18

(Me

MeOTM 8 n,e

1 . C6H6, 85 "C 2. BZl2NH2'TFACO. c&. 50 "c

OMe

17

[(P~~P)CUHIG C6H6, HzO

-

88 %

OHC

OHC

2 85 %

OHC

4

19

Scheme 3. Preparation of the tricyclic ikarugamycin building block 2 according to W. R. Roush.

4 steps

3 steps

1

51 70

55 %

2

20

t-BuOK

1 75 %

NO*

22

No,

21

Scheme 4. Conversion of intermediate 7 into ikarugamycin (1) according to R. K. Boeckmann

4 is achieved in a 5-step sequence via the ester 18. The intramolecular Diels-Alder reaction of 4 (+3) is directly followed by an aldol ring closure to give 19, which is converted to the ikarugamycin precursor 2 by 1,4-reduction.

At this point, the synthesis of W. R. Roush 141 ends. It can, however, be considered as a formal total synthesis of ikarugamycin because the conversion of 2 into the target molecule 1 had been achieved by Boeckmann et al. (Scheme 4) [6a].

Total Synthesis of Ikarugamycin

Conclusion In comparison to the other syntheses of ikarugamycin [6, 81 or tricyclic precursors [9), the (formal) total synthesis according to Roush [4] and Boeckmann [6a] is particularly convincing because of its relatively small number of steps, its extremely high selectivity and its significant overall yield (> I % over 28 steps). The key of this success lies in the opening of the synthesis in which Roush and Wada utilize the various possibilities offered by the butadiene-Fe(C0)3 chemistry for acyclic stereocontrol. They thus impressively demonstrate that the use of transition metal n-complexes as synthetic building blocks opens new and powerful strategies for the synthesis of complex target molecules.

References Reviews: a) A. J. Pearson, Iron Compounds in Organic Synthesis, Academic Press, London, 1994, chapter 4; b) L. S. Hegedus, Trunsition Metuls in the Synthesis of C(iinp1e.u Organic Molecules, University Science Books, Mill Valley, CA, 1994, chapter 7.3; c) R. Cree, Synthesis 1989, 341; d) M. Franck-Neumann, in: Organonzetal1ic.s in Organic Synthesis; A. de Meijere, H. Loin Dieck (eds.) Springer-Verlag, Berlin, 1987, p. 247. a) A. J . Pearson, K. Chang, D. B. McConville, W. J. Youngs, Orgunometullics 1994, 13, 4; b) H . 4 . Schmalz, E. HelJler, J. W. Bats, G. Diirner, Tetruhedron Lett., 1994, 35, 4543.

21 I

[31 W. R. Roush, J. C. Park, Tetrahedron Lett. 1990, 31,4707. [4] W. R. Roush, C. K. Wada, J. Am. Chenz. Soc. 1994, 116, 2151. [5] a) S. Ito, Y. Hirata, Tetruhedron Lett. 1972, 1181: I 1 85; 2557: b) S . Ito, Y. Hirata. Bull. Chem. Soc. Jupn. 1977, 50, 227; 1813. [6] First total synthesis: a) R. K. Boeckmann. Jr., C. H. Weidner, R. B. Perni, J. J. Napier, J. Am. Chem. SOC. 1989, I l l , 8036; b) R. K. Boeckmann, Jr., J. J. Napier, E. W. Thomas, J. Org. Chem. 1983, 48, 4152 [GSE] [7] W. R. Roush, K. Ando, D. P. Powers, A. D. Palkowitz, R. L. Haltermann, J. Am. Chern. Soc. 1990, 112, 6339. [8] Second total synthesis: a) L. A. Paquette, D. Macdonald, L. G. Anderson, J. Wright, J . Am. Chem. Soc. 1989, 111, 8037; b) L. A. Paquette, J. L. Romie, H . 3 . Lin, J. Wright, J. Am. Chem. Soc. 1990, 112, 9284: c) L. A. Paquette, D. Macdonald, L. G. Anderson, J. Am. Chem. Soc. 1990, 112, 9292. [9] For the synthesis of ikarugamycin precursors, see: a) M. J. Kurth, D. H. Burns, M. J. OBrien, J. Org. Cliem. 1984, 49, 733; b) J. K. Whitesell, M. A. Minton, J. Am. Clzenz. Soc. 1987, 109, 6403; c) R. C. F. Jones, R. F. Jones, Tetrahedron Lett. 1990, 31, 3363: d) R. C. F. Jones, R. F. Jones, Tetrahedron Lett. 1990, 31, 3367.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Palladium-Catalyzed Synthesis of Vitamin D-Active Compounds Sandra Krause and Hans-Giinther Schmalz Institiit $ir Organische Chemie, Universitat Kliln, Germany

Vitamin D, (1) is an essential factor for the life of animals and man. It is formed in the skin under the influence of UV light from provitamin D, (2) and is one of the most important regulators of calcium metabolism. For instance, children lacking vitamin D develop rickets and adults suffer from osteoporosis.

to develop efficient and flexible synthetic routes to such compounds.

Ho."

OH

3

1

2

The discovery that vitamin D, (l),also called calciol [I], is actually a pro-hormone and not a vitamin as previously assumed has induced intense worldwide research activities within the last 20 years. Nowadays, it is known that the prohormone is transformed in liver and kidney into physiologically much more active metabolites by hydroxylation. In particular, the 1 cr,25-dihydroxylated derivative, calcitriol (3), performs a key function in the regulation of different physiological events [2]. Some hydroxylated vitamin D derivatives and structural analogs are currently being clinically tested as drugs for the treatment of a range of human diseases such as cancer, psoriasis or immune defects. In order to cover the increasing demand for vitamin D-active substances and to make available labeled or structurally modified derivatives for research purposes, chemists are challenged

Since the completion of the first total synthesis of calciol (1) by H. H . Inhoffen, H. Burkhardt and G . Quinkert in 1959 [3], several research groups have focussed their activities on the synthesis of vitamin D derivatives [4]. In the course of these investigations, two particularly powerful strategies have been identified, which still today [ 5 ] form the basis of many syntheses of lu-hydroxylated vitamin D derivatives (Schemel). The biomimetic approach (strategy A) starts from the intact steroid skeleton and follows the construction principle ABCD + ACD. Irradiation of suitable functionalized dehydrocholester01s (4) leads to the formation of (6Z)-tacalciol derivatives (5) by electrocyclic ring opening. These intermediates are subsequently converted into the desired products (6) by thermal isomerization (sigmatropic 1,7-H-shift). The main disadvantage of this method is the circumstance that the functionalized starting materials have to be prepared in long linear sequences, which usually results in poor overall yields. The second strategy is based on the modular ACD and acconstruction principle A + CD ---f

Palladiuin-Catal~zedSynthesis of Vitamin D-Active Compounds

dR

213

Strategy A (ABCD -ACD):

H I H

R'O

A

\

4

5

Strategy B (A + CD -ACD):

8 7

Scheme I

cordingly offers high flexibility. Following a protocol developed by B. Lythgoe [ 6 ] ,ring A building blocks of type 7 are coupled with C D building blocks of type 8 by Wittig olefination. Whereas useful total synthetic methods have been established for the preparation of ring A building blocks, no really competitive approaches are yet available for the total synthesis of C D building blocks [7]. Therefore, the latter are usually prepared from Grundmann's ketone (9) or the Inhoffen-Lythgoe diol (lo), which are obtained by partial synthesis (degradation) of vitamin D, or vitamin D2, respectively.

9

10

In recent years, the development of powerful methods for palladium-catalyzed C-C bond formation I S ] has led to the development of novel and highly efficient synthetic avenues to vitamin D-active compounds, which, at least in many respects, are superior to the "classical" routes mentioned above. One of these new strategies was developed in the laboratories of A. Mourifio [9] and W. H. Okamura [ 101 and has been successfully applied

in the synthesis of a variety of vitamin D derivatives [9, lo]. Following this strategy (Scheme 2), the target molecules 11 are derived from ynedienes of type 12, which in turn represent products of a palladium-catalyzed coupling reaction [S] between the building blocks 13 and 14. Enol triflates of type 13 are easily accessible from Grundmann's ketone (15) or related ketones, while ring A building blocks of type 14 can be prepared, for instance, from (S)-carvone (16). As an example, a remarkable synthesis of calcitrio1 (3) will be discussed here (Scheme 3), which was described by A. Mouriiio [9g]. This synthesis starts with the Inhoffen-Lythgoe diol (10) which is first converted to the iodide 17. From this intermediate, the CD building block 18 is obtained by coupling with acrylic acid methyl ester in aqueous ethanol under sonochemical conditions. Using Pd-catalyzed coupling, triflate 18 is then coupled to the ring A building block 19, which i s accessible in seven steps (36 o/o yield) from (S)-carvone (16) [ll]. The coupling product 20 is transformed by hydrogenation and isomerization in excellent yield to 21, from which calcitriol 3 is finally obtained by treatment with methyl lithium and tetrabutyl ammonium fluoride. All in all, this synthesis impresses because of its low number of steps and high overall yield. In addition, since the tertiary OH group in the side chain is generated in the last step of the synthesis, there is only a minimum need for protecting groups.

A. Tofu1Synthesis of Natural Products

214

q5 0

15

&

HO

R'o."

111

'

OR'

11

12

Me

FCo ke

14

-

Me ,,..H

82 %

6

OH

0

"

-

PZn, GO Cul, 2 M)I)e

Me ,$..H

1$

3 steps

\

65 '10

:

17

18

19

2 mol % (Ph3P)zPdC12 NEt3, DMF, 75 "C, 1 h

"'i(E

A

Me

1. MeMgI. EtzO 2. TBAF,THF

73 %

isooctane, reflux

93 %

20

Another very elegant approach towards the vitamin D skeleton has been developed by B. M. Trost and his co-workers [12]. In contrast to all

"O.'\

2 OH

11

Pd(o)

86 o/v

-CO2Me

C02Me

21

G)

1

1. Hz, Lindlar cat. I 2.

+

I n

OTBS

TBSO'"

TfO

TfO

10

Scheme 2

16

other strategies, the A ring need not be preformed in this case. According to Trost, the target molecules (11) are retrosynthetically disconnected to form CD building blocks of type 22 and enynes of type 23. By Pd-catalyzed coupling of the components 22 and 23, the construction of ring A and its attachment to the CD building block (under stereoselective establishment of the complete triene unit) is achieved in a single synthetic operation. Mechanistically, this magic-looking transformation can be rationalized as follows (Scheme 4). In the first step a Pd(0) species reacts with the alkenyl bromide 22 to an intermediate of type 24 (oxidative addition). A subsequent syn-inser-

p eR' 22

Br

R'O."'

23

Scheme 3

Pulladium-Cutalyzed Synthesis of Vitamin D-Active Compounds

215

I"

t

\

PdL,Br

f,

23 25

" n

46%

26

Br

Scheme 4

30 mol % PPh3,

J

NEt3,toluene 120 "C, 2 h 2. TBAF, THF

27

52 %

OH

3 28

Scheme 5

29

tion of the alkyne 23 then leads to a complex of type 25, which is finally transformed into the desired product in a Heck-type reaction, i.e. by olefin insertion (cycloisomerization) and /I-H-elimination. The Trost synthesis of calcitriol (3) is shown in Scheme 5. In a Wittig reaction, the hydroxylated Grundmann's ketone 26 (obtained by partial synthcsis) is transformed into the alkenyl bromide 27 with astonishingly high diastereoselectivity (EIZ 2 50 : 1). The chiral enyne 29, which is needed as the second building block for the coupling step, is prepared from the aldehyde 28

in only a few steps. The enantioselectivity is achieved by kinetic resolution (applying Sharpless' method). The crucial Pd-catalyzed coupling step then proceeds smoothly (despite the presence

'O'

&; z

RO<,&R

OR

30

OR

31

216

A. Total Synthesis of Natural Products

x:lg

uo

L i F ~ ~ ~ 1. MeOCH2CI.~ i-PrzNEt

o..,,

BF3'EtZO THF, 0 "C

= o o 32

f

33

LiAIH4,NaOMe

MOMO~"

-

60%

o

&:

*

34

10 11 mol% rnol %Pd(OAc)* PPh3

KzC03, CH3CN 80 "C, 5 h

MOMO.."

Of

38

*

58%

of the unprotected hydroxyl group). After fluoride-induced cleavage of the silyl protecting groups, isomerically pure calcitriol (3) is obtained in excellent overall yield. An approach to trihydroxylated ring A building blocks of type 30, which is also based on an intramolecular Heck reaction (of substrates of type 31), was described by T. Takahashi [ 131. In this synthesis (Scheme 6), the C,-symmetrical triacetonide of D-mannitol (32) is converted via the epoxide 33 and its nucleophilic addition product 34 to the propargylic alcohol derivative 35. From this intermediate, the Z-configured vinyl iodide 36 is stereoselectively obtained by hydroalumination/iodination. The Pd-catalyzed Heck cyclization then affords the isomerically pure product 37, which represents a potential building block for the synthesis of la,2p,25-trihydroxy-vitamin D, following the classical Wittig strategy of Lythgoe. Of course, one could also think about opening the epoxide 33 with lithium acetylide to the enyne 38, which could eventually be further reacted by Trost'u method (e.g. with the vinyl bromide 27).

O-jc

44 %

960h

Of

37

36

......*

*

Ho.'\

O-jc

f

35

33

CHzC12,O "C 2. PPTs. MeOH, 25 "C

Scheme 6

The examples discussed in this paper demonstrate that Pd-catalyzed coupling reactions can be successfully utilized in the convergent (modular) synthesis of vitamin D-active compounds. The new synthetic routes open an efficient and highly selective access to a variety of vitamin D analogs. While reliable methods exist today for the construction of the triene system and for the synthesis of the ring A precursors, the search for efficient total synthetic approaches to the C D building blocks still remain a challenging task for the future.

References [ I ] For the nomenclature of vitamin D and related compounds, see: Pure Appl. Chern. 1982, 54, 151 1; ihid. 1989, 61, 1783. 121 Reviews: a) H. F. DeLuca, J. Burmester, H. Darwish, J. Krisinger, Comprdzensive Medicinul Chemistry, Pergamon, New York, 1990, Vol. 3, 1129; b) A. W. Norman, R. Bouillon, M. Thomasset (eds.) Vitamin D: Gene Regulation, Structure Function Anulysis and Clinical Application, de Gruyter, Berlin, 1991; c) A. W. Norman, R. Bouillon, M. Thomasset (eds.) Vitamin D: Chemi.yrry, Biology und Clinical Application cf the Steroid Hormone, Vitamin D workshop, Inc: Riverside, CA, 1997. [3] H. H. Inhoffen, H. Burkardt, G. Quinkert, Chern. Be< 1959, 92, 1564.

Pulladium-Catalyzed Synthesis of Vitamin D-Active Compounds [4] a) B. Lythgoe, Chem. Soc. Rev. 1980,449 and refs. cited therein; b) G.-D. Zhu, W. H. Okamura, Chem. Rev. 1995, 9.5, 1877; c) For a concise collection of total- and partial syntheses of vitamin D active compounds, see: G. Quinkert (Ed.), Synfonn 1985, 3. 41; ihid. 1986, 4, 131; ibid. 1987, 5, I ; d) H. Dai, G. H. Posner, Synthesis 1994, 1383, e) see also ref. 5c and refs. cited therein. (51 Selected more recent publications: a) K. Yamamoto, J. Takahashi, K. Hamano, S. Yamada, J. Or,?. Cliern. 1993, 58, 2530; b) G . H. Posner, H. Dai, K. Afarinkia, N. N. Murthy, K. Z. Guyton, T. W. Kensler, J. Or,?. Ckrnr. 1993, 58, 7209; c) M. de 10s Angeles Rey, J. A. Martinez Pkrez, A. Fernandez-Gacio, K. Halkes, Y. Fall, J. R. Granja, A. Mouriiio, J . Org. Chenz. 1999, 64, 3196. 161 B. Lythgoe, T. A. Moran. M. E. N. Nambudiry. J. Tideswell, P. W. Wright. J . Chern. Sot,. Perkin Truns. I 1978. 590. [7] P. Jankowski, S. Marczak. J. Wicha. Trtrtillet/ro/~. 1998, 1207I . [ZJSee, for instance: a ) R. F. Heck. Pu//rrt/innr Reagent.s in Orgtinic .Yxnthe.tic. Academic Pre\\. London, 1985. b) F. Diederich. P. J . Stan: ieds.) Meful-catn/x:et/ Cro.c.c- u i i i p / i / i , q Reuc.tion c. Wi leyVCH, Wcinheirn. 1998. 191 a) L. Castedo. A. Mouriiio. L. A. Sarandeses. Tetrtrheclrori Leu. 1986. 27. 1523: b ) L. Ca\tedo. J. L. Mascareiias, A. Mouriiio. fi,t/.ti/ietli.ori Lrrr.

217

1987, 28, 2099; c) L. Castedo, J. L. Mascareiias, A. Mouriiio, L. A. Sarandeses, Tetrahedron Leu. 1988, 29, 1203; d) J. L. Mascareiias, L. A. Sarandeses, L. Castedo, A. Mourifio, Tetrahedron 1991, 47, 3485; e) M . Torneiro, Y. Fall, L. Castedo, A. Mouriiio, Tetrzrhedron Lett. 1992, 33, 105; 9 L. A. Sarandeses, M. J. Vallis, L. Castedo, A. Mouriiio, Tetrahedron 1993, 49, 731; g) J. P. Sestelo, J. I>. Mascareiias, L. Castedo, A. Mouriiio, J. OrL?. Chern. 1993, 58, 118; h) J. R. Granja, L. Castedo, A. Mouriiio, J. Org. Chem. 1993, 58, 124. 1101 a) S. A. Barrack, R. A. Gibbs, W. H. Okamura, J. Org. Chem. 1988,53, 1790; b) M. L. Curtin, W. H. Okamura, J. Am. Chem. Soc. 1991,113,6958; c) A. S. Lee, A. W. Norman, W. H. Okamura, J. Org. C/iein. 1992, 57, 3846; d) A. S. Craig, A. W. Norman, W. H. Okamura, J. Org. Chem. 1992, 57, 4374; e ) W. H. Okamura, H. Y. Elnagar, M. Ruther, S. Dobreff, J. Org. Chern. 1993, 58, 600; f ) K. R. Muralidharan, A. R. de Lera, S. D. lsaeff, A. W. Norman, W. H. Okamura, J. Org. Chrrn. 1993, 58, 1895. 1 I I ] W. H. Okamura, J. M. Aurrecoechea, R. A. Gibbs, A . W. Norman, J. Org. Chem. 1989, 54, 4072. [ 121 a ) B. M. Trost, J. Dumas, J. Am. Chem. Soc. 1992, 114. 1924; b) B. M. Trost, J. Dumas, M. Villa, J . Ain. Chenz. Soc. 1992, 114. 9836. 1 131 T. Takahashi, M. Nakazawa, Synlett 1993, 37

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Syntheses of Oligo(thiazo1ine) Natural Products Sahine Hoppen and Ulrich Koert Institut fur Chemie, Humboldt- Universitat, Berlin, Germuny

Oligo(thiazo1ines) are a class of natural products with interesting structural features and promising biological activities (Scheme 1). Typical members are mirabazole C (1) [l], mirabazole B (2) [I], tantazole B (3) [2], and thiangazole (4) [3,4]. The mirabazoles were isolated from the bluegreen alga Scytonemea mirabile [l]. The tantazoles were named after the place of their first isolation, Mount Tantalus on Hawaii. The biological source of thiangazole is strain PI 3007 of the bacterium Polyangium spec. [3]. The mirabazoles and tantazoles offer selective cytotoxicity profiles [ l , 21. Thiangazole is a potent HIV-1 inhibitor [ 3 ] . The biosynthesis of the oligo(thiazo1ines) is considered to involve 2-methylcysteine, an amino acid of rare occurrence in nature. Stimulated by these interesting new lead structures, several research groups focussed on the total synthesis of oligo(thiazo1ine) natural products. Here we discuss the synthetic work of Fukuyama et al. [5] (tantazole B, 1993), Ehrler et al. [6] (thiangazole, 1994), Pattenden et al. [7]

(thiangazole, 1994), Heathcock et al. [8] (mirabazole C, 1994), Wipf et al. [9] (thiangazole, 1995) and Kiso et al. [lo] (mirabazole C, 1996). Special emphasis is given to - the preparation of the enantiomerically pure (R)- and (S)-2-methylcysteine, - the closure of the thiazoline rings - the synthetic strategy (sequential or multiple formation of thiazoline rings). The groups mentioned above have used their synthetic expertise to prepare other oligo(thiazoline) natural products as well [ I l l . This work is methodologically related to the total syntheses discussed below.

Enantiomerically Pure (R)- and (S)-2-Methylcysteine Building Blocks Access to enantiomerically pure (R)- and (S)-2methylcysteine is necessary to assemble these oligomeric heterocyclic compounds. The decisive

d R = H: rnirabazole C 1 R = CH,: mirabazole B 2

tantazo'e

Scheme 1. Oligo(thiazo1ine) natural products.

thiangazole 4

Syntheses of Oligo(thiazo1ine) Natural Products

219

H enzyme

chromatographic resolution

C02Me

6

C02Me

Fukuyama

7

Ehrler

BnS

/ C B z N V L O

Pattenden

alkylation

Heathcock BnS

CBzN L O p< 12

Kiso

Wpf

stereoselective

H stereoselective alkylation

Cbz’

Cbz’

13

c\n

SeSN

14

CO~H

15

Scheme 2. Preparation of the enantiomerically pure (R)- and (S)-2methyIcysteine building blocks.

pig liver H

NaBH4,

esterase pH 7.5.23OC

H C02H

91%

C02Me

C02Me

6

THF-EtOH (lO:l), 50%

*

90%

H Boc/N*,, I O ‘H

7

Ph3P. DEAD, CH2C12. O°C

H

16

AcSH. K2CO3, THF2 ,3d :h

Boc/N,+

C02H

74%

H

AcS

la

17

CIC02Ef Et3N. THF, 5%. then NaBH4

-

1.6M HCI, 100°C 2 . 6 0 ~ 0 NaOH. , THF-H20 3. Ph3P, DEAD,

H

H

786%

OH ent-16

Me,CHCOSH,

54%

ent-I7

H

I

19

Scheme 3. Fukuyama’s synthesis of the ( R ) and (S)-2-methylcysteine building blocks.

220

N C , Q

A . Total Synthesis of Nutural Products

-

1) HCI. EtOH 2 ) ethyl-L-cysteine x HCI Pr2NEt,EtOH

CO,Et

LDA. Mel,

90%

81%

8

20 prep. HPLC (cellulose triacetate, EtOH,/HZO, 94:6)

1 ’

ent-21

21

I

1) 4M HCI, 2 ) EtOH. HCI, reflux (95%)

1) 4M HCI, 2 ) EtOH, HCI, retlux (95%)

3

I

,.CO2Et

CI- H ~ N +

HS

5 xHCI

steps for the construction of the chiral center of 2-methylcysteine are shown in Scheme 2. Fukuyama [ 5 ]obtains the building blocks by an enzymatic ester hydrolysis (6 + 7). As both enantiomers are needed in the synthesis, Ehrler [6] uses the separation of a racemate by chromatography of 8. A stereoselective alkylation is the key step in the work of Pattenden [7] (9 -+ lo), Heathcock [8] (11 + 12) and Kiso [ l o ] (13 + 14). Wipf [9] starts from (S)-methylserine 15 (Scheme 3). The preparation of protected (R)-2-methylcysteine by Fukuyama starts with the enantioselective discrimination of the prochiral ester groups in 6 with pig liver esterase (Scheme 3) [Sl. The ester function of the resulting product 7 is selectively reduced (7 + 16). Cyclization to the p-lactone gives compound 17. Attack of the thioacetate at the p-lactone methylene carbon atom provides the (R)-compound 18. Selective reduction of the carboxylic acid function in 7 gives the (S)-compound 19 in an analogous fashion. Ehrler’s synthesis was carried out in the CibaGeigy laboratories. There exists not only plenty of expertise on chromatography on chiral columns, but also the equipment for chromatographic resolution on a preparative scale. Therefore Ehrler’s

HS entd HC,

Scheme 4. Ehrler’s synthesis of the ( R ) - and (S)-2-methylcysteine building blocks.

key step for the synthesis of (R)- and ( 9 - 2 methylcysteine (Scheme 4) is the separation of thiazoline (8) on cellulose triacetate. Thiazoline (8) is readily available from cysteine ethyl ester and benzonitrile. The separated enantiomers 18 and erzt-18 can be converted to (R)- and (S)-2-methylcysteine ethyl ester hydrochloride 5 x HCI and ent-5 x HCI under standard conditions. Pattenden’s synthesis of (R)-and (S)-2-methylcysteine 1121 is based on Seebach’s self regeneration of chirality [ 131. Scheme 5 shows the synthesis of the (R)-isomer 5b. From the (R)-cysteine methyl ester 22 the thiazolidine 9 is obtained, which can be deprotonated with LDA. The attack of the methyl iodide on the enolate takes place from the side opposite to the bulky tert-butyl group (23 4 10). The auxiliary chiral center is removed under acidic conditions and (R)-2-methylcysteine methyl ester hydrochloride 5b x HCI is obtained. (S)-2-Methylcysteine methyl ester hydrochloride ent-5b x HCI can be prepared in the same way from (Qcysteine. The synthesis of the ( R ) - and (S)-2-methylcysteine by Heathcock (Scheme 6) uses a similar stereoselective alkylation for the introduction of the methyl group [8].

Syntheses of Oligo(thiazo1ine) Natural Products 1) tBuCHO. EbN. penlane

-

Dean-Stark conditions

HC0,Na HS

LDA. DMPU. THF, - g o y

,.\'332Me

81%

22 1

tBut"C>

9

22

5M HCI HS

ds 99:l 10

5b xHCl

Scheme 5. Pattenden's synthesis of the (R)- and (S)-2-methylcysteine building blocks.

BnS

!H C B z (S) NlroH

benzaldehyde. p-tsOH, 1.1,I-trichloroethane Dean-Stark conditions

40%

BnS

KHMDS. THF -78'C, 5 min then Me1 -> 20°C

BnS

*

cBzN!, ' 0

80%

P6

Pti 11

24

CBzN " 0

12

BnS

I

HCI, MeOH CI- H3N'

&M ,e

CBz-N

0

26

25

Scheme 6. Heathcock's synthesis of the ( R ) - and (S)-2-methylcysteine building blocks.

-

PhCH(OMe)2 BF3' OEt2, -1 5°C Cbz I

27

Cbz'

13

SBn

14

SBn

LiOH

28% over 3 steps

Cbz

Cbz

28

29

Scheme 7. Kiso's synthesis of the ( R ) - and (S)-2-methylcysteine building blocks

First, the diprotected cysteine 24 is converted into the oxazolidinone 11. Then a stereoselcctive alkylation takes place introducing the methyl group from the side opposite to the phenyl group (11 + 12). After removal of the auxiliary chiral center, the (S)-2-methylcysteine compound 25 is obtained. The (R)-2-methylcysteine compound 26 is accessible along the same route. The use of oxazolidinones

of the type 11 for the enantioretentive alkylation of acyclic amino acids originates from the work of Karady et al. [14]. A modification of the Karady method is used by Kiso [lo] (Scheme 7). BF3.0Et,-mediated condensation of Cbz-protected D - a h i n e with benzaldehyde dimethyl acetal provides the oxazolidinone 13. Stereoselective alkylation of 13 with bromomethyl ben-

222

A. Total Synthesis of Nuturul Products

1, TrCI, DMAP 2. NaN,, MeOH 3. Ph3P. CH$N k

O

1. Ses-CI, NEt3 2. BnOH, NaH

H

H

89-95%

43-64%

30

31

1. TsOH, MeOH 2. py 'SO3. DMSO 3. NaC102, THF

OTr

Ses: ( tnmethylsilyl)ethylsulfonyl OH

86%

Ses

Ses

32

Scheme 8. Wipf's synthesis of diprotected (S)-2-methylserine.

15

zylsulfide leads to the oxazolidinone 14. Again the electrophile is introduced from the less hindered side. The choice of base was crucial. Only with lithium diethylamide was a reasonable yield achieved. Subsequent hydrolysis of 14 provides the (R)-2-methylcysteine derivative 28. The related (S)-enantiomer 29 is available on the same way, starting with Cbz-protected L-alanine. To simplify the handling of intermediates, Wipf introduces the sulfur atoms very late in the course of thc synthesis [9]. Here 2-methyl-

serine 15 serves as masked 2-methylcysteine (Scheme 8). Starting from the (S)-2-methylglycidol 30 the aziridine 31 is obtained via 0-tritylation, ring opening with sodium azide and subsequent reductive cyclisation. After N-activation of the aziridine 31, treatment with sodium benzyloxide leads to a regioselective ring opening of the aziridine. The product 32 is detritylated and the resulting primary alcohol is oxidized to the 2-methylserine derivative 15.

35 34

17

1. TFA 2. benzene, -H20

Fukuyarna

r

EtOH. 180°C

sealed tube

A0

R

37

Ehrler

Heathcock (R2 = NHR) Ehrler (R2 = OEt)

R2 = OEt

5b

xHCI

36

5

xHCI

+

E"

36

Scheme 9. Closure of the thiazoline rings.

Syntheses .f Oligo(thiazo1ine) Natural Products

Closure of the Thiazoline Rings After the preparation of the 2-methylcysteine compounds, the ring closure to the thiazoline 33 is the next step in most of the synthetic strategies. The key reactions used are summarized in Scheme 9. Fukuyama [ 5 ] obtained the thioester 35 from the reaction of the thiocarboxylic acid anion 34 with the p-lactone compound 17. After acidic deprotection of the Boc group, the thiazoline ring is successfully closed in benzene under Dean-Stark conditions (35 ---$ 33) in yields between 60 and 80 %. Ehrler [6] and Pattenden [7] choose a more classical way. They close the thiazoline ring by condensation of the aminothiol hydrochloride 5 x HCI with a nitrile. The yields are generally modest (45 and 55 %) except in one case [6]. Installation of the necessary nitrile function hinders its repetitive use, as this procedure causes a considerable loss of material. Heathcock [8] and Ehrler [61 choose the thiolamide 37 as a key compound. Titanium tetra-

chloride in dichloromethane turned out to be the best choice for the thiazoline ring closure. Thus, Heathcock successfully closes all four rings of mirabazole C at once in a remarkable 45 % yield. In one synthetic step all four thiazoline rings are set up! Ehrler uses titanium tetrachloride for the consecutive construction of single thiazoline rings. The yield for one closure is between 30 and 35 %. Wipf [9] and Kiso [ 10) use a multiple ring closure with titanium tetrachloride according to Heathcock's procedure.

Synthesis of Tantazole B by Fukuyama Fukuyama starts with the synthesis of three of the four thiazoline rings of tantazole B in a linear fashion (Scheme 10). Closure of the (S)-2-methylcysteine compound 19 (see Scheme 3) provides the thiazoline carboxylic acid 38. For the addition of the next thiazoline ring, the carboxylic acid 38 has to be converted to a thiocarboxylic acid. Fukuyama C02Me

1) TFA, 23'C. 30 min. 2 ) benzene, 8OoC, 4h

COOH

HSCH2CHZC02Me, BOP-CI, Et3N. 23OC, 5h

19 77%

3a

39 H I LCOOH Boc-Nt<,

1) 1-BuOK. t-BuOH,

THF, O°C, 30 min, ___)

41

1) TFA; benzene. 8OoC, 4h 2 ) HSCHZCH2CO2Me, BOP-CI, EtSN,

I O y S

*

74%

223

1) f-BuOK, t-BuOH. then 17, 2) TFA; benzene, 8OoC. 4h

-

63%

$3''' 42

Scheme 10. Fukuyama's synthesis of tantazole B (part I).

N y S

$5 N

43

5

224

A. Total Synthesis vf Natural Products

introduces the stable thioester 39 to circumvent the very unstable free thioacid. After a p-elimination of 39 under basic conditions, the desired thiocarboxylate 40 is generated in situ. Addition of the p-lactone 17 gives the thioester 41. Thiazoline ring closure leads to the corresponding bis(thiazo1ine) carboxylic acid derivative 42. The tris(thiazo1ine) carboxylic acid 43 is accessible by addition of another thiazoline unit. The target molecule tantazole B contains an oxazole ring as well as the four thiazoline rings. Because of the less nucleophilic oxygen, oxazoles or oxazolines have to be prepared under more drastic conditions than those for sulfur counterparts. Under these conditions, the thiazolines could be damaged. Because of that, Fukuyama prepares the oxazole first. Then he couples the

1 ) rac-threonine, BOPCI. Et3N,

CHzC12,23OC

18

2) Jones-oxidation Boc'

60%

oxazole with the tris(thiazo1ine) carboxylic acid 43 (Scheme 11). The synthesis of the oxazole compound 45 starts with the coupling of the N-protected (R)methylcysteine compound 18 with threonine terj-butyl ester using bis(2-oxo-3-oxazolidiny1)phosphinyl chloride (BOP-Cl) [ 151 as a coupling reagent. Jones oxidation of the threonine hydroxy group leads to the ketoamide 44. The desired oxazole ring is closed by treatment with thionylchloride/pyridine. After deprotection, the oxazole, compound 45 is obtained. In the next step the oxazole compound 45 is coupled with the tris(thiazo1ine) compound 43 to yield the thioester 46. Now Fukuyama closes the fourth and last thiazoline ring (46 + 47). After conversion of the carboxylic acid function into a methyl-

!pzk

CHzCIz. 23OC, 24h. COztBu 2) NaOH. MeOH. 23"C, then A g H tBuO

'I'

H-N Bo!

40%

AcS

45

44

43, BOPCI, Et3N,

1) TFA. 23OC, 30 min, 2) benzene, 80°C. 4h

CH~C1~.23°C

r

74%

80%

46

47

Scheme 11. Fukuyarna's synthesis of tantazole B (part 2).

tantazoleB

3

Syntheses qf Oligo(thiazo1ine) Natural Products

amide, the target molecule tantazole B (3) is reached.

Ehrler 's Synthesis of Thiangazole Thiangazole contains an oxazole ring as well as three thiazoline rings and a styrene group. Ehrler [6] decides to introduce the styrene group by a Wittig-type reaction. He prepares the necessary diphenylphosphinoxide function right at the beginning and carries it successfully through the whole synthesis. So he has the option to install either the styrene function or a related group at every synthetic step. This synthetic strategy is flexible enough to obtain several analogs on the way to the lead structure. The biological activity of all these compounds can be evaluated. The synthesis starts with the condensation of nitrile 48 with the (R)-2-methylcysteine compound 5 x HCl (Scheme 12). The resulting ethyl ester 49 is hydrolyzed and coupled with another (R)-2-methylcysteine (5) to the amide 50. Using the method of Heathcock, the thiazoline ring closure with titanium tetrachloride leads to the bis(thiazo1ine) 51. Another coupling

0

Ph

with 5 and subsequent thiazoline ring closure provides the tris(thiazo1ine) 52. The further progress of the synthesis is shown in Scheme 13. First the styrene function is generated (52 53). Now only the construction of the oxazole remains to be accomplished. In contrast to the ideas of Fukuyama, Ehrler decides to prepare the oxazole in the presence of the other thiazoline rings. The conversion of the ester 53 into the amide 54 succeeds with 76 % yield well enough. But the yields drop in the following cyclocondensation with the bromoketoester 55. After conversion of the ester to the methylamide (56 + 4), thiangazole is isolated in only 20 % yield. Nevertheless, Ehrler successfully reached the target.

-

Pattenden's Synthesis of Thiangazole The synthetic strategy of the thiangazole synthesis of Pattenden [7] is similar to the strategy of the tantazole B synthesis of Fukuyama. The oligo(thiazo1ine) compound and the oxazole compound are synthesized separately. At the end, the two compounds are coupled to give the last

1) NaOH. EtOH. then HCI 2) 5, DCC,

5 x HCI

I

80% Ph' I Ph

Ph

49

48

50

1 ) NaOH. EtOH, then HCI 2) 5, DCC. 3)TiC14. CH2CIz

35%

51

Scheme 12. Ehrler's synthesis of' thiangazole (part

225

52

I

226

A. Total Synthesis of Natural Products 0

52

benzaldehyde, OBU, LiCI, CH3CN

>+s

1) NaOH. EtOH; 2) Ghosez-reagent, CHzC12 3) NH3, CHzCI?

-

*

"=?7

H2N

N+S /

-

76%

66%

54

0

1) NaOH. EtOH;

-

2) Ghosez-reagent, CH2CIz 3) MeNH2, CH2CI2

dioxane, reflux 2) TFA, PY

N v S

P

20%

Q thiangazole 4

56

Scheme 13. Ehrler's synthesis of thiangazole (part 2).

threonine methyl ester CHzCIz.

HF JLfs\.s~oc

Me0

5

"I

0

68%

N-Boc i

H

THF Burgess reagent

Me0

70%

N-BOC

0

57

58

tBuOCOOPh, 59 Cu(l)Br, C6H6

HCI. €120

68%

Me0 34%

M ~ O G > " * N PH; S CI H'

N-Boc

ti

0

0

61

60

8 +I,

O EtO

-

PFB Burgess reagent PYBOP

Scheme 14. Pattenden's synthesis of thiangazole (part I ) .

Syntheses of Oligo(thiazo1ine) Natural Products

-

1) NH3. HzO EtOH, 25% 2) PPh3. CCI4 THF, 5OoC

5b. Et3N. MeOH. A, 48 h

227

;"N ;

L S

40%

52%

62

5b. Et3N. MeOH. A

1) NH3, Hz0 EtOH. 25% 2) PPh3, CCll THF. 5OoC ____)

10%

54%

64

1)61, Et3N. MeOH. A? 48 h 2) MeNH2 52%

66

thiangazole 4

thiazoline ring. The synthesis of the oxazole compound 61 is shown in Scheme 14. First, the (R)-2-methylcysteine compound 5 is N- and S-protected and coupled with the threonine methyl ester to the hydroxyamide 57 with benzotriazole- 1- yloxy-tripyrrolidino-phosphonium hexafluorophosphate (pyBOP) [ 161. Burgess reagent [I71 turns out to be the best choice for the conversion of 57 into 58. The use of Burgess reagent for the synthesis of oxazoline was examined extensively by Wipf et al. [ 181. For other methods of synthesizing oxazoles, which were developed in connection to the synthesis of calyculin A, see [19]. The oxidation of oxazoline 58 to oxazole 60 turns out to be problematical in Pattendens synthesis. Even with special oxidation techniques (rev[-butyl peroxybenzoate 59kopper (I) bro-

Scheme 15. Pattenden's synthesis of thiangazole (part 2).

mide), only the moderate yield of 34 % is achieved. The acidic deprotection of the Boc group finally leads to the oxazole compound 61. The further route of Pattenden's thiangazole synthesis is shown in Scheme 15. Cyclocondensation of the nitrile 62 with the (R)-2-methylcysteine building block 5b provides the thiazoline ester 63. After conversion of the ester to the nitrile 64, cyclocondensation with 5b leads to the bis(thiazo1ine) 65. The subsequent conversion of the ester to the nitrile function (65 + 66) nearly failed, with 10 % yield. In the last synthetic sequence the bis(thiazoline) compound 66 is coupled with the oxazole compound 61 to provide the third and last thiazoline ring. Formation of the methylamide is the final step of the thiangazole synthesis of Pattenden.

228

A. Total Synthesis of Natural Products

Heathcock's Synthesis of Mirabazole C The strategy of this synthesis is different from that for the examples described above. Heathcock assembles a peptide chain of the S-protected 2methylcysteines and closes all four thiazoline rings simultaneously at the end. The synthesis of the peptide (Scheme 16) starts with the coupling of the 2-methylcysteine compounds ent25 and 26. Bromo-tris-pyrolidinophosphonium hexafluorophosphate (PyBrOP) is used as a benzotriazole-free coupling reagent [20]. After deprotection of the Boc group, the dipeptide 67 is obtained in 90 % yield. The same coupling is re-

peated with the (R)-2-methylcysteine compound

ent-26 to yield the tripeptide 68. After deprotection of the Boc group, an isobutyryl amide 69 is installed. The peptide precursor 70 for the multiple ring closure is prepared from 69 in 93 % yield. The multiple ring closure for the construction of the tetra(thiazo1ine) backbone is shown in Scheme 17. After reductive removal of the benzyl groups of 70, the tetrathiol 71 is obtained. 71 is cyclisized to the tetra(thiazo1ine) 72 using titanium tetrachloride (45 % yield!). Final oxidation of the terminal thiazoline to the thiazole with nickel dioxide provided mirabazole C (1).

ent-26, PyBroP, iPrZNEt, DMAP, CHzCIz. 24h

1) PyBroP, iPrZNEt, DMAP,CHzCIz. 4h 2 ) HBr, HOAc ent-25

+

26

:

HZN

OMe

70%

90% SBn

67

&f{4!$ BnS

BnS

&if{Ai$

H

CBz'

-

H

0

SBn

;

OMe iiT::ZALt3N ___+ 84%

0

SBn

'

H

O

68

T:

SBn

SBn

69

1) NaOH

R"S

93%

70

Scheme 16. Heathcock's synthesis of mirabazole C (part I ) .

71

72

Scheme 17. Heathcock's synthesis of rnirabazole C (part 2).

mirabazole C I

OMe

Syntheses c$Oligo(thiazoline) Natural Products

Synthesis of Thiangazole by Wipf The synthetic strategy of Wipf [9] is quite different. He decides to prepare oligo(oxazo1ines) instead of oligo(thiazo1ines). Then a new multiple oxazoline + thiazoline conversion is used. Wipf chooses the oxazoline route for two reasons. The first reason is a synthetic one: oxazolines are easier to prepare than thiazolines. The second reawn is a pharmacological one: the oxazolines obtained along this route may be interesting drug candidates. Wipfs enantiomerically pure building block is not (S)-2-methylcysteine, but the (S)-2-methylserine compound 15 (Scheme 18). Coupling of 15 with D-threonine methyl ester in the presence of PyBroP and DMAP gives the dipeptide 73. The oxazole 74 is formed after Dess-Martin oxidation and cyclodehydration with triphenylphosphinehodine.After formation of the methylamide function, an iterative sequence of deprotection with TBAF and coupling with 15 leads to the dipeptide 75, then to the tripeptide 76 and finally to the tetrapeptide 77. The coupling reagent is PyBroP in each case. The overall yield (74 -+ 77) is 21 %. After catapyBroP, DMAP CH2CIz. threonine methyl ester H

y\y -

lytic hydrogenation of 77 with Pd(OH),, a subsequent multiple ring formation with Burgess’s reagent 1181 leads to the tris(oxazo1ine) 78 with 6 0 96 yield (Scheme 19). Now an oxazoline + thiazoline conversion is achieved by nucleophilic opening of the tris(oxazo1ines) to the 2-methylcysteine peptide 79 with thioacetic acid. For the ring closure Wipf uses titanium tetrachloride according to Heathcocks protocol. The side chain of tris(thiazo1ine) 80 is oxidized with benzeneselenic acid to provide the desired natural product thiangazole 4.

Kiso’s Synthesis of Mirabazole C Kiso’s synthetic strategy follows the work of Heathcock [8]. He also uses titanium tetrachloride as the reagent for the multiple ring closure. His work focusses on an effective preparation of the peptide precursor for the multiple ring closure. For this purpose he introduces a new coupling reagent: 2-chloro- 1,3-dimethylimidazolidium hexafluorophosphate (CIP) 81 (Schcme 20).

1,Dess-Martin-oxidation 2.Ph3P. 12, NEt3. THF

Me0G 60%

T

0

1. TBAF, dioxane 2. 15, PyBroP, DMAP

OBn

55%

MeNH OBn

0

75

HN\ Ses

OBn

MeNH

,$;::+

O ,,Bn

1. TBAF, dioxane

M~NH

2. PhCH2CH2COOH. PyBroP, DMAP

0 69% 77

76 I Ses

Scheme 18. Wipf’s synthesis oi‘ thiangazole (part I).

O

B

bi

74

73

55%

Y

N-Ses

bBn

1. MeNH2. MeoH 2. TBAF, dioxane 3. 15, PyBroP. DMAP

229

Ph

n

230

77

A. Total Synthesis of Natural Products

I

1. Pd(OH)2, H2, MeOH 2. Burgess-reagent,THF

'

N y O

AcS H

5

w 60%

56%

N L O 9

HN

Ph

PhSeOOH, benzene,60"C

thiangazole 4

79%

Scheme 19. Wipf's synthesis of thiangazole (part 2). Cbz

28

+

H

~

ClPiHOAt ___) N quant.

1. HBr/AcOH 2. 28, CIP/HOAt

0

~

~

~ (60%)

H

Hiy '

~

BnS

H

SBn

SBn

84

O

T SBn

85

BnS

/ q b C l PFL

\ CIP 81

OH HOAt 82

Scheme 20. Kiso's synthesis of mirabazole C

Syntheses of Oligo(thiuzo1ine) Natural Products

The (R)-2-methylcysteine derivative 28 is coupled with (S)-benzyl-2-aminoethanethiol using CIP/HOAt [21] (81/82) to provide 83 quantitatively. After N-deprotection with HBr/AcOH, coupling with 28 using CIP/HOAt gives the dipeptide 84, which, after deprotection, is coupled again using CIP/HOAt with the (S)-2-methylcysteine compound 29 to provide the tripeptide 85. The yields are 60 % and 55 %, respectively. 85 is N-deprotected with HBr/AcOH, and the resulting amine is acylated with isobutyryl chloride to obtain the precursor 86 for the multiple ring closure. From this stage onwards, the synthetic route follows that one of Heathcock (Scheme 17). In summary, these examples show an impressive insight into modern heterocyclic chemistry. Basically, two strategies have been adopted for the total syntheses of this class of bioactive compounds. One is the sequential formation of the thiazoline ring and the other is the multiple ring closure of a peptide precursor. Heathcock’s strategy of TiC1,-mediated simultaneous formation of several thiazoline rings proved to be the most efficient. Wipf’s approach via oxazolines is ideally suited for the construction of oligo(thiazo1ine) analogs, with potential applications in biology and medicine.

References [ I ] S . Carmeli, R. E. Moore, G. M. L. Patterson, Tetrahedron Lett. 1991, 32, 2593. [2] S. Carmeli, R. E. Moore, G. M. L. Patterson, T. Corbett, F. A. Valeriote, J. Am. Chem. SOC. 1990, 112, 8195. [3] R. Jansen, B. Kunze, H. Reichenbach, E. Jurkiewicz, G. Hunsmann, G. Hofle, Liebigs Ann. Chem. 1992, 357. [4] R. Jansen, D. Schomburg, G. Hofle, Liebigs Ann. Chem. 1993, 701. 151 T. Fukuyama, L. Xu, J . Am. Chem. SOL..1993, 115, 8449. [6] J. Ehrler, S. Farooq, Synlett, 1994, 702.

23 1

[7] R. J. Boyce, G . C. Mulqueen, G. Pattenden, Tetruhedron Lett. 1994, 35, 5705. [8] R. L. Parsons Jr., C. H. Heathcock, Tetrahedron Lett. 1994, 35, 1379. [9] P. Wipf, S. Venkatraman, J. Org. Chem. 1995, 60, 7224; P. Wipf, S. Venkatraman, C. P. Miller Tetruhedron Lett. 1995, 21, 3639. [lo] K. Akaji, N. Kuriyama, Y.Kiso, J . Org. Chern. 1996, 61, 3350. [ I l l Pattenden: G. Pattenden, S. M. Thom, Synlett, 1992, 533 and G. Pattenden, S. M. Thom, J. Chem. Soc. Perkin Trans. I, 1993, 1629 (epimer of didehydromirabazole A); R. J. Boyce, G. Pattenden, Synlett, 1994, 587 (didehydromirabazole A); R. J. Boyce, A. G. C. Mulqueen, G. Pattenden, Tetrahedron 1995, 26, 7321 (thiangazole). B. Heathcock: R. L. Parsons Jr., C. H. Heathcock, Tetrahedron Lett. 1994, 35, 1383 (mirabazole B); M. A. Walker, C. H. Heathcock, J. Org. Chem. 1992, 57, 5566 (epimer of mirabazole C); R. L. Parsons Jr., C. H. Heathcock, 1. Org. Chem 1994, 59, 4733 (thiangazole); R. L. Parsons Jr., C. H. Heathcock, Synlett 1996, 1168 (tantazole B). N. Kuriyama, K. Akaji, Y. Kiso, Tetrahedron 1997, 25, 8323 (mirabazole B). P. Wipf, S . Venkatraman, Synlett 1997, 1 (thiangazole review). 1121 G. Pattenden, S. M. Thom, M. F. Jones, Tetrahedron 1994, 49, 2131. 1131 A. Jeanguenat, D. Seebach, J. Chem. SOC.Perkin Truns. I, 1991, 2291. [14] S. Karady, J. S, Amato, L. M. Weinstock, Tetruhedron Lett. 1984, 35, 4337. [IS] J. Cabre, A. L. Palomo, Synthesis 1994, 413. [ 161 J. Coste, D. Le-Nguyen, D. Castro, Tetruhedron Lett. 1970, 21, 205. 1171 G. M. Atkins, E. M. Burgess, J. Am. Chem. SOC. 1968, YO, 4744. [ 181 a) P. Wipf, P. C. Fritch, Tetrahedron Lett. 1994,35, 5397; h) P. Wipf, C. P. Miller, Tetruhedron Lett. 1992, 33, 907; c) P. Wipf, C. P. Miller, J. Org. Chem. 1993, 58, 3604. [I91 a) D. A. Evans, J. R. Gage, J. I,. Leighton, J . Am. Chem. SOC. 1992, 114, 9434; b) H. A. Vaccaro, D. E. Levy, A. Sawabe, T. Jaetsch, S . Masamune, Tetrahedron Lett. 1992, B. 33, 1937; c) B. A. Salvatore, A. B. Smith 111, Tetrahedron Lett. 1994,35, 1329. 1201 J . Coste, E. Frerot, P. Jouin, B. Castro, Tetruhedron Lett. 1991, 32, 1967. 1211 L. A. Carpino, J . Am. Chern. Soo. 1993, 115,4397.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Camptothecin - Synthesis of an Antitumor Agent Stefan Baurle and Ulrich Koert Institut ,fur Chemie, Htimholdt Universitut, Berlin, Germany

Camptothecin (1) was first isolated in 1966 from the Chinese tree carnptotheca cicurninata [I]. As shown in Fig. 1, the five rings of the natural compound are named A, B, C, D and E. The stereogenic center in the E ring is S-configured. The antitumor activity of camptothecin quickly made the compound an interesting target for synthetic chemists. After a short time, successful total syntheses were reported. Especially three synthetic approaches should be mentioned here:

those of Stork (1971) (21, Winterfeldt (1972) [3] and Corey (1975) [4]. However, the high clinical expectations for camptothecin turned to disappointment in the 1970s because in some clinical studies no effect was observed. So the compound disappeared from the scene. Later, the reason for that failure was discovered. Instead of compound 1, which has a very poor water solubility, the water-soluble sodium salt 2 was used in these early clinical

9

Camptothecin (1 )

Camptothecin, sodium salt (2)

Figure I

thecin (4)

0, lrinotecan (5) (CPT-11)

I

*,+-& OH

0

Figure 2

Camptothecin

-

Synthesis of an Antitumor Agent

233

Comins

ShenlDanishefsky Camptothecin 1

Curran

% Scheme 1. Retrosynthetic analysis of carnptothecin (1) according to Cornins, Curran, Shen/Danishefsky and Ciufolini.

studies, and compound 2 with the open E ring proved to be pharmacologically ineffective. In trying to get good bioavailability, the pharmacophor had been destroyed by the change from 1 to 2. Keeping that in mind, the solubility problem was solved by additional substituents in the A ring in positions 9 to 12 without loss of pharmacological effect. Then a second important discovery was made. The mode of action of camptothecin is based on the inhibition of topoisomerase I-DNA complex [5]. The DNA double strand in the cell is coiled and knotted. For replication and cell division, this DNA tangle has to be unwound. And that is the exact function of the topoisomerases. In continually replicating cancer cells, topoisomerase 1 is overexpressed. Camptothecin is thought to interact at this point. It binds at the topoisomerase I-DNA complex, inhibits the activity of the enzyme and stops cell division [6]. Today, several soluble camptothecin derivatives such as topotecan (3), 9-aminocamptothecin (4) and irinotecan (CPT-11) (5) are of clinical importance. Positive results were achieved, especially against intestinal, breast and ovarian can-

cer. After camptothecin returned like the phoenix from the ashes, it again became a target for the synthetic chemists. Recent developments are summarized in this review. It is interesting to note how the number of steps could be reduced from 15-20 in the 1970s to under 10 nowadays with the help of the modern synthetic methods of the 1990s. Scheme 1 shows a retrosynthetic synopsis of the syntheses of Comins [7-91, Curran [ l o 141, ShedDanishefsky [ 161 and Ciufolini [17]. Comins connects an A,B ring building block (6) with a D,E building block 7 and closes the C ring last - a classic example of a convergent synthetic strategy! Curran uses an A ring building block (8) and a D,E ring building block (9) in order to build up the rings B and C in one step. Shen and Danishefsky take the classical route. They connect an A ring building block (10) with a C,D,E ring building block (11), creating the B ring last. Ciufolini starts with an A,B quinoline (12) and closes the C ring in the final step. The camptothecin synthesis of Comins (Scheme 2) commences with the ortho-directed

234

A. Total Synthesis of Natural Products

1. n-BuLi

MeOH H O:$$C I

0 3. p-PhPhCOCl

I I

7

92%

18

60%

19

R*= (-)-8-Phenylmenthyl

I

,,,kCO,R’ OCO-p-PhPh

76%

a+..

I

C02H

77%

OH

22

21

H2, PdlC ___)

76%

23

Scheme 2. Comins’ synthesis of camptothecin (part 1).

7

t-BuOK Br

87%

24

6

I*’’&

0

Pd(OAc), BqNBr KOAc, DMF ___)

59%

Scheme 3. Cornins’ synthesis (part 2).

Carnptothecin - Synthesis of an Antitumor Agent 1. MesLi

d"'

2. n

-N

' '

N-CHO

16

____)

25

3. n-BuLi

1. CeCI3 0

OMe

L.

-

qco2Me (i-PrO)$l 0 27 i-PrOH

3. H30'

___)

0

42%

28

lithiation of pyridine (15). The aryllithium compound obtained is allowed to react with the formamide (16) to yield an a-amino alkoxide, which is converted to the intermediate 17 by directed ortko-lithiation. Reaction of 17 with iodine affords the aryl iodide 18. Conversion of the aldehyde function of 18 to a methyl ether group provides compound 19. Iodine-lithium exchange at 19 and subsequent reaction with mketo ester 20 yields ester 21. Comins uses (-)-8-phenylmenthol as chiral auxiliary. The conversion of 19 to 21 shows a stereoselectivity of 93 : 7. After recrystallisation, the product (21) is obtained as a pure stereoisomer in 60 % yield. The chiral auxiliary is cleaved off (21 --t 22) and the E ring of 23). The chlorine camptothecin is closed (22 substituent can be removed by catalytic hydrogenation. Next, the D,E ring building block 7 is coupled with the A,B ring fragment 6 by N-alkylation to provide compound 24 (Scheme 3). The final step of Comins' synthesis of camptothecin is an intramolecular Heck reaction which closes the C ring. Comins was able to shorten the (racemic) synthesis of the D,E ring building block to three steps by further optimization of the ortko-directed --f

I N HCI

rac-7

57%

29

Scheme 4. Cornins' synthesis of the D,E ring building block.

1. = Y B r NaH, LiBr

1. PC15 2. HBr 3 MeOH

2. KOt-BU

66% 30

61%

31

t

C02Me

32

1. Hydroxymethylation 2. Oxidation (scheme 7)

t

C02Me

33

*

rac-I

35%

Scheme 5. Curran's synthesis of carnptothecin.

235

236

A. Total Synthesis of Natural Products PhNC 8

Me3SnSnMe3 hv. 80 OC

+

40%

34

39 + Me3Sn.

- Me3SnBr

35

a

PhNC

i

36

37

metalation (Scheme 4). The decisive improvement is based on the transmetalation of the aryllithium intermediate 26 to the corresponding arylcerium compound. The organocerium compound, as a weaker base, allows the addition to the a-keto ester 27 and the formation of the lactol 28. Meerwein-Ponndorf-Verley reduction and acidic cleavage of the pyridone-0-methyl ester 29 affords the desired D,E ring building block rac-7. Curran’s synthesis (Scheme 5) is an instructive example of applied radical chemistry. His racemic synthesis [ l o , 111 of camptothecin starts with compound 30. Via 31, the D ring building block is reached by some standard steps. Treatment of 32 with phenyl isonitrile (8) provides compound 33 in one step. The final construction of the E ring follows Danishefsky’s synthesis (see below). The simultaneous construction of the B and C rings leading to compound 33 was accomplished by a radical cascade reaction. The mechanistic details of this cascade are summarized in Scheme 6, where the reaction of 34 with phenyl isonitrile (8) is shown [ 121. First, a trimethylstannyl radical, derived from hexamethyldistannane, attacks the C-Br bond of 34. The resulting pyridone radical 35 reacts intermolecularly with the isonitrile 8 to yield the radical intermediate 36.

Scheme 6. Curran’s synthesis: mechanism of the radical key step.

An intramolecular attack of the radical center in 36 on the alkyne functionality leads to radical 37. Finally, the A ring is attacked by the radical center of 37 leading to 38, which rearomatizes to the desired compound 39. The second generation of Curran’s camptothecin synthesis [ 13, 141 is based on the same radical key step, but an enantiomerically pure D,E ring fragment 7 is used. His asymmetric approach to compound 7 follows Comins’ strategy. A research team at Glaxo [ 151 elaborated this synthesis in a similar way. A Sharpless dihydroxylation (AD reaction) is applied to introduce the stereogenic center at C20. Scheme 7 shows the enantioselective synthesis of 7 according to the Glaxo group. An ortho-directed lithiation allows the conversion of 25 to aryl iodide 40. Reductive ether formation of aldehyde 40 with crotyl alcohol yields compound 41. Intramolecular Heck reaction of 41 affords a mixture of the olefins 42 and 43. The undesired alkene 42 can be isomerized quantitatively to the desired enol ether 43 with Wilkinson’s catalyst. Sharpless dihydroxylation (ee 94 96)of the enol ether 43 provides lactol 44, which is oxidized directly to lactone 45. Finally, the pyridone-0-methyl ester is cleaved under acid conditions (45 + 7).

Camptothecin

-

Synthe.yis qf an Antitumor Agent

237

1, t-BuLi

n

' ' dMe 2.

-N

N-CHO

HO-

16

3. n-BuLi 4. 12

I

63%

25

OMe

EtsSiH, TFA \

40

Pd(OAc)2 K2C03

42

43

I

(PPh3)3RhCI

44

I N HCI cryst. 74%

7

The camptothecin synthesis of Shen/Danishefsky 1161 (Scheme 8) starts with the construction of the D ring: reaction of 46 with 47 affords 48. The next step (48 + 49) introduces the C20 ethyl group. Hydroxymethylation of 49 delivers lactone 50. The B ring of the camptothecin precursor 52 should be accomplished by a Friedlander condensation of 10 with 11. For this purpose, a keto group at C2 of the C,D,E ring building block had to be installed. Shen and Danishefsky solved this problem by combination of an aldol condensation (50 + 51) and a subsequent ozonolysis (51 + 11). Important for

Scheme 7. Asymmetric synthesis of the D,E ring building block.

the aldol condensation is the methyl ester functionality. It allows the regioselective deprotonation at the benzylic position. After the methyl ester has done its job it is removed by heating with HBr to afford compound 53. The final step of ShedDanishefsky's camptothecin synthesis is the oxidative introduction of the alcohol function at C20. Unfortunately, this hydroxylation leads only to the racemic target compound. Ciufolini 1171 reaches camptothecin in 5 steps, connecting the building blocks 12, 13 and 14 (Scheme 9). Condensation of the quinoline phosphonate 12 with aldehyde 13 afforded enone 54.

238

A. Total Synthesis of Nuturul Products Me02C-HC=CCI-CH2C02Me

47 EbN

Me02C

92%

C02Me

46

48

- Y

-

t-BUOK Etl, DME

(CH20),1H+

qo91%

C02Me

NaHMDS PhCHO

P

90%

Me02C

50

95%

Me02C

.

9

:

H02C

0

51 94%

1. 0 3 , Me+

2. TMSCHN2

I

p-TsOH, toluene

I ~

75%

Me2NH cuc12 0 2 , DMF

52 R=C02Me

71% A HBr,

L53 R = H

Michael addition of the potassium enolate of cyanacetamide (14) provided the precursor 55 of the pyridone 56. This intermediate was obtained by oxidation of 55 with t-BuOOH in the presence of 20 mol% SeO, on SiO,. The addition of 10 % H,SO, to the reaction mixture directly delivered the lactone 56. Lactones like 56 are not easy to reduce, but treatment with NaBH4/CeC1, provided the diol 57 in 95 % yield. 57 could be easily converted to camptothecin by heating it to 115 "C in 60 % H,SO, in EtOH.

rac-I

Scheme 8. Danishefsky's synthesis of camptothecin.

The preparation of compound 12 started with the quinoline derivative 58, which can be carbomethoxylated in the presence of [Pd(dppp),Cl,]. Radical bromination, methanolysis and reaction with (MeO),P(O)CH,Li delivers 12 (Scheme 10). The stereogenic center at C20 is introduced by enantioselective enzymatic hydrolysis of MOMprotected malonic acid dimethyl ester derivative 60 (Scheme 10) with pig liver esterase (PLE). The asymmetric compound 61 is obtained in 90 % yield and 98 % ee. Amide formation with Mu-

239

Camptothecin - Synthesis of an Antitumor Agent

1. 0.2 eq Se02 tBuOOH AcOH

OMe

NaBH4

2. H2S04

CeCI3

68% from 54

Et dONEt2

H2S04

94% from 56

57

Scheme 9. Ciufolini’s synthesis of camptothecin (part I ) .

Et”’fiCONEt2 HO

kaiyama’s reagent and DIBAH reduction provides aldehyde 13. Ciufolini’s strategy allows the synthesis of camptothecin in 10 steps and 30 % overall yield, starting with dimethyl malonate acid dimethyl ester. Like the other synthetic strategies discussed, this synthesis is open to variations in the A ring and thus allows the preparation of pharmacologically interesting camptothecin derivatives. ShedDanishefsky’s approach is efficient but has to be improved to an asymmetric level. The stereoselective 2”d generation of Curran’s synthesis constructs the B and C ring in one elegant step. New variations even allow the regioselective introduction of different substituents in positions 9- 11 [ 141. In summary, the development in the field of total syntheses of the antitumor agent camptothecin nicely illustrates the progress of modern synthesis over the last decade. Radical reactions and organometallic coupling reactions, for example, have reached such a level of maturity that they now belong to the standard repertoire of key steps in the construction of complex molecules.

[Pd(dppp)nClzl 105 atm CO MeOH, DMF COOMe

98% 59

58

1. NBS 2. H2SO4, MeOH ______f

12

3. (Me0)2P(0)CH2Li

54 %

1. MOMCI

Etx::iMe OH

2. PLE, DMSO

60

a

@y

CI

10

NEt3, NHEt2

90%

COOMe

Et”’bCOOH MOMO

90%, 98% ee

61

COOMe

Et”’bCONEt2 MOMO 62

DIBAH quant.

Scheme 10. Ciufolini’s synthesis (part 2).

13

240

A. Total Synthesis of Natural Products

References [ I ] M. E. Wall, M. C. Wani, C. E. Cook, K. H. Palmer, A. T. McPhail, G. A. Sim, J. Am. Chenz. SOC.1966, 88, 3888. [2] G. Stork, A. G. Schultz, J . Am. Chem. SOC.1971, Y3, 4074. [31 a) M. Boch, T. Korth, J. M. Nelke, D. Pike, H. Radunz, E. Winterfeldt, Chem. Ber: 1972, 105, 2126; b) K. Krohn, E. Winterfeldt, Chem. Rer: 1975, 108, 3030. 141 E. J. Corey, D. N. Crouse, J. E. Anderson, J. Org. Chem. 1995, 40, 2140. [5] a) Y. H. Hsiang, R. P. Hertiberg, S. M. Hecht, L. F. Liu, J. B i d . Chem., 1985, 260, 14873; b) C. D. Lima, J. C. Wang. A. Mondragon, Nature 1994, 367, 138. [6] W. J. Slichenmeyer, E. K. Rowinrky, R. C . Donehower, S. H. Kaufinann, J . Nut. Cunc. Inst. 1993, 85, 271. 171 D. L. Comins, M. F. Baevsky, H. Hong, J. Am. Chem. SOC. 1992, 114, 10971.

[8] D. L. Comins, H. Hong, J. K. Saha, G. Jianhua, J. Org. Chem. 1994, 59, 5120. [Y] D. L. Comins, H. Hong, G. Jianhua, Tetruhedroiz Lett. 1994, 35, 533 1. [ l o ] D. P. Curran, H. Liu, J. Am. Chenz. SOC.1992, 114, 5863. [ 1 I] D. P. Curran, S.-B. KO, J. Org. Chem. 1994, 59, 6139. 1121 U. Koert in J. Mulzer, H. Waldinann (eds.), Organic Synthesis Highlights I l l , Wiley-VCH, Weinheiin 1998, 235. [I31 D. P. Curran, S.-B. KO, H. Josien, Angew. Chem. 1995, 107, 2948. 1141 H. Josien, S.-B. KO, D. Bom, D.P. Curran, Chem. Eur: J . 1998, 4, 61. [IS] F. G. Fang, S. Xie, M. W. Lowery, J . Org. Chenz. 1994, 59, 6142. [I61 W. Shen, C. A. Coburn, W. G. Bornmann, S. J. Danishefsky, J . Org. Chem. 1993, 58, 611. [I71 M. A. Ciufolini, F. Roschangar, A q e w Chern. 1996, 108, 1789.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Polycyclic Guanidines From Nature's Shaped Cations to Abiotic Anion Hosts Huns-Dieter Arndt and Ulrich Koert Institut fur Chemie, Humboldt Universitat, Berlin, Germany

Marine rather than terrestrial organisms produce a large variety of structurally intriguing metabolites endowed with guanidine functions [I]. The most well known probably are saxitoxin (l),an extremely potent Na+ channel blocker, and tetrodotoxin (2), the powerful poison of the puffer fish family (Scheme 1). Recently, several new alkaloids containing guanidines in complex polycyclic frameworks have been isolated from sponges. Their novel structural features stimulated considerable synthetic efforts, supported by interesting bioactivity profiles. An early account was the isolation of ptilocaulin (3) by the Rinehart group, which displayed a broad range of activities (Scheme 2 ) [2]. In 1989, ptilomycalin A (4) was isolated from the Caribbean sponge Ptilocaulis spiculifer and from the Red Sea sponge Hemimycale sp [3]. Its unique pentacyclic guanidinium core is linked to an w-hydroxy fatty acid side chain terminated by a N2-spermidine amide. The closely related

Scheme I .

H

3

crambescidines 800, 816 and 844 (5-7) from Crarnbe crambe 141, celeromycalin (8) and fromiamycalin from Celerina heffernani and Fromia monilis respectively were reported there after 1.51. Because of to pronounced differences in their antiviral and cytotoxic properties, the major role of the pentacyclic guanidine in the strong biological activity was soon identified. Using ptilomycalin A and simplified model compounds, a host-like behavior towards anions became evident expcrimentally [6]. The precise mode of action has yet to be elucidated, but the competitive interaction with ATP at its binding site in Na+/K+/ Ca' + -ATPase suggests anion receptor behavior and highlights these compounds in resembling artificial anion hosts (see below) [71. The remarkable hexacyclic alkaloid palauamine (10) from Stylotella agrninata was reported in 1993 (Scheme 3) [S]. Its high immunosuppresive activity - whilst being reasonably nontoxic - has provoked preclinical studies [8c]. Interestingly, the isomer styloguanidine (11) is a powerful chitinase inhibitor [8b]. Targeting the treatment of AIDS, a group at Smith Kline Beecham established a screening method to identify bioactive substances which inhibit the HIV binding to human CD4+ receptor.

242

A . Total Synthesis of Nuturul Products

10 X=C, Y=N 11 X-N, Y=C

Scheme 3.

14 R-OH. n=7

Scheme 4. Biomimetic synthesis of (-)-ptilocaulin by Snider et al.

On scanning numerous natural sources only the extracts from the Caribbean sponge Batzella sp. proved to be active [9]. This led to the isolation of the batzelladines A (12) and B as the first lowmolecular-weight compounds able to inhibit this interaction. Subsequently, batzelladines F (13) and G (14) were shown to induce dissociation of thyrosin kinase p56ICkand CD4 cells highly specific in an immunosuppressivity-based assay [lo]. Several of the compounds mentioned show similarities, and in fact some of them are produced together from the same species. A biosynthetic rationale for their synthesis was suggested early by Rinehart [2a] for (+)-ptilocaulin, and the findings of Snider [ l l a l and Roush [ I l b ] strongly supported him. Condensation and Michael addition of guanidine to an enone could deliver these systems, and their thermodynamic equilibration is feasible. The brevity of this pioneering synthesis remains challenging (Scheme 4) [ l l a ] . The kinetic enolate of enone 15, accessible from natural (+)-pulegone, was crotylated, and a 3,s-trans specific addition of a Grignard-derived cuprate, followed by hydrogenation and acid-catalyzed ring closure, furnished enone 17 in 23 % overall yield. Treatment of

17 with excess guanidine under dehydrating conditions delivered unnatural (-)-ptilocaulin [(-)-31 (40 %, as its nitrate salt). As (-)-pulegone is not readily available, subsequent work addressed the natural enantiomer by different methods [ 121, but all completed their synthesis via Snider's enone (17). Asaoka utilised a TMS group as temporary directing volume (Scheme 5 ) [ 12aI. Cossy applied a photoreductive cyclopropane ring opening, which was obtained by a diastereoselective Simmons-Smith reaction [12b]. Schmalz finally used a planarchiral arene complex to synthesise enone 17 with interesting Cr(CO), chemistry [ 1 2 ~ 1 . The pentacyclic ptilomycalin A was originally targeted by conceptually related biomimetic strategies. A retrosynthetic analysis comprising the Snider [I31 and Murphy [14] approaches is outlined in Scheme 6. After disconnection of the aminal functions (A and E rings), the tricyclic precursor could principally be formed by wrapping a bis-enone around guanidine via consecutive Michael addition and condensation reactions. The apparent simplicity of this approach is opposed by difficulties in stereocontrol, as a directing influence of the pendant C 13 and C 19 stereocenters remains speculative at this stage.

Polycyclic Guanidines COSSY

PhWph

1

243

ASAOKA

I

SCHMALZ

Scheme 5. Methods approaching natural (+)-ptilocaulin (3.)

Ptilomycalin A

Scheme 6. Apparent retrosynthetic disconnection of ptilomycalin A (4).

In their successful synthesis of the ptilomycalin A core structure, Snider et al. had to divide the crucial tricyclization into two steps. The attempted multiple ring closure failed to yield the product sought (Scheme 7) [ 131. After Knoevenagel condensation of P-keto ester 19 with aldehyde 20, bis-enone 21 was condensed with O-methylisourea to close the C and D rings to give 22. Treatment with buffered ammonia then furnished the B ring, albeit as a 1 : 1 mixture of diastereomers 23 and 24. After separation and silyl ether cleavage, the A ring closed spontaneously (25), whereas the E Ring then needed forcing assistance by NEt,. Again, stereoselection was negligible (26/27 = 4 : 3 ) , and the procedure required tedious purification. The outlined ”zipper” concept does indeed work, on condition that the C14 ester is omitted (Scheme 8) [ 141. Treating a such simplified precursor as 28 with guanidine and then HCI gave racemic pentacyclic guanidine 29, in one step and in 20 % yield, as its tetrafluoroborate salt, which could be characterized by X-ray analysis. Being more concerned about specific stereocontrol, Overman et al. decided to install the C ring stereocenters first before elaborating the

polycyclic framework [ 151. In their successful total synthesis of ptilomycalin A (Scheme 9), the central C ring building block evolves from a reliable P-keto ester reduction of 30. Mitsunobu displacement with azide, double reduction and urea formation gave after ozonolysis the ureido aminal 31 in 42 % total yield (98 % ee). A tethered Biginelli condensation [ 161 with /I-keto ester 32 (available from methyl acetoacetate) as the kcy step led to cis-fused dihydropyrimidine 33 (7.5 : I ) , which was deprotected and cyclized to the C,D,E ring fragment 34 in 59 % combined yield. Unfortunately the less strained C- 14 a-epimer was formed exclusively, a significant drawback. Preparing to install the A and B rings, 34 was converted to isourea 35, remarkably without erosion of the C7 stereochemistry. The missing part was introduced with Grignard compound 36, and after oxidation and 0-deprotection the two final rings were closed via guanidine formation with buffered ammonia (20 % overall) to yield pentacycle 37. Having established the spermidine amide 38, the wrong stereochemistry at C14 had to be corrected. After three cycles of partial epimerization

244

A. Total Synthesis of’Nutural Products

20

19

23

A.

A

24

TBDPSO

TBDPSO

HF, CHJCN, -30% 3d I

25

26

HOA

21

NH 1, HzNK NH2 , DMF. 3h 2. HCI, MeOH. 0°C -z FIT, 24h 3. NaBF4

3

‘

4

w I

20%

.

;i@ i. , A

OTBDMS

29

28

Scheme 8. “Zipper” Condensation according to Murphy et al

and separation, the natural isomer so obtained (50 % yield) was deprotected with neat formic acid to yield (-)-ptilomycalin A quantitatively ( 1 8 steps, 1 % total yield). The isolation of the batzelladines attracted the attention of several groups, and some work has appeared in recent years concerned with partial syntheses, mainly in the racemic series [ 17, 18, 191. The efforts of Snider culminated in a ninestep synthesis of racemic batzelladine E, following the biomimetic strategy [ 1 Sb]. The only enantioselective synthesis reported to date established the absolute stereochemistry of batzelladine B (Scheme 10) [20a]. Diol 39 (obtained by /I-keto estcr chemistry) was transformed into guanidine 41 via the diazide. An improved Biginelli type condensation with methyl acetoacetate in tri-

fluoroethanol gave the methanolysis product of batzelladine B (42) with 10 : 1 selectivity in excellent 94 % yield. Further experiments proved fruitful [20b]. N-sulfonylguanidine aldehyde (43) could be transformed selectively to the respective cis- (7: 1) and truns-products (20: I ) just by changing the reaction conditions. This approach seems ideally suited for delivering the batzelladines and related molecules using an acidlabile sulfonamide as the protecting and modulating moiety. The synthesis of palau’amine (10) was addressed by Overman [21]. Its dense functionalization, with two quaternary carbons being most prominent, presents a formidable challenge to synthesis. Taking advantage of the molecules folded shape, a retrosynthesis reduces the structure’s

245

Polycjclic Guanidines

Meom -

69% (98% ee)

1. KOCN, HCI. 70°C 2. 03,MeOH, -78°C 61%

30

1

Ha: 31

a

1 . 3 6 , THF, -78% 2. Swern oxd. 3. TBAF 4. NHdNH4OAc

32

BrMg

36

30%

I

Scheme 9. Total synthesis of ptilomycalin A (4) by Overman et al.

u,

1. HN3, PPhj, DEAD, 94% 2. LiAIHo 85% 3. 40, CHzCiZ. 82% 4. Zn, HOAc, 100%

H

O

q

Me0 morpholinium acetate, Na$304, TFE, 90°C

I

HNAWhC7H,6 94% (101 cis)

PPE, CHpCll RT, 48h

B

n

O

I

42

41

39

F o N,kN.MTr H

B

n

C 61% (20:l) --

-

morpholinium acetate, TFE. 60"C, 48h

*OBn

Ho

AN.MTr N HzN

84% (71)

43, MTr p-Me0 2,3,6-lr~melhylbenzene-sulfonyl

Scheme 10. Partial synthesis of batzelladine B and improved Biginelli condensation

complexity (Scheme 1 I ) . A crucial azomethine ylide cycloaddition reveals a dihydropyrrole bearing an a-keto ester side chain. In their elegant model study (Scheme 1 I), a-keto ester 44 was condensed with thiosemicarbazide to deliver tetracycle 45 in excellent yield. When OP(NCS), was applied in excess to form the isothiocya-

nate, not only ring closure but also reductive cleavage of the strained N-N bond was observed. After guanidinylation, protected bis(spiroguanidine) 47 was reached in 55 % overall yield. Bearing their biological activity in mind, the total synthesis of the compounds mentioned will be mastered sooner o r later. Up to now the

246

A. Total Synthesis of Nuturd Products

10

,COOMe

w

-

HN

NH2

G

o

OR

72%

ACOH, 70°C 90%

44

1. Mel, NaOH 2. BnNH2,70°C

1. LiOH 2. O=P(NCS)J

AH2

45

86%

46

41

Scheme 11. Disconnection and partial synthesis of palau'amine (10).

48

0

50

51

Scheme 12. Representative anion receptors.

so-called biomimetic approaches suffer from quite drastic reaction conditions and unpredictable thermodynamic control, often leading to product mixtures. This severely limits their applicability. Lacking the cell's enzymatic armament, chemistry has to develop new methods and strategic improvements. Thus these nitrogen-rich, oxidized -synthetic targets apparently remain a challenge. But, apart from synthetic endeavors, which factors make these compounds biologically ac-

tive? Guanidine functions are fully protonated in aqueous media (pK, ca. 13-14), and thus these compounds behave as large, lipophilic cations of defined shape. Their competitive interaction with (de-)phosphorylating enzymes or with sulfated recognition motives and so modulating signal transduction seem to be two likely modes of action. In other terms, they may behave as anion receptors. Studying the molecular recognition of anions has been a growing part of supramolecular chem-

Pnlycyclic Guanidines

Hosseini have devoted a lot of effort to aza crown complexes with ATP 48, showing them to be true yet weak ATPase mimics [24]. Schmidtchen reported tetrahedral zwitterions 49 to discriminate between spherical anions [25]. Reetz was able to show that ditopic receptor 50, which includes both Lewis-acidic and basic centers will complex a whole ion pair 1261. Incorporation of transition metals into anion receptors such as 51 renders neutral species positively charged and susceptible to spectroscopic and electrochemical manipulations [ 2 7 ] . Guanidines have been implemented early as recognition elements, guided by the apparent function of arginine in protein structures. The C,-symmetric, chiral anion receptor 52 was introduced by Lehn, Schmidtchen and de Mendoza consecutively and studied in various modifications (Scheme 13) [23c]. For example, an elaborate system based on 52 provided reasonable enantioselective recognition of amino acids [23c, 281. Furthermore, bis(guanidinium) compounds catalyze RNA hydrolysis in the presence of external base via phosphodiester complexation [29]. These functional elements were joined in receptor 53 to yield a functional transesterification catalyst [301. An elegant modular synthesis of the 52 scaffold originates from methionine, which is transformed to isothiocyanate 54 by standard operations (Scheme 14) [3l]. Condensation with an appropriate 1,3-diamine, here 55 derived from aspartate, is followed by exhaustive S-methylation inducing a smooth double ring closure. After deprotection, guanidine 58 was isolated in gratifying 85 % yield.

LO,

52

I

NO2

53

Scheme 13. Functional guanidiniurn-bajed receptors.

istry for a long time 1221. Its biochemical importance is clear: any kinase or phosphatase will primarily have to complex phosphate(s). Sulfated sugars and sugar acids - e.g. neuraminic acid are often involved in recognition processes on the cell surface. And a hereditary mutation of merely one residue on the chloride ion channel protein induces its malfunction, leading to cystic fibrosis. So recently more and more groups have become involved in the design of synthetic anion receptors. These topics are covered by several reviews [23], and a representative selection may illustrate the field (Scheme 12). Lehn and

-

-

2. 1. TBDMSCI, BH3xSMe2, IrnTHF

("OTBDMS

3. S=CC12. NaHC03

&OH SMe NH2

74%

NH2 NHTs

(\~OTBDMS

55

CH&N. 85%

SMe .N ,

56

methionine

TBDMSO

1'

5a

247

Ts

OTBDMS

57

Scheme 14. Key sequence to yield the scaffold 58 by Schmidtchen et al.

Me

248

A . Total Synthesis of Natural Producls

1.10% NaOH, S O T 2.Mel MeOH rtx. 3. 62, kuOH.’rfX.

59

NH O

acetone,rtx.

53 (Nh4.2

Me2N

60

Scheme 15. Synthesis of the RNAse mimic 53

65

Scheme 16. Guanidinum hosts as polyanion sensors.

Scheme 17. Entropy-driven SO:-

complexation found for 66.

The RNAse model compound of Hamilton was constructed in a few steps (Scheme IS) [ 301. Benzoyl isothiocyanate was allowed to react with diamine 59 to yield bis(thiourea) 61 after deprotection. S-methylation activated the urea moieties for guanidine formation with N,N-dimethyl-ethylenediamine 62 to reach the desired compound 53. Receptors showing useful selectivity for polyanions have been invented by the Anslyn group 1311. Tris(guanidinium) compound 63 displays a binding constant of 6900 for citrate in water with remarkable selectivity (Scheme 16) [31a]. This was utilized to set up a competition assay for the direct determination of citrate in the mM range [31b]. Steric gearing forces the

recognition elements to one face of the hexasubstituted benzene ring, which was further used for the hexacationic receptor 64. Applying 64 to the competition assay, the inositol-l,4,Striphosphate 65 concentration - an important second messenger in cell signalling - could be measured down to 1 p M [ ~ I c ] . The strong Coulomb interactions present in the guanidine-anion complexes may be largely balanced out by solvation energies in a polar medium. By the means of isothermal titration calorimetry, Schmidtchen et al. studied the exceptionally high binding constants of‘ receptor type 66 for SO,’- ( lo6- lo7 in MeOH) [ 321. A large binding entropy gain overrules an unfa-

Polycyclic Guanidirzes

vorable A H , in this case, indicating a solvophobic collapse (Scheme 16). These findings coincide with modern models about protein-ligand interactions [33]and should lead to new design conccpts, overcoming the “rigid cavity”-type receptors. In summary, all of the examples shown outline the significance of the guanidine function for anion recognition in general, whether in bioactive natural products or man-made tools. Joining the concepts and methods should seed ideas in the respective fields and lead to a better understanding of supramolecular interaction in the future.

References [ I ] Berlinck, R.G.S.: Nut. Prod. Rep. 1996, 13, 377 and references cited therein. 121 a) Harbour, G.C.; Tymiak, A.A.; Rinehart, K.L.; Shaw, P.D.; Hughes Jr., R.G.; Mizsak, S.A.; Coats, J.H.; Zurenko, G.E.; Li, L.H.; Kuentzel, S.L.; J. Am. Chem. soc. 1981. 103, 5604. On related metabolites see b) Berlinck, B.G.S.; Braekman, J.C.: Daloze, D.; Hallenga. K.; Ottinger, R.; Bruno, I.: Riccio, R.; Teiruhedron L w . 1990, 31. 653 I ; c ) Tavarea, R.; Daloze, D.; Braekman, J.C.; Hajdu, E.; van Soest, R.W.M.; J . Nur. Prod. 1995, 58, 1139; d) Barrow, R.A.; Murray, L.M.; Lim, T.K.: Capon. R.J.; Aitsi. J . Chem. 1996, 49, 767; e ) Patil. A.D.: Freyer, A.J.; Offen, P.; Bean, M.F.; Johnson, R.K.; J. Nut. Prod. 1997, 60, 704. [ 3 ] Kashman, Y.: Hirsh, S.: McConnell, O.J.: Ohtani, 1.; Kusumi, T.; Kakisawa, H.; J. Am. Chem. Soc. 1989, 111. 8925. The assignment of the species as Priloctrdis has been questioned [2c, 91. 141 Jares-Eriyman. E.A.: Sakai, R.; Rinehart, K.L.; J . Org. Chem. 1991. 56, 5712; Jares-Eriyman, E.A.; Ingrum, A.L.; Carney, J.R.; Rinehart, K.L.; Sakai, R.; J. Org. Chenz. 1993,58,4805;Berlinck, R.G.S.; Braekman, J.C.; Daloze, D.; Bruno, 1.; Riccio, R.; Ferri, S.;Spampinato, S.; Speroni, E.; J. Nur. Prod. 1993. 56, 1007. 151 Palagiano, E.; de Martino, S.; Minale, L.; Riccio, R.; Zollo. F.; Iorizzi, M.; Carre, J.B.; Debitus, C.; Lucarain; L.; Provost, J.; Tetrahedron 1995, 51, 3675. [6] a) Ohtani, 1.; Kusumi, T.; Kakisawa, H.; Kashman, Y., Hirsh, S.; J. Am. Chrm. Soc. 1992, 114, 8472. b) Murphy, P.J.; Williams, H.L.; Hibbs, D.E.; Hursthouse, M.B.; Abdul Malik, K.M.; Chem. Commun. 1996, 445. 171 Ohizumi, Y.; Sasaki, S.; Kusumi, T.; Ohtani, I.; Eur: J. Phtirmucol. 1996, 310, 95.

249

181 a) Kinnel, R.B.; Gehrken, H . 2 ; Scheuer, P.J.; J . Am. Chem. Soc. 1993, 115, 3376; b) Kato, T.; Shizuri, Y.; Izumida, H.; Yokoyama, A,; Endo, M.; Tetruhedron Lett. 1995, 36,2133. Several brominated analogues: c) Kinnel, R.B.; Gehrken, H.P.; Swali, R.; Skoropowski, G.; Scheuer, P.J.; J . Org. Chem. 1998, 63, 3281. [V] Patil, A.P.; Kumar, N.V.; Kokke, W.C.; Bean, M.F.; Freyer, A.J.; de Brosse, C.; Mai, S.; Truneh, A,; Faulkner, D.J.; Carte, B.; Breen, A.L.; Hertzberg, R.P.; Johnson, R.K.; Westley, J.W.; Potts, B.C.M.; 1.Org. Chem. 1995, 60, 1182. The structures of Batzelladine A, D and E have been revised by partial synthesis [17a, b]. [ l o ] Patil, A.P.; Freyer. A.J.; Taylor, P.B.; Carte, B.; Zuber, G.; Johnson, R.K.; Faulkner, D.J.; J . Org. Chem. 1997, 62, 1814. The relative stereochemistry of Batzelladine F is in doubt [18, 19aJ. [ I l l a) Snider, B.B.; Faith, W.C.; J. Am. Chem. SOC. 1984, 106, 1443; b) Roush, W.R.; Walts, A.E.; J. Am. Chem. Soc. 1984, 106, 721. 1121 a) Asaoka, M.; Sakurai. M.; Takei, H.; Tetruhedron Lrtt. 1990, 31, 4159; b) Cossy, J.; BouzBouz, S.; Tetrahedron Leii. 1996, 37, 509 I ; c) Schellhaas, K.; Schmalz, H.-G.; Bats, J.W.; Chem. ELK J. 1998.4. For stimulating racemic work see d) Hassner, A.; Keshava Murthy, K.S.; Tetrahedron Lett. 1986, 27, 1407; e) Uyehara, T.; Furuta, T.; Kabawawa, Y.; Yamada, J.; Kato, T.; Yamamoto, Y.; J. Org. Chem. 1988, 53, 3669. [I31 Snider,B.B.; S h i , Z . ; J . Am. Chem. Soc. 1994, 116, 549. [ 1 4 ] a ) Murphy, P.J.; Williams, H.L.; Hibbs, D.E.; Hursthouse, M.B.; Abdul Malik, K.M; Tetruhedrun 1996, 52, 8315; b) Howard-Jones, A,; Murphy, P.J.; Thomas, D.A.; J . Org. Chem. 1999, 64, 1039. [ 151 Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A.; J. Am. Chem. Soc. 1995, 117, 2657. [ 161 a) Biginelli, P.; Guz,. Chim. I r a / . 1893, 23, 360; review: b) Kappe, C.O.; Teirrrhedron 1993, 49, 6937; for recent improvements see c) Kappe, C.O.; Falsone, S.F.; Synlett 1998, 718. [ 171 a) Snider, B.B.; Chen, J.; Patil, A.D.; Freyer, A.J.; Teiruhedrori Lett. 1996, 37, 6977; b) Snider, B.B.; Chen, J.; Teirahedron Lett. 1998, 39, 5697. [I81 Black, G.P.; Murphy, P.J.; Walshc, N.D.A.; Tetruhedron 1998, 54, 9481. [I91 a) Rama Rao, A.V.; Gurjar, M.K.; Vasudevan, J.; J . Chem. Soc. Chem. Commun. 1995, 20, 1369; b) Gurjar, M.K.; Lalitha, S.V.S.; Pure & Appl. Client 1998, 70, 303. 1201 a) Franklin, A.S.; Ly, S.K.; Mackin, G.H.; Overman, L.E.; Shaka, A.J.; J . Org. Chem. 1999, 64, 1512; b) McDonald, A.I.; Overman, L.E.; J. Org. Chem. 1999, 64, 1520. 1211 Overman, L.E.; Rogers, B.N.; Tellew, J.E.; Trenkle, W.C.; J. Am. Chem. Soc. 1997, 119, 7159.

250

A. Total Synthesis of Natural Products

[22] Lehn, J.-M.; Supramolecular Chemistry, VCH, Weinheim 1995. [23] Reviews: a) Dietrich, B.; Pure Appl. Chern. 1993, 65, 1457; b) Scheerder, J.; Engbersen, J.F.J.; Reinhoudt, D.N.; Recl. Trav. Chim. Pays-Bas 1996,115, 307; c) Schmidtchen, F.P.; Berger, M.; Chem. Rev. 1997, 97, 1609; d) Antonisse, M.M.G.; Reinhoudt, D.N.; Chenz. Cotnmun. 1998, 443. [24] Hosseini, M.W.; Lehn, J.-M.; Jones, K.C.; Plute, K.E.; Mertes, K.B.; Mertes, M.P.; J. Am. Chetn. Soc. 1989, I l l , 6330. (251 Worm, K.; Schmidtchen, F.P.; Atzgew. Chem. 1995, 107. 71; Angew. Chetn. Int. Ed. 1995, 34. 65. [26] Reetz, M.T.; Johnson, B.M.; Harms, K.; Teirahedron Lett. 1994, 35, 2525. [27] Beer, P.D.; Acc. Chem. Res. 1998, 31, 71. [28] For receptors discriminating amino acid dcrivatives see: Davies, A.P.; Lawless, L.J.; Chem. Conzmun. 1999, 9 and references cited therein. (291 Oivanen, M.; Kuusela, S.; LBnnberg, H.; Chenz. Rev. 1998, 98, 961.

[30]Juiban, V.; Veronese, A,; Dixon, R.P.; Hamilton, A.D.; Angew. Chem. 1995, 107, 1343; Angew. Chrm. Int. Ed. 1995, 34, 1237. A more elaborate Zn2 + -based catalyst: Molenveld, P.; Kapsabelis, S.; Engbersen, J.F.J.; Reinhoudt, D.N.; J . Am. Chem. Soc. 1997, 119, 2948-49. [31] a) Metzger, A,; Lynch. V.M.; Anslyn, E.V.; A n g e w Chem. 1997,109,911;Angew. Chem. Int. Ed. 1997, 36, 862; b) Metzger, A,; Anslyn, E.V.; Angew. Chem. 1998, 110, 682; Angew. Chem. Int. Ed. 1998, 37, 649; c) Niikura, K.; Metzger, A.; Anslyn, E.V.; J . Am. Cheni. Soc. 1998, 120. 8533. 1.321 Berger, M.; Schmidtchen, F.P.; Angew. Chem. 1998, 110, 2840; Angew. Chem. Inr. Ed. 1998. 37, 2694. [331 a) Williams, D.H.; Westwell, M.S.; Chem. Soc. Rev. 1998, 27, 57; b) Davis, A.M., Teague, S.J.; Angew Chem. 1999, 111, 778; Angew. Chem. Int. Ed. EngI. 1999, 38, 736.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Synthetic Access to Epothilones - Natural Products with Extraordinary Anticancer Activity Ludger A. Wessjohann and Giinther Scheid Bio-organic Chemistq Vrije Universiteit, Amsterdum, The Netherlands

General Aspects and Biology Epothilone B (2b) and derivatives (2a, 2 c - e ) are among the most exciting drug candidates of the new millennium. They have an extraordinary potential to become the most important antitumor agents of their time, either directly as active drug components or through the enhanced possibility of finally obtaining enough data from quantitative structure activity relationships to understand antimitotic action. Although structurally unrelated to paclitaxel (TaxolO), discodermolide and eleutherobine, they exhibit the same if not a better effect, inducing the polymerization of tubulin to stabilized microtubules. The consequent massive complication during mitosis [ I ] , among possible other actions, finally triggers apoptosis (programmed cell death). This type of tubulin activity has s o far been exclusively found in the four above-mentioned natural products and some derivatives, although far more then 140000 synthetic compounds and extracts have been tested. Of these four compounds, epothilones appear to be the best candidates. They are equally or even more active, e.g. up to 35 000 times better then Taxol in resistant cell lines [2]. They also have better cytotoxic potential connected to the tubulin activity, as not all microtubule stabilizers lead to sufficient cell death, and they allow extensive derivatization much faster then Taxol or discodermolide [3, 41. Also, improvements in the applicability to patients compared to the sparingly soluble Taxol arc expected, eliminating some of the severe side effects connected to the latter drug. Since the binding sites of Taxol and epothilones overlap, epitope comparisons and models of binding

have been proposed, as well as synthetic combinations of the two structures synthesized or suggested [ S , 61. Epothilones were isolated from the myxobacterium Sorungium cellulosurn by the groups of Hofle and Reichenbach in Germany [7, 81. The constitution of the epothilones suggests that they are derived from polyketide metabolism, like similarly built macrolides. The synthesis apparently commences with N-acetylcysteine, which later becomes part of the thiazole. Apart from this ring, the epoxide and the geminal dimethyl group are among the less common features. Under basic conditions, epothilones can undergo retro-aldol cleavage of the C3-C4 bond when the C3 hydroxy group is deprotonated.

Retrosynthetic Analysis So far, the groups of Danishefsky [9- 121, Nicolaou [13-201, Schinzer [21, 221, Mulzer [23], White [24] and Grieco [251 have published total syntheses. Many other groups submitted advanced identical intermediates by different routes, i.e. delivered formal total syntheses. Overall, a multitude of permutations of existing building blocks and strategies were published, pushed to the extreme by the numerous permutating contributions of Nicolaou et al. Thus, single start-tofinish syntheses will not be discussed here, but the most important concepts and building blocks, arranged as far as possible according to the following retrosynthetic analysis. Epothilone numbering is used in all cases. The first retrosynthetic transformation on epothilones A and B (2a,b) is the removal of

252

A. Total Synthesis of Natural Products

X = 0, CHI

J

b

X”.’

OPG

0

1

OR’ 3a Y = CHpP(0)Ph, 3b CH2P(O)(OEt),. 3c CH2P+Bu3HaV, 36 CHzPtPh3Hal’, 4 CHO

5 6 7

2a

R=H

2b

R = M e EDothilone B

Epothilone A

OR2 0

X=O R’=H,R2=TBS X = H.H R’ =R’=TBS X = H , H R’-R2= CMe2

Scheme 1. Epothilone A and B and the retrosynthetic analysis followed in this highlight. (PG = Protecting Group, TBS = tert-butyldimethylsilyl, Hal = C1, Br, I)

the epoxide to give the C12-Cl3 doublebonded desoxyepothilones ( = epothilones C and D - see Scheme 3: 2c and 2d, resp.). The thus simplified molecules allow many reasonable disconnections of macrocycle and side chain of which almost all possibilities were followed. However, some fragmentations have been more successful (Scheme I).These also separate regions of different functionalization within the molecule as they are often found in macrocyclic polyketides in general: a heteroaromatic side chain (cf A), a lipophilic macrocycle half ( c t B), and a more hydrophilic aldol-type macrocycle half ( c t C). All strategies, with the exception of Danishefskys first-generation approach [9], placed disconnections at the CI ester bond and the C6-C7 aldol bond to leave behind the aldol fragment C (qf 5-6 and Chapter 6). The thiazole fragment A was usually split off by breaking the C16-CI7 double bond, but modern palladium methods

alternatively render the C 17 -C 18 bond strategic (cf Chapter 4).

The remaining “northern half’ B (C7-CI 6/ C17, c$ Chapter 5 ) superficially appears to offer fewer strategic disconnections for a convergent approach, with only a C- 15-hydroxy-group, and a double bond in the middle pai-t at C12-Cl3. The latter being the obvious disconnection, it has been the most frequent one too, with the additional possibility of attaching the corresponding subfragments of this disconnection to A and C respectively and using the connection C12C 13 for the macrocyclization. However, almost all other disconnections conceivable have been used in part B (cf: I), although they are often not immediately obvious. This makes a unified description of synthetic approaches to this part of the molecule difficult. Of all disconnections, only three have been used for the macrocyclization, the starting point for the following discussion.

Synthetic Access to Epothilones - Natural Products wiih Extraordinary Anticancer Activity

253

R' ring closing metathesis (RCM)

- H&=CH2

8a 8b

8c

R'=H, R ~ = H R ' = H , R2=TBS R' = Me, R2 = TBS

9a 9b 9c

R'=H, R ~ = H R'=H, R2=TBS R' = Me, R2 = TBS

B

R or Keck-

*

Macrolactonization

HO

0

OTBSO

10a R = H 10b R = M e

0

OTBSO

9b R = H 9c R = M e

35:3R lla R = H l l b R=Me

12a R = H 12b R = M e

51% (6.O:l.O) 60% (2.1:l 0)

Scheme 2. Macrocyclization reactions applied in epothilone total syntheses. From top to bottom: ring-closing metathesis (RCM); macrolactonization, and C2-C3 rnacroaldolization. (TBS = trrt-butyldimethylsilyl, TPS = triphenylsilyl, HMDS = hexamethyldisilazide).

Macrocyclization and Epoxidation The final steps, macrocyclization and epoxidation, will be discussed first, in order to later have a better understanding of the positioning and requirements of the building blocks leading to the open chain precursors. For the cyclization to the 16-membered macrolactone structure of epothilones C and D (= desoxyepothilones A and B, resp. [26]), three different strategies have been used successfully so far: (1) Ring-closing olefin metathesis (RCM) between C12 and C13. RCM is a comparably new method in total synthesis and underwent enor-

mous improvements in recent years, especially because defined stable catalysts have been developed. Because of the complexity of the open chaii, bisolefin this approach was challenging initially but had the appeal of novelty. Certainly the epothilone results contributed considerably to the current success of this method in total syntheses; (2) macrolactonization - probably the safest and most promising method with many successful variations known; and (3) the macroaldolization between C2 and C3 as the least conventional approach.

254

A. Total Synthesis of Natural Products

Ring-Closing Metathesis (RCM) Reactions The RCM of 8a-c shown in Scheme 2 (top) allows the synthesis of the macrocycles 9a-c. Nicolaou et al. were the first to publish a successful RCM of 8a with 15 mol % Grubb's catalyst [RuCI,(= CHPh)(Pcy,),] under high dilution conditions (0.006 M in CH,Cl,) [20]. They obtained a mixture of cyclized olefins in 85 % yield with a Z:E ratio of 1.2: 1.0. Generally, this ratio could not be improved much towards the desired Z-isomer, something which also holds true for RCMs of other precursors. Danishefsky et al. studied a variety of derivatives of 8 (e.g. other or no protective groups or other stereoisomers at C3 and C7 or a CS-hydroxygroup etc.) with SO mol% catalyst (boiling benzene, 0.006 M). In general, the yields of cyclized products were greater than 80 %, but the Z:E ratio changed with small variations in the bisolefin structure [ 1 I , 271. Their cyclization of 8b to 9b (86 % yield) with a Z:E-ratio of just 1.7: 1.0 is still the best result reported so far. In CH,CI,, Schinzer could improve the yield to an excellent 94 %, but the Z:E ratio dropped to 1.0: 1.0 [21]. The cyclization of 8c to 9c created a trisubstituted double bond, thus preparing new ground for the application of RCM in complex systems. Actually the substrate failed to cyclize with thc ruthenium-based Grubb's catalyst, but 20 mol% of a molybdenum-based catalyst described by Schrock led to the cyclized product 9c in 86 % yield (benzene, SS "C), unfortunately again with a 1.0: 1.0 ratio of Z to E isomers [ I l l . In a solid phase bound synthesis of epothilone A and derivatives, Nicolaou et al., in an early stage of the synthesis, connected the vinylic carbon C12a ( c t 8a) via a linker chain to Merrifield

resin. After building up the C 12a-attached 8a-precursor, RCM not only formed the macrocycle Ya, but at the same time released it from the resin, leaving C 12a=C 13a behind [20]. Overall, the new possibilities of RCM were impressively demonstrated on the epothilones. Unfortunately it is too early to address substantial problems with RCM in a satisfactory way. The relatively large amounts of catalyst (15-50 mol%) and the low diastereoselectivity make the syntheses very expensive, because half of the advanced material lost in one of the last steps of the syntheses in form of the wrong double-bond isomer. With the current efforts and the excitement about the truely unique possibilities of metathesis, it is predictable that these drawbacks will be overcome in the future, especially regarding catalyst quantity.

Macrolactonization The IS-hydroxy acids 10a and 10b (Scheme 2) were cyclized with the reliable Yamaguchi (2,4,6-trichlorobenzoylchloride,TEA, DMAP, toluene) [lo, 11, 13, 161 and Keck methods (DCC, DMAP, DMAPxHCl, CHCI,) [23, 281. Both delivered the macrolactones in good to excellent yields, the first (90 % 9b and 78 % 9c) being superior to the latter.

Macroaldolization In the first syntheses of epothilone A 191 and B 1121 by Danishefsky et al., the acetates l l a and Ilb were treated with the base K-HMDS in T H F at low temperature to generate the C I , C2

9 &PEA

at low temp.

or dimethyldioxirane or methyl(trifluor0methy1)dioxirane

2c R = H Epothilone C 26 R=Me Epothilone D

2a R = H 2b R = M e

Scheme 3. Chemo-, regio- and stereoselective oxidation of epothilones C and D (2c and 2d) to epothilones A and B, respectivcly (niCPBA = rnetu-chloroperbenzoic acid).

Synthetic Access to Epothilones

-

Natural Products with Extraordinary Anticancer Activity

enolates, which reacted intramolecularly with the C 3 aldehyde moiety to obtain the cyclized products 12a and 12b. The yields of 51 % and 60 % are comparable, but the considerable change in diastereoselectivity at C3 demonstrates the somewhat unpredictable influence of small changes in the structure. Thus, the selectivity drops from 6 : 1 to only ca. 2 : 1 with just one additional methyl group at C12 in the linear precursor, i.e. a small steric change 8 atoms away from the actually formed stereocenter. It should be noted that this macroaldolization approach requires the protection of the C5 keto group, in this case as triphenylsilyloxy group, in order to avoid the otherwise facile retroaldolization along the C3-C4 bond (see below).

Completion of the Syntheses, Epoxidation The syntheses of epothilone A and B are usually completed by the epoxidation of the C 12-C13 double bond in epothilone C (desoxyepothilone A, 2c) and epothilone D (desoxyepothilone B, Zd), obtained from the deprotection of the precursors 9a-c, or, after an additional oxidation at C5, of 12a-b. To epothilones C (Zc) and D (2d), four epoxidation reagents of two classes were applied, betting on the regio- and stereoselective formation of epothilones A (2a) and B (2b) respectively. The electron-rich C 12-CI 3 double bond is indeed attacked preferentially by all reagents applied and the dominant diastereoselectivity is in agree-

ment with the natural structures too (Scheme 3). Epoxidations to epothilone B are superior to those to epothilone A with respect to both yield and diastereoselectivi ty. It turned out that mCPBA is the least selective reagent (drs from 2.8 : 1 [20] to 4 : 1 [23]), also giving rise to many side products e.g. by oxidation of the side chain double bond and of the aromatic system, depending on the conditions 1261. Nicolaou et al. used the alternative H,O,/ MeCN-system with KHCO, in methanol to epoxidize desoxyepothilone E (Ze, Scheme 13) derivatives with good yields and selectivities [181. The best reagents so far are dimethyldioxirane and methyl(trifluoromethyl)dioxirane, the first allowing the epoxidation of 2c to 2a in 49 % yield and dr > 16: 1 and of 2d to 2b in 97 % yield and dr > 20 : 1 [ 1I]. The fluorinated dioxirane was superior in yield in the formation of 2a but in all other aspects was inferior to dimethyldioxirane [ 131.

Synthesis of the Thiazole Fragment A We begin our discussion of the retrosynthetic fragments with the thiazole moiety A (cf Scheme I), i.e. the least problematic building block. Indeed, they appear to be so easily accessible that some authors do not mention their synthesis or references, and sometimes even “forget” to count the necessary steps in their final conclusion.

3d R = P h

13a Hal = CI

13b Hal=Br

255

,,

3~ R = B u

(Hal = CI)

3a

\

3b

Scheme 4. Syntheses of 2-methyl thiazole-4-methyl phosphorus reagents (fragment A building blocks).

256

A . Totul Synthesis

of Nuturul Products from 1,3-dichloroacetone and thioacetamide followed by dehydration [311. Mulzer reported the synthesis of Wittig salt 3d in 85 % overall yield (no reaction conditions given) [32]. Schlosser salt 3c can be obtained in 87 % yield by heating 13a and PBu, without solvent at 70°C [23, 331. Phosphinoxide 3a was used by Danishefsky; no yields were given 19. 341. In a different approach, bromide 13b synthesized from cysteine methyl ester hydrochloride and acetaldehyde [35], gave phosphonate 3b in 89 % yield with P(OEt), in an Arbuzov reaction [36].

Two different strategies for the incorporation of the thiazole moiety were used so far: either Stille coupling reactions of 4-stannylthiazoles by one group [18, 191 or Wittig-type olefination reactions by all others. The latter approach requires either 2-methyl-thiazole-4carbaldehyde (4, Scheme 1) available from the corresponding ester by reduction 113, 20, 29, 301 or suitable 4-phosphorusmethyl derivatives (3a-d, Schemes 1 and 4) for the more common inverse approach. The phosphorus derivatives 3a, 3c and 3d were synthesized from 13a, readily available

14

I1

i M e 1.1 eq LDA, THF, 0°C. 8h,

N I

-

M (e N

then -1Oo"C, 1.5eq ICH2(CH2)2CH208;1,

I

I

O"C, 6h, 92% (>98% de)

h

O

B

11

TBS0*

(5 steps, 75%)

16

15

0

0

X

n

(7 steps, 60%)

17a X = CHO 17b X = C(0)Me

(6 steps, 63%)

17C X = PPh3'1.

0

1.1eq NaHMDS. THF, -78°C.

X 2 steps

then 5.0 Me1 eq , -78"C, 11h

(82%)

18a X = CH,OTBS 18b X=CH=CHz 18c X = C(Me)=CH,

(n.r.)

(87%)

19a X = CHzOTBS 19b X=CH=CHz 19c X = C(Me)=CHz

(73%)

20a X = CH20TBS 20b X = CH=CHz (75%) 2Oc X = C(Me)=CH (n.r.)

1.1 eq DIBAH,

1.1 eq BuLi, THF, -78% 2h 30 rnin. then 5.0 Mel, 3.0 eq HMPA, -5o"C, 0.5h (94%, 97% de)

21 X = CHZCH~CH=CH~

.

22 X = CHZCHzCH=CH2

12

CHZCIz (86%)

20b

Scheme 5. Partial syntheses of fragment B: introducing the C7 connecting point and the C8 stereocenter by auxiliary induced alkylation (n.r. = no yield reported).

Synthetic Access to Epothilones

-

Synthesis of the Northern Half of epothilones (Fragment B) and the Introduction of the Thiazole Side Chain (Fragment A) The “deoxy-northern half’ C7 -C 1.5 is barely functionalized apart from the marginal connection points, i.e. the central C8 to C14 area contains only a double bond with imperative cis configuration and one stereocenter at C8 (instead of three in the final target). Possible disconnections are much less predetermined than in the CI-C7 “aldol-region”. Therefore all six C-C-bonds within the seven-carbon chain from C8 to C14 were used as strategic bonds.

Synthesis of Building Blocks C7-Cl2 and C13-C21 (Including Side Chain) The control of the C8 stereocenter was achieved by alkylation directed by an auxiliary at C7 involving Oppolzer sultams, Enders hydrazones and Evans oxazolidinones (Scheme 5: 1-111, resp.). Either the corresponding propionate [ 14, 371 or propionaldehyde [13, 161 equivalents were alkylated with an alkyl iodide representing the principal part of the northern half of epothilones (Scheme 5 : I, 11). or C-8 of a sui-table chain was methylated diastereoselectively (Scheme 5 : 111, IV).

N’

3’‘

benzene. awc, l h , 90%

0

-

“

17

While the sultame and the oxazolidinone auxiliaries represent carboxylate equivalents, which have to be reduced (and sometimcs re-oxidized) to the required aldehyde function at C7, the strength of Enders SAMP and RAMP auxiliaries is their direct use as aldehyde and ketone equivalents. However, Nicolaou et al. [13, 161 for the synthesis of the protected building blocks 17a-c had to give up the correct oxidation state in order to allow necessary later manipulations. Considering the necessity of reduction, the cheaper and recoverable Evans-oxazolidinones 18 appear to be the auxiliaries of choice, as demonstrated by Schinzer et al. [21, 22, 361. A similar methylation is described in an early publication of De Brabander et al. [38] where sultame 21 was methylated and reduced to the a-methylaldehyde 20b in only two steps in good yield and enantiomeric excess. The thiazole-substituted homoallylic alcohol 25 (Scheme 6) is a key intermediate, not only for RCM strategies, but also for other routes. Thiazole aldehyde 4 (Chapter 3) after homologation to enal 24 (90 c/c yield) [ 11,20j was subjected to asymmetric allylation with allylboron and tin reagents. Interestingly 25 with identical absolute stereochemistry was synthesized by Nicolaou et al. with (+)-Ipc,B(allyl) in 96 % yield and > 97 % ee [ 13, 201, and by Danishefsky et al. with the enantiomeric (-)-Ipc,B(allyl) in 83 % yield and > 9.5 % ee [ 1 I ] , i.e. in one case an er-

15

17

24

4

257

Natural Products with Extraordinary Anticancer Activity

25

:

OH

Scheme 6. Synthesis of a C13-C21 building block ( a partial A-B fragment).

+ i u- +\;uo . Nicolaou, Danishefsky 4 (3 steps)

6H

25

(3 steps)

Schinzer (n steps)

6PG

26a 26b

OPG-OTBS OPGZOAC

Scheme 7. Switching the C 13-functionalization of CI 3-C2 I building blocks

OTBS 27

25 8

A. Total Synthesis of Natural Products

26a

OPG = OTBS

26b

OPG=OAc

Nicolaou I1

\

~TBS J !

R=Me

31

33

I jj +ism

R

2 steps

-

N4

’ s.

5 steps

d

l

6PG

AN

s

d

38a

l

R=Me

OPG=OTBS

36b R = H 3%

~TBS

OPG 28a 28b 2 8 26d

I

N

OPG=OAc

R=Me

OTBS

OPG=OAc

OPG

~~~

OPG = OTBS R = Me OPG = OTBS ~ R = H OPG=OAc R=M e OPG = OAc R=H

2 steps

29a R = H 29b R = Me 2% R = H 29d R=Me

OPG=OTBS OPG = OTBS OPG = OAC OPG=OAC

1

R

oy OTBS

17a R = H 17b R = Me

Wessjohann

Nicolaou I

E:Z= 1.9 E:Z = 1:l

27

3c

40

Scheme 8. Syntheses of C7-C21 of the epothilones according to Schinzer (& Danishefsky), Nicolaou 11, Wessjohann. Nicolaou 1 and Mulzer (clockwise from 12 : 00).

Synthetic Access to Epothilones

-

Natural Products with Extraordinary Anticancer Activity

259

Grubbs-cat. CHpC12,reflux,

OH 41

NaHMDS. THF, Mel.

-78"C, 82%

-

PMBO

3 h, 63%, E:Z= 1:12

PMBO

3 steps

PMBO

6 43

42

0

7

0

2 steps

..,,,,

0

0

Scheme 9. Diastereoselective ring-closing metathesis and C8 methylation according to Kalesse et al. to synthesize C7-C2 I (fragment A-B) (PMB = p-methoxybenzyl).

roneous configuration was published. The catalytic asymmetric allylation with tri-n-butylallylstannane was achieved in the presence of 10 mol% of a Lewis acid catalyst formed in situ from Ti(OiPr), and (S)-BINOL in CH,CI, at -2OCC, a method originally described by Keck. This procedure was independently used by Taylor et al. (62 %, > 86 o/o ee) 1301 and Danishefsky et al. (> 95 % re) [ 1 I]. Compound 25, if not used in the RCM strategy, can be converted to aldehydes 26 by protection of the alcohol group and oxidative double bond cleavage (Scheme 7) [ I I , 131. It is interesting to note that Schinzer et al. go the opposite way and synthesize alkene 25 from this aldehyde 26a obtained via a different route [olefination of protected (2S)-2-hydroxybutyrolactone with ArCH,P(O)(OEt), (3b) [2 1, 221 or ArCH,PBu,+CI(3c) 12311. Nicolaou then transformed aldehyde 26b to the phosphonium salt 27 in three steps.

Syntheses of Complete A-B Fragments (Northern Half and Side Chain) An overview of the most important routes to complete A-B fragments from the intermediates discussed in the previous chapter is given in Scheme 8. Nicolaou (I, Scheme 8: lower left corner) coupled the phosphoniumiodide 27 with the carbony1 compounds 17a and 17b, bringing the

synthesis of northern half building blocks 28a and 28b to completion after cleavage of the C7-TBS group and oxidation to the aldehydes 29a and 29b 1131. Unfortunately, while the double bond in 28a is formed in high Z selectivity, 28b is formed without diastereoselection. The inverse combination of phosphonium iodide 17c ( c t Scheme 5 ) and aldehyde 26a lead to 28a with almost identical results. The problem of E:Z selectivity in 28b was overcome when aldehyde 26a was olefinated with the stabilized ylide 30, giving 31 in 95 % yield exclusively with the desired configuration (Scheme 8: upper right) [ 131. However, now the methyl ester had to be transformed to the C12 methylgroup with an additional three steps. Further transformations afforded iodide 32 which can be used for asymmetric alkylation with a C, building block according to Scheme 5 1-11 [ 131. Mulzer (Scheme 8: upper left) obtained the a, p-unsaturated ester 33 with Z configuration from aldehyde 26a via a Still-Gennari olefination with phosphonate ester 34. Reduction of the ester with DIBAH and application of I,-imidazolePPh, gives allylic iodide 35. This acts as electrophile on the u-anion of sulfone 36. After reductive removal of the phenylsulfone, group 28b is obtained [23]. Danishefsky et al. (Scheme 8: upper center) were able to extend aldehyde 26b using ylides Ph,P = CHI (37a) and Ph,P = C(Mc)I (37b) and provide vinylic iodides 38b and 38c, which

260

A. Total Synthesis of Natural Products

was shown, that the reaction conditions also allow the isomerisation of pure E olefin to the thermodynamic ratio of E:Z = 1 : 12. The methylation of lactone 42 at C8 is noteworthy also, because it luckily gives 82 % 43 with perfect control of the stereochemistry. Overall, the new chiral centers at C8 and C1S are introduced via the starting material (S)-ethyllactate without the need of additional chiral auxiliaries. Further transformations led to the known intermediate 28a.

were then connected to a C3-Cll borane (not shown) via Pd"-catalyzed Suzuki coupling to give precursors of l l a and l l b (cf Scheme 2) [ 1 1 , 121. The same reaction sequenze was used later by Schinzer et al., synthesizing iodoolefin 38a with phosphorane 37b followed by PdO-coupling with zinc organyl 39 to building block 28b P21. Several other publications offered alternative solutions for northern half building blocks. Selected examples are briefly discussed. Wessjohann et al. (Scheme 8: lower right) [39-411 use the cheap C,, alcohol nerol (40) as a C7C14 synthon with the correct branching and correctly configured double bond already in place, thus avoiding C12-C 13 E/Z problems and nonfunctionalized carbon-carbon bond formations altogether. In another creative strategy, in order to circumvent the C12-Cl3 E L diastereoselectivity problem, Kalesse et al. (Scheme 9) 142, 431, use the RCM of 41 to obtain a strained ten-membered ring, ensuring the excess formation of Z olefin 42 under thermodynamic conditions. It

44

Synthesis of the Aldol Fragments C and Aldol Reactions between C6 and c7 The syntheses of the CI -C6 aldol fragment (C) and similar building blocks with defined stereochemistry at C3 reveal several general problems. On one hand, it is difficult to transfer an acetate unit to an aldehyde with good B-induction, this usually is referred to as the "acetateproblem" [44]. On the other hand the CI-CS

45

7

1) Protection

(+)-lpc2Wllyl), THF.-78"C

2) Ozonolysis t

0

0-0

0

74%(61%de)

(3 steps, 95%)

i

dMP

PMP

46

(+)-lpczB(aW), THF, -78°C

0

0 49

BMP

48

47

1) Protection 2) Ozonolysis

74% (97% ee)

3) Oxidation (3 steps, 82%)

TBSO

50

0

5

1) Protection 2) Ozonolysis

50

b

3) Reduction

4) Protection (4 steps, 62%)

Scheme 10. The allylation/C=C-degradation strategy (Ipc

=

isopinocarnpheyl).

TBSOTBSO 6

0

Synthetic Access to Epothilones

-

part of epothilones is prone to retroaldolization, especially between C3 and C4 enhanced by the geminal C4 dimethyl group, rendering the bond very labile under basic conditions. A somewhat minor problem is the chemoselective addition of carbon nucleophiles to one of two carbonyl groups, e.g. in b-ketoaldehyde 49. In view of these facts it is not astonishing, that the first syntheses avoided the obvious aldol approach to

'F

H T q Ph o ) f 0+

0

51

fi

TBSO

0

build up the C3 stereocenter, but instead opted for indirect multistep reaction sequences. The first solutions to this problem were devised by Schinzer et al. [36] and Mulzer et al. [45] with allylic isopinocamphenyIborane reagents; later Nicolaou et al. [13, 20, 461 also followed this strategy (Scheme 10). In Schinzers approach, (-)-Ipc,B(prenyl) as C4-C5 substitute is added to aldehyde 44, obtained in two steps from 1,3-

2 eq. CDA, THF, -78°C. 75%, 96% de

O x 0

1 eq. N-Tos-D-valine/BH3.THF,

CHzCIz.rt 0.5h,then -78°C

& M ,e

TBSO ~TMS

OH

O 7

53

52

+

26 1

Natural Products with Extraordinary Anticancer Activity

0

addn. 44+54, -78°C. 4h

-

TBSO

OTBSO

88% (90% de) 44

55

54

6

56, Et2BOTf/CPrzNEt, CH2C12, O"C, 30 min. then 49, -78"C, 1h

HO&+

0

TBSO

80%, 88% de

56

57

49

OP&

$-Ph

2.2 CrCl2, 0 lLil THF, 20°C. 8h

63%. 84% de

0 58

49

O + B

2.2 Sml,, THF,0°C r

T

o

0

5

-

HOzC*

0

TBSO

O H 0 59

5

61

7

*

98%. 90% de

0 60

Scheme 11. Aldol-type strategies to the CLC6 fragment C.

262

A. Total Synthesis

of Nutural

Products

propandiol in 74 % yield. Further manipulations, including protection, oxidative cleavage of the double bond to the aldehyde, Grignard addition of EtMgBr and TPAP-oxidation of the resulting alcohol to the ketone, lead to the protected 1,3diol 7 in 42 % (15 % overall) yield. The other authors used (+)-Ipc,B(allyl) as a CLC2 building block. Mulzer applied it on the advanced C3-C9 building block 46 in 74 % yield, but with only 61 % de, whereas addition to b-ketoaldehyde 49 gave Nicolaou homoallyl alcohol 50 with 97 % ee and the same yield, and further on ketoacid 5 (Scheme 10). Mulzers approach obviously had to face negative double stereodifferentiation. Because Schinzers building block 7 showed better diastereoselectivities in the later C6-C7 connection, Nicolaou synthesized the similar C1-hydroxy derivative 6 from 50 in four steps instead of acid 5 113). Unfortunately, all allylation approaches required lengthy redox and protection procedures. In a more recent approach (Scheme 1 I ) , Schinzer solved the problem of the C4-C5 retro-aldol reaction with Braun’s (S)-HYTRA (51) [44] by replacing the keto group in ,6-ketoaldehyde 49 with a C=C double bond (c$ 52, derived in four steps from ethyl-2-bromo-iso-butyrate and 3-pentanone in 13 % overall yield). The thus formed intermediate 53 is later deprotected and cleaved oxidatively to give the desired C5 ketone 7 in 52 % yield and 96 % ee from aldehyde 52 [221. Also Mulzer applied a new approach, a stereoselective Mukaiyama-type aldol reaction of methyl trimethylsilyl dimethylketene acetal 54 to the known aldehyde 44 mediated by a chiral borane reagent formed in situ from N-tosyl-u-valine and BH,xTHF [23].Noteworthy is the fact that the conversion of the ester intermediate 55 to ethylketone 6 was not performed by following the common Weinreb procedure, but made use of the Peterson reagent TMSCH,Li as a sterically protected methyllithium equivalent to avoid double addition to the ester. The TMS group was then “substituted” by a methylgroup to yield the ethylketone (cf 6). Direct aldol reactions on building block 49 appear to be much more straightforward, but are problematic because of the retroaldol problem. Nevertheless, two successful non-basic methods

were discovered (Scheme 11). De Brabander et al. [38] used the boron enolate from Oppolzer sultam 56. Wessjohann et al. [41] favored the readily available 2-bromoacylated Evans oxazolidinones (in two ways) in their newly developed chromium(I1)-mediated Keformatsky reaction, and could e.g. add an acetate-enolate generated from 58 to aldehyde 49 in a one-pot reaction (Scheme 11). The intermediates 57 and 59 can be converted to carboxylic acid 5 in almost identical overall yield and r e . An intramolecular diastereoselective Reformatsky-type aldol approach was demonstrated by Taylor et al. 1471 with an Sm(l1)-mediated cyclization of the chiral bromoacetate 60, resulting in lactone 61, also an intermediate in the synthesis of Schinzer’s building block 7. The alcohol oxidation state at C5 in 61 avoided retro-reaction and at the same time was used for induction, with the absolute stereochemistry originating from enzymatic resolution (Scheme 1 I). Direct resolution of racemic C3 alcohol was also tried with an esterase adapted by directed evolution 1481. In other, somewhat more lengthy routes to C1-C6 building blocks, Shibasaki et al. used a catalytic asymmetric aldol reaction with heterobimetallic asymmetric catalysts [49], and Kalesse et al. used a Sharpless asymmetric epoxidation [ 501.

Putting together Fragments (A-)B and C: The C6-C7-Aldol Reaction With C I -C6 aldol fragments C and fragments B (C7-Cn) accessible, the strategic aldol reaction between C6 and C7 (Scheme 12), with the demand to form two stereocenters in the right way, is the final major task prior to the already discussed macrocyclization. Stereocenters C 6 and C7 are in syn relationship (Please note that in Scheme 12 the main chain is twisted between these atoms, thereby pointing s y z substituents in different directions). Therefore a Z-enolate of the ethylketone is required, and on the electrophile component an anti-Cram approach regarding the influence of C8 on C7. While control of enolate geometry is often possible, little can affect the adjustment of the relative stereochemistry between C7-C8 apart from trying different substrates.

Synthetic Access to Epothilones - Natural Products with Extraordinary Anticancer Activity

The first C6-C7-aldol reactions were reported by Nicolaou’s group with the dianion of ketocarboxylic acid 5 (Scheme 12). Aldehydes 29a, 29b and 20b give the desired aldols 62, 63 and 66 in “high yields” (?) at -78°C. As expected, excellent control of the enolate configuration had taken place to result in a perfect C6-C7 syn relationship. Nevertheless, there was no or mini-

29a 29b

R3=H R3=Me

5

6 7

ma1 anti-Cram selectivity, up to a mere 2 : 1 maximum [13, 16, 201. The main improvement was achieved by Schinzer et al. with acetonide 7. The desired aldo1 products 65, 67 and 68 were obtained in high yield and perfect formation of the 6R,7S stereochemistry, with ratios generally better than 9 : 1 for the correct C7-C8 stereochemistry by means

-

6TBS

+

X=O X = H,H X=H.H

263

LDA

c

62 63

R’=H,RZ=TBS R1 = R2=TBS R’-R2=CMe2

64 65

X=O X=O X = H,H X = H,H

R’=H,R2=TBS R ’ = H, R2=TBS R’ = R‘= TBS R’-R2 = CMe2

R3=H R3=Me R 3 = Me R3 = Me

X=O X = H,H X=H,H

R ’ = H , R2=TBS R’-R2 = CMe, R1-R2=CMe2

R3=H R3 = H R3=Me

hy. (1:l) hy, (5:4) 71%,(10:1) 94%. (9:l)

+

66 5

7

X=O X = H,H

67 68

R’=H,R‘=TBS R’-R2=CMe2

69

70

Scheme 12. The C6-C7 aldol reaction has to proceed with double stereodifferentiation. The ratios refer to the anti-syn diastereoselectivity at the C7-C8 bond,

71

hy, (21) 70%, (excl.) 75%,(10:1)

74% (5.5:l.O)

of which the main component, the natural 6-syn, 7-anti compound is shown (TES = triethylsilyl, hy = high yield).

264

A. Total Synthesis ojNatural Products

of double stereodifferentiation [2 I , 221. Following these convincing results, Nicolaou et al. also used doubly protected dialcohol 6 and thus improved the anti-Cram selectivity with aldehyde 29b, first to a ratio of 3 : 1 and and later to 10: 1 with optimized reaction conditions [13, 511. Mulzer used the same disilylated diol 6 to obtain aldol 64 in 69 % yield with 4 : 1 selectivity [23]. An unusual enolate of the 3-triethylsilyl-protected 1,3,5-tricarbonyl compound 69 was applied to aldehyde 70 by Danishefsky et al., forming aldol71 in 74 % yield and with a 5.5 : 1.0 ratio -remarkable considering that in this case no double stereodifferentiation improves the induction [ 10, 521. A systematic study with different aldehydes revealed that an interaction between the double bond and the carbonyl group of the aldehyde is superior to minimization of steric hindrance in the transition state, thus leading to the desired C7-C8 unti relationship 1531. Later in the synthesis of epothilone B, in Danishefsky’s approach, the triethylsilyl group was removed and the C 3 ketone converted to the desired C 3 alcohol by enantioselective catalytic Noyori reduction [ 101. Compounds 62-65 by selective deprotection could be processed to macrolactonization precursors 10; whereas compounds 66-68 needed attachment of (protected) 25 either by metathesis reaction (C 12-C 13) or esterification (C 1- 0 - C I S), prior to macrolactonization or RCM respectively ( c t Scheme 2).

72

Derivatives of Epothilones: Syntheses and Structure-Activity Relationship With the established synthetic routes in hand, many of the more obvious derivatives have been synthesized in order to obtain a quantitative structure-activity relationship (QSAR) and to maybe enhance the activitiy and pharmacological profile of epothilones. These derivatives also include epothilone E (2e, Scheme 13), which is emphasized because it also is an active natural derivative, hydroxylated at C21.

Synthesis of Aromatic Derivatives of Epothilones, Including Epothilone E The group of C. Hofle, the discoverer of the epothilones, was able to isolate sufficient epothilones from fermentations to examine classic derivatization. They examined the products of “Oxidative and reductive transformations of epothilone A” [54], “Derivatizations of the C 12-C 13 functional groups of epothilones A, B and C” [55]as well as “Substitutions at the thiazole moiety of epothilone” [56]. They were among the first to discover that the epoxide can be formed with predominantly correct diastereoselectivity in a final transformation from (protected) epothilones C and D. Recently a more thorough investigation of the epoxidation with mCPBA to the epothilones A and B was finally

73

1) K P B A

Nicolaou et al.

2e

21

Hofle et al.

1

R= H Epothilone E R = Me Epothilone F

0

OH

0

Scheme 13. Total and partial synthesis routes to epothilone E (2e)

Synthetic Access to Epothilones

-

Natural Products PLith Extraordinary Anticancer Activiw

A) 1. BuLi, 2. R+ or

B) Re Br

or

C) RSnBu,, Pdo

75

NIB^ S

265

A) 1 . BuLi, 2. CISnBu, or

B)(MesSn),,Pdo *

n

76

R' = Me. BU

R = CH20H, CH20TBS, CHZ(CH~),OAC.Et, CH=CH2,SMe, OMe, OEt, N(CH& etc.

Scheme 14. Synthesis of substituted thiazole building blocks for QSAR studies.

published [26]. It was shown that at low temperature, the desired epothilones A and B were obtained (see Chapter 3), while at room temperature oxidation of the thiazole nitrogen to the corresponding N-oxide also occurs, a reaction not reported in the early total syntheses using this reagent. The epothilone A and B N-oxides could be rearranged to epothilone E (2ej and F with activated carboxylic acids such as acetic anhydride (Scheme 13). In the total synthesis of epothilone E and other C20-derivatives, substituted thiazole (and other aromatics) have been coupled according to Stille's method to the macrocyclic vinyl iodide 74 obtained with selective RCM, leaving the vinyl iodide unaffected (Scheme 13) [ 18, 191. The 2-substituted 4-trialkylstannyl-thiazoles 77 were synthesized from 2,4-dibromothiazolc 75 in five steps, as shown in Scheme 14.

Structure-Activity Relationships Structure-activity relationships of published epothilone derivatives have been included in the review article and publications of Nicolaou et al. [57, 581 and Danishefsky et al. [2, 59, 601. The most active compound published (!) so far remains epothilone B. All derivatives show decreased activity, but areas of high, medium or low impact upon modification can be assigned to the molecule. These interestingly follow somewhat the common retrosynthetic separation, being C I -C8, C9-C 15, and the side chain respectively [59]. The only variation accepted well in the aldo1 region is a C2-C3 trans double bond. Removing or adding methylene groups between C9 and C11 in order to decrease or increase the ring size also results in significant loss of activity [59,61].

The C 12-C 13 E-configured desoxy-compounds have decreased biological activity, as have C 15 stereo inverted ones. The side chain requires an olefinic spacer between macrocyclic and aromatic ring. As at C12, also at C16 a methyl group is optimal. An oxazole ring is tolerated, as well as substitutions at C20 (cf epothilone E), if they are sterically not too demanding. With the data published, it should be kept in mind that comparability of results from different sources may greatly deviate depending on the test used. Simple microtubule assays do not necessarily give relevant data for selective cytotoxicity or induction of apoptosis, as these two properties are not always coupled sufficiently. Also the significance of tests in vitro, even on cell lines, sometimes bears little significance for in vivo application. Thus it was reported that epothilone D (2dj despite a lower activity, is a much better drug candidate because of its greatly reduced toxic side effects, which therefore have to be attributed to the oxirane-ring [60]. Also, while studying publications at this stage of development, one should keep in mind that the most interesting derivatives are probably not yet published, even if known, owing to the looming commercial potential for a billion dollar drug.

References [ I] D. M. Bollag, P. A. McQueney, J . Y hu, 0. Hensens,

L. Koupal, J. Liesch, M. Goetz, E. Lazarides, C. M. Woods, Ciincer Res. 1995, 5.5, 2325-2333. [2] T. C. Chou,X. G. Zhang, C. R. Harris, S. D. Kuduk, A. Balog, K. A. Savin, J. R. Bertino, S. J. Danishefsky, Proc. Nntl. Accid. Sci. USA 1998, YS. 15798- 15802.

266

A. Total Synthesis of Natural Products

131 L. Wessjohann, Angew. Chem. 1994, 106, 101I 1013; Angew, Chem. Int. Ed. Engl. 1994, 33, 959-96 1. 141 L. Wessjohann, Angew. Chem. 1997, 109, 739742; Angew. Chem. Int. Ed. Engl. 1997, 36, 138-742. 151 I. Ojima, S. Chakravarty, T. Inoue, S. Lin, L. He, S. B. Horwitz, S. D. Kuduk, S. J. Danishefsky, Proc. Natl. Acad. Sci. USA 1999, 96, 4256-4261. [6] M. Wang, X. Xia, Y. Kim, D. Hwang, J. M. Jansen, M. Botta, D. C. Liotta, J. P. Snyder, Org. Lett. 1999, I , 43-46. [7] G. Hofle, N. Bedorf, H. Steinmetz, D. Schombnrg, K. Gerth, H. Reichenbach, Angew. Chem. 1996, 108, 1971-1673; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567- 1569. [8] K. Gerth, N. Bedorf, G. Hofle, H. Irschik, H. Reichenbach, J. Antibiot. 1996, 49, 560-563. [9] A. Balog, D. Meng, T. Karnenecka, P. Bertinato, D.-S. Su, E. J. Sorensen, S. J. Danishefsky, Angew. Chem. 1996, 108, 2976-2978; Angew. Chem. Int. Ed. Engl. 1996, 35, 2801-2803. [ 101 A. Balog, C. Harris, K. Savin, X. G. Zhang, T. C. Chou, S. J. Danishefsky, Angew. Chem. 1998, 110, 2821 -2824;Angew. Chern. In?. Ed. Engl. 1998,37, 2675-2678. 1111 D. Meng, P. Bertinato, A. Balog, D . 3 . Su, T. Kamenecka, E. J. Sorensen, S. J. Danishefsky, J. Am. Chem. Soc. 1997, 119, 10073- 10092. [I21 D.-S. Su, D. Meng, P. Bertinato, A. Balog, E. J. Sorensen, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, Angew. Chem. 1997, 109, 775-777; Angew Chem. Int. Ed. Engl. 1997, 36, 757-759. [I31 K. C. Nicolaou, S. Ninkovic, F, Sarabia, D. Vourloumis, Y. He, H. VdIlbtXg, M. R. V. Finlay, Y. Yang, J . Am. Chem. Soc. 1997, 119, 7974-7991. 1141 K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, F. Roschangar, F. Sarabia, S. Ninkovic, Z. Yang, J. I. Trujillo, J. Am. Chem. Soc. 1997, 119, 79607973. [151 K. C. Nicolaou, N. Winssinger, J. Pastor, S. Ninkovie, F. Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou, E. Hamel, Nuture (London) 1997, 387, 268-272. (161 K. C. Nicolaou, F. Sarabia, S. Ninkovic, Z. Yang, Angew. Chem. 1997,109,539-540; Angew. Chem. Int. Ed. Engl. 1997, 36, 525-521. [I71 K. C. Nicolaou, N. Winssinger, J. Pastor, S. Ninkovic, F. Sarabia, Y. He, D. Vourloumis, Z. Yang, T. Li, P. Giannakakou, E. Hamel, Nature (London) 1997, 390, 100. [I81 K. C. Nicolaou, Y. He, F. Roschangar, N. P. King, D. Vourloumis, T. Li, Angew. Chern. 1998, 110, 89-92; Angew. Chern. Int. Ed. Engl. 1998, 37, 84-81.

[ 191 K. C. Nicolaou, N. P. King, M. R. V. Finlay, Y. He, F. Roschangar, D. Vourloumis, H. Vallberg, F. Sa-

rabia, S. Ninkovic, D. Hepworth, Bioorg. Med. Chem. 1999, 7, 665-697. [20] Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chern. 1997, 109, 170- 172;Angew. Chem. In/. Ed. Engl. 1997, 36, 166-168. 1211 D. Schinzer, A. Limberg, A. Bauer, 0. M. Bohm, M. Cordes, Angew. Chem. 1997, 109, 543-544; Angew. Chem. Int. Ed. Engl. 1997, 36, 523-524. (221 D. Schinzer, A. Bauer, J. Schieber, Synlett 1998, 861-863. [23] J. Mulzer, A. Mantoulidis, E. Ohler, Tetruhedron Left. 1998, 39, 8633-8636. [24] J. D. White, R. G. Carter, S. K.F., J. Org. Chem. 1999, 64, 684-685. [25] S. A. May, P. A. Grieco, J. Chem. Soc., Chem. Commun. 1998, 1597- 1598. [26] G. Hofle, N. Glaser, M. Kiffe, H.-J. Hecht, F. Sasse, H. Reichenbach, Angew. Chem. 1999, 111, 20902093. [27] D. Meng, D.-S. Su, A. Balog, P. Bertinato, E. J. Sorensen, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, J. Am. Chem. Soc. 1997, 119, 2733-2734. [28] A. Balog, P. Bertinato, D . 3 . Su, D. Meng, E. J. Sorensen, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, Tetrahedron Lett. 1997, 38, 4529-4532. 1291 M. W. Bredenkamp, C. W. Holzapfel, W. J. van Zyl, Synth. Commun. 1990, 20, 2235-2249. 1301 R. E. Taylor, J. D. Haley, Tetruhedron Lett. 1997, 38, 206 1 - 2064. [31] G. Marzoni,J. Heterocyclic. Chem. 1986,23, 577580. [32] J. Mulzer, A. Mantoulidis, E. Ohler, Tefruhedron Lett. 1997, 38, 7725-7728. [33] Z.-Y. Liu, C.-Z. Yu, R.-F. Wang, G. Li, Tetrahedron Lett. 1998, 39, 5261 -5264. [34] D. Meng, E. J. Sorensen, P. Bertinato, S. J. Danishefsky, J . Org. Chem. 1996, 61, 7998-7999. [35] S. Mensching, M. Kalesse, J. Prakt. Chem. 1997, 339, 96-97. [36] D. Schinzer, A. Limberg, 0. M. B(ihm, Chem. ELI): J. 1996, 2, 1477-1482. [371 P. Bijoy, M. A. Avery, Tetrahedron Lett. 1998, 39, 209 -2 12. [38] J. De Brabander, S. Sosset, G. Bernardinelli, Synleft 1997, 824-826; ihid. 1998, 328; ibid. 1998, 692. [39] G. Scheid, L. A. Wessjohann, U. Bornscheuer, Manuscript in prepuration 2000. [40] L. A. Wessjohann, M. Kalesse (Anmelder: Wessjohann, L.), Deutsche Offenlegungsschrift 1998, DE 19713970.I . [41] T. Gabriel, L. A. Wessjohann, Tetrahedron Lett. 1997, 38, 1363- 1366.

Synthetic Access to Epothilones

-

Nuturul Products with Extraordinury Anticancer Activity

(421 K. Gerlach, M. Quitschalle, M. Kalesse, Tetruhedron Lett. 1999, 40, 3553-3556. (431 K. Gerlach, M. Quitschalle, M. Kalesse, Synlett 1998, 1108-1109. [44] M. Braun, S. Graf, O r , . Synth. 1993, 72, 38-47. [451 J. Mulzer, A. Mantoulidis, Tetruhedroti Lett. 1996, 37, 9179-9182. (461 K. C. Nicolaou, H. Vallberg, N. P. King, F. Roschangar, Y. He, D. Vourloumis, C. G. Nicolaou, Chrm. ELMJ. 1997, 3, 1957- 1970. (471 R. E. Taylor, M. G. Calvin, K. A. Hilfiker, Y. Chen, J . Org. Cheni. 1998, 63, 9580-9583. (481 U. T. Bornscheuer, A. J., H. H. Meyer, Riotechnology & Bioengineering 1998, 58, 554-559. [49] N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M. Shibasaki, J. Am. Chern. Soc. 1999, 121,41684 178. [SO] E. Claus, A. Pahl, P. G. Jones, H. M. Meyer, M. Kalesse, Tetrahedron Lett. 1997, 38, I359 - 1362. [ S I ] K. C. Nicolaou, D. Hepworth, M. K. V. Finlay, N. P. King, B. Werschkun, A. Bigot, J. Chem. Soc., Clzeni. Conimim. 1999, 5 19-520. 1521 C. R. Harris, S. D. Kuduk, K. Savin, A. Balog, S. J. Danishefsky, Tetrahedron Lett. 1999. 40, 2263 2266. 1531 C. R. Harris, S. D. Kuduk, A. Balog, K. A. Savin, S. J. Danishefsky, Tetrahedron Lett. 1999, 40, 22672270. -

267

1541 M. Sefkow, M. Kiffe, D. Schummer, G. Hotle, Bioorg. Med. Chem. Lett. 1998, 8, 3025-3030. [ S S ] M. Sefkow, M. Kiffe, G. Hofle, Bioorg. Med. Cliem. Lett. 1998, 8, 303 1 - 3036. [56] G. H M e , M. Sefkow, Heterocycles 1998, 48, 2485 -2488. [57] K. C. Nicolaou, F. Roschangar, D. Vourloumis, Angew. Chem. 1998.110, 2 120-2 153;Angew. Chem. Int. Ed. Engl. 1998, 37, 2015-2045. [SS] K. C . Nicolaou, D. Vourloumis, T. Li, J. Pastor, N. Winssinger, Y . He, S. Ninkovic, E Sarabia, H. Vallberg, F. Roschangar, N. P. King, M. R. V. Finlay, P. Giannakakou, P. Verdier-Pinard, E. Hamel, Angew. Chem. 1997, 109, 2181 -2187; Angew. Chem. Int. Ed. Engl. 1997, 36, 2097-2103. 1.591 D.-S. Su, A. Balog, D. Meng, P. Bertinato, S. J. Danishefsky, Y.-H. Zheng, T.-C. Chou, L. He, S. B. Horwitz, Angew Chem. 1997, 109, 21782187; Angew. Chem. I n r . Ed. Engl. 1997, 36, 2093 -2096. [60] T. C. Chou, X . G. Yhang, A. Balog, D. S. Su, D. F. Meng, K. Savin, J. R. Bertino, S. J. Danishefsky, Proc. Nutl. Acad. Sci. USA 1998, 95, 9642-9647. [61] K. C. Nicolaou, F. Sarabia, S. Ninkovic, M. R. V. Finlay, C. N. C . Boddy, Aiigew. Cheni. 1998, II0, 85-89; Angew. Chrm. Int. Ed. Engl. 1998, 37, 81-84,

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Total Syntheses of the Marine Natural Product Eleutherobin Thomas Lindel Pharmuzeutisch-chemisches hstitut, Universitat Heidelberg, Germany

In 1994, the soft coral Eleutherobia sp. was discovered as the source of a marine natural product with outstanding biological activity. In a bioassay-guided fractionation of its extract, Fenical et al. (Scripps Institution of Oceanography, San Diego, USA) were able to attribute the cytotoxic activity to the glycosylated diterpenoid eleutherobin (1, Fig. 1). The structure of 1 was elucidated by extensive 2D NMR spectroscopy and mass spectrometry [ 11. The eunicellane carbon skeleton ofeleutherobin (1) is exclusive to natural products from gorgonians and alcyonaceans, and was observed for the first time in eunicellin (2) from Eutzicella stricta in 1968 [ 2 ] .Compounds 1 and 2 differ with respect to the position of their oxygen

bridges between C2 and C9 in 2, and C4 and C7 in 1. Other members of the small group of natural products with a 4,7-oxaeunicellane skeleton include the eleuthosides 131 and the non-glycosylated sarcodictyins [4] and valdivones [S] from related soft corals. Eleutherobin (1) competes with paclitaxel for its binding at the microtubuli, inhibits their depolymerization, and thereby prevents the division of

Nimhou et al.

Danishefsky et al.

0 4

~TBS OTBS

1: deutherobin

5

I)

(1 8 steps)

(22steps)

OH

9 steps

1: eleutherobin 2: eunicellin

Figure I . The marine natural products eleutherobin (1) and eunicellin (2).

Scheme I . The synthetic strategies towards eleutherobin (1) of Nicolaou et al. ( k f t )and Danishefsky et al. (right).

269

Total Syntheses of the Marine Natural Product Eleuthevobin

cancer cells [6]. Until 1994, paclitaxel (Taxol) had remained the only compound showing that mode of action [7], despite intense efforts. Since then, additional natural products, the epothilones [8], discodermolide [9], and laulimalide [ 101, have shown very similar effects. Eleutherobin (1)

showed an in vitro cytotoxicity of about 10- 15 nM (IC50) against a diverse panel of tumor tissue cell lines with an approximate 100-fold increased potency toward selected breast, renal, ovarian, and lung cancer cell lines (National Cancer Institute). It exhibited a similar tumor-type selectivity

Ho%p

2) 1) L-Seledride. MsCI, Et,N, CH2C12, THF. -78°C 0°C

1) H,O,, NaOH, MeOH 2) Hz, PtOz. EtOH

e

*, ,.

3) LDA, CH,O, THF, -78°C 4) TBSCI. DMAP, CH7CIz,Et,N

OTBS 3) NaC8H,,. THF. r. 1.

46 96

,OTBS

..,,t

79 96

10: Scarvone

11

12

OEl

1) H,SO,

Et,O. r. t., 2 min

2) =-MgBr

1) MeC(OEt),, "PC02H, 170°C. 72 h

&oEt, ,...e

OTBS

2) DIBAL, CHzC17,-78°C

THF, -78°C to r. 1.

'BuLi

D

t#,..,OTBS

THF, -78°C to -40°C

3)TBAF, THF, r. t. 4) TESOTi, EbN. CH,CI, 32 OA (5 deps, sep. of diastereomers)

72 96 I4

13

NU

OTES

OTES 1) PPTS. MeOH, CHZCi7 2) TPAP, NMO, CH2C17,4 A

3) N C ~ C o , E '

A

, p-alanine

EtOH. 50"C, 72 h 4) DIBAL, hexanes, -7810 -10°C

15

0°C 75 % ( 2 1 for

82 90

:+

p)

OTES

Q T 3

1) DDQ. CH,CI,

1) LiHDMS, THF, -3O"C, 20 min

H,O

2) AqO, DMAP, EbN, CH,CI, D

D

3) Et3N.3HF-THF (1:7)

2) Dess-M. periodinane. NaHCO, pyridine. CH,CI,. 0°C

' \

0

-0

G

O

T

B

S

L O

93 %

OTBS

6

16

OH

70 %

=F

OTBS

1) PPTS, MeOH

0

H, Lindlar's cat.

EbN, DMAP, CH,CI,

toluene, r. 1. 20 min

3) TBAF. HOAc, THF

71 96 (4 steps)

17

OTBS

ia

OTBS

Scheme 2. Complete total synthesis ol' eleutherobin (1) by Nicolaou et al.

*

I

270

A. T h l Synthesis o j Natrirnl Products

as paclitaxel (correlation coefficient 84 %, COMPARE protocol [ 1 I]). Recently, the microtubule-

stabilizing natural products were compared with respect to their biological effects, confirming the potency of eleutherobin (1) L12). From natural sources, eleutherobin (1) and the cleuthosides are available only in very small amounts (0.01-0.02 c/o of the dry weight of the rare alcyonacean Electtherobin sp.). The lack of

Ql;;;cNMe2

1) CgCCOCl, Zn, ultrasound,

1) pTsCJH-H,O, MeOH, A

2) Zn, Et,O.NH,CI, 0°C MeOH

A

3) 'BUOCH(NM~,),,

material for comprehensive biological testing was overcome by two total syntheses of eleutherobin (1) by Nicolaou et al. [ 131 and by Danishefsky et al. [ 141. Full details are given in Schemes 2 and 3, respectively. Both research groups take advantage of the chiral pool and start from D-arabinose to synthesize their glycosylation building blocks 4 and 7, respectively (Scheme I ) . The two approaches

2)pTsOH.H,O, Me,CO, A

wc

60 96

42%

20: R-a-phellandrene

21

22

OH

TBDPSO

97 '*yo

D

THF, -78°C separation of diastereorners

1) TBDPSCi, irnidazde, DMAP, 0°C 2) DIBAL-toluene,toluene, -78°C

B~ 3) MsCI, DMAP, pyridine, 0°C

OCH3

57 %

88%

24

25

0

TBDPSO 1) KCN, 18-crown-6. MeCN, 80°C

1) TMSOTf. 2.6-lutidine, -78°C

2) DiBAL-hexane,toluene. -78°C tor. 1.

2) TBAF, THF

D

3) CCI,-NiCI,,

D

3) DMDO-acetone,

DMF

CHzCI,, -78°C

OH

65%

86%

26

OH

OTBS

1) TBSOTf, 2,6-lutidine. -78°C 2) DIBAL-hexane, CH,CI,

-78°C U

3) TPAP, NMO, CH,CI, 4) KDA. THF. -78" to r. 1.;

20

c'n N

N*Tf Tf

$2 OTBS

.-

0

0

66%

45 % 1) TBAF, THF 2) DCC, DMAP, toluene, 70°C

0

1

w.L

H0%N-CH3

OCH3

3) PPTS, MeOH, A

8

Pd(PPh& LCl 2-arnino-5-chloropyridine. THF, A

OTf

-78°C

29

73 %

27

-

38 %

0

Scheme 3. Complete total synthesis of eleutherobin (1) by Danishefsky et al.

1: eleutherobin

*

27 1

Total Syntheses of the Marine Natural Product Eleutherobin

strategically differ with regard to the order of the glycosylation step and the contruction of the oxygen-bridged, ten-membered ring. While Nicolaou et al. make use of Schmidt's method, employing a trichloroacetimidate to glycosylate the monocyclic allylic alcohol 5, [15] Danishefsky et al. first generate the norterpenoid tricycle 8, which is then subjected to a modified Stille coupling, simultanously introducing the carbon atom C15 and the arabinose moiety [ 161. In both approaches, the required diastereomeric purity of the glycosylated intermediates 6 and 9, respectively, is reached in a laborious way. Nicolaou et al. obtain 6 as a mixture of anomers from which the desired p-form is separated by column chromatography (a: 28 %, p: 54 %). Danishefsky et al. stereospecifically couple the anomerically pure arabinosyloxymethyl stannane 7 to the vinyl triflate 8, but they achieve a yield of only 40-50 %. In addition, 7 has to be separated from its n-anomer prior to use. The monoterpenes S(+)-carvone (10;Scheme 2, Nicolaou et al.) and R( -)-u-phellandrene (20; Scheme 3, Danishefsky et al.) are chosen as the starting materials for the syntheses of the diterpenoid skeleton of eleutherobin (1). Again, both routes require the separation of diastereomers by chromatography. The addition of 1ethoxyvinyllithium to the TBS-protected aldehyde 13 (Scheme 2) leads to a mixture of diastereomeric alcohols (5 : 4 ratio in favor of the desired configuration at C8), which is separated by Nicolaou et al. after the alkynylation with ethynyl magnesium bromide in a later step. 13 was synthesized in close analogy to Trost et al. with bond formation between C9 and CIO via Claisen rearrangement (Scheme 2) 1171. Danishefsky et al. have to separate a mixture of diastereomeric alcohols after addition of 2-bromo-5-lithiofuran to their aldehyde 22 (Scheme 3), obtaining the desired diastereomer in a yield of 57 %. 22 was synthesized in an interesting pathway via the ring opening of the cyclobutanone 21. Key step of Nicolaou's synthesis is the stereoselective hydrogenation of the unsaturated cyclododecanone 17 which was obtained via intramolecular acetylide-aldehyde condensation of 6. The intermediate (a-olefin immediately rearranges to the tricyclic dihydrofuran 18 (Scheme 2). Solely the hydroxyl group at the quaternary carbon atom

C 7 takes part in the intramolecular formation of the hemiacetal. Danishefsky et al. achieve the ring closure in a Nozaki-Kishi reaction, coupling the bromofuran ring to the aldehyde generated by homologization of 25. Protection and oxidation of the furan 26 (Scheme 3) by dimethyldioxirane at -78°C give the dihydropyranone 27. In an improvement of their synthesis of eleutherobin (l),Danishefsky et al. silylate the hemiketal hydroxyl group at C 4 of 27 prior to the subsequent nucleophilic methylation 114~1.In comparison to the earlier version, the overall sequence from 27 to 28 is shortened by one step and proceeds in a higher yield. The conversion of the intermediate silylated rearrangement product to the dihydrofuran 28 proceeds smoothly via acid-catalyzed methanolysis. Both total syntheses of eleutherobin (1) are completed by the introduction of the (E)-N(6')methylurocanic acid moiety via acylation of the free hydroxyl function at C8, followed by the removal of the TBS or isopropylidene protecting groups, respectively. The longest linear sequences cover 28 (Nicolaou et al., 2.4 % overall yield) and 26 steps (Danishefsky et al., 0.6 % overall yield), respectively. The reactivity of the strained, tricyclic skeleton of the 4,7-oxaeunicellanes was studied by Pietra in 1988 [4]. Treatment of sarcodictyin A (31) with methanolic potassium hydroxide led to the formation of the butenolide 32 (Scheme 4). The Michael acceptor property of the carbon atom C2 favors this rearrangement, leading to a relaxation of the strained ring system. After methanolysis of the N-methylurocanate, the newly formed hydroxyl group attacks at C2 and the fragmentation of the carbon-carbon bond between C 3 and C 4 immediately follows.

31: sarcudictyinA

32

Scheme 4. The rearrangement of sarcodictyin A (31) observed by Pietra et al.

272

A. Total Synthesis of Natural Products

OH

A

*: 0

31: A' = H, R2 = Me (sarcodidyin A) 34:R' = Me, R2 = "Pr 35: R' = Et, R2 = Me

Figure 2. The sarcodictyin scaffold linked to a polystyrene resin (Nicolaou el a].). The derivatives 34 and 35 showed improved cytotoxicity and tubulin polymerization, respectively.

The absolute stereochemistry of eleutherobin (1) had not been determined when the compound was first isolated, because biological testing was given preference. However, results obtained by Pietra et al. strongly suggested the proposed absolute configuration of the diterpenoid 4,7-oxaeunicellane skeleton [4]. Nicolaou et al. and Danishefsky et al. unambiguously identified the sugar unit of 1 as D-arabinose. In addition to a comparison of optical rotations, Danishefsky et al. synthesized the L-arabinosyl diastereomer neoeleutherobin. Eleutherobin (1) and the non-glycosylated sarcodictyins continue to be subject of extensive biological testing. Although the sarcodictyins are about ten times less cytotoxic than eleutherobin (l),their simpler structure gave rise to the development of a solid-phase synthesis [ 181. Nicolaou et al. loaded the sarcodictyin scaffold onto a polystyrene resin via a 10-membered linker chain (33, Fig. 2). The double bond was generated via a Wittig olefination, with the resin bearing the triphenylphosphorane part. The synthesized library of more than 60 sarcodictyin derivatives allowed some structure-activity relationships to be assigned. The presence of the unmodified urocanyl side chain appears to be required for both tubulinpolymerizing and cytotoxic activity, while different ketal substitution is tolerated. In the absence of the sugar side chain, the reduction of the ester

function of the sarcodictyins results in loss of activity. The highest cytotoxicity was measured for the n-propyl ester 34 (IC50 3-5 nM against the ovarian cancer cell line 1A9 and the paclitaxelresistant 1A9PTXIO and 1A9PTX22), while the highest degree of tubulin polymerization was observed for the ethyl ketal35 (85 % [ 191; sarcodictyin A (31): 67 %). Overman et al. were the first to synthesize the eunicellane carbon skeleton [20]. In contrast to eleutherobin (l),(-)-7-deacetoxyalcyonin acetate (45) from the marine soft coral Cludiellu sp. 1211 shows thc oxygen bridge between C2 and C9 instead of C4 and C7. Starting from S(+)-carvone, an elegant Prins-pinacol conden-

I

.

1) 'BuLi, THF. -78°C:

o n T M S 3 7 b

) ,

2) PPTS, MeOH

A

36,2 steps from Scawone

38,d e = 80 96

64 %

KTM 1) HOAc, H,O

39 BFs.Et20, CH2C12 -55to -20%

2) h.v

72 %

79 96

1) P S I , pyridine 2)TBSOTf. lutiiine 3) B-I-9-BBN. HOAc 4) DIBAL 5)TPAP. NMO

40 LOTIPS

-gl

&$ s OTBS 44, de > 90 X '

-

l)PbP%OMe,

THF, -30°C D

OTBS 2) TfOH, 'PrOH, CH,CI, 3) NiCI,-CrC12. DMSO

2) i)AqO,pyridine TBAF

88 %

@ ?

OH 4 5 (-)-7-deacetoxya!qonin acetate

Scheme 5. Total synthesis of (-)-7-deacetoxyalcyonin acetate (45) by Overinan et al.

Ritul Syntheses of the Murine Natural Product Eleutherohin

273

the stepwise syntheses by Nicolaou et al. (six), Danishefsky et al. (eight), and Overman et al. (four), it can be stated that the efficiency of nature still sets the standard for modern organic synthesis.

References n-R’

I I ] a) W. Fenical, P. R. Jensen, T. Lindel (University of

California), US Patent No 5,473,057,1995 [Chem.

Ahst,: 1996, 124, PI94297zJ; b) T. Lindel, P. R.

Figure 3. Carbon -carbon bonds introduced from synthetic building blocks by Nicolaou et al. (A) and Danishefsky et al. (B, C2-C9 broken after ketene cycloaddition). In the putative biosynthesis of the diterpenoid 4,7oxaeunicellanes from ceinbranoid precursors, only one additional carbon-carbon bond (CI-C 10) would have to be formed (C). ( I : RI = (E)-N(6’)-methylurocanyl, R2 = beta-iXl(2)-acetylarabinopyranosyl; stereochemistry has been omitted for clarity). sation-rearrangement was used to assemble the

2-oxabicyclo[4.3.0]non-4-ene 40 (Scheme 5 ) from the diol 38 and the aldehyde 39 in a fully stereoselective manner. Deformylation to 41 was subsequently achieved photochemically. Sharpless epoxidation followed by Red-Al reduction stereoselectively introduced the hydroxyl group at C3. After homologization the oxonane ring (44) was assembled, making use of a remarkably stereoselective Nozaki-Kishi reaction (& > 90 %I). The synthesis of (-)-7-deacetoxyalcyonin acetate (45) proved the proposed structure and was achieved in I 7 steps and a total yield of 9.8 %. In conclusion, three independent syntheses of marine eunicellane diterpenoids have been developed, which will be the basis of the future development of this exciting natural product class. The biosynthesis of the eunicellanes probably involves the oxidative cyclization of a cembranoid precursor lacking solely the bond between CI and C10 (C, Fig. 3). Considering the number of carbon - carbon bonds formed in the course of

Jensen, W. Fenical, B. H. Long, A. M. Casazza, J. Carboni, C. R. Fairchild, J. Am. Chem. Soc. 1997, 119, 8744-8745. 121 0. Kennard, D. G. Watson, L. Riva di Sanseverino, B. Tursch, R. Bosmans, C. Djerassi, Tetruhedron Lett. 1968, 9, 2879-2884. [3] S. KetLinel, A. Rudi, M. Schleyer, Y. Benayahu, Y. Kashman, J. Nut. Prod. 1996, 59, 873-875. [4] a) M. D’Ambrosio, A. Guerriero, F. Pietra, Helv. Chirn. Acta 1987, 70, 2019-2027; b) ibid. 1988, 71, 964-976. IS] Y. Lin, C. A. Bewley, D. J. Faulkner, Tetruhedrorz 1993, 49, 7977-7984. 161 B. H. Long, J. M. Carboni, A. J. Wasserman, L. A. Cornell, A. M. Casazza, P. R. Jensen, T. Lindel, W. Fenical, C. R. Fairchild, Cuncer Rex 1998, S8, 11 1 1 - I 115. 171 For the chemistry and biology of paclitaxel, see K. C. Nicolaou, W.-M. Dai, R. K. Guy, Angew. Chem. 1994, 106, 38-60; Angew. Clzem. Int. Ed. Engl. 1994, 33, 15-44. [8] a) G. Hofle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H. Reichenbach, Angew. Chenz. 1996, 108, 1671-1673; Angew. Chem. In/. Ed. Engl. 1996, 35, 1567- 1569; b) see also L. Wessjohann, Angew. Chenz. 1997, 109, 739-742; Ang e w Chenz. Int. Ed. Engl. 1997, 36, 715-718. [9] a) E. ter Haar, R. J. Kowalski, E. Hamel, C. M. Lin, R. E. Longley, S. P. Gunasekera, H. S. Rosenkranz, B. W. Day, Biochemistry 1996,35, 243-250; b) R. Balachandran, E. ter Haar, M. J. Welsh, S. G. Grant, B. W. Day, Anti-Cancer Drugs 1998, 9, 67 - 76. [ 101 S. L. Mooberry, G. Tien, A. H. Hernandez, A. Plubrukarn, B. S . Davidson, Cancer Rex 1999, 59, 653-660. [ l l ] Information with regard to the COMPARE protocol established at the NCI is available on the internet: http://dtp.nci.nih.gov/docs/compare/ compare.html. [I21 E. Hamel, D. L. Sackett, D. Vourloumis, K. C. Nicolaou, Biochenzisrty 1999, 38, 5490-5498. [I31 a) K. C. Nicolaou, F. van Delft, T. Ohshima, D. Vourloumis, J. Xu, S. Hosokawa, J. Pfefferkorn, S. Kim, T. Li, Angew. Chem. 1997, 109, 2630-

214

A. Total Synthesis of Natural Products

2634; Angew. Chem. Int. Ed. Engl. 1997, 36, 2520-2524; h) K. C. Nicolaou, J.-Y. Xu, S. Kim, T. Ohshima, S. Hosokawa, J. Pfefferkorn, J . Am. Chem. Soc. 1997, 119, 11353-11354. [I41 a) X.-T. Chen, C. E. Gutteridge, S. K. Bhattacharya, B. Zhou, T. R. R. Pettus, T. Hascall, S. J . Danishefsky, Angew. Chen7. 1998, 110, 195- 197; Angew. Chern. In?. Ed. Engl. 1998, 37, 185- 187; h) X.-T. Chen, B. Zhou, S. K. Bhattacharya, C. E. Gutteridge, T. R. R. Pettus, S. J. Danishefsky, ibid. 1998, 110, 835-838; ibid. 1998, 37, 789792; c) S. K. Bhattacharya, X.-T. Chen, C. E. Gutteridge, s. J . Danishefsky, Tetruhedron Lett. 1999, 40, 3313-3316. [IS] R. R. Schmidt, K.-H. Jung in Preparative Curbohydrute Chemisty (Hrsg. S. Hanessian), Marcel Dekker, New York, 1997, S. 283-312.

[ 161 J. K. Stille, Angew. Chern. 1986, 98,504-5 19; An-

gew. Chem. Int. Ed. Engl. 1986, 25, 508-524. (171 B. M. Trost, A. S. Tasker, G. Ruther, A. Brandes, J . Am. Chem. SOC. 1991, 113, 610-672. [ 181 K. C. Nicolaou, N. Winssinger, D. Vourloumis, T. Ohshima, S. Kim, J. Pfefferkorn, J.-Y. Xu, T. Li, J. Am. Chenz. Soc. 1998, 120, 10814-10826. [I91 Percentage of the value obtained on incubation of tubulin with 0.5 M GTP, 10 % glycerol in 100 mM MEM buffer. D. M. Bollag, P. A. McQueney, J . Zhu, 0. Hensens, L. Koupal, J. Liesch, M. Goetz, E. Lazarides, C. M. Woods, Cancer Re.\. 1995, 55. 2325-2333. [20] D. W. C. MacMillan, L. E. Overman, J. Anz. Chem. Soc. 1995, 117, 10391 - 10392. [21] Y. Uchio, M. Kodama, S. Usui, Tetrahedron Lett. 1992, 33, 1317-1320.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Selectin Inhibitors Murkus Riisch and Karolu Ruck-Braun Institut fur Organische Chernie, Universitat Mainz, Germany

Adhesive cell-cell interactions determine several biological events, such as embryogeneses and immunological defence. On a molecular level, cell adhesion and migration are mediated by recognition and binding effects between cell specific adhesion molecules and their ligands of high affinity. The most important adhesion molecules on cell surfaces are cadherins, selectins (E-, P- and L- selectin), glycoproteins of the immunoglobulin superfamily and integrins [ l , 21. There is now general agreement that adhesion events are mediated by protein-protein interactions as well as by carbohydrate-protein interactions. Selectins belong to the family of carbohydrate-recognixing proteins (lectins) carrying calcium-dependent binding domains for carbohydrate structures. Sialyl Lewis’ tetrasaccharide was identified as a weak ligand of all three selectins by in vitro investigations (Scheme I ) . It is a common segment of the natural ligand and involved in adhesion processes during inflammatory responses.

Inflammatory Processes Carbohydrate selectin-mediated cell-cell recognition plays an important role in physiological processes such as inflammation reactions. The inflammation cascade begins with the stimulation of the endothelium by cytokines to express P-selectin followed by massive formation and presentation of E-selectin receptors. Neutrophile granulocytes and monocytes display glycoproteins such as polylactosamine sialomucine PSGL- 1 [3 I or sialoglycoproteins such as ESL-I [4] on their surface. These are the natural ligands to E- and P-selectin-presenting sialyl Lewis’ and related carbohydrates. Carbohydrate-selectin interactions result in rolling of the circulating leucocytes on the endothelium. Other adhesion molecules such as integrins are simultaneously activated, mediating the binding of the leucocytes to the endothelium. This stronger protein-protein interaction leads to the migration of leucocytes through the endothelial layer to the site of the injury.

/ granulocyte

Scheme I

27 6

A. Total Synthesis of Natuml Products

Also, transplant rejection is an inflammatory process characterized by lymphocyte and monocyte infiltration into the transplant tissue. On a molecular level, this process seems to depend largely on L-seIectin/siaiyi Lewis' recognition [ 5 ] . Lymphocytes express constitutively L-selectin on their cell surface. The homing of lymphocytes is mediated by the L-selectin ligand GlyCAM 1 [6]. This glycoprotein is exclusively expressed on the endothelial cells of the postcapilar venoles in the lymph nodes and presents a high density of multiple oligosaccharide units with sialyl Lewis' and sulfated sialyl Lewis' structures. It has recently been shown that rejection of kidney transplants is initiated by a massive de novo expression of sialyl Lewis' on the transplant's peritubular endothelial cells IS]. Selectin-dependent adhesion inhibitors offer a new therapeutical approach to the prevention of transplant rejection. They should also enable treatment and prophylaxis of various other pathological inflammation processes and diseases (i.e. rheumatic arthritis, dermatitis and bacterial meningitis) initiated by a massive invasion of leucocytes [ 1, 71. First clinical trials of a tetrasaccharide sialyl Lewis' analog as an inflammation blocker are already complete 17, 81. But saccharidical sialyl Lewis' analogs are inactive in oral application, and intravenous injection leads to a fast enzymatic decomposition: this is a challenge to clinical pharmacology. Furthermore, chemical synthesis of oligosaccharides is sophisticated, timeconsuming and expensive. For a therapeutical approach, metabolic-stable selectin inhibitors have to be developed that are easily available on a large scale.

tional groups involved in the carbohydrate-selectin interactions. In the course of these studies, several structural analogs of the tetrasaccharide were synthesized, in which the carbohydrate building blocks were systematically modified or replaced. By biological examination in vitro and in vivo, respectively, six essential functional groups of the carbohydrate epitope for the binding to E-selectin were identified: all three OH groups of fucose, the 4- and 6-OH group of galactose and the carboxylic acid function of neuraminic acid. In the case of P-selectin binding, the 2- and 4-OH groups of fucose seem not to be critical. NMR studies of sialyl Lewis'/selectin complexes, combined with molecular-mechanic calculations, lead to additional information about the bioactive conformations of the ligands 19- 1 I]. Apparently, the conformation of sialyl Lewis' in the L-selectin complex [9] corresponds to the preferential conformation in solution. The E-selectin complex, however, shows another bioactive conformation, with the carboxylate of neuraminic acid oriented differently (Scheme 2 ) . Especially the flexibility of the neuraminic acid-galactose linkage (Nl-3G) seems to be responsible for the different specificity of sialyl Lewis' to E-, P- and L-selectin as shown in biological adhesion assays. The staggered, rather rigid alignment of the trisaccharide fragment galactose-fucose-glucosamine seems not to be involved in this specificity.

Inhibitor Design A thorough understanding of structure-activity relationships is essential for the rational design of adhesion inhibitors based on partial structures of natural ligands [9- 1 I]. The required amino acids for the binding between glycoprotein E-selectin and sialyl Lewis' were identified by X-ray structure analysis and site-directed mutagenesis. On the other hand, binding studies of selectively modified sialyl Lewis' analogs revealed the func-

Black: solution conformation White: bound conformation Scheme 2

277

Selectin Inhibitors

Sialyl Lewis’ Mimetics A number of functional sialyl Lewis’ mimetics have been synthesized. Their activities in vitro are equal or even better than those of the tetrasaccharide itself. To overcome synthetic problems, efficient stereoselective glycosylations as well as new chemoenzymatic methods for C-C bond formations had to be developed. The substitution of neuraminic acid by (S)-phenyl- and ( S ) cyclohexyl lactic acid, as less flexible glycol acid residues, turned out to be very successful [ l o ] . Also, a phosphate and a sulfate group, respectively, mimic neuraminic acid without loss of activity [ 1 I]. (S)-Cyclohexyl lactic acid-mimetic 2 shows a more than ten-fold efficacy compared with sialyl Lewis’, whereas the corresponding (R)-isomer 3 is almost inactive [ 101. The deviating orientation of the carboxylic acid functionality compared to the bioactive sialyl Lewis’ conformation leads to the examined loss of activity. It was shown by transfer-NOE measurements of the corresponding E-selectin complexes that the coordinates of the bioactive conformation of sialyl Lewis‘ and of compound 2 are similar. Consequently structure 2 should bind to E-selectin in the same manner as that of sialyl Lewis’ [ 10a, b].

?’

Scheme 3

The N-acetylglucosamine unit seems to act as a spacer, positioning the other sugar units. Glucose, diols and amino alcohols, e.g. (R,R)-cyclohexandiol (see Scheme 3, compounds 1-3) or (R,R)-2amino cyclohexanol, as well as amino acid-building blocks such as L-threonine (5,6), proved to be an effective replacement for N-acetylglucosamine 11 0- 131. Several mimetics carry dihydroxyamino acids, other diols and residues with carboxylic acid groups [ 13, 141, such as glutaminic acid, instead of galactose (see Scheme 3, compound 7). Fucose is mainly substituted by glycerine, mannose 7 or galactose 8 112- 141. Fucose compound 5 bears 2-amino-3,4-dihydroxy butanoic acid, which mimics the 4- and 6-hydroxyl group of galactose and a glutaric residue to replace the carboxylic acid functionality of neuraminic acid [13, 141. The glycosylation of the tribenzyl fucosylphosphite 9 and the amino acid benzylester 10 with trifluoromethanesulfonic acid as catalyst was achieved in 84 % yield and 99 % a-selectivity using the phosphite method (Scheme 4) [13]. C-Fucopeptide l l b as well as compound 7 bear a long-chain hydrophobic group which causes an activity eight times that of the unsubstituted compound l l a [14]. In compound 8 L-fucose is

OH

5:R=

HOJH

6:R=

A

O

H

278

A. Total Syntliesis of Natural Products

replaced by L-galactose. In this glycosylated peptide, once again dihydroxy-a-amino acid mimics galactose [15]. These amino acid building blocks are enzymatically synthesized utilizing L-threonine-aldolase starting from glycine (Scheme 4) [ 161. Compound 7,bearing two carboxylate residues, shows five times the activity of sialyl Lewis', although galactose is missing. Other modifications at the galactose and fucose residues, especially substitutions of essential hydroxyl groups, resulted in loss of activity. The most active sialyl Lewis' mimetics are shown in Schemes 3 and 4. The efficacies of these compounds were examined by established selectin-adhesion assays, but different methods and standards complicate the direct comparison of the results obtained.

Concept of Multivalency/Polyvalent Mimetics Tetrasaccharide sialyl Lewis' represents only a part of the natural recognition region on selectin ligands, and a number of experimental data show that it is not cxclusively responsible for the specific receptor binding. PSGL-1 [3], expressed on cell surfaces of human neutrophile granulocytes, is one of the natural ligands of the selectins. A sulfated peptide unit of this 0-glycosidic polylactosamino sialomucin was identified as an element

'

Scheme 4

S

for recognition of P-selectin. In vitro there is only a weak interaction between an isolated sialyl Lewis' molecule and its receptor, whereas in vivo a stronger binding between the natural ligands and selectins is based on several recognition events. For example, natural glycoproteins such as PSGL-I or GlyCAM-1 bear a great number of oligosaccharide units with sialyl Lewis' structure. Therefore, multivalent binding is expected to enhance the efficiency of binding. To obtain a deeper understanding of the nature of selectin-ligand recognition, artificial, multivalent sialyl Lewis' conjugates were synthesized and examined for their efficacy in vitro [17-191. The coupling of tetrasaccharide sialyl Lewis' with polyfunctional templates such as nitromethanetrispropionic acid, cyclohexan- 1,3-diol or cyclic and acyclic peptides leads to artificial, multivalent mimetics. The rcaction of partially protected sialyl Lewis' amine 12 (see Scheme 5) with the succinate of nitromethane-trispropionic acid gives, after a two-stage reductive and hydrogenolytic cleavage sequence, the tris-coupled product in 82 % overall yield [ 17aI. Fragment condensation of 12 with a cyclopeptide template was realized in 48 % yield to furnish sialyl LcwisX-Nglycopeptide 13 [ 17bl. Inhibition analysis in vivo, however, does not show a superior inhibition of leucocyte adhesion compared to the biological efficacy using monovalent ligands. Poly-

O

B

,

lla:R=H llb: R = CH2CONH(CH2),,CH?

Selectin Inhibitors

279

RHN

BnOI OBn

12

% ' OH

15

Scheme 5

vaIent presentation of siaIy1 Lewis' mimetic 5, realized by connecting monomer 14 with liposomes, resulted in only a poor increase of activity [ 181. A ten-fold binding activity to L- and E-selectin was achieved with polymers made of sialyl Lewis' acrylamide monomers [ 191. Tetravalcnt compound 15 bearing sialyl Lewis' moieties on an oligolactosamine backbone was identified as a very effective L-sclectin inhibitor [20]. Initial investigations with oligo- and polyvalent sialyl Lewis' derivatives and mimetics confirm the cluster model after all. The true functional binding situation, however, remains unclear. Further investigations identifying the size and orientation of sialyl Lcwis'/seIectin cluster complexes are essential for a rational design of polyvalent adhesion inhibitors.

Conclusion Based on the results obtained so far, the design of potent, non-saccharidical, orally available sialyl

Lewis' mimetics of low molecular weight should be possible in the near future. Besides indications already mentioned above, selectin antagonists could offer a new approach in cancer therapy to prevent metastasis. A number of tumor cells present tissue- and tumor-specific oligosaccharides with sialyl Lewis' structures on their cell membrane. Cleavage or release during an operation leads to circulation of tumor cells in the blood stream that are able to bind to activated endothelium by a selectin-mediated mechanism [21]. Recent efforts show that this process is mainly responsible for migration of tumor cells into the tissue and the subsequent formation of secondary tumors. The design of anti-adhesive and anti-inflammatory drugs based on new biological binding assays would intensify the understanding of the structure of natural selectin ligands and their bioactive conformation. The complexity of the involved molecular structures and biological processes distinguish glycobiology [2] as an exciting and challenging field for physicians, biologists and chemists.

280

A. Total Synthesis of Natural Products

References [ I ] A. Giannis,Angew. Chen7. Int. Ed. Engl. 1994, 106, 178. [2] R.A. Dwek, Chem. Rev. 1996, 96, 683. 131 PSGL-1 = P-selectin-glycoprotein-ligand-1; a) D. Sako, K.M. Comess, Cell 1995, 83, 323; b) T. Pouyani, B. Seed, ibid. 1995, 83, 333. [4] ESL-I = E-selectin-ligand-I; M. Steegmaier, A. Levinowitz, S. Isenmann, E. Borges, M. Lenter, H. Kocher, B. Kleuser, D. Verstweber, Nufirre 1995, 373, 615. 15) A. Seppo, J.P. Turunen, L. Penttila, A. Keane, 0. Renkonen, R. Renkonen, Glycobiology 1996, 6 , 65. 161 GlyCAM- 1 = glycosylated “Cell-adhesion-molecule-I”; a) D. Crommie, S. D. Rosen, 1. B i d . Chem. 1995, 270, 22614; b) S. Komba, H. Ishida, M. Kiso, A. Hasegawa, Bioorg. Med. Chenz. 1996, 4 , 1833. [7] J.C. McAuliffe, 0. Hindsgaul, Chem. & Ind. 1997, 170. [8] T. Murohara, J. Margiotta, L.M. Phillips, J.C. Paulson, S. DeFrees, S. Zalipsky, L.S.S. Guo, A.M. Lefer, Curdiovasc. Res. 1995, 30, 96.5. [9] L. Poppe, G.S. Brown, J.S. Philo, P.V. Nikrad, H.H. Shah, J. An7. Chem. Soc. 1997, 119, 1727. [ 101 a) H.C. Kolb, B. Ernst, Pure AppI. Chem. 1997,69, 1879; b) R. BLnteli, B. Ernst, Tetruhedron Lett. 1997, 38, 4059; c ) W. Jahnke, H.C. Kolb, M.J.J. Blommers. J.L. Magnani, B. Ernst, Ar7gew. Chem. Int. Ed. Engl. 1997, 109, 2603. [ 1 I ] G. J. McGarvey, C.-H. Wong, Liebigs Arzn./Recueil 1997, 1059. 1121 M. J. Bamford, M. Bird, P. M. Gore, D. S. Holmes, R. Priest, J. C. Prodger, V. Saez, Bioorg. Med. Chern. Lett. 1996, 6, 239.

[I31 C.-C. Lin, M. Shimazaki, M.-P. Heck, S. Aoki, R. Wang, T. Kimura, H. Ritzen, S.Takayama, S.-H. Wu, G. Weitz-Schmidt, C.-H. Wong, J . Am. Chern. SOC. 1996, 118, 6826. [ 141 a) C.-H. Wong, F. Moris-Varas, S.-C. Hung, T. G . Marron, C.-C. Lin, K. W. Gong, G. Weitz-Schmidt, J. Ani. Chem. Soc. 1997, 119, 8152; b) S.-H. Wu, M. ShiinaLaki, C.-C. Lin, L. Qiao, W.J. Moree, G. Weitz-Schmidt, C.-H. Wong, Angew. Chem. Int. Ed. Engl. 1996, 108, 88. IS] M. W. Cappi, W. J. Moree, L. Qiao, T. G. Marron, G. Weitz-Schmidt, C.-H. Wong, Angew. Cheni. Ir7t. Ed. Engl. 1996, 108, 2346. 161 S. Takayama, G. J. McGarvey, C.-H. Wong, Cl7em. Soc. Rev. 1997, 26, 407. 17J a) G. Kretzschmar, U. Sprengard, H. Kunz, E. Bartnik, W. Schmidt, A. Toepfer, B. Horsch, M. Krause, D. Seiffgc, Tetrahedron 1995, 51, 1301.5; b) U. Sprengard, M. Schudok, W. Schmidt, G. Kretzschmar, H. Kunz, Angew. Chem. Int. Ed. Engl. 1996, 108, 32 1 . [ 181 C.-C. Lin,T. Kimura, S.-H. Wu, G. Weitz-Schmidt, C.-H. Wong, Bioorg. Med. Chem. Lett. 1996, 6, 2755. [ 191 0. Renkonen, S. Topipila, L. Penttila, H. Salminen, H. Maaheimo, C. E. Costello, J. P. Turunen, R. Renkonen, Glycobiology 1997. 7, 453. 1201 H. Miyauchi, M. Tanaka, H. Koike, N. Kawamura, M. Hayashi, Bioorg. Med. Chem. Lett. 1997, 7, 985. [21] a) T. Nakashio, T. Narita, M. Sato, S. Akiyama, Y. Kasai, M. Fujiwara, K. Ito, H. Takagi, R. Kannagi, Anticancer-Re.r. 1997, 17(1A), 293; b) R. Renkinen, P. Mattila, M.-L. Majnri, J. Rabina, J. P. Turunen, 0. Renkonen, T. Paavonen, Glycoconjugrcte J . 1997,14,.593;c ) R. Kannagi, ihid. 1997,14,.577.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Crossing the Finishing Line: Total Syntheses of the Vancomycin Aglycon Holger Herzner and Karola Ruck-Braun Institut fur Organische Chemie, Universitut Mainz, Germany

The antibiotic vancomycin 1 (Scheme I), discovered in 1956, has been used for the treatment of infections caused by gram - positive bacteria since 1958 [ I ] . Up to now, the compound has been commercially obtained from microorganisms. In clinics throughout the world, vancomycin is generally seen as the last line of defense for the treatment of infections caused e.g. by bacteria multi-resistant to the commonly used p-lactam antibiotics or in cases of penicillin hypersensitivity. The glycopeptide (l),structurally elucidated in the early 1980s [I], consists of an arylglycine-rich heptapeptide aglycon (2), the main characteristics of which are three atropisomeric moieties. Caused by the high rotational barrier of the biaryl linkage, an element of axial chirality emerges. In addition, the rotation of the aryl residues of the amino acids 6 and 2 (Scheme 1) around their longitudinal axes is hindered, resulting in two elements of planar chirality. The unu-

Scheme 1

2:R=H

sual complexity of the aglycon's structure (2) is a special challenge for synthetic chemists. The construction of this aglycon unit and of some of its individual fragments has kept a number of research groups busy over the last years and has led to the development of a number of new synthetic methods. Applying an elaborate concept, Evans et al. recently reached the finishing line and presented the first total synthesis of the vancomycin aglycon [2, 31. Only a few days later, Nicolaou and co-workers presented their total synthesis [4-61. In the following, strategic considerations about the concepts of these syntheses as well as their key steps and key reactions will be presented.

Total Synthesis by Evans et al. For several years Evans and co-workers focussed on synthetic strategies and methods for the construction of target structure 2 (Scheme I). After the development of diastereoselective amino acid syntheses with oxazolidinones as chiral auxiliaries [2, 31, new methods for the construction of the biaryl- and biarylether-containing macrocyclic subunits were investigated [7, 81. During this time, serious set-backs had to be dealt with. Despite earlier studies, the thallium(II1)-mediated oxidative cyclization strategy for the construction of the macrocyclic biarylether units, published in 1989 by Yamamura et al. and Evans and co-workers [8], had to be abandoned. In the course of the synthesis of the bisdechloro vancomycin aglycon of orienticin C, unexpected difficulties were encountered [91. However, to achieve the total synthesis of 2, Evans and co-

282

A. Total Synthesis qf Natural

product.^

7 4q Fq,;+o

HO 3

Because of the versatility of the Sandmeyer reaction (NO2 + H or NO, + CI), the new synthetic strategy permits the synthesis of the desired M(4-6)-chloro atropisomer independently of the stereochemical course of the macrocyclization (Scheme 3, 10 and 11). According to the planned synthetic route, ortho-nitro-substituted halogen-containing P-hydroxyphenylalanine derivatives were prepared as synthons for the arnino acids 6 and 2 (see, Scheme 2, compound 5, and Scheme 4, compound 13) by diastereoselective oxazolidinone methods, as well as a central phenolic arylglycine derivative for amino acid 4 (Scheme 2, compound 3) [2,3]. The fluorine-containing nitroarenes require accurate control of the reaction conditions to avoid undesired S,Ar reactions causing substitution of the fluorine [2]. The creation of the structure element of axial chirality has to be considered as a further key step within the total synthesis [2,3,7]. The ortho-alkoxy-substituted derivative of amino acid 5 (Scheme 2, compound 4) has been designed in accordance with the synthetic route and was synthesized applying chiral oxazolidinone methods. The general synthetic strategy starts with the construction of the 12-membered ( 5 -7)-tripeptide macrocycle from tripeptide 7 (Scheme 3).

NHBoc

0

OMe

OPN 5

M e H N k B o C

HOPC Boc

Me0

\

OMe

Scheme 2. TBS = tert-butyldimethylsilyl, Boc = fert-

butyloxycarbonyl.

workers adjusted their strategy to the results obtained from studies of intramolecular S,Ar-cyclizations [9b, 10- 131. The synthetic route is based on the preparation of the M(4-6) and the M(2-4) subunit by intramolecular S,Ar cyclizations of suitable precursor peptides with ortho-nitro-substituted haloarene residues and a central phenolic unit (Schemes 2 and 4). This concept was originally developed by Zhu and co-workers and applied successfully to the synthesis of cyclic peptides of the vancornycin family, e. g. to the synthesis of K-13 [ 131. CI

F

'

a. Vanadium(V) b. NaBH(OAc13

CI

AllvlO

P

OPiv

f

10: R = NO?, R i = OTf, R2 = BOC,R3 = Me

Scheme 3. Tfa

=

trifluor-oacctyl, Tf

trifluoromethanesulfonyl. fonyl. = trifluoromethanesul

-

11: R = Rl = R 3 = H, R2 Tfa

Crossing the Finishing Line: Total Syntheses oj the Vancomycin Aglycon A biomimetic oxidative cyclization procedure of these tripeptide precursors for the construction of the M(5-7) biaryl unit was described in the literature by Evans et al. in 1993 for the first time [7]. The vanadium(V)-mediated intramolecular coupling procedure is only successful in the presence of an alkoxy substituent in the ortho-position of the aryl moiety of amino acid 5 . For the purpose of the total synthesis of the vancomycin aglycon 2, the construction of the cyclic M(5-7)-tripeptide unit 8 (Scheme 3) was achieved by such an oxidative cyclization (VOF,, BF;OEt2, AgBF,, TFA/CH,CI,) starting from the N-methylamide derivative 7. By reductive work-up with NaBH(OAc), with simultaneous fission of the amino acid 5 benzylether, the (R)-atropisomer 8 was isolated under preservation of the nitro group with high stereoselectivity (d.r. = 95 : 5, 65 % yield). In this case, an epimerization of the C-terminal stereocenter, previously seen with the corresponding amino acid-7-ester analog of 7, was not observed. Thus, the ortho-alkoxy residue furnishes a high

283

kinetic atropselectivity, though in favor of the unnatural (R)-isomer. Studies with the epimeric arylglycine synthon proved that A( 1,3) strain and consequently the absolute configuration of the stereogenic center of amino acid 5 controls the stereochemical course of the construction of the M(5-7) biaryl unit [3, 71. However, after building the rigid M(4-6) macrocycle (see Scheme 3, compound ll), the desired (S)-biaryl configuration can be obtained (Scheme 4, compound 12) by M(5-7) atropisomerization (MeOH, 24 h, 55 'C, d.r. = 95 : 5, 54 % yield). In the product, the 5 - 6 amide already exists in the desired cis configuration (see Scheme I).

S,Ar-Macrocyclization For the construction of the 16-membered M(4-6)-macrocycle, special attention had to be directed to the correct arrangement of the chloro-substituent at ring 6. The S,Ar macrocyclization gave the cyclization product diastereoselectively (d.r. = 5 : 1) in favor of the desired

OPiv

NHR'

'0

O

MeHN

Y

7

OR

""2

RO Tfa 12a: R = H, R' = Tfa Bn. R ' = H 12b: R = Bn,

N(Me)Boc

13

,,,N(Me)Boc

14a: R = NOp 14b: R = CI

4. Ddm = 4,4'-dimethoxydiphenylrnethyl, Ms = rnethanesulfonyl

Scheme

284

A. Total Synthesis of Nuturul Products

atropisomer in 79 % yield (Na,CO,, DMSO, RT, 1.5 h, then TfNPh; see Scheme 3, compound 10). The product 11 was obtained by reduction (Zn", HOAc, EtOH, 40 "C) and subsequent protecting group manipulations. After the M(5 -7) atropisomerization to 12a. described above, the coupling step with building block 13 was prepared. Thus, starting from 12b, the corresponding heptapeptide was synthesized to afford the complete scaffold of the vancomycin aglycon by a second S,Ar cyclization (Scheme 4, 14). With CsF in DMSO at room temperature, the ring closure to the (R)-configured M(2-4) atropisomer 14a was achieved in a yield o f 9 5 % with a diastereoselectivity of 5 : 1. Detailed examinations of Evans et al. reveal that the diastereoselectivity of this M(2-4) cyclization is controlled by the natural conformation of the M(5-7) macrocycle [3j. The final functionalization to the chlorine-containing, protected vancomycin aglycon includes a chromatographic separation of the mixture of atropisomers by column chromatography. In the course of the deprotection sequence yielding the vancomycin aglycon, the N-methyl amide at the carboxylic acid terminus was nitrosated highly regioselectively (N,O,, NaOAc, CH,CI,, MeCN, 0°C) and then cleaved with lithium hydroperoxide, furnishing the corresponding carboxylic acid in 68 % yield [2, 141.

Triazene Method According to Nicolaou et al. Key reactions of the total synthesis of the vancomycin aglycon presented by Nicolaou and coworkers [4-61 are a Suzuki coupling [15] for the synthesis of the M(5-7) unit (Scheme 5) and the triazene method, described recently for the construction of macrocyclic biaryl ethers (Scheme 6) [ 161. Starting material for the bicyclic peptide 22a of desired configuration are the amino acid building blocks 15 and 16, and the dipeptide 19, shown in Scheme 5. Compound 19 was synthesized starting from 17 and 18 by the Suzuki reaction ([Pd(PPh,),], Na,CO,) as a 2 : 1 mixture of atropisomers (84 % overall yield) in which the natural (S)-diastereomer predominated. By introduction of the azido function under inversion of the configuration followed by ester hydrolysis, compound 19 was finally obtained. Key step of the synthesis of compound 15, a derivative of amino acid 6. is an asymmetric Sharpless aminohydroxylation. The central building block 16 (amino acid 4), however, was built up from 4-aminobenzoic acid by an asymmetric dihydroxylation (AD) in 12 steps. Coupling of the biaryl fragment 19 with the corresponding amino acid derivatives (Scheme 6) gave tripeptide 20. By treatment with CuBr . SMe,, K,CO, and pyridine in acetonitrile under re-

Q -

15

16

n

0

Me0

OMe

BnO

OMe Me0 17

18

19

Scheme 5

Crossing the Finishing Line: Total Syntheses of the Vancomycin Aglycon

285

B"ow;F

20

Me0

21a: R = E t , R' = TBS, = N~ 21b: R = R' = H. R2 = N3 21C:R=R'=H,RZ=NH2

Q

flux, the 16-membered M(4-6) macrocycle is obtained within 20 min as an inseparable mixture of atropisomers (d.r. = 1 : 1) in 60 % overall yield. In this reaction, the triazene unit functions as a coordinative anchoring group for metal ions, exerting a directing effect on the metalated nucleophile (Scheme 6, structures A and B). In addition, it activates the arene and thus facilitates the substitution of the halogen atom in the orrho-position by its electronic influence. Beyond that, the triazene residue can be transformed into various other functional groups [ 161. Following protecting group manipulations to prepare the next coupling step, the macrolactamization to the bicyclic building block 22a, shown in Scheme 7, is carried out under the action of FDPP (pentafluorophenylphosphinate, 3.0 equiv. FDPP, 5.0 equiv. i-Pr,NEt, DMF, 25"C, 12 h, 71 % yield). Subsequent coupling of the tripeptide 23 in the presence of EDC/HOAt ([( L(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride]/[7-aza1 -hydroxy- 1 H-benzotriazole]) yielded the corre-

sponding heptapeptide in 8 I % yield. The derivative of amino acid 2 (Scheme 7 , compound 23), required for the construction of the 16-membered M(2-4) macrocycle, was synthesized in four steps, including an enantioselective Sharpless dihydroxylation. The final ring closure to the M(2-4)-macrocycle 24 (Scheme 7 ) produced an atropisomeric mixture in 72 % yield, favoring the unnatural (S)-atropisomer (d.r. = 3 : 1 ) . However, after chromatographic separation, the latter can be converted thermally into a 1 : 1 mixture of atropisomers (I,?. dichlorobenzene, I40 T, 4 h), thus opening up a stepwise route to the desired isomer 24.

Last Hurdles To complete the total synthesis, the unexpectedly difficult transformation of the triazene unit into the corresponding phenol had to be undertaken as a last hurdle [ 15, 61. At first, the triazene unit was transformed into the aniline derivative 25 by re-

286

A. Total Synthesis of Natural Product.r

r

BnO

I

NHDdm

23

26: R' = H, R = I 27: R' = H , R = B(0Me)P 28: R' = H , R = H 29:R'=H,R=OH 30: R' = H, R = OMe

duction (Scheme 7), resulting in simultaneous cleavage of the benzyl protecting group of amino acid 7. Diazotation (HBF,, isoamyl nitrite) and subsequent treatment with potassium iodide yielded aryl iodide 26. Halogen-metal exchange and simultaneous deprotonation of all NH groups and of the homobenzylic OH group with an excess of MeMgBr and i-PrMgBr, transformation to the boronic acid ester 27 and final treatment with alkaline hydrogen peroxide solution gave the desired product 29 with the phenolic hydroxyl group in 50 % overall yield, as well as the corresponding reduction product 28 (40 % yield). Prior to the cleavage of all protecting groups, starting from 30, the homobenzylic hydroxyl group was oxidized to the carboxyl group of the carboxy termi-

Scheme 7

nus (Dess-Martin periodinan, CH,CI,, then KMnO,, r-BuOH, 5 % aqueous Na,HPO, solution) and subsequently transformed to the methyl ester with diazomethane (90 % yield). Only recently, the synthesis of the complete vancomycin framework was described by Nicolaou et al. [ 171. Prior to the glycosylation of the aglycon 2 at the phenolic hydroxy group of amino acid 4, all hydroxyl groups were silylated with TBSOTfhtidine. In addition, the C-terminal carboxylic acid was protected with diazomethane and the amino terminus with the Cbz group. Subsequently, the TBS ether of amino acid 4 was selectively cleaved with KFAI,O, [IS], furnishing the glycosyl acceptor 31 in 60% yield (Scheme 8).

Crossing the Finishing Line: Total Syntheses of the Vancomycin Aglycon

287

288

A. lbtal Synthesis of Natural Products

Boron trifluoride etherate-promoted glycosylation with the 2-allyloxycarbonyl-protected trichloroacetimidate 32 as the donor yielded the P-glucoside 33 in 82 % yield. Selective deprotection of the 2-hydroxy group of the glucopyranoside was achieved with n-Bu,SnH/Pd(O) after prior glycosylation with the protected vancosamine fluoride 35,furnishing the a-glycosidically linked disaccharide 36 in 84 % yield (Scheme 8). The silyl ether protecting groups were then cleaved with HF/pyridine, and this was followed by removal of the acetyl protecting groups. The Cbz-groups were simultaneously hydrogenated with Raney nickel/H2 in n-PrOHIH,?O, whereas the C-terminal methyl ester was cleaved by treatment with LiOH in THF/H,O, yielding vancomycin 1 in 42 % yield (4 steps). With the presented total syntheses of the vancomycin aglycon, for the first time comprehensive methods and strategies for the synthesis of vancomycin antibiotics and the construction of modified structures are available. Recently, bacterial strains have been discovered that displayed resistance against vancomycin [2]. Against this background, new biological studies with synthetically modified members of the vancomycin class of natural substances could be promising for the future.

References [ I ] C. M. Harris, T. M. Harris, J. Am. Chern. Soc. 1982, 104, 4293 and literature cited therein. [2] D. A. Evans, M. R. Wood, €3. W. Trotter, T. I. Richardson, J. C. Barrow, J. L. Katz, Angew. Chem. 1998, 110, 2864; Angerv. Cherw. Int. Ed. 1998, 37, 2700 and litcraturc cited therein. [3] D. A . Evans, C. J. Dinamore, P. S. Watson, M. R. Wood, T. I. Richardson, B. W. Trotter, J. L. Katz, Angew. Chein. 1998, 110, 2868; Angew: Chern. h i . Ed. 1998, 37, 2704 and literature cited therein. [4] K. C. Nicolaou, S. Natarajan, H. Li, N. F. Jain, R. Hughes, M. E. Solomon, J. M. Ramanjulu, C. N. C . Boddy, M. Takayanagi, Angew Chem. 1998, 110, 2872: Angew. Chem. Inr. Ed. 1998, 37, 2708.

[ 5 ] K. C. Nicolaou, N. F. Jain, S. Natarajan, R. Hughes, M. E. Solomon, H. Li, J. M. Ramanjulu, M. Takayanagi, A. E. Koumbis, T. Bando, Angew. Chem. 1998, 110, 2879; Angerv. Chem. Int. Ed. 1998, 37, 2714 and literature cited therein. [6] K. C. Nicolaou, M. Takayanagi, N. F. Jain, S. Natarajan, A. E. Koumbis, T. Bando, J. M. Ramanjulu, Angew. Chein. 1998, 110, 2881; Angewl. Chern. Int. Ed. 1998, 37, 2717. (71 a) D. A. Evans, C. J. Dinsmore, D. A. Evrard, K. M. DeVries, J . Am. Chem. Soc. 1993, 115,6426; b) D. A. Evans, C. J. Dinsmore, Tetrahedron Lett. 1993, 34. 6029. [8] a) Y. Suzuki, S. Nishiyama, S. Yamamura, Tetrahedron Lett. 1989, 30, 6043; D. A. Evans, J. A. Ellman, K. M. DeVries, J. Am. Cheni. Soc. 1989, 111, 8912. [9] a) D. A. Evans, C. J. Dinsmore, A. M. Ratz, D. A. Evrard, J. C. Barrow, J. Am. Chem. SOC.1997, 119, 3417; b) D. A. Evans, J. C. Barrow, P. S. Watson, A. M. Ratz, C. J. Dinsmore, D. A. Evrard, K. M. DeVries, J. A. Ellman, S. D. Rychnovsky, J. Lacour, J. Am. Chem. SOC.1997, 119, 3419; c) D. A. Evans, C. J. Dinsmore, A. M. Ratz, Tetrtihedroii Lett. 1997, 38, 3 189. [ 101 Review: A. V. Rama Rao, M. K. Gurjar, K. L. Reddy, A. S. Rao; Chem. Rev. 1995, 95, 2135. [ 1 I ] A. V. Rama Rao, T. K. Chakraborty, K. L. Reddy, A. S. Rao; Tetrahedron Lett. 1992, 33, 4799. [ 121 D. L. Boger, R. M. Borzilleri, S. Nukui, R. T. Beresis, J. Org. Chem. 1997, 62, 4721. [ I31 a) R. Beugelmans, G. P. Singh, J. Zhu, Tetrahedron Lett. 1993. 34, 7741; b) review: J. Zhu, Synlett 1997, 133. [I41 D. A. Evans, P. H. Carter, C. J. Dinsmore, J. C. Barrow, J. L. Katz, D. W. Kung, Terrczhedron Lett. 1997, 38, 4535. [ 151 K. C. Nicolaou, J. M. Ramanjulu, S. Natarajan, S. Brise, H. Li, C. N. C . Boddy, F. Riibsam, Chenz. Coinniun. 1997, I899 and literature cited therein. [ 161 K. C. Nicolaou, C. N. C. Boddy, S. Natarajan, T.-Y. Yue, H. Li, S. Briise, J. M. Ramanjulu, J . A m Chem. Soc. 1997, 119, 3421 and literature cited therein. [I71 K. C. Nicolaou, H. J . Mitchell, N. F. Jain, N. Winssinger, R. Hughes, T. Bando, Angrw,, Cl?eln.1999, I l l , 253: Angebv. Chein. Int. Ed. 1999, 38, 240. [ 181 E. A. Schmittling, J. S. Sawyer, Girtihedron Lett. 1991, 32, 7207.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

B. Synthesis of Non-Natural Compounds and Materials An Update on the New Inductees in the $ 9Hall of Phane" - No Phane, No Gain! Graham J. Bodwell Department of' Chemistry, Memorial University of Newfbundland, Canada

Since their emergence as a distinct class of compounds in the 1950s, the general appeal of cyclophanes has shown no signs of waning. They possess unusual and aesthetically pleasing structures. They pose unique synthetic challenges. They undergo interesting conformational processes. They exhibit peculiar chemical reactivity, spectroscopic properties and physical properties. They can also be designed to be chiral. From the ever smaller and more strained cyclophanes to the ever larger and more complex cyclophanes, chemists continue to push back the frontiers of all aspects of this captivating field of chemistry. The [n]cyclophanes are the archetypal small cyclophanes and, within this area, it is the [nlparacyclophanes (Fig. 1) that have received by far the most attention. A detailed computational study of [4]paracyclophane [ I ] , which has only been prepared as a transient species via matrix isolation [ 2 ] , was recently reported. An energy difference of 9 kcal mol-' between it and its Dewar benzene isomer was predicted. This paper also provides a comprehensive summary of the literature of the [n]paracylophanes.

i - \ L H d "J Figure 1. Structural diagram of the [nlparacyclophanes.

[SIParacyclophane, which exists as the minor component of an equilibrium with its valenceisomeric Dewar benzene, is the smallest member of this series to exhibit sufficient stability to be studied directly [ 3 ] .In order to further stabilize the [Slparacyclophane unit, Bickelhaupt [4] recently synthesized a benzannulated version, namely [5]( 1,4)naphthalenophane (2, Scheme I). Even though this compound also exists in equilibrium with the Dewar naphthalene 1 from which it was produced, the proportion of the cyclophane (35 % of the mixture) is higher than that in any previously reported case. A particularly interesting feature of this system is that there are two observable bridge conformers of 2 in solution in a ratio of 95 : 5. Unfortunately, despite considerable effort, assignment of the two conformers was not possible.

290

B. Synthesis of Non-Natural Compounds and Materials TMSHzC,

,CHZTMS

CN CHZTMS 4 A = CONMe2

3

5

7

6

Seemingly impossibly strained, but kinetically stabilized, cyclophanes 3 and 4 have been prepared by the group of Tsuji (Scheme 2). A small, but observable, proportion (6 : 94) of [4] paracyclophanediene 3 was formed upon low-temperature irradiation of the corresponding Dewar benzene [5]. Weak ‘H NMR signals at 6 values of 5.85 and 7.97 were assigned to the bridge and ring protons, respectively. The bend angles a and p were calculated (B3LYP/6-31G*) to be 28.6“ and 43.0”. The observation of [ 1.1 ] paracyclophane was first reported by Tsuji in 1993 [6] and the heavily substituted version 4 in 1998 [7], both by irradiation of the appropriate Dewar benzenes. The fairly air-sensitive 4 was stable enough to allow the determination of its structure in the crystal. The angles a (24.3” and 25.6”) a n d p (22.9” and 26.8“) are the largest ever measured for a paracyclophane, but slightly less than those calculated for [5]paracyclophane [8]. The ring protons of 4 were observed at 6 7.67. Other advances in paracyclophane chemistry have been covered recently by de Meijere and Konig [9]. In the area of metacyclophanes, the existence of 7,14-dichloro [ 1. I]metacyclophane (5) was

8 9

n=3

n=4

10 n=5

11 n=3 12 n=4 13 n=5

Scheme 2

Scheme 3

postulated in 1997 by Bickelhaupt et al. (Scheme 3) [lo]. Related work from this group led to the synthesis of the benzannulated [ S]metacyclophane 6 [ 111 and the 7-phosphanorbornadiene 7 by an apparent [4 I ] cycloaddition to [5]metacyclophane [12]. The aromatic portion of a cyclophane does not necessarily have to be benzenoid. Some very appealing non-benzenoid cyclophanes have been prepared by Gleiter et al. over the last decade (Scheme 4). Examples of these are the cyclopropenyliophanes 8 - 10 [ 131 and the cyclopropenonophanes 11-13 [ 141. This and related work is discussed in a recent review [15]. Over the years, a number of [n]cyclophanes based on polycyclic aromatic hydrocarbons have been prepared [ 161. However, the absolute limits to which any of these systems can be bent has not been systematically investigated. Hafner’s [nl(l, 6)- (15) and [n](2, 6)azulenophanes ( n = 1 1 - 13, 16) are a promising step in this direction [17]. They were produced by an intramolecular azulene-forming reaction of the 4 - (w-cyclopentadienyla1kyl)-1-methylpyridinium salts 14 (Scheme 5 ) . The crystal structure of

+

Scheme 4

An Update on the New Inductees in the "Hall of Phane"

6"-D

--

NaH NaH DMF, 15" 150 O"CC

Y+

15 n=11-13

19 n=6 20 n=5

17 n=6 l a n=5

Scheme 6

[13](2,6)azulenophane (16) (n = 13) revealed a 3.7" angle between the mean planes of the two rings. Hopefully, lower homologs of this series will soon be prepared. Our group was able to impart much greater deviations from planarity in the pyrene framework [ IS]. The remarkably distorted I ,8-dioxa [8](2, 7)pyrenophane 19 was prepared by the valence isomerization and dehydrogenation of the tethered [2,2]metacyclophanediene17 (Scheme 6 ) . In its crystal structure an overall bend of nearly 90" was observed. The curvature of the aromatic surface approximates to that expected for the corresponding part of the equatorial belt of D,, CS4.Bond angles of up to 119" were observed in the aliphatic bridge as well as a very high field proton resonance at 6-1.47 ppm. The next smaller member of this series 20 was initially elusive, but modification of the workup allowed the isolation of the [7](2,7)pyrenophane, albeit it in somewhat reduced yield 1191.

sym22 n = l l

-

No Phane, No Gain!

29 1

-@

/

Me

14 n = l l - 1 3

-

anti-22 n = l l anfi-23 n=12

16 n=12,13

Scheme 5

Nevertheless, a crystal structure was determined, and this revealed an enormous end-toend bend of IO9.1", slightly more than that of the corresponding part of the equatorial belt of D,, C,,,. The highest field protons of the bridge appear at 6-2.10. Related work in our group led to the synthesis of the cyclophanes 21-23 (Scheme 7) [20]. It was found that 21 adopted the syn conformation exclusively and 23 adopted the anti conformation exclusively. However, cyclophane 22 was observed to exist in a ca. 6 : 1 anti:syn ratio at equilibrium. The two conformers can be separated by flash chromatography and the return to the equilibrium ratio monitored by 'H NMR. Noteworthy here is the direct observation of an anti to syn flip of a [2,2]metacyclophane. There have been only two other reports of such anti to syn flips [21]. Also noteworthy is the chemical shift of the internal proton of the inner ring of anti-22, which appears at 6 3.03. It has long been known that appropriately substituted [2,2]paracyclophanes are chiral, chemically stable and do not racemize under normal reaction conditions. With these seemingly ideal prerequisites for use in chiral synthesis, it is perhaps surprising that only three examples have appeared in the literature, all of them in recent years (Scheme 8). Reich employed [2.2]paracyclophane-derived selenides such as 24 to administer chirality transfer in selenoxide [2,3] sigmatropic rearrangements. Using this methodology, he was able to synthesize optically active linalool 25

Scheme 7

292

B. Synthesis of Non-Nuturul Compounds and Materials

v

v

26

(S:R ratio = 5 : 1) [22]. Ydnada and Yoneda constructed the deazaflavinophane 26, which exhibits complete facial selectivity in its oxidation and reduction reactions, e.g. the reduction with NaBD, to afford 27 [23]. Belokon and Rozenberg used scalemic 4-formyl-5-hydroxy[2.2]paracyclophane (FHPC) 28 in the synthesis of a-amino acids (ee 45-98 %) [24]. An alternative approach to FHPC was more recently reported by Hopf [25]. Other interesting advances in the area of chiral cyclophanes include the homochiral [2.2]paracyclophane-derived amino acids 29 and 30 [26], as well as (S)-PHANEPHOS (31) [27], which has been shown to be an effective ligand for highly enantioselective Ru-catalyzed asymmetric hydrogenations of p-ketoesters and

t

27

Rh-catalyzed asymmetric hydrogenations of dehydroamino acids. Many cyclophanes are conformationally mobile, and the study of their behavior in solution has proved to be most intriguing. A particularly striking example of conformational analysis was recently reported by Fukazawa [28]. The [4.4]paracyclophane derivative 34 was synthesized by a photoinduced double S,,1 reaction of the precursors 32 and 33 (Scheme 9). In the low-temperature 'H NMR spectrum of 34, signals due to three distinct conformers were observed. Assignment of the structure of the major conformer was then accomplished in a unique way. The crystal structure was determined, and this corresponded to the calculated lowest energy

COCH3

CI

,YOCH3

32

33

34

lowest E conformer

Scheme 9

rc

An Update on the New Inductees in the “Hall of Phane” - No Phane, No Gain!

Bu3SnSiMe,

x2 P

293

/

II

II

Br 35

37

30

39

conformer. When crystals of 34 were dissolved in precooled (-80 “C) solvent, the ‘H NMR spectrum of the resulting solution exhibited signals arising only from the major conformer of the previous mixture. [6.6]Paracyclophane-l, 5, 12, 16-tetrayne (37) was synthesized by Hopf via the reaction of dibromide 35 with Bu,SnSiMe, (Scheme 10) [29]. The intermediacy of the novel cumulated para-quinodimethane 36 was invoked. Reaction of the ortho-substituted isomer 38 under the same conditions presumably gave the intermediate 39, which did not afford the corresponding orthocyclophane, but rather gave the highly strained 3,4-benzocyclooct-3-ene1,S-diyne 40. In addition to Hopf’s elegant work, a variety of other alkyne-containing cyclophanes have been prepared in the 1990s (Scheme 11). Examples of these are cyclophanes 41 (Bodwell) [30], 42 (Ensley) [31], 43 (Gleiter) [32], 44-46 (Oda) 1331, 47 (Fox) [34], and 48-49 (Rubin) [3S]. Seventeen years after Boekelheide’s landmark synthesis of [26]( I , 2, 3, 4, 5 , 6)cyclophane (also known as superphane) [36], Shinmyozu very recently described the synthesis of the homologous superphane [361(I , 2, 3, 4, 5, 6)cyclophane (53, Scheme 12) 1371. Formation of the final bridge of this “molecular pinwheel” was accomplished with an intramolecular aldol condensation. While the double bond of enone 50 could be

40

Scheme 10

easily hydrogenated, the carbonyl of the resulting ketone 51 proved to be quite inert towards reduction. This was finally achieved by the action of Sm12/1 M KOH. Treatment of the alcohol 52 with LiAIH,/AICI, finally afforded the long sought after cyclophane 53. The well averaged ’ H NMR signals of the bridge protons were said to be consistent with a correlated inversion of all six trimethylene bridges in solution at room temperature, but a subsequent computational study concluded that a synchronous mechanism is ruled out [38]. No report has yet appeared to confirm or refute Osawa’s prediction [39] that 53 will isomerize under irradiation to the [6]prismane derivative 54, but a photochemical study of a lesser bridged cyclophane has recently been published [40]. Other superphanes of note are CpCo-capped cyclobutadiene and cyclopentadienone-containing superphanes prepared by Gleiter’s group. Examples of these are 55-57 (Scheme 13) [41]. Tani recently described the coupling of the tetrabromide 58 with the tetraselenocyanate 59 to give the parallel and crossed tetraselenabiphenylophanes 60 and 61 in a ratio of 1 : 3 (Scheme 14) [42]. The synthesis of the thia-analog of 61 has been previously reported using a thiol-bromide coupling [43]. However, its formation was not accompanied by the isomer corresponding to 60. While desulfurization of the thia-analog of

294

B. Synthesis of Non-Natural CoinpoLinds and Materials

61 was not achieved, 60 and 61 were successfully deselenated in 40-50 % yield upon photolysis in the presence of P(NMe& to give the structurally interesting bridge-contracted phanes 62 and 63. The in-cyclophanes 64-67 described by Pascal are excellent vehicles for the study of functional group interactions resulting from enforced pro-

41

42

ximity (Scheme IS). While original work was directed towards compounds containing alkane CH groups projected towards the center of an aromatic ring (viz. 64, 6, = -4.03) [44], it has since been expanded to include second row elements. The silaphane 65 [4S] exhibits a proton resonance at 6 1.04, some 5 ppm higher field

43

44

47 R=CON(CBHI~)P

0

Scheme I1

An Update on the New Inductees in the “Hall of Phane” - No Phane, No Gain!

295

*+-* KOH

Pt02

HO

50

51

52

53’

53

???

54

Scheme 12

Brx;r 57

56

55

Scheme 13

Nz+ :+TeiN

SeCN

Br

NCSe

58

I Me0 -0Me

59

pX$; -/

Se 60

61

1 OMe

Me0 -0Me

MeO62

63

Scheme 14

296

B. Synthesis of Non-Natural Compounds and Materials

@ 6A

Scheme 15 1-BU

1-Bu

I

I

I-Bu

I-BU

89

68

1-611

I

1-Bu

T

70A

1-BU

T

11

I

I

708

1-Bu

Scheme I6

t-Bu

I-?u

70C

than that of an appropriate model compound. In addition there is a 280 cm-’ hypsochromic shift of the infrared Si-H stretching frequency arising from steric compression. For the phosphaphane 66 [46], which is resistant to protonation with HBr, the 13C and 3’P NMR spectra indicate that there is an electronic interaction between the phosphine and the basal ring. However, the presence of an attraction between them (i.e. a bond) could not be determined. Subsequent functionalization of the basal ring with a nitro or amino substituent allowed for HPLC resolution of the enantiomers which exhibit exceptionally high optical activity [46]. The most recent addition to this family is fluorosilaphane 67 [47]. The Si-F bond is particularly short (1.59 A). The elusive dibenzannulated dimethyldihydropyrene 69 was prepared by the group of Mitchell (Scheme 16) [48]. A Diels-Alder cycloaddition between an aryne and furan was employed to introduce the key benzene rings to the metacyclophanediene framework 68. The colorless 68 switches to green 69 on UV irradiation, and 69 reverts thermally or photochemically. More recently, the same group reported the synthesis of the three-way molecular switch 70 [49]. Vogtle’s group continues to produce a steady stream of fascinating cyclophanes. Among these are the nanometer-scale molecular ribbons 71, which were synthesized using an iterative synthetic approach (Scheme 17) [SO]. The longest one reported to date, 71 ( n = 7), has nine layers. Layered cyclophanes based on the [3.3]orthocyclophane skeleton, e.g. 72, have also been described [Sl]. The conversion of some of Vogtle’s ribbons into molecular belts such as 73-75 has also been reported [52]. Cyclic side-products containing up to 40 (!) benzene rings were observed by plasma desorption mass spectrometry, although none of these higher oligomers has been isolated. The eventual conversion of these macrocycles into fully aromatic belts 76 should provide an entry into the direct study of nanotube fullerene fragments. The “spheriphanes” 77 and 78 were also prepared by the same group [53]. The lormer of these exhibits a high affinity for silver cations and, by virtue of its sixty carbon framework, may serve as a direct precursor to C,,, [S4]. The same can also be said for Rubin’s cyclophanes 48 and 49.

An Update on the New Inductees in the “Hall of Phane”

-

N o Phane, No Gain!

297

NTs I

72 71 E=C02Me

73

75

76

TI

One of the most spectacular cyclophanes to be prepared in recent years is the “Kuratowski cyclophane” 79 (Scheme 18) 1.551. This nanodimensional multicyclophane is the first reported example of an achiral molecule possessing non-pla-

78

Scheme I 7

nar K3,3 topology. The straightforward synthesis of this intricately entwined macrocyclophane should pave the way to a whole new family of molecules possessing novel architecture and vast dimensions. A further contribution from

298

B. Synthesis of Nan-Natural Compounds and Materials

79

L2

80

Scheme 18

Siegel's group is the synthesis of the first corannulene cyclophane 80 [56].A striking feature of its 'H NMR spectrum is that the endo aromatic protons (He) of the benzene ring, which are positioned almost directly over the center of the corannulene system, appear at remarkably high field (6 = 1.89). Furthermore, with no peak broadening up to 148 "C, it was established that dynamic conformational processes in the thioether bridges and bowl-to-bowl inversion of the corannulene moiety both have lower limits of 18 i 1 kcal mol-I. From its rudimentary beginnings over four decades ago, cyclophane chemistry has developed into an ever-evolving, multifaceted discipline which overlaps with many other areas of chemistry. A rough cross-section (by no means exhaustive) of some of the recent developments in the mainstream of this field, as highlighted here, certainly attests to that.

References [ I ] B. Ma, H. M. SulLbach, R. B. Remington, H. F. Schaefer 111, .I. Am. Chem. Soc. 1995, 117, 8392-8400. [2] G. B. M. Kostermans, M. Bobeldijk, W. H. de Wolf, F. Bickelhaupt, J. Am. Chem. Soc. 1987, 109, 2471-2475; T. Tsuji, S. Nishida, ibid. 1988, 110, 2157-2164; F. Bickelhaupt, Pure Appl. Chem. 1990, 62, 373-382.

L. W. Jenneskens, F. J. J. de Kanter, P. A. Kraakman, L. A. M. Turkenburg, W. E. Koolhaas, W. H. de Wolf, F. Bickelhaupt, Y. Tobe, K. Kakiuchi, Y. Odaira, J. Am. Chem. Soc. 1985, 107, 3716-3717. D. S. van Es, F. J. J. de Kanter, W. H. de Wolf, F. Bickelhaupt, Angew. Chem. 1995, 107, 2728 2130; Angew. Chem. Int. Ed. Engl. 1995, 34, 2553 -2555. [S] M. Okuyama, T. Tsuji, Angew Chem. 1997, 109, 1157-1158; Angew. Chem. Znt. Ed. Engl. 1997, 36, 1085- 1086. [6] T. Tsuji, M. Ohkita. T. Konno, S , Nishida, J. Am. Chem. Soc. 1997, 119, 8425-8431; T. Tsuji, M. Ohkita, S. Nishida, J. Am. Chem. Soc. 1993, 115, 5284-5285. [7] H. Kawai, T. Suzuki, M. Ohkita, T. Tsuji, Angew Chem. 1998,110,827-829;Angew. Chem. Int. Ed. Engl. 1998, 37, 817-819. [El S. Grimme, J. Am. Chem. Soc. 1992, 114, 10542; M. von Arnim, S . D. Peyerimhoff, Theor: Chim. Acta 1993, 85, 43. [9] A. de Meijere, B. Konig, Sytilett 1997, 1221- 1232. [IOJ M. J. van Eis, F. I. J. de Kanter, W. H. de Wolf, F. Bickelhaupt, .I. Org. Chem. 1997, 62, 7090-7091. [ 111 M. J. van Eis, F. J. J. de Kanter, W. H. de Wolf, F. Bickelhaupt, .I. Am. Chem. Soc. 1998,120,337 I 3375. [ 121 M. J. van Eis, C . M. D. Komen, F. J. J. de Kanter, W. H. de Wolf, K. Lammertsma, F. Bickelhaupt, M. Lutz, A. L. Spek, Angew. Chem. 1998, 110, 1656-1658; Angew. Chem. Int. Ed. Engl. 1998, 37, 1547- 1550. [ 131 R. Gleiter, M. Merger, Tetrahedron Lett. 1992, 33, 3473-3476; R. Gleiter, M. Merger, T. Oeser, H. Irngartiner, Tetrahedron Lett. 1995, 36, 6425-6428.

An Update on the New Inductees in the "Hall [ 141 R. Gleiter, M. Merger, A. Altreuther, H. Imgartiner, J. Org. Chem. 1996, 61, 1946-1953. 1 1 51 R. Gleiter, M. Merger, Angew. Chem. 1997, 109, 2532-2546; Angew. Chem. Int. Ed. EngI. 1997, 36, 2426-2439. I 161 For some examples, see J. A. Reiss in Cyclophunes, VOl 11 (Eds.: P. M. Keehn, S. M. Rosenfeld), Academic Press, New York, 1983, p. 443-484. [I71 P. Schuchmann, K. Hafner, Tetrahedron Lett. 1995, 36, 2603 -2606. 1181 G. J. Bodwell, J. N. Bridson, T. J. Houghton, J. W. J. Kennedy, M. R. Mannion, Angew. Chem. 1996, 108, 1418- 1420; Angew Chem. Int. Ed. Engl. 1996, 35, 1320-1321. [191 G. J . Bodwell, J. N. Bridson, T. J. Houghton, J. W. J. Kennedy, M. R. Mannion, Clzenz. ELK J. 1999,5, I823 - 1827. 120) G. J. Bodwell, J. N. Bridson, T. J. Houghton, J. W. J. Kennedy, M. R. Mannion, Angew. Chem. 1996, 108, 2280-2281; Angew Chem. Itzt. Ed. Engl. 1996, 35, 2121-2123. 1211 Y.-H. Lai, 2.-L. Zhou, J. Org. Clzem. 1994, 59, 8275-8278; T. Yamato, H. Kamimura, T. Furukawa, J. Org. Chem. 1997, 62, 7560-7564. 1221 H. J. Reich, Y. E. Yelm, J. Org. Chem. 1991, 56, 5672 -5679. 1231 R. Yanada, H. Higashikawa, Y. Mura, T. Taga, F. Yoneda, Tetrciliedron Asymmetry 1992, 3, 1387-

1390. [24] D. Y. Antonov, Y. N. Belokon, N. S. Ikonnikov, S. A. Orlova, A. P. Pisarevsky, N. 1. Raevski, V. 1. Rozenberg, E. V. Sergeeva, Y. T. Struchkov, V. 1. Tararov, E. V. Vorontsov, J. Chem. Soc., Perkin Trans. 1 1995, 1873- 1879. [25] H. Hopf, D. G. Barrett, Liehig.s Ann. 1995, 44945 I . [26] A. Pelter, R. A. N. C. Crump, H. Kidwell, Tetrahedron Lett. 1996, 37, I273 - 1276. [27] P. J. Pye, K. Rossen, R. A. Reamer, N. N. Tsou, R. P. Volante, P. J. Reider, 1. Am. Chem. Soc. 1997, 119, 6207: P. J . Pye, K. Rossen, R. A. Reamer, R. P. Volante, P. J . Reider, 7ktruhedron Lett. 1998, 39, 4441-4444; P. W. Dyer, P. J. Dyson, S. L. James, C. M. Martin, P. Suman, Or;qunometcillics 1998, 17, 4344-4346. [28] Y. Fukazawa, H. Kitayama, K. Yasuhara, K. Yoshimum, S. Usui, J. Org. Clfem. 1995, 60, 16961703. 1291 H. Hopf, P. G. Jones, P. Bubenitschek, C. Werner, Angrw. Chem. 1995, 107, 2592-2594; Angrw. Chem. Int. Ed. EngI. 1995, 34, 2367-2368. 1301 G. J. Bodwell, T. J. Houghton, D. Miller, Tetruhedron Lett. 1998, 39, 2231 -2234. 1311 H. E. Ensley, S. Mahadevan, J. Mague, T~tralzedron Lett. 1996, 37, 6255-6258. 1321 M. Ramming, R. Gleiter, J . O r , . Chrm. 1997, 62, 5821 -5829.

of

Phane"

-

No Phane, N o Gain!

299

[33J T. Kawase, N. Ueda, H. R. Darabi, M. Oda,Angew. Chem. 1996, 108, 1658- 1660; Angew. Chem. Int. Ed. Engl. 1996, 35, 1556- 1558; T. Kawase, H. R. Darabi, M. Oda, Angew Chem. 1995, 108, 28032805; Angew. Chem. Int. Ed. Etzgl. 1996, 35, 2664-2666. [34] J. M. Fox, D. Lin, Y. Itagaki, T. Fujita, J . Org. Chem. 1998, 63, 203 1-2038. 13-51 Y. Rubin, T. C. Parker, S. I. Khan, C. L. Holliman, S. W. McElvany, J. Am. Chem. Soc. 1996, 118, 5308-5309; Y. Rubin, T. C. Parker, S. J. Pastor, S. Jalisatgi, C. Boulle, C. L. Wilkins, Angew Chenz. 1998, 110, 1353- 1356; Angew. Clzem. Int. Ed. Engl. 1998, 37, 122661229, 136) Y. Sekine, M. Brown, V. Boekelheide, J . Am. Chem. Soc. 1979, 101, 3126-3127; Y. Sekine, V. Boekelheide, h i d . 1981, 103, 1777- 1785. [37] Y. Sakamoto, N. Miyoshi, T. Shinmyozu, Angew. Chem. 1996, 108, 585-586; Angew. Chem. Int. Ed. Engl. 1996,35,549-550; see also T. Shinmyozu, S. Kusumoto, S. Nomura, H. Kawase, T. Inazu, Chenz. Ber: 1993, 126, 1815-1818. 1381 H. E Bettinger, P. v. R. Scheleyer, H. F. Schaeffer 111, J. Am. Chem. Soc. 1998, 120, 1074-1075. 1391 0.J. Cha, E. Osawa, S. Park,.I. Mol. Struct. 1993, 300, 73 - 8 I . 1401 Y. Sakamoto, T. Kumagai, K. Matohara, C. Lim, T. Shinmyozu, Tetrahedron Lett. 1999, 40, 919922. 141 I R. Roers, F. Rominger, C. Braunweiler, R. Gleiter, Tetrcihedron Lett. 1998, 39, 783 1-7834. See also R. Roers, F. Rominger, R. Gleiter, Tetrahedron Lett. 1999, 40, 3141-3144. [42] K. Tani, H. Seo, M. Maeda, K. Imagawa, N. Nishiwaki, M. Ariga, Y. Tohda, H. Higuchi, H. Kuma, Tetrcihedrori Lett. 1995, 36, 1883- 1886. [43] F. Wgtle, G. Hohner, E. Weber, J. Chem. Soc., Cheni. Commun. 1973, 366-367; K. Matsumoto, M. Kugimiya, Z. Kristallogi: 1975, 141, 260-274. [44] R. A. Pascal Jr., R. B. Grossman, D. Van Engen, J. Am. Chem. Soc. 1987, 109, 6878-6880. See also R. A. Pascal Jr., C. G. Winans, D. Van Engen, J. Anz. Chem. Sac. 1989, 111, 3007-31 11: A. Pascal Jr., R. B. Grossman, J. Org. Chenz. 1987, 52, 46 16-46 17. [45] R. P. L'Esperance, A. P. West Jr., D. Van Engen, R. A. Pascal Jr., J. Am. Chem. Soc. 1991, 113, 26722676. 1461 A. P. West Jr., N. Smyth, C. M. Crarnl, D. M. Ho, R. A. Pascal Jr., J. Org. Chem. 1993, 58, 3502-3506. 1471 S. Dell, N. J. Vogelaar, D. M. Ho, R. A. Pascal, Jr., J. Am. Chern. Soc. 1998, 120, 6421-6422. [48] R. H. Mitchell, Y. Chen, Tetrahedroti Lett. 1996, 37, 5239-5242. [49] R. H. Mitchell, T. R. Ward, Y. Wang, P. W. Dibble, J. Am. Chum. Soc. 1999, 121, 2601-2602.

300

B. Synthesis of Non-Natural Compounds and Materials

[50] S. Breidenbach, S. Ohren, F. Vogtle, Chem. EUI:J. 1996, 2 , 832-837: S. Breidenbach, S. Ohren, M. Nieger, F. Vogtle, J. Chem. SOC., Chem. Commun. 1995, 1237- 1238. [51 J S. Mataka, K. Shigaki, T. Sawada, Y. Mitoma, M. Taniguchi, T. Thiemann, K. Ohga, N. Egashira, Angew. Chem. 1998,110,2626-2628; Angew. Chem. hit. Ed. Engl. 1998, 37, 2532-2534. [521 W. Josten, D. Karbach, M. Nieger, F. Vogtle, K. Hagele, M. Svoboda, M. Przybylski, Chem. Brr: 1994, 127, 767-777; W. Josten, S. Neumann, F. Vogtle, M. Nieger, K. Hagele, M. Przybylski, F. Beer, K. Mullen, ibid. 1994, 127, 2089-2096; A. Schroder, D. Karbach, R. Guther, F. Vogtle, ihid. 1992, 125, 1881 - 1887.

[53] J. Gross, G. Harder, F. Vogtle, H. Stephan, K. Gloe, Angew. Chem. 1995,107,523-526; Angew. Chem. Int. Ed. Engl. 1995, 34, 481 -484. [54] R. Taylor, G. J . Langley, H. W. Kroto, D. R. M. Walton, Nature 1993, 366, 128-731; F. T. Edelmann, Angew Chem. 1995, 107, 1071- 1075; Angew. Chem. Int. Ed. Engl. 1995, 34, 981-985. [55] C.-T. Chen, P. Gantzel, J. S. Siegel, K. K. Baldridge, R. B. English, D. M. Ho, Angew. Chem. 1995, 107, 2870-2873; Angew Chem. lnt. Ed. Engl. 1995, 34, 2657-2660. [56] T. J . Seiders, K. K. Baldridge, J. S. Siegel, J. Am. Chem. Soc. 1996, 118, 2754-2755.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Well-Rounded Research: Nanotubes through Self-Assembly Burkhard Kiinig lnstitut ,fur Organische Chemie, Universitat Regensburg, Germany

Tube-shaped structures with nanometer dimensions are currently being reported from completely different fields of chemistry: on one hand, carbon chemists keep surprising us with new shapes [ 11 and properties [2) of carbon nanotubes; on the other, synthetic chemists are introducing highly functionalized nanotubes, which are of some interest as models for biological ion channels. This account is concerned with topical developments in the latter field. The construction of synthetic nanotubes is achieved through self-assembly of suitable subunits. Among the various possibilities for such self-alignment, stacking of macromolecules is a particularly promising starting point. As early as 1974, DeSantis and co-workers predicted a roughly

planar structure for cyclopeptides made up of aiternating D and L amino acids [ 3 ] .In this conformation the amide chain would be orientated at a right angle to the plane of the macrocycle; thus the carbony1 groups would be set in ideal positions for the formation of intermolecular hydrogen bonds between the stacked rings. The side chains would protrude outwards in the D/L motif to give an open channel whose diameter is determined only by the number of amino acid residues. Based on this model, Lorenzi et al. constructed cyclopeptides consisting of D- and L-valine units in 1987; however, their low solubility prevented structure investigations [4]. A breakthrough was then achieved in 1993 by Ghadiri's group with the octapeptide c y c l o [ - ( ~ - A l a - G l u - D - A l a - ~ h ) ~ - ]

Cyclic peptides of alternating chirality spontaneously form nanotubes. For reasons of clarity

most side chains were omitted

Scheme 1.

302

B. Synthesis of Non-Naturcil Compounds ~iridMaterids

[ 5 ] .The glutamic acid residue renders this compound soluble in alkaline media; stacking to form nanotubes occurs after acidification (Scheme I ) . The more hydrophobic side chains in cyclo[-(TrpD-Leu),-Gh-D-Leu-] even enabled the construction o f a transmembrane ion channel with a proton transport activity similar to that of gramicidin A or amphotericine B [ 61. Measurements of singlechannel conductivity showed fast transport of sodium and potassium ions; the channels pore diameter of 7.5 A led to weak potassium selectiv-ity [7]. Larger cyclopeptides yield nanotubes with a larger inner diameter [S]. Thus, macrocycles with 10-12 amino acid residues result in tubes in whose cavities molecules can be transported. The pore size of the channel leads to exclusion selectivity: a panotube build from cyclic decapeptides with 10 A diameter is permeable by glucose, whereas a tube of cyclic octapeptides is not [9]. Partial amide N-alkylation has been shown to block peptide aggregation and limit self-assembly to cylindrical p-sheet peptide dimer formation. The dimerization process tolerates a number of N-alkyl substituents, whereas disubstitution of the peptide a-position prevents association [ 101. Crystalline cyclic peptide nanotubes have been detected at the air-water interface by X-ray diffraction. Films of cyclic octapeptides were transferred onto a solid support and visualized by scanning force microscopy [ l l ] . In a detailed biophysical investigation the angle of peptide nanotube orientation relative to the lipid bilayer was investigated using IR spectroscopy. In accordance with the structure-function model hypothesis for a transport-competent channel the central axis of nanotubes composed of cydo[( L-Trp-D-Leu),-L-Gln-~-Leu] is aligned parallel to the lipid bilayer hydrocarbon chains, at approximately 7" from the axis normal to the bilayer plane [12]. The biological activity of selfassembling transmembrane channels was determined by in vitro assays. These channels are antibacterially active against gram-positive strains and cytotoxic in a test with human kidney cells [7]. The very efficient non-covalent approach to nanotubes by molecular self-assembly of cyclic peptides is limited by the kinetic instability of the resulting constructs. An elegant solution to

Scheme 2. Covalent capture of a self-assembled cyclic peptide dimer using the Grubbs ruthenium catalyst.

this difficulty is the covalent capture of assembled cyclopeptides that bear alkene groups using ring-closing metathesis. The ring-closing reaction was mediated by the Grubbs catalyst, a ruthenium carbene complex (Scheme 2). Alternatively, self-assembled cyclic peptides with thiol groups were covalently captured upon oxidative formation of disulfide bridges [ 131. Molecular modeling suggested that, like their cyclic D,L-a-peptide counterparts, cyclic peptide subunits composed of homochiral p'-amino acids could adopt flat, disklike conformations with amino acid side chains occupying equatorial positions on the exterior of the peptide ring, while axial and interior positions remain unobstructed. Cyclic /I3octapeptides were synthesized and examined in liposome-based proton transport assays and single-channel conductance experiments [ 141. The investigations revealed for some compounds a greater potassium conductivity than that of gramicidin under similar conditions, which indicates an effective nanotube and ion channel formation [ 151.

Not only cyclopeptides are suitable for the construction of nanotubes. [ 161 Stacked cyclo-

Well-Rounded Research: Nanotubes through Selj-Assembly

Figure 1. View into the cavity of an isolated nanotube consisting of stacked cyclodextrins 3-RR in the solid.

dextrins [ 171 also form tube-shaped structures with an internal diameter of up to 1.3 nm, as has been proven by Stoddart, Williams, and co-workers through X-ray structure analysis (Fig. 1) [IS]. The similarity of the design principles used here is striking: the cyclodextrin macrocycles consist of alternating D and L sugar units! A whole series of new cyclodextrin derivatives

Po*, o n

1-MM

1-RM 2-RM

1-RR 2-RR 3-RR 4-RR 5-RR

CH20H Me Me Me Me Me Me Me

CHpOH CH20H CHpOH Me Me Me Me Me

Scheme 3. D/L-Cyclooligosaccharides synthesized so far. M = mannopyranose, R = rhamnopyranose.

303

from alternating D and L rhamnopyranose and D and L mannopyranose units has been presented by this research group (Scheme 3). Among these are also the first achiral cyclic oligosaccharides (RR and MM derivatives) as well as the largest cyclooligosaccharide known to date (5-RR), with 14 sugar units. The synthesis of the cyclodextrin analog 1-RM and 2-RM succeeded efficiently by polycondensation-cycloglycosilation of the disaccharide 1, in which the cyanoethylidene group serves as glycosyl donor and the trityloxy function as glycosyl acceptor. The key intermediate 1 is available in 15 steps from L-rhamnose and D-mannose. The results obtained by Fujita, Lichtenthaler, and co-workers show that cyclooligosaccharides with sugar units other than glucose do not necessarily have to assemble as tubes. Via the 2,3 anhydro compound as intermediate, u- and p-cycloaltrin were obtained from the corresponding cyclodextrins (Scheme 4) [ 191. The X-ray structure analysis of the a-cycloaltrin revealed a highly unusual structure with alternating 'C4/4C, chair conformations and a cavity open on only one side. Instead of the now impossible formation of tubes, the layers lie on top of each other in a staggered way with water molecules in the gaps. Other than with ion channels, it is not the inner void, but the groups pointing outwards that are crucial for the function of a tube-shaped selfreplicating system [20] built up on the base of a-helical peptides (Scheme 5). For this purpose a peptide consisting of 32 amino acids whose sequence resembles the GCN4 leucine zipper region was used. Ghadiri and co-workers showed that this compound catalyzes its own formation by accelerating amide bond formation between appropriate peptide strands. The most important interaction responsible for the specific interhelical recognition between template and reactant is the hydrophobic interaction of the leucine and valine residues, which increases because of electrostatic forces. If this interaction is interrupted, for example, through the addition of guanidinium hydro-

Well-Rounded Research: Nanotubes through Self-Assembly transmembrane channel: J.-C. Meillon, N. Voyer, Angew. Chem. 1997, 109, 1004 - 1006; Angew. Chem. Int. Ed. Engl. 1997, 36, 967 - 969 ; g) an ion-binding, tubc-shaped calix[4]arene dimer: P. Schmitt, P. D. Beer, M. G. B. Drew, P. D. Sheen, ibid. 1997, 109, 1926 - 1928; 1997, 36, 1840 1842. 171 Recent results show that ion conductivity changes discontinuously with the number of stacked units: M. R. Ghadiri, personal communication (1997). [8] N. Khazanovich, J. R. Granja, D. E. McRee, R. A. Milligan, M. R. Ghadiri, J . Am. Chem. Soc. 1994, 116, 6011 - 6012. [9] J. R. Granja, M. R. Ghadiri, J. Am. Chcm. Soc. 1994, 116, 10785 10786. [ 101 T. D. Clark, J. M. Buriak, K. Kobayashi, M. P. Isler, D. E. McRee, M. R. Ghadiri, J. A m Chem. Soc. 1998, 120, 8949 - 8962. 1111 H. S. K. H. Rapaport, K. Kjaer, P. B. Howes, S. Cohen, J. Als-Nilsen, M. R. Ghadiri, L. Leiserowitz, M. Lahav, J. Am. Chein. Soc. 1999, 121, 1186 - 1191. [I21 H. S. Kim, J. D. Hartgerink, M. R. Ghadiri, J. Am. Cheiiz. Soc. 1998, 120, 4417 - 4424. [ 131 T. D. Clark, K. Kobayashi, M. R. Ghadiri, Chem. EUI:J . 1999. 5, 782 792. [ 141 T. D. Clark, L. K. Buehler, M. R. Ghadiri, J. Am. Chem. Soc. 1998. 120, 651 - 656. [IS] The actual mechanism of channel-mediated ion transport is, so far, not established unequivocally. Alternative possibilities exist, such as formation of tubular bundles with holes large enough to serve as a conduit for water and ions. [ 161 For the formation of tubular ion channels from oligonucleotide analogs, see: L. Chen, N. Sakai, S. T. Moshiri, S. Matile, Tetrahedron Lett. 1998, 39, 3627 - 3630. [ 171 a) Three general types of structures have heen observed in solid cyclodextrins (CD): cage structures, which arc found in all CD hydrates, channel structures and layer structures for host-guest complexes: K. Harata in Comprelieiisive Supramolecular Chemistry Vol 3, (Eds.: J. Szejtli, T. Osa), Elsevier, Oxford, 1996, 279 - 304; b) For a rccent review of cyclodextrin chemistry, see: v. T. D Souza, K. B. Lipkowitz (Eds.), Chem. Rev. 1998,98, 1741 - 2076. [ 181 a) P. R. Ashton, C. L. Brown, S. Menzer, S. A. Nepogodiev, J. F. Stoddart, D. J. Williams, Chem. Eur: J. 1996, 2, 580 - 591; b) S. A. Nepogodiev, G. Gattuso, J. F. Stoddart, Proceedings ofthc 8th International Cyclodextrin Symposium (Eds.: J. Szejtli, L. Szente), Kluwer Academic Press, Dordrecht, 1996, pp, 89 94; c) P. R. Ashton, S . J. Cantrill, G. Gattuso, S. Menzer, S. A. Nepogodiev, A. N. Shipway, J. F. Stoddart, D. J. Williams, Chem. Eur: J. 1997, 3, 1299 - 1314; d) G. Gattuso, S. Menzer, S. A. Nepogodiev, J. F. Stoddart, D. J. Williams, ~

~

~

Angew: Chem. 1997, 109, 1615

305

- 1617; Angew. Cliem., Int. Ed. Engl. 1997, 36, 1451 - 1454. [ 191 a) K. Fujita, H. Shimada, K. Ohta, Y. Nogami, K. Nasu, T. Koga, Arzgew. Clzem. 1995, 107, 1783 1784; Angew. Chem. In?. Ed. Engl. 1995, 34, 1621 - 1622; b) Y. Nogami, K. Nasu, T. Koga, K. Ohta, K. Fujita, S. Immel, H. J. Lindner, G. E. Schmitt, F. W. Lichtenthaler, ibid. 1997, 109, 1987 - 1991; and 1997, 36, 1899 - 1902. [20] a) D. H. Lee, J. R. Granja, J. A. Martinez, K. Severin, M. R. Ghadiri, Nuture 1996,382, 525 - 528; b) K. Severin, D. H. Lee, J. A. Martinez, M. R. Ghadiri, Chenz. EUI:J. 1997, 3, 1017 - 1024; c) The kinetic analysis of the self-replication progress revealed parabolic growth; for other self-replicating systems, see: d) D. N. Reinhoudt, D. M. Rudkevich, F. de Jong J . Am. Chenz. Soc. 1996, 118, 6880 - 6889 and referenccs therein.; e) G. von Kicdrowski, Nature, 1994, 369, 221 - 224; f) A. Tcrfort, G. von Kiedrowski, Angeu: Chem. 1992, 104, 626 - 628; Angew. Chem. Int. Ed. EngI. 1992, 31, 654 - 656. [21] a) D. H. Lee, K. Severin, Y. Yokobayashi, M. R. Ghadiri, Nature 1997, 390, 591 - 594; correction: ibid., 1998, 394, 101; b) K. Severin, D. H. Lee, J. A. Martinez, M. Vieth, M. R. Ghadiri, Angew Chem. 1998, 110, 133 - 135; Angew. Chem. Int. Ed. Engl. 1998, 37, 126 - 128; c) K. Severin, D. H. Lee, A. J. Kennan, M. R. Ghadiri, Nature 1997,389, 706 - 709; d) S. Yao, I. Ghosh, R. Zutshi, J. Chmielewski, Nature, 1998, 396, 447 450; e) for a new surface-promoted replication process (SPREAD), see: A. Luther, R. Brandsch, G. von Kicdrowski, Nature, 1998, 396, 245 - 248; f) for a coverage of recent achievements in “self-replicating systems”, see: Chem. Eng. News, 1998, December 7, 40. 1221 a) Recent research by Whitesides et al. shows that the strategy of spontaneous association of molecules is not restricted to nanometer dimensions, but is also suitable for the construction of aggregates of millimeter size: A. Terfort, N. Bowden, G. M. Whitesides, Nature 1997, 386, 162 - 164; b) N. Bowden, A. Terfort, J. Carbcck, G. M. Whitesides, Science 1997, 276, 233 - 235. 1231 a) K. Namba, G . Strubbs, Scienor 1986,231, 1401 - 1406. b) The in vitro reconstitution of the intact virus from the isolated components shows impressively that the information about the supramolecular structure is stored in the subunits and that the process of self-assembly is highly cooperative: A. Klug, Angew. Chem. 1983, 95, 579 - 596; Angew. Chem., Int. Ed. Engl. 1983,22, 565 - 582; c) H. Conrat-Fraenkel, R. C. Williams, Proc. Nut/. Acad. Sci. USA 1955, 41, 690 - 698.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

From Random Coil to Extended Nanocylinder : Dendrimer Fragments Shape Polymer Chains Holger Frey lnstitut fur Makromolekulur-e Chemie und Freihurger Mater~ialfoi=vchungszentru~ (FMF), Albert-Ludwigs- Universitat Freiburg, Germany

Dendrimers usually exhibit spherical (isotropic) shape. However, wedge-like dendrimer fragments (“dendrons”) that have been attached to linear polymers as side groups can be used to create anisotropic “nanocylinders”, leading to uncoiling and extension of the polymer chains. Synthetic macromolecules of this type can be visualized directly on surfaces and their contour length determined from the images. Unexpected acceleration effects in the “self-encapsulated” polymerization of dendron monomers used to prepare such polymers as well as the structural consequences of dendritic “pieces of cake” on linear polymer chains are discussed. Dendrimers, perfectly branched, highly symmetrical tree-like macromolecules have evolved from a curiosity to an important trend in current chemistry, attracting rapidly increasing attention from an unusually broad community of scientists [ 11. Various dendrimer construction strategies have been developed on the basis of classical organic chemistry, heteroatom chemistry [2], and transition metal complexation [3,4]. Based on these now well-established synthetic “algorithms”, increasing research efforts are currently directed at peculiar supramolecular structures and self-assembly processes of dendrimers as well as the elucidation of structure-property relationships, as documented by several reviews [ 5 ] . For instance, flexible dendrimers with mesogenic branching points [61 or end groups [7] have been constructed that are able to induce anisotropic liquid crystalline order despite the isotropic dendrimer topology. Furthermore, self-assembly of dendrimers on surfaces to ultrathin films with a thickness of a few nanometers has been investigated by a number of groups 181, aim-

ing at application in catalysis, sensors or chromatographic separation [9]. For polymer chemists it is interesting to know how well-known linear polymers can be linked with dendritic architectures and what the supramolecular consequences of this approach might be. Combination of dendrimers with linear polymers in hybrid linear-dendritic block copolymers has been employed to achieve particular self-assembly effects. Block copolymers with a linear polyethylene oxide block and dendritic polybenzylether block form large micellar structures in solution that depend on the size (i.e., the generation) of the dendritic block [lo]. Amphiphilic block copolymers have been prepared by the combination of a linear, apolar polystyrene chain with a polar, hydrophilic poly(propy1ene imine) dendrimer [ I l l as well as PEO with Boc-substituted poly-a,&-L-lysine dendrimers, respectively [ 121. Such block copolymers form large spherical and cylindrical micelles in solution and have been described as “superamphiphiles” and ,,hydra-amphiphiles“, respectively. In contrast to these successful efforts to link dendrimers and linear polymer chains in the manner of block copolymers, only very recently has a breakthrough been achieved in the synthesis of linear polymers with dendritic side groups, and this will be highlighted in this contribution (Scheme 1). Considerable synthetic effort is required in preparing suitable dendritic monomers. The amazing kinetic and structural features observed for such monomers and the respective polymers are nevertheless highly rewarding.

308

B. Synthesis of Non-Nuturul Compounds und Materials

lumnar) superstructures are formed, which are further packed in cubic or hexagonal columnar phases, as illustrated in Scheme 2. It was demonstrated that first- and second-generation dendrons possessed shapes that are fragments of a disklike molecule, i.e., a quarter and a half of a disk, respectively. The third-generation dendron, in contrast, represented one-sixth of a sphere. From these results, Percec et al. concluded that in general at a certain critical generation, depending on the dendron architecture and functional groups in its core and on its periphery, a change from cylindrical to spherical superstructures occurs [ 1 5 ~ 1 .

2. Preparation of polymers with dendron side-chains Obviously, there are three approaches that can be used to prepare polymers with dendron side groups: (i) divergent construction in analogy to divergent dendrimer synthesis, using a multifunctional linear polymer as B,,-type core instead of a small “point-like’’ core; (ii) attachment of prefabricated dendron building blocks to a reactive polymer chain via polymer-analogous reaction, similar to the final coupling step to the core in convergent dendrimer synthesis [ 131, and (iii) polymerization of dendron monomers (Fig I ) . The idea to string dendron “pieces of cake” to a polymer chain as a core, was mentioned by Tomalia and Kirchhoff [ 16a] in a patent as early as 1987 (“comb-burst” polymers). In B recent paper, the results of this work based on strategy (i) have been published in more detail. A poly-

ethylenimine prepared by living cationic polymerization of 2-ethyl-2-oxazoline and subsequent deprotection was used as core for the synthesis of rod-shaped poly(amidoamine) structures [ 16bl. Unfortunately, little information is given by the authors concerning control of molecular weights and polydispersities of the dendronized polyethylenimine that would permit this concept (i) to be compared with strategies (ii) and (iii) discussed below. The second strategy (ii) was investigated by Schliiter et al., using Frtchet-type polybenzylether wedges and hydroxy-functional poly(p-phenylene) (PPP) [17a]. The key problem encountered in this case lies in the limited conversion achievable in polymer-analogous reactions, particularly if higher generation dendritic wedges (i.e., larger than G2) are employed [ 17b,c], leading to incompletely covered polymer chains, e.g. for a G 3 dendron only 90 %>of the reactive groups at the PPP backbone are linked with dendrimer fragments. This drawback of the polymer-analogous approach has motivated intense efforts along the lines of concept (iii), based on polymerizable dendrons. If a polymerizable function is attached to a dendron at the focal point, “dendron monomers” are obtained (Fig 1). Dependent on the dendrimer generation employed, large polymerizable building blocks of variable size with conical topology may be prepared. Can such dendronmonomers actually be polymerized, and if so, what are the properties of the resulting polymer chains with unusually large substituents? A styrene-based copolymer with approximately 40 w% (2 mol%) of repeat units carrying dendrons was reported by

==LO

R R

R

X

x R = OC12H25

x

X = H. CO2CHj

Figure I . Examples of dendron monomers described by Pcrcec et al., Schluter et al. and Xi et al.

From Random Coil to Extended Nanocylinder: Dendrimer Fragments Shape Polymer Chains

Hawker and Frkchet in 1992 [ IS]. However, only in the last 4 years has the maturing of dendrimer synthesis and related characterization methods made it possible to study dendron (macro)monomers and to exploit their potential for the synthesis of dendron-bearing polymers. One would intuitively expect polymerization of such monomers to be troublesome, because of the steric requirements of the large dendrimer fragments as well as the shielding effect of the polymerizable moiety, which incrases with increasing generation number. These problematic aspects are well known in macromonomer chemistry [ 191 and are expected to be even more severe for dendron monomers. This assumption has been confirmed by a number of authors [20] who studied the polymerization of methacrylates with various dendritic fragments attached. Indeed, polymerization of monodendrons to macromolecules with a high degree of polymerization was only possible when a spacer was inserted between the polymerizable unit and the bulky dendron group, using very long reaction times. In contrast, recent kinetic investigation of the polymerization of spacerless G2 dendron-substituted styrene and methylmethacrylate, respectively, in solution lead to the unexpected conclusion that above a certain critical monomer concentration a strong increase in the rate of the free radical polymerization is observed [2 I]. The results can be explained by self-organization of the growing polymer chain to a spherical or columnar superstructure in solution, depending on the degree of polymerization (DP, Fig. 2). The rate constants and low initiator efficiency lead one to conclude that the self-assembled

Figure 2. Dependence of self-assembly of dendronized polymer chains on the degree of polymerization; monomers and short polymer chains assemble in spheres; longer chains assemble in cylinders. This effect leads to rapid polymerization of such dendron monomers due to “self-encapsulation” 1211.

309

structure acts like a supramolecular nanoreactor that leads to a strongly enhanced local concentration of polymerizable groups. Thus, the kinetics of the polymerization is determined by self-assembly and can be viewed as “self-encapsulated” and “self-accelerated”. Polycondensation of suitable monomers represents an alternative route to high-molecularweight dendronized polymers e.g., PPP with attached dendron segments has been prepared using Suzuki cross-coupling of dendron-substituted dibromobenzenes with alkyl chain-substituted diboronic acids in a polycondensation type of reaction [ 17~1.In this case, high-molecular-weight dendronized PPP with DP exceeding 100 was obtained. Similarly, polyaddition reactions of dendronized diols with semirigid and flexible diisocyanates have been employed by Jahromi et al. to prepare polyurethanes with pending dendrons [17d].

Properties and Visualization of Dendronized Polymers If dendrimer fragments are attached to polymer chains, the conformation of the polymer chain is strongly affected by the large dendrimer wedges attached. “Dendronized” polymers can be considered as a subclass of comb polymers, i.e., linear polymer chains densely substituted with polymeric side chains, which are known to be extremely rigid in solution, exhibiting Kuhn lengths 1, of 10-20 nm (in some cases as much as 120 nm! [22d]), in comparison to 1-2 nm for polystyrene or polymethylmethacrylate [22]. For that reason, such comb polymers are sometimes designated “cylindrical brushes”. In recent work, Schmidt et al. have given a detailed summary of peculiarities encountered in the characterization of this class of macromolecules (22dl. Consequently, cylindrical shape is also expected for polymers with large dendron side chains. Of course, biomolecules such as DNA or RNA with rigid cylindrical or wormlike shapes are well known, although in these cases the supermolecular structure (i.e., the secondary and tertiary structure) is the result of well-controlled secondary bonds.

3 10

B. Synthesis qf Non-Nuturul Compounds arid Materials

For flexible synthetic polymers, the chain conformation is commonly controlled by the degree of polymerization (DP), with low-DP polymers having a rather extended chain conformation and high-DP polymers adopting random coil conformations in solution. Recently, Percec, Moller et al. reported extensive studies concerning the chain conformation and supramolecular structure of dendron-substituted polystyrene and polymethacrylate [23]. Remarkably, at low DP

Figure 3 4 b. Topographic scanning force microscopy (SFM) images (tapping mode) of monomolecular films of dendron-bearing polystyrene; a) M, = 10 800; b): M, = I86 500. Spherical and cylindrical features are observed; cylindrical features are due to single dendronized macromolecules [23].

(i.e., short chains) the conical monodendrons assemble to produce a spherical superstructure with random-coil backbone conformation (Fig. 3a). On increasing the DP, the self-assembly pattern of the dendrons changes, leading to cylindrical polymers with rather extended backbone (Fig. 3b). It is remarkable that this correlation between polymer conformation and the DP is opposite to that usually seen in most synthetic and natural macromolecules. A detailed understanding of this effect was obtained by Percec et al. on the basis of “libraries” of dendron monomers of different shape [23b]. Usually, synthetic macromolecules cannot be visualized directly, because of the very small size, particularly the diameter (several angstroms) of the backbone of such polymer molecules. Therefore, the present knowledge of the shape, size and conformation of polymers was mostly obtained from the interpretation of scattering results (X-rays, electrons, neutrons). However, in the case of dendronized synthetic polymers it is a fascinating consequence of the stiffness and densely covered surface of such cylindrical macromolecules that single polymer chains can actually be visualized. MBller et al. demonstrated impressively that the imaging of dendron-substituted polystyrene and polymethacrylate can be employed for an analysis of the molecular size distribution and conformation, using dendron-substituted polystyrene and polymethacrylate [24a]. The image shown in Fig. 4a was obtained by scanning force microscopy (SFM) and shows single chains of dendronized polystyrene deposited on a pyrolytic graphite substrate. Clearly to be seen, the molecules exhibit short, straight segments with bends of a characteristic angle of 60” and 120” corresponding to the threefold symmetry of the graphite. In addition, within near region, the molecules tend to align parallel, forming hairpin bends. The height of the chains is in the region of 1.6 nm, and the lateral diameter of the chains is 5.3 nm (SFM, tapping mode), which illustrates that the macromolecules are collapsed on the surface. The worm-like contour of the macromolecules can be approximated by segments of 10-20 nm, and a distribution of the contour lengths may be calculated from the images, which is a remarkable feature of these novel comb poly-

From Random Coil to Extended Nanocylinder: Dendrimer Fragments Shape Polymer Chains

311

Figure 4. Single “worm-like” polymer chains of dendronized polystyrene deposited on pyrolytic graphite, imaged by topographic scanning force microscopy (SFM) [24]; the inset illustrates the structure of the dendron-substituted chains

Figure 5. SANS scattering curve Z(4) vs. y of a G3dendronized polystyrene, obtained by Forster, Schliiter et al. [25].The scattering curve at larger 4 follows the Porod 4-4 law, arising from the scattering at the surface of a cylinder, evidencing the stiff, worm-like character of the macromolecules.

mers. It is an intriguing question whether the molecular weight distribution can be determined in the solid state. Comparison of the apparent length of the macromolecules determined from the images shows that for large dendron side groups this is in good agreement with expectation, whereas for lower generation dendrons attached, the contour length determined from the images is considerably lower than the calculated length of the extended chains. This demonstrates that the degree of extension (i.e., uncoiling) of the chains is determined by the size of the dendrons attached. Besides these data, detailed information on packing defects, such as hairpin structures and intersections, could be obtained from the images [24b]. As interaction with the substrate may affect the images, it is an interesting question, whether the polymers actually possess cylindrical shape in solution. Small angle neutron scattering (SANS) experiments have been employed to answer this question. Figure 4b shows the scattering curve of a dendron-substituted polystyrene (G3 -dendrons) [25a]. It is possible to describe the scattering curve by assuming that the dendron-substituted polystyrene exhibits a rod-like structure,

as shown in the inset of the figure. Thus, the persistence length of the molecule is on the order of the contour length, supporting the presence of stiff, cylindrical macromolecules in solution. Detailed neutron-scattering studies by Forster et al. have shown that the chain diameter of the dendronized macromolecules indeed increases with increasing dendron generation, showing that the diameters of the dendronized polymer chains :re comparable to those of DNA (d = 24 A). In this study, also the first example of a charged dendronized polymer chain was analyzed.

Conclusion In summary, it is obvious that the attachment of dendron building blocks to common monomers leads to dramatic kinetic and structural consequences. Once more, it should be kept in mind that it is only the shape of the side groups attached that governs the conformation and structure of the resulting polymer chains, not hydrogen-bonding interactions, which are ubiquitous in self-assembly in biological processes.

312

B. Synthesis qf Non-Naturul Cornpounds and Materials

Based on the breakthrough in the synthesis and visualization of “dendronized” polymers achieved, is a safe bet that this novel class of extremely stiff macromolecules will stimulate further interdisciplinary efforts to understand their physical behavior in bulk and in solution as well as assess their usefulness for a future nanotechnology based on “molecular objects”. On the other hand, these developments can lead to libraries of shapes that can be combined to create any nanometer-size cylindrical object with programmed length and diameter [26]. Block copolymers with one “dendronized” cylindrical block and one coiled block can also be envisaged [27]. Dendron side groups may also function as protective layers for “insulated molecular wires”, as suggested by Diederich et al. 128). In addition, dendrons bearing protected functionalities developed by Schluter et al. offer further possibilities for the functionalization of such nanocylinders [ ~ O C ]We . now look forward to seeing the shapes of other exciting molecular objects based on dendrimer wedges to come!

References [ I ] a) D. A. Tomalia, A. M. Naylor, W. A. Goddard 111, Angew. Chem. 1990, 102, 1 19 - 157; Angeh.: Cheni lnt. Ed. Engl. 1990, 102, 138- 175: b) D. A. Tomalia, H. D. Durst, Top. Cwr: Chern. 1993, 165, 193313; c) G. R . Newkome, C. N. Moorefield, F. Vogtle, Dendritic Mucromolecules: Concepts, Syntheses. Perspectives; I . Aufl., VCH, Weinheim, Germany, 1996; d) J. M. J. Frkchet, C. J. Hawker, React. Funct. Polym. 1995, 26, 127150: e ) B. 1. Voit, Actu Polymer. 1995, 46, 8799: 9 H. Frey, K. Lorenz, L. Lach, Chemie imserer Zeit 1996, 75-85; g) 0. A. Matthias, A. N. Shipway, J. F. Fraser-Stoddart. Prog. Polym. Sci. 1998, 23, 1-56; h) M. Fischer, F. Vogtle, Angew. Chem. hit. Ed. G i g / . 1999,38,885-905: i) A. W. Bosman, H. M. Janssen, E. W. Meijer, Cheni. Rev. 1999, 99, 1665-1688 121 a) H. Frey, C. Lach, K. Lorenz, Adv. Muter: 1998, 10, 279-293; b) C. Schlenk, H. Frey, Monatsh. Cheni. 1999, 130, 3- 14. a) C. Gorman, Adv. Muter: 1998, 10, 295-309; b) G. R. Newkome, E. He, C. N. Moorefield, Cheni. Rev. 1999, 99, I689 - 1746. W. T. S. Huck, F. C. J. M. van Veggel, D. N. Reinhoudt, Angew. Chem. lnt. Ed. Engl. 1996, 35, 1304-1306; Aizgew. Chem. Int. Ed. Erigl. 1996, 35, 1213- 1215.

151 a) F. Zeng, S. C. Zimmerman, Chem. Rev. 1997, 97, 1681 - 1712: b) S. C. Zimmerman, Curs Op, Coll. Inre$ Sci. 1997, 2, 89-99; c) J. S. Moore, Acc. Cheni. Re.?. 1997, 30, 402-413. [6] a) V. Percec, P. W. Chu, G. Ungar, J. P. Zhou,J. Am. Chem. Soc. 1995,117, 11441 - 11454; b) J. F. Li, K. A. Crandall, P. W. Chu, V. Percec, R. G. Petschek, C. Rosenblatt, macromolecule,^ 1996, 29, 78 13 7819. [7] a) K. Lorenz, D. Holter, B. Stuhn, R. Mulhaupt, H. Frey, Adv. Muter: 1996, 8, 414-416; b) S. A. Ponomarenko, E. A. Rebrov, A. Y. Bobrovsky, N. I. Boiko, A. M. Muzafarov, Liq. Cryst. 1996, 21, 1 12; c) K. Lorenz, H. Frey, R. Mulhaupt, Macronzolecules, 1997, 30, 6860-6868; d) M. W. P. L. Baars, S. H. M. Sontjens, H. M. Fischer, H. W. 1. Peerlings, E. W. Meijer, Chem. Eur: J. 1998, 4,2456-2466; e) J. Barber;, M. Marcos, J. L. Serrano, Chem. Eur: J. 1999, 5, 1834- 1840. [S] a) S. Watanabe, S. L. Regen, J . Am. Chem. Soc. 1994, 116, 8855-8856; b) M. Wells, R. M. Crooks, ihid. 1996, 118,3988-3989; c ) S. S. Sheiko, G. Eckert, G. Ignat’eva, A. M. Muzafarov, J. Spickermann, H. J. Rader, M. Moller, Mucroniol. Rapid Comnzun. 1996, 17, 283-297; d) M. Collaud Coen, K. Lorenz, J. Kressler, H. Frey, R. Mulhaupt, Macromolecules 1996, 29, 8069- 8076. [ 9 ] a) S. A. Kuzdzal, C. A. Monnig, G. R. Newkome, C. N. Moorefield, C. N . J . Chem. Soc. Chem. Commun. 1994, 18, 2139-2140; b) P. G. H. M. Muijselaar, H. A. Claessens, C. A. Cramers, J. F. G . A. Jansen, E. W. Meijer, E. M. de BrabenderVan den Berg, S. Vanderwal, HRC J . High Rex Chrorncit. 1995, 18, 121-123. [ l o ] a) I. Gitsov, K. L. Wooley, C. J. Hawker, P. T. Ivanova, J. M. I . Frechet, Macromolecules 1993, 26, 5621 -5627; b) I. Gitsov, J. M. J. Frkchet, ibid. 1993, 26, 6536-6546; c) J. M. J. Frechet, I. Gitsov, M~icroniol.Symp. 1995, 98, 441-465. [ 11 I a) J. C. M. van Hest, D. A. P. Delnoye, M. W. P. L. Badrs, M. H. P. van Genderen, E. W. Meijer, Science 1995, 268, 1592-1595; b) J. C. M. van Hest, M. W. P. L. Baars, R. C. Elissenroman, M. H. P. van Genderen, E. W. Meijer, Mucromoleciiles 1995, 28, 6689-6691. [I21 T. M. Chapman, G. L. Hillyer, E. J. Mahan, K. A. Shaffer, J. Am. Chem. Soc. 1994, 116, 111951 1 196. [ 131 a) C. J. Hawker, J. M. J. Frichet, J. Am. Chem. Soc. 1990, 112,7638-7647; b) R. Klopsch, S . Koch, A. D. Schluter, Eur: J. Org. Chem. 1998, I, 12751283: c) A. Ingerl, 1. Neubert, R. Klopsch, A. D. Schluter, Eur: J . Org. Chem. 1998, 2551-2556; d) S. M. Grayson, M. Jayaraman, J. M. J. Frechet, Chem. Commun. 1999, 1329- 1330. 1141 S. C. Zimmerman, F. W. Zeng, D. E. C. Reichert, S. V. Kolotuchin. Science 1996, 271, 1095-1098. -

From Random Coil to Extended Nanocylinder: Dendrinzer Fragments Shape Polymer Chains [I51 a) V. S. K. Balagurusamy, G. Ungar, V. Percec, G. Johansson, J. Am. Chem. Soc. 1997, 119, 15391555; b) S. D. Hudson, H.-T. Jung, V. Percec,

W. D. Cho, G. Johansson, G. Ungar, V. S. K. Balagurusamy, Science 1997, 278, 449-452; c) V. Percec, W.-D. Cho, P. E. Mosier, G . Ungar, D. J. P. Yeardley, J. Am. Cheni. Soc. 1998, 120, 11061-11070. 1161 a) D. A. Tomalia. P. M. Kirchhoff, US patent 4,694,064 (1987); b) R. Yin, Y. Zhu, D. A. Tomalia, H. Ibuki, J . Am. Chem. Soc. 1998, 120, 26782679. [ 171 a) R. Freudenberger; W. Claussen, A. D. Schluter, H. Wallmeier, Polymer 1994, 35, 4496-4501; b) B. Karakaya. W. Claussen, A. Schafer, A. Lehmann, A. D. Schluter, Actu Polym. 1996, 47, 79-84; c) B. Karakaya, W. Claussen, K. Gessler, W. Saenger, A. D. Schluter, 1. Am. Chern. Soc. 1997, 119, 3296-3301; d) S . Jahromi, B. Coussens, N. Meijerink, A. W. M. Braam, J. Am. Chem. Soc. 1998, 120, 9753-9762. [IS] C. J. Hawker, J. M. J. FrCchet, J. M. J. Polynzer 1992, 33, 1507-1513. I 191 Chetnistp und Industry of Macromonomers (Hrsg.: Y. Yamashita), Huthig & Wepf, Basel, Heidelberg, New York 1993. [20] a) G. Draheim, H. Ritter, Muci-omol. Clirm. Plzys. 1995, 196,2211--2222;b)Y. M.Chen,C.-F. Chen, Y.-F. Liu, Y. E Li, F. Xi, Macrornol. Rapid Commun. 1996, 17, 401-407; c) 1. Neubcrt, R. Klopsch, W. Claussen, A. D. Schlueter, Actu Polym. 1996, 47, 455-459. 1211 V. Percec, C.-H. Ahn, B. Barboiu, J. Am. Chem. Soc. 1997, 119. 12978- 12979.

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[22] a) Y. Tsukahara, Y. Tsutsumi, Y. Yamashita, S. Shimada, Mucrurnoleclrles 1990, 23, 5201 -5208; b) M. Wintermantel, M. Gerle, K. Fischer, M. Schmidt: 1. Wataoka, €1. Urakawa, K. Kajiwara, Y. Tsukahara, ibid. 1996, 29, 978-983; c) S . S. Sheiko, M. Gerle, K. Fischer, M. Schmidt, M. MOIler, Langnzuir 1997, 13, 5368-5372; d) M. Gerle, K. Fischer, S. Roos, A. H. E. Muller, M. Schmidt, S. S. Sheiko, S. Prokhorova, M. Mdler, Macromolecules 1999, 32. 2629-2637. 1231 a) V. Percec, C.-H. Ahn, G . Ungar, D. J. P. Yeardley, M. Moller, S. S. Sheiko, Nature 1998, 391, 161-164; b) V. Percec, C.-H. Ahn, W.-D. Cho, A. M. Jamieson, J. Kim, T. Lernan, M. Schmidt, M. Gerle, M. MOller, S. A. Prokhorova, S. S. Sheiko, S. Z. D. Cheng, A. Zhang, G. Ungar, D. J. P. Yeardley, J. Am. Chem. Soc. 1998, 120, 8619 -8631. 1241 a) S. A. Prokhorava, S. S. Sheiko, M. Moller, C.-H. Ahn, V. Percec, Macromol. Rupid. Coinmun. 1998, 19, 359-366; b) S. A. Prokhorava, S. S. Sheiko, C.-H. Ahn, V. Percec, M. Mbller, Macromolecules 1999, 32, 2653-2660. [25] a) W. Stocker, B. L. Schurmann, J. P. Rabe, S. Forster, P. Lindner, I . Neubert, A. D. Schluter, A&. Mute,: 1998, 10, 793-797; b) W. Stocker, B. Karakaya, B. L. Schurmann, J. P. Rabe, A. D. Schluter, J. Am. Chem. Soc. 1998, 120, 76917695; c) S. Forster, 1. Neubert, A. D. Schluter, P. Lindner, Macroinolrcules 1999, 32, 4043 -4049. (261 V. Percec, Makromolekulares Kolloquium Freiburg, Feb. 1998. 1271 A. D. Schluter in Dendrimers; Top. Cum Chem., F. Vogtle, Ed., 1998. pp. 165-191. [28] A. P H. J. Scheming. R. E. Martin, M. Ito, F. Diederich, C. Boudon, J. P. Gisselbrecht, M. Gross, Chem. Comm. 1998, 1013- 1014.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

C. Solid Phase Synthesis and Combinatorial Chemistry Combinatorial Methods - Prospects for Catalysis? Reinhard Racker and Oliver Reiser Institut fur Organische Chemie, Universitat Regensburg, Germany

In no time the concept of combinatorial chemistry has become a valuable tool in the process of drug discovery. The popularity of this approach is based on the possible synthesis and screening of libraries containing millions of compounds. In the field of asymmetric catalysis, combinatorial methods could help to discover new efficient catalysts as the number of possible metal-ligand combinations is immense. In an ideal case a substrate would be screened against a library of catalysts or a library of substrates against one catalyst to find out the most efficient conditions for the reaction in question. Up to now this has been essentially a utopian idea, but the first examples of the efficient detection of new catalysts and their reactions using combinatorial methods were recently described in the literature [l].

Substrates

Substrates

6")

(S")

Substrates

*

Principles of Combinatorial Chemistry Several reviews have been published lately which provide detailed information on general aspects of combinatorial chemistry [2]. For this reason, only a short survey of the basic strategies is given here (Fig. I): The first step is the synthesis of a library of compounds, i. e. the aim is to generate a large number of compounds at the same time. Despite this seemingly unselective approach, the rules applied are the same as for the preparation of single compounds. The reactions used for the generation of the compound mixture have to proceed with high yields and without side reactions to assure the desired composition of the library. For the synthesis of a large number of

K3K2K1

\?

13'2

(SO)

Library selective for R

Receptor

(R)

n

U

Deduction of the substrate structure

KxKyKz

-

Analysis

of the labels

~SxSyS:R KxKyKz

Figure I . Principles of combinatorial chemistry.

I

Comhinutoriul Methods

-

Prospects for Cutu1ysi.v:)

315

3 groups of separated polymer beads

0-x

&-.-A

e

&X-B

x

M&X-C)

& Separate into three groups

I

2. Cycle

j

D M3

he E

X-0-F

'&X-C-D M3

X-C-

x-c-F

E

compounds, the single reaction steps have to be iterative, i. e. in each step a new functionality has to be created which allows another transformation in the subsequent step. The products must be separated from the reagents in an efficient manner, which can be achieved most easily by filtration. As a consequence, the products have to be solids, and this can be realized most efficiently if the reactions are carried out with polymer-bound substrates (solid-phase synthesis). All of these demands were fulfilled for the synthesis of peptides long before combinatorial chemistry gained the importance that it has to-

MA

Figure 2. Encoded libraries prepared through split synthesis.

day, and therefore it is not surprising that peptides and their analogs are the most widely used compounds in combinatorial libraries. Nowadays, a large number of different reactions have been optimized for solid phase synthesis [3]. Furthermore, it has to be possible to determine the exact structure of a single compound within a library. As each compound in a combinatorial library is synthesized on a picomole scale, standard analytical methods are usually not applicable. These days, small amounts of peptides can be directly analyzed and identified using sequencing methods, but usually the compounds of a library

316

C. Solid Phase Synthesis and Comhincitorial Chemistry

have to be labeled in order to allow their identification. A library obtained in this way can then be examined with regard to its interaction with a receptor. It is challenging to find an easy way to identify substances which are capable of interacting with the receptor. If a binding interaction takes place, the identification of the responsible structure can be carried out as follows: the receptor is labeled with a dye molecule so that an interaction can be detected optically by a change in color caused by the substrate -receptor complex. Finally, the structure of an active molecule can be deduced from the label to which it is correlated.

Combinatorial Libraries via “Split Synthesis” One of the most powerful and systematic methods for the synthesis of an encoded combinatorial library is the so called “split synthesis” procedure (Fig. 2) [4]. Polymer beads serve as the solid phase, and synthesis is set up in such a way that eventually evcry bead carries just one compound (about 100 pmol E molecules). As a consequence the obtained polymer-bound products are spatially separated. In each cycle, one reagent (A-F, e. g. an amino acid) and an encoding tag molecule (M, -M4) are attached to separate samples of resin beads. After this, the beads are thoroughly mixed and split up into equal quantities, and this is followed by the next reaction cycle. Diazoketones (l),which can be selectively incorporated into the excess polymer backbone using the corresponding acylcarbcnes, being activated by rhodium catalysis, proved to be good tag molecules. As part of the subsequent analysis, the tag molecule 2 is cleaved from the resin, and its iden-

tity is determined by an especially sensitive capillary gas chromatography method (ECGC). By this means the tag molecules may be used in much smaller amounts ( 1 mol%) than the substrate molecules. To keep the number of tag molecules low, they are employed as mixtures. However, it is crucial that every single compound in a library is correlated to a distinctively different combination or tags.The libraries described in the following paragraph were prepared according to the method depicted above.

New Metal Complexes through Combinatorial Chemistry For the discovery of new ligands for transitionmetal complexes, two different approaches were applied. Still and co-workers modified the known ligand cyclen in a combinatorial way by attaching peptide chains, and thus obtained 3 [5]. The screening of this ligand library against Cu(I1) or Co(1) ions revealed different binding affinities depending on the peptide which was used for modification. Jacobsen and co-workers synthesized a library of compounds with no predefined functionalities or subunits (Fig. 3): Two amino acids (positions 1 and 2), a turn-inducing fragment and a terminating group were used as variables [6]. This library was exposed to a solution of Ni(I1) acetate or Fe(II1) chloride in order to find the most efficient ligands for these ions among the synthesized compounds. The detection of the most stable complexes could easily be accomplished using classic color reactions (dimethylglyoxime for nickel and potassium rhodanide for iron). The colored resin beads were then selected under the microscope. Actually, certain structures proved to have a very high affinity for each of these ions. In the case of sufficiently dilute Ni(I[)-solutions the metal

0 Me

GH2CH2NHR

C H,C HzNHR

n = 2-11, m = 2-5

1

2

Scheme 1

3 R = peptide

Scheme 2

Cornbinatorial Methods

I end group

turn-element

-

Prospects f o r Catalysis?

317

I

position 2

Figure 3. Composition of a ligand library and two out of four ligands with the highest affinity to Ni(I1)

could only be detected on 6 out of 24 000 polymer beads. However, the properties of the new complexes derived from these projects have not been investigated. Furthermore it is questionable whether this approach allows the discovery of new catalysts because the screening procedure led to the most stable complexes. However stability is a property that does not favor catalytic activity. Nevertheless, a recent study by the same authors revealed that libraries made by this approach can indeed point at least towards new lead structures for catalysts [7]. For the identification of efficient catalysts from a large library, strategies of parallel

testing and deconvolution were employed. However, to distinguish between highly reactive and less reactive species remains problematic because of the large numbers of compounds and small quantities of each. A new strategy makes use of thermographic methods, which detect the heat which is set free in the exothermic reactions at the metal centers [S]. Also, resonance-enhanced multiphoton ionization (REMPI) techniques have been used to selectively and quantitatively determine the product formation in catalyzed reactions [9]. Yet another efficient assay for the discovery of active catalysts was shown by Hartwig et al. PalladiumAigand combinations

3) Red-A1

4

+

i

PPTS'BUoH

5

PhCHO + Et,Zn

-

7

6 or 7

6

R = Ph: 89% ee

7 R = Ph: 94% ee

Figure 4. Synthesis of amino alcohols on a solid phase as potential ligands for the addition of diethylzinc to aldehydes.

318

C. Solid Phase Synthesis and Cornhinutorial Clzemistry

were tested for Heck reactions in a way that a tethered fluorophore was coupled to an aryl halide attached to a solid support [ lo]. A successful coupling is signaled by fluorescence of the solid support.

Attempts at a More Efficient Screening of Catalysts The synthesis of 2 -pyrrolidinemethanol ligands on a polymer support was recently demonstrated by Ellman and coworkers and used for the preparation of single compounds, but not for combinatorial synthesis (Fig. 4) [ 1 I]. The resulting amino alcohols were tested as chiral ligands for the addition of diethylzinc to aldehydes while still bound to the polymer support or after cleavage from it. In both cases high enantioselectivities were observed depending on the ligand structure. However, this paper showed that there is no correlation between the selectivity of the polymer-bound and the free catalyst. Mikami et al. also chose a combinatorial approach for the optimization of ligands for the addition of diethylzinc to aldehydes [12]. The authors postulate a zinc complex containing a diol ligand and a diimine ligand as the actual catalyst. Various diol-diimine combinations were prepared in a parallel synthesis in solution, and the enantiomeric excesses obtained with the corresponding complexes in the diethylzinc addition to aldehydes were determined using HPLC -circular dichroism techniques (HPLC-CD). A library of 63 peptides, each containing one of the two phosphine-substituted amino acids 8 or 9, was prepared by Gilbertson and coworkers in a parallel synthesis on polymer beads [ 131. After complexation of all peptides with rhodium, the obtained polymer-bound complexes were employed in the asymmetric hydrogenation of 10 (Fig. 5 ) . For that purpose the set-up was reduced in size to an extent that allowed the simultaneous hydrogenation with all catalysts in spatially separated vessels. The enantioselectivities which were determined for each catalyst were only moderate (< 20 % ee) in all cases, but nevertheless this approach is interesting because of the possibility of carrying out a highthroughput screening of ligands.

9

\

Incorporation of 8 or 9 at positions1./2., 1 ./5.of the penta- or 3./4. of the tetrapeptide, respectively

/

.

. .

w

\

/

altogether 63 peptides NHAc

&CO,M~

HP Rh+ complexesof the peptid; on the solid phase

N HAc

ACO,Me c 20%

10

ee

11

Figure 5. Synthesis of a peptide library with phosphine-containing amino acids as potential ligands for

the asymmetric hydrogenation.

In a similar approach, Burgess et al. investigated a C-H-insertion reaction with different metal -1igand combinations on microtiter plates [ 141. By these means it was possible to test 96 catalyst systems at a time, indeed in single reactions, but still faster than by conventional methods. The uncertainty of the results due to the sinall scale of the experiments is a drawback of this screening procedure, as was (laudably) revealed by the authors themselves. Other approaches for screening catalysts in parallel have also been successful [ 151. A remarkable strategy for the optimization of catalysts which also utilizes the parallel synthesis of ligands was presented by Snapper, Hoveyda et al. (Fig. 6) [16]. Based on the fundamental perception that the titanium-catalyzed addition of trimethylsilyl cyanide to mesa-epoxides can be carried out in an asymmetric fashion in the presence of a dipeptide Schiff base, the authors were able to raise the enantioselectivity of the cyclohexene oxide ring opening systematically through a successive variation of the building blocks AA I +AA2+ aldehyde in 12. In this way tert-leucine was recognized in the first screening to be optimal for AAI (although a closer look at the original publication reveals that p-trityl-L-asparagine is

Combinatorial Methods - Prospects for Catalysis?

319

---

'-"-'

aldehyde-AAi-

AA2-Gly-OMe

12

*-HydroxyNaphth+A+

13 Phe-

Gly-OMe TMSCN Ti(O'Pr)4 /12

2-HydroxyNaphth- t - L e u M Gly-OMe 14

aldehydef t-Leu-

3. Screening

F

I

Thr(t-Bu)-Gly-OMe

aldehyde = 3-fluorsalicylaldehyde= 89% ee

O'Bu 15

at least equally suitable). In the second screening step 0-tert-butyl- L-threonine was found to be the best choice for AA2 while keeping tert-Leu as A A I , and in the third step tert-leu and Thr(t-Bu) were kept and 3 - fluorosalicylaldehyde was determined to be the most suitable aldehyde. This led to ligand 15, which allowed the titanium-catalyzed addition of TMSCN to 13 with remarkable 89 % ee. As not all combinations are tested when following this procedure, the question remains whether the best ligands were really found. This would certainly be the case if the effects of the single building blocks were additive but, in general this should not be true. For the ligand system just described, an independent influence

Figure 6. A new screening procedure for catalysts via variation of single subunits.

of the ligand subunits seems indeed to exist, since the authors also find 15 as the best ligand when they reverse the screening strategy to aldehyde +AA2+AAI. The authors also showed that the catalyst optimization leads to equal results no matter whether the catalyst is polymerbound or not [17]. Similarly, catalysts for the asymmetric Strecker reaction have been discovered [18]. The high-throughput screening of asymmetric catalysts requires efficient techniques for the determination of enantiomeric excesses. Siuzdak and Finn recently developed a method for that purpose which makes use of kinetic resolution and mass spectrometry [19]. Various chiral secondary alcohols and amines were esterified on

320

C. Solid Phase Sjnthesis and Combinatoricil Chemistry

screening against the immune system of the mouse

O2N 18

Figure 7. Regio- and enantioselective reduction of a dicarbonyl compound using a catalytic antibody.

a nanomole scale with a 1 : 1 -mixture of two chiral carboxylic acids that differ by their molecular weight, i. e. by one methyl group. The authors showed that even if the ratio of the reaction rates for the formation of diasteriomeric esters or amides is as small as 1.2, the enantiomeric excess of the sample can be determined with an accuracy of 1 1 0 %. The relative amounts of the derivatized compounds were determined by electrospray ionization mass spectrometry (ESIMS). Reetz et al. developed a method for the determination of the enantioselectivity in asymmetric catalytic reactions of chiral substances and of prochiral compounds containing enantiotopic groups [20].Their approach is based on the use of isotope-labeled pseudo-enantiomers or pseudo-prochiral compounds. Enzymatic kinetic resolution processes and the desymmetrization of meso-compounds were investigated, and the conversion as well as the enatiomeric excess were determined by ESI-MS.

Catalytic Antibodies The discovery of catalysts using combinatorial methods was successfully demonstrated for the generation of catalytic antibodies [21]. This method exploits the great number of indeed highly complex compounds of the immune system. The strategy for the detection of a catalyst for a certain reaction is as follows: the compound should be the most suitable catalyst which best stabilizes the trcznsition state of the reaction, i. e. lowers its energy most. As a transition state is an energy maximum and can thus not be iso-

lated, a stable analogon is prepared which is as similar to the transition state as possible, and the substance with the highest affinity to it is searched for from the immune system. For example, to detect an appropriate catalyst for the reduction of 16 to 17 Schultz et al. used the N-oxide 18, which should simulate the tetrahedral geometry as well as the charge distribution of the hydride attack on a carbonyl group (Fig. 7) [22]. Actually an antibody was found which not only allowed the preparation of 17 with an excellent regioselectivity (>75 : 1 ) in favor of the carbonyl group adjacent to the nitrobenzoyl unit but also effected an outstanding enantioselectivity (> 96 7c ee) in favor of the (S)-enantiomer because of the chirality of antibodies. With conventional chemical methods such a transformation would have been difficult to carry out. This procedure made the identification of a multitude of effective catalysts for organic reactions possible. The general availability of antibodies and their high substrate specifity pose a problem, however. For this reason the detection of small compounds as catalysts for organic reactions will remain an important goal for synthesis. A real combinatorial testing of libraries of small compound catalysts is hampered by the problem that the information about which catalyst reacted with the substrate to which product needs to be transferred. In the case of the highly inventive encoding techniques for libraries (e. g. via radio frequencies or bar codes), this problem may be solved in the future 1231. Although there is general euphoria about combinatorial chemistry, the question whether the

Combinatorial Methods

chosen approach is really important for the target envisaged should be critically considered. Furthermore, it should be more severely questioned whether selectivity is still an outstanding goal in research on catalysis. Almost universal ligands like the binaphthyls [24] or the bisoxazolines [25] were developed through rational design, and because of their non-modular structure they would probably not have been detected using combinatorial methods. While high selectivities can be achived for almost all known catalytic reactions after optimization, most catalytic reactions suffer from low turnover rates and turnover numbers of the catalysts. Increased investigations and new approaches to raise reactivity are necessary, and, for this, combinatorial chemistry can contribute even more to the discovery of new and highly reactive catalytic systems. Give me rute, I p r o b a b l y can give you selectivity later is a rule from many lectures by B. Sharpless which one should bear in mind. Acknowledgement: The authors acknowledge support from the Fonds der Chemischen Industrie.

References [ I ] Earlier reviews: a) C. Gennari, H. P. Nestler, U. Piarulli, B. Salom, Liebigs Ann./Rec/. 1997, 637-647; b) H. B. Kagan, J. Organornet. Chern. 1998, 567, 3-6; c ) W. F. Maier, Angerv. Cheni. 1999, 111, 1294-1296: d ) T. Bein, Angew. Chern. 1999, 111, 335-338, e) R. Schliigl, Anger~,Chrni. Int. Ed. Engl. 1998, 37, 2333-2336; f) P. Cong, R. D. Doolen, Q. Fan, D. M. Giaquinta, S.Guan, E. W. McFarland, D. M. Poojary, K. Self, H. W. Turner, W. H. Weinberg, Angnv. Cheni. 1999, I l l , 508-512; g) 0. Reiser, Ncrchl: Chenz. 7 k h . Lrrh. 1996.44, I 182- I 188; h) S. Borman, Chem. Eng. N e w s 1996, 74, 37. 121 a) F. Balkenhohl, C. von dem Bussche-Hunnefeld, A. Lansky, C. Zechel, Angew Chrm. 1996, 108, 2437; b) A. W. Czarnik ct al.. Cornhiritrtorirrl Chemistry (Specid Issue), A N . . Chenz. Res. 1996, 29, 112; c ) L. A. Thompson, J. A. Ellmann, Cheni. Re\: 1996, 96, 955. 131 J. S.Fruchtel, G. Jung, Angerr: Cl7en7. 1996, 108, 19-46. 141 Review: W. C. Still, A K . Cheni. Rex 1996, 29. 155. 151 M. T. Burger, W. C. Still. J. Org. Chen?.1995, 60, 7382. 161 M. B. Francis, N. S. Finney, E. N. Jacobsen,J. Atn. Chenz. Soc. 1996. 118, 8983.

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Prospects ,for Catulysis?

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171 M. B. Francis, E. N. Jacobsen, Angew. Chem. 1999, 111, 987-991. [81 a) S. J. Taylor, J. P. Morken, Science 1998, 280, 267 - 270; b) D. E. Bergbreiter, Chemtracts 1997, 10, 683-686; c) A. Holzwarth, H.-W. Schmidt, W. F. Maier, Angew. Chem., Int. Ed. Engl. 1998, 37, 2644-2647; (d) M. T. Reetz, M. H. Becker, K. M. Kuhling, A. Holzwarth, Angew. Chem. 1998, 110, 2792-2795. [9] S. M. Senkan, Nuturr 1998, 394, 350-353; b) S. M. Senkan, S. Ozturk, Angew. Chenz. 1999, 111, 867-871. [ l o ] K. H. Shaughnessy, P. Kim, J. F. Hartwig, 1.Am. Chem. Soc. 1999, 121, 2123-2132. [ I I ] G. Liu, J. A. Ellman,J. Org. Chem. 1995,60,7712. [ I21 K. Ding, A. Ishii, K. Mikami, Angew. Chen7. 1999, 111, 519-523. 1131 S. R. Gilbertson, X. Wang, Tftruhedron Lett. 1996, 37, 6475. 1141 K. Burgess, H.-J. Lim, A. M. Porte, G. A. Sulikowski, Angew. Chem. 1996, 108, 192. [IS] a) T. Berg, A. M. Vandersteen, K. D. Janda, Bioorg. Med. Chem. Lett. 1998, 8, 1221- 1224; b) C. Gennari, S. Ceccarelli, U. Piarulli, C. A. G. N. Montalbetti, R. F. W. Jackson, J. Org. Cher??.1998, 63, 5312-5313. [ 161 B. M. Cole, K. D. Shimzu, C. A. Krueger. J. P. A. Harrity, M. L. Snapper, A. H. Hoveyda, A17gew Chem. 1996, 108, 1776. 1171 K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W. Kuntz, M. L. Snapper, A. H. Hoveyda, Angerv. Chenz. 1997. I09, 1782- 1785. [ 181 M. S. Sigman, E. N. Jacobsen, J. Am. Chenz. Soc. 1998, 120, 4901 -4902. 1191 J. Guo, J. Wu, G. Siuzdak, M. G. Finn, Angew C/ie/n. 1999, I l l , 1868-1871. 1201 M. T. Reetz, M. H. Becker, H.-W. Klein, D. Stockigt, Angew. Chem. 1999, I l l , 1872- 1875. 1211 a) L. C. Hsieh-Wilson, X.-D. Xiang, P. G. Schultz, Acc. Chern. Res. 1996, 29, 164; b) C. Gao, B. J. Lavey, C.-H. L. Lo, A. Datta, P. Wentworth, K. D. Janda, J. Am. Chem. Soc. 1998, 120, 22 I I 2217; c) K. D. Janda, L.-C. Lo, C.-H. L. Lo, M.-M. Sim, R. Wang, C.-H. Wong, R. A. Lerner, S c i e r ~ r1997, 27.5, 945 -948. [22] L. C. Hsieh, S. Yonkovich, L. Kochcrsperger, P. G. Schultz, Sciet7ce 1993, 260, 337. 1231 For a recent review on combinatorial catalysis, see: B. Jandeleit et al. Angm: Cheni. 1999, 1 1 1 , 2648-2689, At7gerv. Chenr. Inl. Ed. Engl. 1999, 38, 2494-2532. [241 cf. T. Wahnitz. 0. Reiser in Organic Synthe.si.s Highlights IV (Ed. H. G. Schmalz), Wiley-VCH, Weinheim, 2000, pp. 155. [25]cf. M. Glos, 0. Reiser in Organic Synthesis Highlight.s IV (Ed. H. G. Schmalz), Wiley-VCH, Weinheim, 2000, pp. 17. -

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

The Renaissance of Soluble Polymers M. Reggelin lnstitut fur Orgunische Chemie, Universitat Mainz, Germany

In 1963 R. B. Merrifield published his seminal paper on the possibility of peptide synthesis on a solid, polymeric support [l]. On the basis of this work, which helped its author to get the Nobe1 Prize in 1984, the field of chemical synthesis of biopolymers was developed and has been an - . area of great interest since then. It is therefore not surprising that the annual number of citations of this publication (v in Fig. 1, up to Autumn 1997 : 35 11 in total!) increased rapidly between 1975 and 1990 and has now stayed at a very high level with only a slight tendency to fall. Solid-phase synthesis seemed to be the key to a fascinating possibility: the chemical synthesis of proteins able to function. Maybe this “El Dorado”

feeling at the end of the 1960s and beginning of the 1970s is responsible for the lack of work on alternatives; it simply seemed unnecessary. On the other hand, as time passed it became clear that even the brilliant solid-phase method had its problems: 1) Loss of reactivity due to heterogeneous reaction conditions. 2) Incompatibility between the swelling behavior of the solid support and the solvents needed in the reaction. 3) Non-linear reaction kinetics due to locally different reactivities of the polymeric matrix. 4) The solid support hampering reaction monitoring.

1000-

900-

a)

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.

. 600 I)

5

500400-

C

-0-Gallop -A-CombiChem -V-Merrifield

/

7

p

300-

2

4

year Figure 1. (a) Literature statistics illustrating the revival of interest in soluble polymers, time interval: 2 years, linear representation. 7 : number of citations of Ref. 111; D: sum of the citations of Refs. 3a, 3b, 6, and 13a;

-A- CornbiChern

-V-Merrifield

year in the keywords “Combinatorial Chem? or Combinatorial Librar?’; 0 : Number of citations of Ref. [ 141. (b) logarithmic representation (basis 2). A: citations

The Renuissance of Soluble Polymers

Being aware of these difficulties in 1965, a russian group proposed (in a paper now virtually unheard of) the use of soluble polystyrene as polymeric support [2]. Although a tetrapeptide was synthesized in 65 % yield, the method did not gain acceptance, since the polystyrene used became crosslinked during the synthesis and the by-products tended to precipitate with the polymer. It was not until the years 1971 and 1972 that E. Bayer and M. Mutter proposed a practicable concept of peptide synthesis on a linear soluble polymer [3]. It is proven by the number of citations of this work, which steadily increased in the following years (W in Fig. l), that this protocol has been accepted as a interesting alternative. Maybe a certain disillusionment concerning the

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potential of solid-phase synthesis of proteins arising at that time was beneficial for this acceptance [4]. So let us take a closer look at the first “Golden Age” of this interesting methodology.

The Best of Both Worlds The recipe for success was to select the “right” polymer. If polyethylene glycol [PEG; or more correctly poly(oxyethy1ene)l was used, the problems associated with solid phase variation, namely those concerning reactivity and diffusion, were overcome, and conditions typical of chemistry in solution could be restored at the same time. Additionally, the operative advan-

324

C. Solid Phase Synthesis arid Cornbinutorinl Chemistrv

tages of the solid-phase protocol are preserved, because the polymer can be precipitated after completion of the reaction in a homogenous phase. Indeed, kinetic studies on the aminolysis of BOC-protected p-nitrophenyl esters of glycine with glycine esters showed that the presence of the polymer in the alcohol component (MW: 2000-20 000) didn't have any effect on the reaction rate compared to the presence of an ethylester of lower molecular weight [ 5 ] . Figure 2 depicts the protocol of the polypeptide synthesis using soluble MeO-PEG X (MeO-PEG X stands for mono-methylated PEG with an average molar mass of X ; typically X = 5000- 15 000). Protected at the N-terminus (PG polymer), the amino acid is condensed to the free OH group of the polymer and subsequently deprotected. Thus, an amino acid (2) immobilized at the C-terminus [or the conjugate of a growing peptide chain and a soluble polymer, (l),PG polymer] is obtained which can be separated in (at least) [6] two ways from the by-products and excessive reagents. The initial suggestion by Bayer and Mutter was ultra-filtration through a semi-permeable membrane [3], but the precipitation technique introduced in 1974 is more covenient, faster and more flexible with regard to the solvents used 171. Due to their helical structure, PEG and MeO-PEG with molecular weights between 2000 and 20 000 exhibit a strong tendency to crystallize [S]. Since this is true for polypeptide conjugates as well 191, precipitation by addition of ether or t-butyl methyl ether seems to be the method of choice [lo]. If the degree of purity obtained by precipitation and washing is not sufficient, the polymer can be further purified, almost without loss, by reprecipitation from ethanol, in which it shows a strong temperature gradient of solubility [9]. Another advantage of the liquid-phase method is the opportunity to apply all spectroscopic methods known for reactions in solution for evaluation of purity and effectiveness of coupling. After the reaction has been monitored, the polymer is redissolved and coupled to the next N-terminal-protected amino acid. Now the cycle of deprotection and coupling can either be run again or the product is cleaved from the polymer (e.g. with NH,, hydrazine or NaOH). It is obvious that the application of MeO-PEG as a soluble support has the advan-

tages of both worlds: quick, diverse chemistry in solution and convenient separation of the excess reagents using the properties of the polymer. Of course, it cannot escape notice that polymer-bound by-products or erratic sequences generated by failed coupling reactions cannot be avoided. In order to cope with this problem, Frank et al. developed an interesting procedure (Fig. 2) [ l l ] . The idea behind this is to grow the peptide on the soluble polymer, as described, but to attach solid-supported monomers for elongation. In this way, only successfully extended polymers become insoluble bipolymers (1, PG = polymer). Excess non-coupling PEGpeptides can be separated by washing, and thus, even with incomplete coupling, erratic sequences will never be obtained [12].

Limitations Iterative peptide synthesis on a soluble support is feasible as long as the properties of the polymerbound peptides are determined by the polymer. In the case of random coil sequences or helical peptides, this is guaranteed for up to about 20 amino acids. But with peptides which tend to form P-sheets, this limit is hit much earlier. Also, problems arose in the automation, giving a competitive edge to the solid-phase variant. Certainly these circumstances contributed to the change from maximum interest in the 1970s (Fig. 1, m) to a low level of interest 1131. In the early 1990s. However, interest was resurrected and seems to have been growing disproportionately since 1993 (Fig. lb, m). The temporary coincidence with combinatorial chemistry, which has been in an explosive phase of expansion since about 1991 (Fig. 1, A and 0 [14]), strongly suggests a relationship between the renaissance of soluble polymers and this development.

Liquid-Phase Combinatorial Synthesis (LPCS) The early days of combinatorial synthesis have been dominated by technical aspects such as the development oj' methods for the generation and analysis of molecular diversity [ 1.51. After these problems had been solved, e.g. for biopoly-

The Renaissance qf Soluble Polymers

mer libraries, people started thinking about the content of the libraries which had to be synthesized. As a logical consequence of this change in interest, today’s library synthesis increasingly aims at small molecules with favorable pharmacological features [15, 161. In order to adapt the most effective strategy for the synthesis of equimolarly composed combinatorial libraries (the “split-mix’’ method) [ 171, to this class of compounds, reactions optimized in solution had to be transferred to the solid phase. However, this implicates research and development activities, and this obviously discourages the non-chemist managers of the chemical industry. Chemical innovation and industrial success no longer follow the same time scale. One consequence of this

325

development is the preferential use of parallel synthesis in chemical industry. Here, the opportunities possibly inherent in combinatorial synthesis cannot be exploited. The tentative transfer of reactions from solution to the solid phase (which of course was also encouraged by the tentative acceptance by chemists at universities) and the associated problems led to an increased consideration of alternatives. In this state it was obviously recollected that both are possible: the diversity of chemistry in solution and the polymer-mediated advantages in the reaction process. This and the perception that additionally there is the possibility of library synthesis following the “splitmix” protocol mark the beginning of the renaissance of soluble polymers. The following para-

Figure 3. Liquid phase combinatorial synthesis (LPCS) and recursive deconvolution.

326

C. Solid Phase Synthesis and Comhinatorial Chernistv

graph describes Janda’s approach to combinatorial chemistry using soluble polymeric supports (Fig. 3) [18]. The three building blocks A, B and C are coupled to the soluble polymer MeO-PEG 5000, whereby three reaction channels were opened up. In each reaction channel, precipitation is achieved by the addition of ether, separation and purification by filtration and/or recrystallization from ethanol. In every channel, the precipitate is redissolved in (e. g.) dichloromethane, and a portion of the solution is set aside and labeled as partial library p(l), consisting of three members (MeOPEG-N,) in three different vials. The remaining polymer solutions are then combined and again divided among the three reaction vessels. After another coupling cycle, portions of the purified PEG-bound products were again sampled to generate a second sub-library [p(2), 3 containers, each with 3 substances = 9 compounds]. This procedure is repeated until all coupling reactions necessary have been carried out [ (Pn); in this case n = 3, 3 containers with 9 substances = 27 compounds]. This approach corresponds to Furkas “split-mix’’ protocol [ 171 with the modification of generating sub-libraries, which are very important for the analysis of the library. They facilitate the search for active members in a combinatorial library, which is an advancement of Houghten’s iterative deconvolution method 1191 and was named “recursive deconvolution” by Janda. The way it works is depicted on the righthand side of Fig. 3. The pronounced solubilizing power of MeO-PEG [9, 201 opens up the opportunity to test the library in a multiplicity of solvents in a homogeneous phase for (biological) activity, which is another important advantage compared to the solid phase version! The deconvolution starts with the final library p(3). In the example, the highest activity is found in the group of 9 compounds denoted with C. The next step uses this information. The sub-library p(2) is coupled to C, and the new library containing 3 x 3 compounds, in which positions 2 and 3 are known, is again tested for activity. In this example the highest activity is displayed by the group denoted by AC. For that reason in the last step p ( l ) is coupled to AC, and BAC is identified to be the most active compound. Janda et al. validated this

concept by the synthesis of a sulfonamide library and a pentapeptide library ( I024 members) [ 181. By application of an affinity assay the library was searched for binders for a monoclonal antibody which itself exhibits a strong affinity to the p-endorphin sequence (Tyr-Gly-Gly-Phe-Leu). Besides the native epitope a set of other peptides with high affinity towards the antibody was found. It is important to note that the MeOPEG peptide conjugates bind comparably to their polymer-free counterparts [ 20c] ! The advantages of this method are enormous:

a) No problematic “on-bead-assays” are necessary. b) The soluble conjugate of polymer and substrate allows for the direct application of known biological tests. c ) The “split-mix’’ technique is applicable for the generation of large, equimolarly composed libraries. d) Sub-libraries render repeated “split-mix’’ syntheses during the deconvolution superfluous. e) In each deconvolution cycle the number of simultaneously tested compounds decreases by a factor of X”/X’-’ = X ( X : number of building blocks, n: number of cycles). This increases the s i g n a h o i s e ratio, which reduces the incidence of “false-positives”. f) If the final library contains several active compounds, they all can be identified, since the corresponding deconvolution pathways can be run independently (even in parallel!). g) Recursive deconvolution not only indicates which compound is the active one, but also yields the active compound itself. The amount of substance synthesized can be controlled by the amount of the (very cheap!) polymer used.

Conclusions Chemical synthesis assisted by soluble polymers originally developed as an alternative to solid phase synthesis is now undergoing a second period of expansion. Just like in the early days, the desire to combine the advantages of solution chemistry with those of reactions on a solid phase has triggered this development. Soluble polymers can provide this and have therefore be-

The Renaissance of Soluble Polymers

come important for one of the most dynamic fields of contemporary chemistry: the combinatorial synthesis of non-biopolymer libraries. The results obtained by Janda et al. could be considered a milestone in the search for libraries exhibiting a maximum of constitutional and configurational diversity. The whole arsenal, even stereoselective reactions, could be made available for combinatorial chemistry. Thereby the “dreariness of heteroatom acylation” would finally come to an end!

References [ 11 R. B. Merrifield, J. Am. Chem. Soc. 1963,85.2 149.

[2] M. M. Shemyakin, Yu. A. Ovchinnikov, A. A. Kinyushkin, Tetrahedron Lett. 1965, 2323. [ 3 ] (a) M. Mutter, H. Hagenmaier, E. Bayer, Angew. Chem. 1971,83,883. (b) E. Bayer, M. Mutter, NatLire 1972, 237. 512. [4] The small proteins (55- 129 amino acids, e. g. the ribonucleases A and T, as well as lysozyme) synthesized in the years 1968- 1973 did not satisfy chemical purity demands. E. Bayer, Angew. Chem. 1991, 103, 117. [5] E. Bayer, M. Mutter, R. Uhmann, J. Polster, H. Mauser, J. Am. Chem. Soc. 1974, 96, 7333. [6] Alternatives are centrifugation and gel permeation chromatography: K. E. Geckeler, Adv. Polym. Sci. 1995, 121, 31. [7] M. Mutter, E. Bayer, Angew. Chem. 1974,86, 101. IS] (a) J. M. Harris in Poly(Ethy1ene Glycol) Chemistry: Biotechnical and Biomedical Applications (Ed.: J. M. Harris), Plenum Press, New York, 1992, p. 2. (b) In the crystal, PEG is present as a 7,-helix: H. Tadokoro, Y. Chatani, T. Yoshihara, S. Tahara, S. Murahashi, Mucromol. Chem. 1964, 73, 109. [9] V. N. R. Pillai, M. Mutter, Ace. Chem. Rex 1981, 14, 122. [lo] The solubilities of MeO-PEG 5000 (in wt %) at room temperature in various solvents are: water: 55; dichloromethane: 53; chloroform: 47; DMF: 40; pyridine: 40; methanol: 20; benzene: 10; ethanol (60 %): 50; ethanol (100 %): 0.1; ethanol ( 1 00 %, 34 ”C): 20; ether: 0.01. E. Bayer, M. Mutter, J. Polster, R. Uhmann, Pept., Proc. EUK Pept. Symp. 13‘” 1974, 129. [ 1 I ] H. Frank, H. Hagenmaier, Experientia 1975, 31, 131. 11 21 In a recent publication (Angew. Chem. 1997, 109, 1835) H. Han and K. D. Janda picked up this approach for the transfer of the asymmetric Sharpless dihydroxylation into a “multi-polymeric environment”.

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[ 131 This does not mean that interest disappeared completely. But it is a fact however that the procedure

described so far as well as the ideas developed by Bayer (197.5 and 1986) concerning catalysis with soluble polymers [(a) E. Bayer, V. Schurig, Angew. Chem. 1975,87,484; (b) E. Bayer, W. Schumann, J. Chem. Soc., Chem. Commun. 1986, 9491 have only been taken up in the 1990s. The application of soluble polymers in the synthesis of oligosaccharides [(c) S. P. Douglas, D. M. Whitfield, J. J. Krepinsky, J. Am. Chem. Soc. 1991,113,5095] and oligonucleotides [(d) G. M. Bonora, G. Biancotto, M. Maffini, C. M. Scremin, Nucleic Acids Res. 1993,21, 12131took place in the same time period. [ 141 In the early days of combinatorial chemistry two important reviews were published: (a) M. Gallop, R. W. Barrett, W. J. Dower, s. P. A. Fodor, E. M. Gordon, J. Med. Chem. 1994, 37, 1233. (b) E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor, M. A. Gallop, J. Med. Chem. 1994, 37, 1385. The number of citations on these two articles correlates to the number of matches on a keyword survey on the topic of combinatorial chemistry, as expected (Fig. 1). For an excellent review, see: F. Balkenhohl, C. von dem Bussche-Hiinnefeld, A. Lansky, C. Zechel, Angew. Chem. 1996, 108, 2436. (a) M. Reggelin, V. Brenig, Tetrahedron Lett. 1996, 6851. (b) J. B. Backes, J. A. Ellman, J. Am. Chem. Soc. 1994, 116, 11171. (c) B. A. Bunin, J. A. Ellman, J. Am. Chem. Soc. 1992, 114, 10997. [I71 (a) A. Furka, F. Sebestyen, M. Asgedom, G. Dibo, lnt. J. Pept. Prot. Res. 1991, 37,487. (b) F. Sebestyen, G. Dibo, A. Kovacs, A. Furka, Bioorg. Med. Chem. Lett. 1993, 3, 413. [ 181 (a) Review: D. J. Gravert, K. D. Janda, Chem. Rev. 1997, 97, 489. (b) H. Han, M. M. Brenner, K. D. Janda, Proc. Natl. Acud. Sci. U.S.A. 1995, 92, 6419. (c) H. Han, K. D. Janda, J. Am. Chern. Soc. 1996, 118, 2539. (d) Recursive deconvolution: E. Erb, K. D. Janda, S. Brenner, Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 11422. [I91 R. A. Houghten, C. Pinilla, S. E. Blondelle, J. R. Appel, C. T. Dooley, J. H. Cuervo, Nature 1991, 354, 84. [20] This feature was often used to study the folding of a growing peptide chain. (a) R. C. de L. Milton, S. C. F. Milton, P. A. Adams, J . Am. Chern. Soc. 1990, I I Z , 6039. (b) M. Mutter, H. Mutter, R. Uhmann, E. Bayer, Biopolymers, 1976, 15, 917. (c) P. Koziej, M. Mutter, H.-U. Gremlich, G. Holzemann, 2. Nuturforsch. 1985, 40b, 1570. In the articles (b) and (c) the conformational preferences of PEGbound substance P is described, a peptide which underwent a renaissance as well: K. J. Watling, J. E. Krause ,,The rising sun shines on substance P and related peptides“, 7’iPS 1993, 14, 8 1.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Polymeric Catalysts M. Reggelin Institiit jiir Organische Chemie, Univevsitat Muinz, Germuny

Highly efficient selection of substrates and their stereocontrolled transformations are characteristic features of many biological systems. Normally, to obtain these effects, nature uses large, catalytically active polymers. The mass transport as well as the topicity of the substrateheagent interaction is controlled by the secondary or tertiary structure of the macromolecule. At the same time, decoupling of the residence time of the catalyst and the reactants results in high turnover numbers [ I ] , separation of the micromolecular products is straightforward and construction of continuously working systems is possible. Obviously preparative working chemists soon tried to copy this very attractive scenario [2]. An early example is the addition of methanol to methyl phenyl ketene in the presence of an immobilized cinchonaalkaloid (Fig. 1) [ 3 ] .

Under the influence of polycinchonine acrylate (1, 1 mol%) the S-configured ester (3) was formed in 35 % ee at - 78 “C in toluene. Interestingly, if

instead of the polymer the monomeric derivative cinchonine propionate (2) is used under the same reaction conditions the product with inverted absolute configuration [ ( R - 3 ) ,4.4 % eel is formed! This result, which was reported in the original article without any comment, can be interpreted as follows: the polymer exhibits a chiral (probably helical) superstructure, which dominates the chiral induction in the reaction 141.

Definition and Classification Apparently chiral polymeric catalysts offer a new qoality of asymmetric catalysis. If one succeded

0

MeOH

3

@? 0

H

Poly(cinchonine acrylate) 1

Cinchonine propionate 2

Figure 1. Nucleophile catalysis by polymeric cinchona-alkaloids.

Polymeric Catalysts

329

4

A N, I/

BOC

S

5

in the preparation of polymers or oligomers with a stable chiral conformation (e.g. a helix with uniform sense of chirality), this chiral hyperstructure could play the dominant role in the stereo asymmetric [ransformation. These considerations lead to a plausible classification of polymeric catalysts, particularly those with chirally ligated metals: Type A: a chiral ligand with spacially invariant complexation positions bound to a non-stereoregular polymer. Type B: a chiral ligand with spacially invariant complexation positions bound to a stereoregular polymer or part of the polymer backbone. Type C: a stereoregular polymer (oligomer) displaying spacially variable complexation positions. Type A includes the classical approach to chiral polymeric catalysts: a monomeric ligand is synthesized and attached to a “random coil” polymer. If a binding position for the metal is incorporated in every constitutional repeating unit, the catalytically active centres are randomly oriented, which is quite a delicate situation. Their micro-environment is dependent on the position o n the polymer, and it can be expected that this is true for their asymmetric induction as well. Such a catalyst can hardly be optimized rationally. Type B requires the synthesis of a configuratively and/or conformationally homogeneous polymer to which the atoms or groups of atoms constituting the complexation sites are attached. This can be achieved in at least two ways. Firstly it is possible to form the polymer with a uniform secondary

Figure 2. Type C catalysts from stereoregular polymers with spatially variable complexation locations.

structure (for example a helical polypeptide) first and to attach the coordination sites subsequently. On the other hand, a chiral, non- racemic monomer or even a prochiral substrate can be polymerized into a conformationally stable hyper-structure (“helix sense selective polymerisation”) IS]. Last but not least, type C is a system whose synthetic potential is almost completely unexplored. The modification of a-amino acid dodecamers with phosphine ligands in variable positions reported by Gilbertson et al. is the only example so far (Fig. 2) [6]. The constitutional range of monomers (amino acids and phosphine-modified species such as the serine derivative 4 and the tyrosine derivative 5 and the option to vary the distance between the complexating atoms (here P) by the spacer ( X ) allow for a versatile and transparent manipulation of the metal’s ligand sphere. Moreover, this type of polymeric catalyst is easily transferrable into a combinatorial environment, which can at least partially compensate for the high synthetic effort. Although the results in the asymmetric hydrogenation of dehydro-amino acids obtained by these helical oligomers is not yet convincing (only up to about 12 % ‘ e r ) , this concept seems to be promising.

Type A Catalysts Most polymeric catalysts belong to this category and therefore the selection of examples reviewed had to be very strict 171. Chiral metal 1,3-di-

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C. Solid Phase Synthesis and Combirzatorial Chemistry

Ern : M = VOIQ Qm: M = EU113

10m : M = v O i ~ z 11rn : M = ELI113

l o p : M =VOiiz Ilp:M=E~i/3

Figure 3. Chirasil metals in the Danishefsky reaction.

ketonates which are immobilized on polysiloxanes (so called chirasil metals) are materials of manifold applicability [8]. Here, we focus on their application in hetero-Diels-Alder reactions (Fig. 3) [9]. In the reaction between an activated diene and a prochiral aldehyde, which is catalyzed by chiral Lewis acids, 5,6-dihydropyranones such as 6 are formed enantiomerically enriched. By attachment of a chiral auxiliary (3-heptafluorobutanoyl camphor derivatives such as 7 to a soluble polysiloxane by hydrosilylation the catalyst should be recyled easily by precipitation or ultrafiltration while the cycloaddition reaction can bc performed in homogeneous solution [ 101. Starting with both enantiomers of camphor, Schurig and his co-workers synthesized the monomeric complexes 8m-llm as well as the corresponding polymers 8p- l l p . In the course of studies on their catalytic activities a surprising discovery was made (Fig. 4). While the monomeric vanadium complex 8m furnishes the expected levorotatory enantiomer of 6 in high yield [ l l ] (ee = 59 %), an excess

of (+)-6 (Fig. 4 a, ee = 40.5 %) is found in the reaction using the polymeric catalyst 8p with the same sense of chirality in the auxiliary! In contrast to this oxovanadium system, the polymer-induced inversion of the sense of asymmetric induction does not occur with the europium complexes 9m or 9p (Fig. 4 b). In both cases, formation of the levorotatory enone (-)-(6) is favored, although the yield of the polymer mediated catalysis was rather poor (only 6.4 910). In accordance with these observations the symmetry-related results are observed with the compounds 10m and lop (Fig. 4 c) derived from the camphor enantiomer. A satisfying explanation for this rather strange behavior, which is obviously related to the polymer-induced change in the coordination sphere of the metal, is not given. “It is open to speculation why the change of enantioselectivity between monomeric and polymeric catalysts occurs only in bis-chelated oxo-vanadium(1V)- but not in tris-chelated europium(II1) complexes” [9]. In a footnote, the possibility of a polymer-induced epimerization at the vanadium atom is discussed. This would entail an

Polymeric Catalysts

g

100-

s

50-

a

b

33 1

-100

C

h

A

+

-

50

v

0

I

8m

catalyst

8p

9m

9p

1Om

lop

Figure 4. Sense and magnitude of the chirdl induction in the asymmetric Danishefsky reaction with monomeric (rn) and polymeric (p) catalyst3

inversion of the absolute topicity of attack onto the aldehyde. In addition to this speciality it is noteworthy that the enantioselectivities of the polymer-catalyzed reactions are generally lower than those found in the reactions with the monomeric catalysts. Both of these findings refer, ultimately, to the position-dependence of the microenvironment which is typical of type A catalysts. Generally speaking, there are two ways to avoid these complications. Either a stereoregular polymer with a uniform micro-environment should be synthesized (changeover from type A to type B) or the catalytically active unit is bound only once (e. g. terminally) to a stereoirregular polymer. The

second approach was very successfully put into practice by K. Janda and C. Bolm, who published their results on a polymer-based variant of the Sharpless asymmetric dihydroxylation reaction. Since its discovery in 1988 [12]. there have been many attempts to simplify this reaction by immobilization of the catalyst and to develop ecologically and economically improved procedures. Unfortunately, prolongation of reaction times and decrease of enantioselectivity and yield have been the rule [ I 2 a, 81. Janda et al. [13] emphasized the incompatibility of a ligand-accelerated catalysis (LAC) [ 141 and a polymer-bound ligand as being decisive for the lack of

Table I : Polymer-assisted asymmetric dihydroxylations (ma. = not available). Olefin

I 3

4

12

@ i/ :: 16

12

5

~

Liganda)

~~~

"'see Figure 5. b)N-methyl morpholin-N-oxide.

t [hl

Yield I%]Reoxidant

ee

[%I

Ref.

NMO~)

88

I3a

95

K,Fe(CN),

99

13b

91

K,Fe(CN),

99

15

15

93

K3Fe(CN),

99

17

5

80

NMO")

60

13a

5

89

n. a.

55

332

C. Solid Phase Synthesis and Cornhinutorial Chemistry

12

Me?

13 Janda

14 Bolm

w

success. In order to facilitate the hampered access of the ligand to all reaction compartments which are within reach of the metal, the reoxidant and the olefin, MeO-PEG (MeO-polyethylene glycol) [ 101 was chosen as being a soluble polymer (Table 1 and Fig. 5 ) . Janda’s phthalazine derivative (13) [ 13 b] and the pyridazine derived ligand (14) developed by Bolm [15] almost reach the yield and enantiomeric excess achieved with the original catalytic system in a homogenous reaction (tert-butanoll water or acetone/water) [I2 b]. After addition of diethyl ether or tert-butyl methyl ether, the polymer-bound ligand is precipitated quantitatively. Thereby, the product as well as the ligand

Me0

Figure 5. Polymeric dihydroquinine (DHQD) catalysts.

can be obtained in a pure state. Neither the yield nor the ee are diminished on re-use of the recovered polymer.

Type B Catalysts The most self-evident method for formation of a stereoregular polymer is the polymerization of enantiomerically pure monomers with structural properties supporting the assembly of a conformationally uniform and stable secondary structure. Alternatives such as asymmetric polymerization generating stereogenic centers (“asymmetric synthesis polymerization”) or P- or M-he-

Polymeric Cutulysts

333

15

I

/

MMA or HEMA AIBN, PhH, A

17

Figure 7. Polybinaphthols as stereoregular polymers with a well-defined micro-environment of the catalytically active centers.

lix-selective polymerization (“helix sense-selective polymerization”) or finally the enantiomerdifferentiating polymerization have not yet been applied in the synthesis of chiral polymeric catalysts [16]. An interesting hybrid is presented by Song et al. (Fig. 6, Table 1, items 4 and 8) [ 171. Sterically non-demanding methacrylates are used as monomers, but under the influence of an enantiomerically pure cross-linking unit (probably) a polymer with a uniform micro-environment around the catalytically active centers is produced.

The strategy is impressively simple: the phthalazine derivative 15 can readily be prepared from quinine in one step. Being a divinyl derivative, it can be submitted as a cross-linking unit in the radical polymerization of methyl methacrylate (MMA) or 2- hydroxy methacrylate (HEMA). Thereby, an immobilized (DHQ-PHAL) derivative 16 is obtained, which is suited for the asymmetric dihydroxylation of trans-stilbene (>99 9% ee) and (E)-cinnamic acid methyl ester (>99 % ee, Table I ) . The insoluble catalyst can be recovered by simple filtration, and its repeated

334

C. Solid Phase Synthesis and Combinntorial Chemistq

Responsive Polymeric Catalysts

usage is possible. Despite this encouraging result, the constitutional spectrum of olefins suitable for this reaction remains to be seen. A purebred type B catalyst is exemplified by the polybinaphthol derivative 17 (Fig. 7) [18]. These polymers ( M = 6700-24 300) synthesized by Pu et al. in a polymerizing Suzuki coupling of substituted p-diboronic acids with 3,3’diiodine-substituted binaphthol derivatives are characterized as stereoregular macromolecules with a well-defined micro-environment around the complexing positions (so called “minor groove binaphthol polymers”) [ 181. The hexyloxy groups in the p-phenyl bridges guarantee solubility in organic solvents and behave as ligands for the metals. In the addition reaction of diethylzinc to various aldehydes catalyzed by this polymer (5 mol%), the corresponding alcohols (18) were obtained in excellent yield and high enantiomeric excess (74-93 % ee). This applies as well to aliphatic aldehydes, which are known to be problematic since they produce mostly bad results in the catalysis with polymeric aminoalcohols (type A) [ 191. The polymer can be separated from the products by precipitation from methanol.

I

rn

n-1

PPh2

In the introduction of this article it was mentioned that biomacromolecular catalysts not only control the topicity of the reagenthbstrate interaction but also interfere regulatively in the mass transport. Substrates are recognized and transported to the location of reaction and transformed in a stereocontrolled fashion, and the products are released. In addition, regulative mechanisms or features of the material control these processes and, for example, are responsible for the pH- and temperature-dependence of an enzyme-catalyzed reaction. Now there are synthetic polymers which respond to external events with a reversible change in physical or even chemical properties. In this context, materials scientists are interested, for example, in the regulation of the specific resistance, the tensile strength or any other mechanical property. Moreover, when this concept is extended to variation of chemical behavior, the so-called “smart ligands” [20] have to be mentioned. These ligands control catalytical activity as a function of temperature [20 a], pH value [20 bl or solvent. A tl~ernzoresporzsive

n-1

n = 11, rn = 34, LCST = 25°C

3025 c.

2

20-

E

Y

4m

.n

15-

10a, 0

g

( W ,H2

5-

A

0°C c T < 50’C

L

-

-OH

0-

4

0 0

.

n

10

, 20

4

, 30

r . 40

Figure 8. A phosphane modified PEO-PPOPEO block copolvmer as thennoresuonsive catalyst in the hydrogenation of allylic alcohols, I

50

60

70

I

_

Polymeric Catalysts

catalyst can be put into practice when ligands are connected to a polymer which exhibits an inverse temperature dependence of solubility. These polymers are subject to a temperature-dependent phase transition, i.e. they are soluble below a critical temperature (LCST “lower critical solution temperature”) and insoluble above this temperature (Fig. 8). One example of such a “smart ligand” is the rhodium complexating bis(2-diphenyl phosphinoethy1)amide derivative (19) of a PEO-PPOPEO block co-polymer [PEO: poly(ethy1ene oxide); PPO: poly(propy1ene oxide)]. In water its LCST is 25 “ C and it can be used for hydrogenation of allylic alcohols. At 0 “C the rate of hydrogen uptake is about 2 mmol H, / mmol Rh . h. If the reaction mixture is heated above the LCST, the hydrogenation reaction slows down and nearly comes to an end at 40 - 50 “C. If the reaction mixture is cooled down again, the polymer becomes hydrated and resolubilized (following the most simple explanation), and the reaction proceeds at maximum velocity again. In a very recent publication, Bergbreiter, and co-workers studied the extension of this concept using the pH value as a regulatory variable [20 b]. A phosphine-modified polyacid (a copolymer from methyl vinyl ether and maleic acid anhydride, Gantrezu) was taken as a ligand for rhodium. The rate of hydrogenation of various unsaturated substrates was reversibly modified by tuning the pH value.

Conclusions Polymeric catalysts provide advantages in reaction processing. They can easily be separated from low-molecular-weight products, they offer the possibility of performing reactions continuously, and expensive chiral ligands can be unproblematically recovered and recycled. But furthermore, if they are used in asymmetric catalysis, new qualities which are connected with the macromolecular state and are able to control every aspect of the products structure may arise. In the context of polymeric catalysts, fascinating ideas obtrude themselves. Exothermic reactions can be controlled by their coupling to the “Anti-Arrhenius”-behavior of “smart ligands”.

335

Temperature- or pH-dependent changes in selectivity can influence asymmetric syntheses and so on. The complete potential of polymeric catalysts will probably be revealed where configurative features of the polymer backbone and its specific interactions with the environment have a decisive effect on the conversion of matter. Here, the generation of chiral micro-environments which are uniform throughout the whole polymer and the control of mass transport and reactivity by the properties of the polymeric material will be most important.

References [I] The “turnover number” describes the amount of product formed in relation to the amount of catalyst used. [2] An early review: G. Manecke, W. Stark, Angew. Chem. 1978, 90, 69 1. 131 (a) T. Yamashita, H. Yasueda, N. Nakamura, Chem. Lett. 1974, 585. (b) T. Yamashita, H. Yasueda, Y. Miyauchi, N. Nakamura, Bull. Chem. Soc. Jpn. 1977. 50, 1532. 141 Similar effects are found in the enantiomer-differentialing polymerization of oligomers ( n N 30) of chiral, sterically crowded methacrylic acid esters: E. Yashima, Y. Okamoto, K. Hatada, Mucrornolecules 1988, 21, 854. [ 5 ] (a) Y. Okamoto, T. Nakano, Chem. Rev. 1994, 94, 349. (b) Y. Okamoto, E. Yashima, Prog. Polym. Sci. 1990, 15, 263. 161 (a) S. R. Gilbertson, G. Chen, M. McLaughlin, 1. Am. Chem.Soc. 1994, 116,4481. (b) S. R. Gilbertson, X. Wang, J. Org. Chem. 1996, 61, 434. (c) S. R. Gilbertson, G. W. Starkey, J. Org. Chem. 1996, 61, 2922. [7] One of the first (the first?) representatives of this class of chiral polymeric catalysts is worth mentioning: W. Dumont, J.-C. Poulin, T.-P. Dang, H. B. Kagan, J. Am. Chem. Soc. 1973, 95, 8295. [XI (a) As chiral stationary phases i n gas chromatography: M. Schleimer, M. Fluck, V. Schurig, Anal. Chem. 1994, 66, 2893. (b) As chiral, precipitable shift reagents in NMR spectroscopy: H. Weinmann, diploma thesis, University of Tubingen, 1993. [9] F. Keller, H. Weinmann, V. Schurig, Chem. Bel: Recueil 1997, 130, 879. [lo] M. Reggelin, Nuchl: Chem. Tech. Lab. 1997, 45, 1002. [ 1 I ] A. Togni, Organometallics 1990, 9, 3106.

336

C. Solid Phase Synthesis and Cornbitiatorial Chemistty

[I21 (a) E. N. Jacobsen, J. Marko, W. S. Mungall, G. Schroder, K. B. Sharpless, J. Am. Chenz. Soc. 1988, 110, 1968. (b) H. Becker, K. B. Sharpless, Angew. Chenz. 1996, 108, 447. [ 131 (a) H. Han, K. D. Janda, J. Am. Chem. Soc. 1996, 118, 1632. (b) H. Han, K. D. Janda, Tetrahedron Lett. 1997, 1527. [ 141 D. J. Berrisford, C. Bolm, K. B. Sharpless, Angew. Chern. 1995, 107, 1159. [I51 C. Bolm, A. Gerlach, Angew. Chem. 1997, 109, 173. [ 161 T. Nakano, Y. Okamoto in Curulysis in Precision PoLymeriiLition (Ed.: S. Kobayashi), Wiley, 1997, p. 293. [17] C. E. Song, J. W. Yang, H. J. Ha, S.-gi Lee, Tetrahedron: Asytnmerry 1996, 7, 645.

Hu, X.-F. Zheng, J. Ander[IS] (a) W . 3 . Huang, son, L. Pu, J . Am. Chem. Soc. 1997, I I Y , 4313. (b) Application as a chiral Lewis acid in the Mukayama aldol reaction: Q . 3 . Hu, D. Vitharana. X.-F. Zheng, C. Wu, C. M. S. Kwan, L. Pu, J. Org. Chern. 1996, 61, 8370. (c) Q:S. Hu, Zheng, L. Pu, J . Org. Chern. 1996, 61, 5200. [ 191 In contrast the polymer-bound Ti-TADDOLates are very effective: D. Seebach, R. E. Marti, T. Hinterinann, Helv. Chinz. Acta. 1996, 79, I7 10. 1201 (a) D. E. Bergbreiter, L. Zhang, V. M. Mariagnanam, J . Am. Chenz. Soc. 1993, 115, 9295. (b) D. E. Bergbreiter, Y.-S. Lin, Tetrahedron Lett. 1997, 3703.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Combinatorial Chemistry for the Synthesis of CarbohydrateKarbohydrate Mimics Libraries Prabhat Arya, Robert N. Ben and Kristina M. K. Kutterer Steacie Institute ,fov Molecular Sciences, National Research Council of Canada, Ottawa, Canada

The use of combinatorial libraries in the identification and elucidation of structure-activity relationships has become a powerful tool in the pharmaceutical sector [I]. Traditionally, novel lead compounds have been obtained as natural products from a number of sources including extracts from plants, animals, insects or microorganisms. When an extract shows a desired biological activity, the active compound is identified, isolated and then subjected to further biological testing. Optimization of the chemical structure in order to enhance biological activity is a labor intensive, time consuming process, which dictates that each new structure be independently synthesized. This overall approach has made the development of new therapeutics a very lengthy and expensive process. In contrast, combinatorial chemistry has provided an attractive alternative to these traditional synthetic approaches since it allows for the synthesis of a large number of structurally diverse compounds within a short period of time. The approach utilizes a large array of building blocks which are systematically assembled in such a way that all possible combinations are represented. Typically, a solution or solid phase approach may be used in conjunction with either a “split” or “parallel” synthetic strategy. While the technology required to assemble a small molecule library is not new, combinatorial chemistry was not fully exploited until recently, since efficient methods for screening such libraries were virtually nonexistent. Many of these screening strategies, as well as technical aspects of combinatorial chemistry, have been summarized in several well written review articles [2]. Unlike protein-protein and nucleotide-protein interactions, progress in understanding the role

of cell surface carbohydrates in biological and pathological processes has been slow [ 3 ] .While comparatively little is known on this subject, it is these weak, non-covalent interactions between cell surface carbohydrate ligands and various protein receptors that form the basis of recognition events which are fundamental to a vastly diverse range of biological and pathological processes. For instance, interactions of this nature have been implicated in cell to cell communication, bacterial and viral infections, chronic inflammation, cancer/metastasis and rheumatoid arthritis 131. Given their chemical nature, oligosaccharides are very complex and diverse, which makes their synthesis both labor intensive and expensive. As a result, the discovery of new biologically active oligosaccharide ligands is a complex problem. This aside, even when a promising compound has been identified, optimization to enhance activity is a difficult and time consuming process. The synthesis of oligosaccharide libraries using a combinatorial approach offers a feasible solution to these problems. In contrast to peptide and nucleotide libraries, preparation of an oligosaccharide library is not a facile process. The synthesis of such a library is complicated by the issues of stereochemistry at the anomeric position and the fact that multiple hydroxyl groups are present. Traditionally, these groups would be dealt with using a less than elegant orthogonal protectionldeprotection strategy. As an alternative to this, Hindsgaul et al. [4a] have demonstrated that a random glycosylation approach could be used to form small diand tri-saccharide libraries. The random glycosylation strategy utilizes a glycosyl donor which is protected with only one type of protecting group,

338

C. Solid Phase Synthesis and Combinatorial Chemist0

and a glycosyl acceptor in which all hydroxyl groups are unprotected (Scheme 1). Using this approach, Hindsgaul coupled a benzylated glycosyl donor to a disaccharide acceptor which possessed six free hydroxyl groups. After 3 h at room temperature, a complex mixture was obtained in which about 30 % of the starting disaccharide acceptors were fucosylated. Separation of the mixture using reverse phase chromatography furnished individual trisaccharides which were analyzed by NMR. Analysis confirmed that all six expected products were present in 8-23 % yield. Ideally, a statistical mixture would contain 17 % of each product. In an alternate solution phase approach, a latent-active glycosylation method was developed by Boons and co-workers (Scheme 2) [4b]. This strategy uses a glycosyl donor and acceptor, derived from a common building block. Coupling of glycosyl donor and acceptor would produce a disaccharide which could be deacetylated and reacted with other glycosyl donors in a combinatorial manner. Boons demonstrated the feasibility of such a strategy by synthesizing a small trisaccharide library containing anomeric mixtures which was purified by gel filtration column chromatography.

Another important discovery in the area of combinatorial synthesis with di- and tri-saccharides was made by Kahne and co-workers at Princeton [4c]. Kahne's approach utilized solid phase technology to synthesize a saccharide library (Scheme 3), which was especially challenging since, in order for a solid phase approach to be successful, bonds between monomers must be formed in high yields. This is not trivial since most high-yielding coupling reactions in carbohydrate chemistry are not general in nature [ 5 ] . Kahne employed a novel coupling procedure which utilized anomeric sulfoxides as glycosyl donors. Such compounds were attractive intermediates, since it has been previously shown that they could be activated at low temperatures, independent of other protecting groups, and gave nearly quantitative yields (-90 %) in solid phase synthesis [5b]. Using this approach, a sizable library which contained approximately 1300 di- and tri-saccharides, possessing a diverse array of linkages, was synthesized in three steps. The approach utilized a split and mix synthesis and first involved the separate coupling of six dif-

,OAc

Brio OBn

'

3

6KCC'3 NH

+

4

5

2 1. BF3 Et20 (0.2 equiv) 2. H2lPd-C

i-I

six trisaccharides (major)

@-linkedfucosylated trisaccharides (minor)

Scheme 1. Hindsgaul's random glycosylation.

6 Scheme 2. Boons's latent-active glycosylation approach.

Combinutoriul Chemistry f o r the Synthesis of Curbohgdrute/Carbohydrute Mimics Libraries

ferent monomers onto TentaGel resin beads. Next, twelve glycosyl sulfoxide donors were coupled separately to mixtures of beads containing the six monomers. The beads were then combined, and a reductive procedure for the conversion of the azido group present on the glycosyl acceptor to an amine was performed. At this point, the beads were divided again into eighteen groups and reacted with various acylating reagents, after which all the protecting groups were removed. In order to screen the library, a colorimetric assay was performed using a lectin. The library contained approximately six copies of the 1300-compound library, which was exposed to biotinylated lectin, then streptavidinlinked alkaline phosphatase, and was finally

6 glycosyl acceptors (GA)

+

H

339

stained with nitro blue tetrazolium. The beads which stained exhibited the greatest degree of binding and were then removed with the aid of a simple light microscope. Remarkably, only 0.3 % (25 beads) stained and out of these, thirteen were shown to have the same disaccharide core acylated with various hydrophobic groups. The remaining twelve “hits” were discarded since analysis revealed that none of these compounds exhibited any degree of commonality. Surprisingly, the natural ligand for the lectin was not identified as a “hit” even though it was present in the library. Through separate experiments it was proven that all of the thirteen “hits” were, in fact, better ligands than the natural substrate.

~

N

~ ~

H

N

12 glycosyl donors

GA

GD

PivO OPiv

OPMB

PivO PivO

PivO

PhT?&,&S-C6H44-OCH2-COOH AcO

OPiv

’iv0 OPiv

PivO 0 PivO

Yh

Sao OPiv

Scheme 3. Kahne’s di- and trisaccharide library using split and mix synthesis and screening on a solid phase.

340

C. Solid Phase Synthesis arid Cornbiriatorial Chenzistty

FrnocHN

N-COOM~ H

FrnocHN

CHO

H,N*

0

10

MeOOC-NC

12

11

NH2

NHCbz

G) Neomycin (13)

Neomycin mime

HO

CbzHN

0

,,

U

Diversjty NHCbz MeOOC-NC

14

CbzHN$OH

NHCbz

0

10

16

OHC

Scheme 4. Glycomimetics by Ugi four-component condcnsation.

As pointed out by Kahne, it is very interesting that the lectin discriminates so well in its binding of certain di- and trisaccharides. One of the paradoxes of carbohydrate binding is that carbohydrate-binding proteins may bind different substrates in solution but may function with remarkable specificity in cell-to-cell recognition. This work also emphasized that thc presentation of the saccharide on the surface of the bead is also critical to lectin binding since solution affinity experiments demonstrated that both the natural ligand and all thirteen compounds identified as “hits” bound the lectin in solution phase. This is indeed surprising since presentation effects complicate most on-bead screening techniques. The techniques of Hindsgaul’s random glycosylation, Boons’s latent-active glycosylation and Kahne’s solid phase methodology now make the synthesis of di- and trisaccharide combinatorial libraries a feasible process. Also, a colorimetric

assay can make the screening of such libraries a facile, efficient process since the same approach could be applied to other lectins. There can be little doubt that these recent advances in di- and trisaccharide combinatorial chemistry will have a great impact in the understanding of cell surface interactions and aid in the design of polyvalent compounds which inhibit these interactions. While these advances make the synthesis of diand trisaccharide combinatorial libraries a relatively facile process, the synthesis of oligosaccharide libraries (such as tetrasaccharides and higher derivatives) is still quite challenging. This is largely due to the fact that the present glycosylation methods are not quantitative. Because of the complex nature of carbohydrates, interest in combinatorial approaches to obtain carbohydrate mimics has grown in recent years. By applying combinatorial strategies, the

Combinntorial Chemistry for the Synthesis of Carbohydrate/Carbohydrate Mimics Libraries

p:!sAc

Q O

+

base_

J Diversity

34 1

pi&JJ

PO

PO

17

18

19

Diversity

R HNLOOP,

PO p&sQ

PO

Scheme 5. Glycohybrids by Hindsgaul et al.

ultimate challenge is to obtain compounds that are simple in nature and possess similar or even better binding potential with the target receptors. A variety of approaches to carbohydrate diversity have been reported recently, mostly incorporating commercially available sugars as known essential recognition elements. Armstrong et al. have utilized the Ugi four-component condensation reaction in a combinatorial manner to obtain diverse libraries of carbon-linked glycoside peptides [7a,b]. The Ugi condensation reaction is a powerful strategy -. in which an aldehyde, an amine, an isocyanide and a carboxylic acid are reacted in one pot (Scheme 4). A library of neomycin, an

20

aminoglycoside antibiotic, mimetics was obtained by the Ugi condensation on a soluble PEG polymer [7c]. In another approach, Hindsgaul et al. reported a combinatorial strategy to obtain “glycohybrids” (Scheme 5 ) [S]. Glycohybrids are derived from monosaccharides via a Michael reaction, followed by the derivatization of the carbonyl group with several amino acids. This chemistry was further extended to the solution phase parallel synthesis to obtain a library of several compounds. We have developed an automated, multi-step, solid phase strategy for the synthesis of libraries

diversity diversity

J

f

21

22, R3 = CO,CH2

23

example: a-C-linked glycoside-CHO/COOH

Scheme 6. Programmed approach to neoglycopeptides.

342

C. Solid Phase Synthe.sis and Cornhinutorial Clzernistq

of neoglycopeptides (Scheme 6) [9]. In our approach, different a- or P-carbon-linked carbohydrate based aldehyde and carboxylic acid derivatives can be incorporated either at the N-terminal moiety or at the internal amide N of short peptides/pseudopeptides in a highly flexible and control-oriented manner. Using neoglycopeptide derivatives, the contribution of the secondary groups (i.e., peptide/pseudopeptide backbone) to overall binding, through additional sub-site oriented interactions with protein receptors or by mimicking portions of the complex carbohydrate, could also be explored. Compounds such as 21 (Scheme 6) are obtained by reacting a library of short resin-bound peptides (e.g. dipeptide) with a glycoside aldehyde via reductive amination, followed by coupling with a glycoside carboxylic acid. In another approach, reductive amination using a glycoside aldehyde is followed by peptide coupling leading to an internal N-glycosyl derivative. After deprotection, the terminal amine moiety is then glycosylated as previously described (see compounds 22 and 23). The strength of this method for the generation of diverse neoglycopeptides is apparent in that it is possible to obtain 400 derivatives of compound 21 from 2 glycoside aldehydes, 2 glycoside carboxylic acids and 10 amino acids. To summarize, several groups are currently involved in developing combinatorial approaches for carbohydrates and carbohydrate mimics. This is a relatively new area of research and its impact towards understanding the biological function of carbohydrates will be seen in coming years.

References a) Molecular Diversity and Cornbinutorial Clietnistry-Libraries und Drug Discovery. (Eds.: K. D. Janda, 1. M. Chaikcn), ACS Series, Washington, 1996. b) Cornhiriatorial Peptide and Nonpeptide Lihrurie.s-A Handbook. (Eds. G. Jung), VCH, New york, 1996. c) Coinhinaroriul Clzeni.stry-.~yizthe.si.su t d Applicatiorz, (Eds.: S. R. Wilson, A. W. Czarnik), John Wiley & Sons, Inc. New York, 1997. Recent review articles on combinatorial chemistry: a) M. A. Gallop, R. W. Barret, W. J . Dower, S. P. A. Fodor, E. M. Gordon, .I. M e d Ckem. 1994. 37, 1233-1251; b) E. M. Gordon, R. W. Barret, W.

131

141

[S]

[6]

[7]

[8]

191

J. Dower, S. P. A. Fodor, M. A. Gallop, ihid. 1994, 37, 1385-1401; c) L. A. Thompson, J. A. Ellman, Chem. Rev. 1996, 96, 555-600; d) F. Balkenhohl, C. von dem Bussche-Hunnefeld, A. Lansky, C. Zechel, AngeM: Chew. 1996, 108, 24362487; Angew. Chern. lnt. Ed. Engl. 1996, 35, 2288-2337; e ) M. J. Sofia, Drugs Discoveq TOdczy, 1996, I , 27-34. a) N. Sharon, H. Lis, Sci.Am. 1993,26K( I), 82-89: b) P. Sears, C.-H. Wong, Proc. Nutl. Acad. Sci. USA 1996, 93, 12086-12093. c) R. A. Dwek, Chem. Rev. 1996, 96, 683. c) M. Mammen, S.-K. Choi, G. M. Whitesides, A n g e w Cl7em. Int. Ed. Engl. 1998, 37, 2754-2794. d) J. C. McAuliffe, 0. Hindsgaul, Chern. lnd., 1998, 170- 174. a) 0. Kanie, F. Barresi, Y. Ding, J. Labbe, A. Otter, L. S. Forsberg. B. Ernst, 0. Hindsgaul, Angew Chem. 1995, 107, 2912-29 15; Angeie Clzem. lnt. Ed. Engl. 1995, 34, 2720-2722; Y. Ding, J. Labbe, 0. Kanie, 0. Hindsgaul, Bioorg. Med. Chem., 1996,4, 683-692. b) G.-J. Boons, B. Heskamp, F. Hout, Angew Chetn. 1996, 106, 30533056; Angew. Chem. Int. Ed. Engl. 1996, 35, 2845-2847; c) R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N. Horan, J . Glidersleeve, C. Thompson, A. Smith, K. Biswas, W. C. Still, D. Kahne, Science 1996,274, 1520- 1522; R. Liang, J. Loehach, N. Horan, M. Ge, C. Thompson, L. Yan, D. Kahne, Proc. Natl. Acad. Sci. USA 1997, 94, 10554- 10559. a) M. Schuster, P. Wang, J. C. Paulson, C.-H. Wong, J. Am. Chem. Soc., 1994, 116, 1135-1136; b) L. Yan, C. M. Taylor, R. Goodnow, Jr., D. Kahne, J . Am. Chern. Soc., 1994, 116, 6953-6954; c) S . P. Douglas, D. M. Whitfield, J. J. Krepinsky, J. A m . Clzern. Soc., 1995, 117, 2116-2117; d) J. Y. Roberge, X. Beebe, S. J . Danishefsky, Science 1995, 269, 202-204; e) J. A. Hunt, W. R. Roush, J. Am. Chern. Soc., 1996, 118, 99989999; e) K. C. Nicolaou, N. Winssinger. J. Pastor, F. DeRoose. J. Am. Chern. Soc., 1997, 119, 449 -450. a) E. E. Simanek, G. J. McGarvey, J. A. Jablonowski, C.-H. Wong, C k e m Rev. 1998, 98, 833-862. b) Z.-G. Wang, 0. Hindsgaul, Glycoir,zn?unolog~2 1998, 219-236. c) M. J. Sofia, Mol. Diversify 1998. 3, 75-94. a) R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, K. A. Keating, Acc. Chenz. Soc. 1996, 29, 123- 131. b) D. P. Sutherlin. T. M. Stark. K. Hughes, R. W. Armstrong, J . Org. Chenz. 1996, 61, 8350-8354. (c) W. K. C. Park, M. Auer, H. Jaksche, C.-H. Wong, J. Am. Chem. Soc. 1996, 118, 10150- 10155. U. J. Nilsson, E. J.-L. Fournier, 0. Hindsgaul, Bioor,g Med. Chenz. 1998, 1563- 1575. P. Arya, K. M. K. Kutterer, J . Comb. Chetn. submitted for publication, 1999.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Combinatorial Biosynthesis of Polyketides Kui Donsbuch and Kurola Ruck-Bruun Institut f u r Orgunische Chemie, Universitat Muinz, Germany

Macrolides and polyethers such as erythromycin A (4), FK 506, rapamycin or avermectin Ala (5, Scheme 1) are products of modular type I polyketide-synthases. These compounds are distinguished by extraordinary structural diversity and complexity [ 1,2]. Because of' their biological potency, members of this structural class as well as the aromatic polycyclic products of type I1 polyketide-synthases, tetracyclines and antharacyclines, e.g. adriamycin (6), became useful as pharmaceuticals (antibiotics, cytostatics, immunosuppressives) [ I ,2].

A multifunctional biosynthetic machinery mediates the synthesis of these complex natural products from acetyl- and propionyl-coenzyme A [3]. In the case of type I polyketide-synthases, the p-0x0-esters made by polycondensation steps are modified for example by reduction or dehydration after the chain elongation. Additional specific enzymatic transformations, e.g. oxidations and glycosylations, usually take place after the decoupling at the completed macrocyclic ring framework [ 1,3].

a) erythromycin-polyketide-synthase b) post-polyketide-synthase-enzymesof the erythromycin A-biosynthesis

OMe

Scheme I

344

C. Solid Phase Synthesis mid Cotnhitmtorinl DEBS 1

DEBS 2

DEBS 3

start

Modul5 Modul 1 Modul2

Modul3

Modul6 Modul4

end

-OH

OH

-OH

-

1: acyl-transferase (AT)

2: acyl-carrier-protein (ACP) 3: ketoacyl-synthase(KS) 4: keto-reductase (KR)

6: enoyl-reductase(ER)

5: dehydratase (DH)

7: thioesterase (TE)

0

-OH

OH

-J-o"

3 6-dEB

COA-S acyl-transferase

- cop

Polyketides are only available in traces from micro-organisms, fungi and plants. Therefore, these secondary metabolites are a challenge for analysts and geneticists as well as synthetic chemists. In recent years, a milestone in polyketide research was the discovery of the total sequence of the erythromycin polyketide-synthase (PKS) gene by L. Katz and co-workers [4c]. The knowledge of the genetic code of the polyketide-synthases opened up a new approach to specifically altering nature's strategy of biosynthesis, and thus provides a predictable access to structurally new polyketides by fermentation. As a consequence of the initial work of Katz and co-workers [4] concerning gene-techno-

Scheme 2

logical modifications of the erythromycin PKS genes in the year 1991 and the pioneering work on the function of polyketide-synthases in the last few years, combinatorial biosynthesis of modified and unnatural polyketides has come close to realization. For example, in the case of erythromycin polyketide-synthase it became possible to integrate polyketide biosynthesis genes in foreign organisms [5].Today, artificial polyketides, which carry structural elements of different natural polyketides are already available by fermentation. Moreover, combinations of chemical and biological synthetic methods give way to new synthetic pathways to erythromycins.

Combinatorid Biosynthesis ~,f Polykeridcs

Biosynthesis of 6-Desoxy-erythronolide B The molecular backbone of the antibiotic erythromycin A [6-desoxy-erythronolide B (3)] is built up repetitively from one propionyl-coenzyme A (1) and six methyl-malonyl-coenzyme A (2) constituents by the action of polyketidesynthase, which itself consists of three proteins (DEBS 1-3) (Schemes 1 and 2). Each protein contains two modules with several separate, catalytically active domains. In the first section, DEBS 1 carries an additional loading zone, and DEBS 3 contains a thioesterase in the final segment, catalyzing the decoupling of the product by building the lactone ring [6]. The P-ketoacyl-synthases/acyltransferases(KS/ AT) in each module effect the chain elongation by methyl-malonyl-coenzyme A units catalyzing a Claisen ester condensation followed by decarboxylation (Scheme 2). Subsequent domains are module-specific ketoreductases (KR), dehydratases (DH) or enoyl-reductases (ER), which regulate the functionalization of the newly prepared poxoesters. The stepwise growing chain is picked up by an acyl-carrier protein (ACP). The modular organization of this and other polyketide-synthases and the composition in defined domains of enzymatic activity allows the inactivation, the deletion (loss of function), the enlargement (gain of function) and the exchange of separate enzymatic units through genetic manipulation of polyketide-synthase genes. Such modifications of single modules open up the possibility of generating structural diversity using designed unnatural organisms to synthesize the desired polyketides. The synthesis of new structures, however, depends decisively on the substrate tolerance of the enzymes that follow upon the modified segments in the polyketide-sy nthases.

Defined Di- and Triketides: Potential and Possibilities of Genetic Manipulations To examine the function and substrate specificity of the polyketide-synthases, Khosla et al. devel-

345

oped a genetically manipulated organism, Streptomyces coelicolor CH999, lacking the natural actinorhodin polyketide gene cluster. Instead, this cell line was variably equipped with the desired polyketide biosynthetic genes by plasmidtechnology [7]. Thus, it was possible to create an organism (CH999/pCK 12) based on streptonzyces coelicolor CH999 carrying a bimodular system consisting of DEBS 1 and the erythromycin thioesterase from DEBS 3 for the hydrolytic fission of the acyl-enzyme intermediate. This mutant catalyzes the conversion of propionyl-coenzyme A with two molecules of methylmalonyl-coenzyme A to the triketide lactone 7 (Scheme 3). The synthetic pathway contains one reduction step per module. Especially the NADPH-dependent p-ketoacylreductase domains KRI and KR2, which synthesize 5 -(R)- and 3-(S)-configured ,!-hydroxyacylthioester building blocks, respectively, were intensively used to study the impact of genetic manipulations [S - 1 1 1. For instance, the P-ketoreductase in module 1 of DEBS 1 of erythromycin polyketide-synthase was successfully replaced by the P-ketoreductasel dehydratase domains of rapamycin polyketidesynthase [8,9]. Thereby, a mutant with a shortened erythromycin polyketide-synthase consisting of the first three modules and the thioesterase from DEBS 3 was generated from the cell line Strrptornyces coelicolor CH999. This organism (CH999/pCK13) produces the tetraketide-lactone 8 and the decarboxylated tetrahemiketal 9 120 mg/L and 5 mg/L] by fermentation (Scheme 3). However, the cell lines derived from this mutant and the rapamycin polyketide-synthase (RAPS) domains KR4/DH4 from the RAPS module 4 furnish the polyketides 10 and 11 with a trans-configured double bond from propionyland acetyl-coenzyme A starting units after the final decarboxylation [ca. 5 - 10 mg/L]. After implementation of the D H l E R I / K R I domains from RAPS module 1, the artificial mutant (CH999/ pKA04 10) produces the tetraketide lactone 12 as a new metabolite [20 mg/L] (Scheme 3) [9]. In addition, mutants were generated from cell line CH999/pCK 13, which carried a ketoreductase from module 2 or module 4 of the rapamycin polyketide-synthase instead of the natural KR2 domain. These domains effect the formation of

346

C. Solid Phase Synthesis and Cornhinutorial

QH fermentation M

CH999/pCK12

7

--OH

+

fermentation

,

' 9

+R

fermentation CH999/pKOS009-7

-

= CH3

11: R = H

A: DH41KR4 from RAPS-Modul4

0

4 1 2 3 1

2 3 1

2

i

i

0

3

3

i

CH999lpKA0410

-OH -OH B: DHIIERlIKRl from RAPS-Modul 1

(R)-configured building blocks in their natural environment. The product of the fermentation process of both cell lines is the triketide lactone 13 in Scheme 4 with 3-(R)-configuration [ca. 20 mg/L]. The structure of 13 was proved by the synthesis of an authentic sample by applying chemical methods. The synthesis of such triketides is

0 12

Scheme 3

well known by the methods of Evans et al. (Scheme 4) [12]. Probably the formation of 13 is effected by a defined specificity of the KS3 domains from DEBS 2 (module 3) for (S)-configured intermediates. For the first time, this example and comparable studies proved that the individual properties of the ketoreductase domains deter-

Comhinatorial Biosynthesis

~

of Polyketicles

347

fermentation _

_ .___) . .

CH999/pKA0404 13

C: KR4 from RAPS-Modul4

O H 0

0

0

Sn(OTf),, Et,N, ECHO

--

-78"C, CH2C12

Ph

Ph

DIBAL-H, -78"C, THF

'''+,,,A

OH

OH

0

LiOOH, 0°C

;(" Ph

Scheme 4

mine the stereochemistry at the newly formed p-hydroxy carbon. In addition, the stereochemistry and the substitution pattern of the p(ketoacy1)-ACP substrates have no influence on the reduction steps [ 10, 1 I]. In the course of mechanistic investigations covering these enzymatic reductions, labeling experiments were carried out with biologically produced, selectively deuterated NADPH-rnolecules [ 4-(R)-[4-2H]NADPH and 4-(S)-[4-*H] NADPH) [ I 11. The formation of hydroxy derivatives of opposite stereochemistry is caused by the ketoreductase domains KRI and KR2 from the protein DEBS 1 of the erythromycin polyketide-synthase. However, both domains have a preference for the 4-pro-(S)-hydride of the NADPH molecule. Probably the binding of the cofactor in KR domains takes place in an identical manner, whereas the individual p-ketoacylthioester building blocks in the domains KR 1 and KR 2 of DEBS 1 capture a different orientation relative to the cofactor [ 1 I].

Erythromycin A-Analogs with Avermectin Starting Units Recently, Leadlay and co-workers reported the synthesis of biologically active erythromycin A analogs [13]. They were able to exchange the loading zone of DEBS 1 in the erythromycin polyketide-synthase, which exclusively accepts in vitro and in vivo propionyl- and acetyl-coenzyme A as starting units, with the appropriate subunit of the avermectin polyketide-synthase from Streptomyces averniitias [ 131. This domain is distinguished by an extremely broad substrate specificity and, except for isobutyryl- and 2-methylbutyryl-coenzyme A, tolerates more than 40 branched carboxylic acid derivatives. The gene of the enzyme hybrid was expressed in Saccharopolysporu erythrea. The artificial cell line produces new, antibiotic erythromycin A analogs bearing an isopropyl or a sec-butyl group at carbon C13 of erythromycin instead of the native ethyl group (Scheme 1).

348

C. Solid Phase Synthesis and Cornhinatorial

I

14: R = M e 15: R= n-Propyl 16: R= Phenyl

4: R = M e 18: R = n-Propyl 19: R = Phenyl

Erythromycin D Analogs from Synthetic Diketides by Fermentation In 1997, Khosla and co-workers succeeded in realizing a new chemo-enzymatic access to artificial erythromycin D analogs on a multimilligram scale [ 141. Therefore, a mutant (CH999/ pJRJ2) of Streptornyes coelicolor CH999 was equipped with erythromycin polyketide-synthase genes in which the function of the ketosynthase KSI in the gene segment of DEBS I was inactivated in order to inhibit the usual biosynthetic pathway of 6-desoxy-erythronolide B (6-dEB). The resulting cell line produced 6-desoxyerythronolide B (6-dEB, 4) by fermentation conditions only upon addition of P-hydroxy-amethyl-valerianic acid (14), a cell-permeable Nacetyl cysteamine thioester, mimicking the genuine thioester derivative. Starting from 100 mg substrate, they were able to isolate 30 mg of product. In a similar fashion, the synthetic diketides 15, 16 and 17 (Scheme 5 ) of different substitution pattern were accepted by the domains of the erythromycin polyketide-synthase, and new, artificial 6-erythronolide B analogs were obtained [18: 55 mg/L, 19: 22 mg/L]. Substrate 16 bears an aromatic residue instead of the terminal

20

21: R = n-Propyl 22: R = Phenyl

Scheme 5

methyl group of 14. Even compound 17, showing the structure of a biosynthetic tylosin intermediate, is tolerated and cyclized to the 16-membered macrolactone 20 [25 mg/L] (Scheme 5 ) . Moreover, Khosla and co-workers were able to produce a mutant of Sacclzaropolyspora erythrea (A 34), which itself cannot synthesize 6-dEB, but carries the post-polyketide-synthase enzymes of the erythromycin pathways. This organism produced new antibacterial erythromycin D analogs after addition of 18 or 19 to the growing culture by hydroxylation of carbon atom C 6 of the 6-desoxy-erythronolide B building blocks and two subsequent glycosylations. Apparently, the postpolyketide-synthase enzymes of the erythromycin pathway also display a considerable substrate tolerance. In analogy to the synthetic route shown for the triketide 13 (Scheme 4), diketide substrates of variable substitution pattern are available by chemical methods from enolates by aldol reactions and alkylations [12]. Recently, the first solid-phase synthesis of such . in conbuilding blocks was reported [ 1 2 ~ 1Thus, nection with the combinatorial biosynthetic route according to Khosla, a broad access to a large variety of erythromycin analogs is opened. It

Combinatorial Biosynthesis of Polyketides

remains to be seen whether genetically modified organisms will be able to produce polyketides within the bounds of their primary metabolism in the near future. By the methods presented for the combinatorial biosynthesis of polyketides, a multitude of modified and artificial polyketide substances should be available. New antibiotics, potentially with fewer side effects and consequently broader applicability, are desperately needed in the light of increasing resistance of bacteria towards established medications.

References [ I ] Review: J. Staunton, B. Wilkinson in Topics in Current Chemistry 195 (Ed. EJ. Leeper, J.C. Vederas) Springer Verlag, Berlin 1998, 49 and references cited therein. 121 Review: J. Rohr, Angew. Chem. 1995, 107, 963. 131 Review: C.W. Carreras, R. Pieper, C . Khosla in Topics in Current Chemistry 188 (Ed. J. Rohr) Springer Verlag, Berlin 1997, 85 and references cited therein. [4] Review: L. Katz, Chem. Rev. 1997, 97, 2557. [ 5 ]J. Cortes, K.E.H. Wiesmann,G.A. Roberts, M.J.B. Brown, J. Staunton, P.F. Leadlay, Science 1995. 268, 1487.

349

[61 K. J. Weissman, C.J. Smith, U. Hanefeld, R. Aggarwal, M. Bycroft, J. Staunton, P.F. Leadlay, Angew. Chem. 1998, 110, 1503. 171 C.W. Carreras, R. Pieper, C. Khosla, J. Am. Chern. Soc. 1996, 118, 5158. [8] R. McDaniel, C.M. Kao, H. Fu, P. Hevezi, C. Gustafsson, M. Betlach, G. Ashley, D.E. Cane, C. Khosla, J. Am. Chem. Soc. 1997, 119, 4309 and references cited therein. [9] C.M. Kao, M. McPherson, R.N. McDaniel, H. Fu, D.E. Cane, C. Khosla, J. Am. Chein. Soc. 1997, 119, 11339. [lo] C.M. Kao, M. McPherson, R.N. McDaniel, H. Fu, D.E. Cane, C. Khosla, J. Am. Chem. Soc. 1998, 120, 2478 and references cited therein. [ I I ] M. McPherson, C. Khosla, D.E. Cane, J. Am. Chem. Soc. 1998, 120. 3267. [12] a) D.A. Evans, J.S. Clark, R. Metternich, V.J. Novack, G.S. Sheppard, J. Am. Chem. Soc. 1990, 112, 866; b) D.A. Evans, H.P. Ng, J.S. Clark, D.L. Rieger, Tetrahedron 1992, 48, 2127; c) M. Reggelin, V. Brenig, Tetrahedron Lett. 1996, 37, 685 I . [13] A.F.A. Marsden, B. Wilkinson, J. CortCs, N.J. Dunster, J. Staunton, P.F. Leadlay, Science, 1998, 279, 199. 114) J.R. Jacobsen, R. Hutchinson, D.E. Cane, C. Khosla, Science 1997, 277, 367.

Organic Synthesis Highlights ZV Hans-Gunther Schmalz Copyright 0WILEY-VCH Verlag GmbH, 2000

Index

A 1'-acetonaphthone 202 4-acetoxy- 1,3-dioxanes 58 N-acetylglucosamine 277 acylation, nucleophilic catalysis 175 addition - 1,4-additions 19 - Michael additions 11 - of nucleophiles to aldehydes 166- 171 - - allylsilanes 166- 169 - - allyl siliconates 167 - - allylstannanes 166, 167 - - allykitanation 167 - - dialkyl zinc compounds 166 - - silyl enolethers 166 - - trimethyl aluminium 170 adhesion molecules 275 alcohol - allyl 8, 157 - amino 277, 317, 318 - dehydrogenase 196 - diols 277 - homoallyl 157 - optically active 197 - propargylic 178 - secondary, non-enzymatic kinetic resolution 175- 181 aldehydes 3 17, 3 18 - @-unsaturated 101 - addition of nucleophiles to aldehydes 166- 171 aldol - additions, catalytic asymmetric 144 - anti-aldol 160 - Mukaiyama aldol 59, 144, 150, 159 - reactions 50, 59, 104, 348

acetate problem 260 barium aldol 160 - - catalytic asymmetric 144- 154 - - double stereodifferential 59 - - imino-aldol 105 - - nitroaldol 107, 162 - syrr-aldof 160 aldolase 153, 278 alkaloid 25 1F, synthesis 132 alkene, carbonyl compounds to 123 alkenyl triflates 125 alkoxypalladation, intramolecular 83 -90 alkyl - aryl ketones 195 - halides 35-37 alkylation 348 - asymmetric 257 - iterative 58 - reactions 50 - stereoselective 58 alkyllithium compounds 20, 21 alkynes 101 allenes, Pauson-Khand reactions 119 allylation - asymmetric 257, 261 - enantio selective 208 allylborane 208 allylic - alcohol 8, 157 - 1,3-allylic strain 6 - oxidation 191 allyltributylstannane 44 aluminium reagents 164 amidocarbonylation 55, 56 amines 93 - N-oxides 116 2-amino-3-hydroxy acids 200 --

- -

352

Index

1-amino-indan-2-ol 24 amino acids 157 - a-amino acids 14, 26-33, 282, 316 - B-amino acids 16, 27, 28 - multicomponent reactions 53-56 - synthesis of derivatives 26-28, 74 - - l u n g method 28 - - Schri'llkopj method 26 - - Seehach method 26 - - Steglich method 27 - - Strecker method 28, 53, 54 amino alcohols 17, 106, 277, 317, 318 - 1,2-amino alcohols 194 amino ketones 194 9-aminocamptothecin 233 aminoglycoside antibiotic 341 aminohydroxylation 17 amphotericin B 60 anion - guanidine-anion complexes 248 - molecular recognition 246 - polyanions 248 - receptors 246 anomeric sulfoxides 338 ansa-zirconocene 80 anti-aldol 160 antibiotics 157, 343 - aminoglycoside 341 - ikarugamycin 207 - macrolactam 207 - naphthoquinone 84 - polyene macrolide 45, 58 - vancomycin 28 1-305 antibodies - catalytic 320 anticancer compounds 25 I -267, 279 anti-Cram selectivity 262 antitumor - activity 232 - agent camptothecin 239 apoptosis 2.5 I aqueous solution 104 arene-Cr(CO), complex 5 I , 120, 243 aryl - diazonium salts 37, 38 - triflates 137 arylglycine 282 asymmetric - activation 158 - aldol reactions 144

catalysis 107, 155-165 dihydroxylation 33 1 - Heck reactions 136- 143 - induction - - 1,6 asymmetric 209 - Pauson-Khund reactions I 19 - reactions 67-70 - reductions 157 - synthesis 95, 291, 292 ate-complex 8 atom economy 1 16 ATPase mimics 247 atropisomers 20, 48-52 - moieties, atropisomeric 28 1 autocatalysis 304 automation 324 auxiliaries, chiral 6, 11, 17-20, 30, 50, 144, 158, 235, 28 1 axially chiral compounds 48 2-azanorbornylmethanol 20 1 azasugars 94 aziridinations 20 aziridines 192 azirines 30 azlactone 27, 29, 31 azomethine ylide cycloaddition 245 -

-

B Baeyer-Villiger oxidation 13, 24, 73 Bakers yeast 199 bar codes 320 barium - aldol reaction, barium-catalyzed I5 I -complex 150 - enolate 151 barriers of rotation 48 Burton-McComhie deoxygenation 127 batLelladines A 242 benzannulation 75 N-benzylcinchoidinium chloride 155 biarylether 28 1 bifunctional boron acid 8 Bigirzelli condensation 243 (S)-BINAL-H 160 BINAP 137, 138, 156, 158, 161 - Pd(l1)-BINAP 138, 147 - ruthenium(I1) complex 196 BINAP-CuF,-complex 60

Index

binaphthol 166, 167, 182- 186 binaphthyl - ligands I55 - 165 - Ti-complex, binaphthyl-derived 147 binaphthyls 32 1 BINOL 106, 108, 155, 156, 161 - La-BINOL 108 bioactive conformations 276 biological activity 52 biomimetic approaches 246 biosynthesis 343, 344 BIPHEP 158 bis( 1 -phenylethyl)amine 184 bis(oxazo1inyl)pyridine-Cu(l1) complexes 147 bislactim ether 26 bisoxazolines 32 1 bleaching agents 189 BOP-CI 224 boron 146 - acid, bifunctional 8 - boron(II1) 146 Brgnsted base 151 1,4-Brook rearrangement 62 building blocks, permutations 25 1 bullatenone, synthesis 130 Burgess reagent 227 q4-butadiene-Fe(CO)3complexes 207 butenolide 73 butyrolactones - hetero-Puuson-Khund reactions, y-butyrolactones 119 - oxidative degradation of 61

C C2-symmetry/C,-symmetric 155, 159, I84 ligands for catalysis 189 C,-symmetric ligands for catalysis 187- 193 campher sulfvnic acid 1 I camptothecin synthesis 232-240 cancer therapy 279 candida rugosa I74 capnellene sesqiterpenes 139 (+)- 1-carbacephalothin 72 carbocyclic construction by rhodium-mediated intramolecular C-H insertion 130- 133 carbohydrate 275, 240, 341 - binding 340 - biological function 342 -

353

-complex 342 diversity 341 -mimics 340 carbolithiation 5 carbomagnesation of alkenes - enantioselective reaction 80 - Zr-catalyzed 77 - 82 carbometallations 77 carbon-carbon coupling 116 - catalyzed 1 I6 - metal mediated 116 - reaction 144 carbon-linked glycoside peptides 341 carbonyl - addition 35-37 - complexes I 17 - compounds - - addition to alkenes 123 - - methylation 11 1 - olefination 110- 115 - reactions 104, 150 carbonylation 83 carbonyl-ene reaction 148 carboxylic - acid 157 - - a,P-unsaturated 157 - - P,y-unsaturated 157 - acid derivates 71, 157, 347 - - methylenation 11 1 carvone 271 catalystdcatalysis 91, 194, 195, 314-321 - aldol additions, catalytic asymmetric 144 - asymmetric 107, 155-165 - chiral 6, 8, 20, 123, 118, 146, 153, 166, 167 - copper 182- 186 - fluorous biphasic catalysis concept (FBC) 189 - Grubbs catalyst 254 - heterobimetallic 107 - heterogenous 195 - homogenous 162 - Lewis acids 147, 180 - Iigand-accelerated 182, 186, 187- 193 - nucleophilic 175, 178 - palladium 24,56, 83, 136, 147, 212, 262, 317 - phase transfer 31 - polymeric catalysis 328-336 - rhodium 194 - ruthenium I95 - two-center catalysis 107 -

354

Index

Wilkinsons catalyst 236 catalytic - antibodies 320 - cycle 92 catenanes 95 cationkationic - iron-stabilized 209 - palladium(I1) complex 147 C-C bond formation 144 - palladium-catalyzed 21 3 - coupling reactions, metal-catalyzed I36 celeromycalin 241 cell - membrane 279 - recognition, cell-to-cell 340 - surface - - carbohydrates 337 - - interaction 340 cellulose triacetate 220 cembranolide, synthesis 132 cephalosporin, total synthesis 72 (+)-cerulenin 73 C-H - bonds for Rh-mediated intramolecular insertion, activation of 130- 133 - insertion 130-133, 318 - - Rh-mediated intramolecular 130- 133 chair-like transition state 209 chalcone 184 chelation-controlled reaction 44 chemo-enzymatic - access 348 -methods 277 chiral - aluminium complex 146 - auxiliaries 6, 11, 17-20, 30, 50, 144, 158, 235, 281 - axially chiral compounds 48 - binaphthyl ligand 147 - catalysis 6,8,20,123, 118, 146, 153, 166, 167 - - [(S,S)-(EBTHI)Ti(CO),] 118 - cuprates 182 - enolate 26 - hyperstructure 329 - gold complexes 150 - Lewis acid 144 -memory 48 - oxazolines 183, 186 - phosphane 118 - phosphites 186 -

-pool 270 - quaternary - - ammonium fluorides 150 - - chiral carbon centers, enantioselective formation 139 chirality - axial 281 - planar 281 - regeneration 220 chirasil metals 330 chirogenic reaction 136 1-chloro- 1-nitrosocyclohexane 14 chlorosilanes 123- 125 chromatography, capillary gas 3 16 chromium 125, 126 - arene complexes 51, 120, 243 - carbene complexes 71 - chromium(I1) reagents 112 CIP 229 citronellol 157 Claisen - ester condensation 345 - rearrangement 27 CO insertion 71 1 16 [Co,(CO),I cobalt catalyzed reactions 97, 116 coenzyme A 345 colorimetric assay 339, 340 combinatorial - biosynthesis of polyketides 343-349 - chemistry 314, 315, 324, 337 - library 325, 326, 337-342 - methods 314-321 - strategies 340 - synthesis 324 complexation 208, 329 condensation, Ugis 53, 54, 341 cone-shaped molecules 307 conformational analysis 291 -293, 298 conjugate addition 11, 19, 64 coordination spere 146 copper - arenethiolates 182, 183 - catalysis 182- 186 - complexes 191 - copper(1) complex 188 copper-bis(oxazo1ine)-complexes 20 coral, soft coral 268 Corey lactone, synthesis 132 [Cp,TiCI,] 125

Index

[Cp,ZrCI,l 77 crambescidine 24 1 Criegee rearrangement 61 cross-linking unit 333 cupric triflate 183- 186 cuprous triflate 183- 186 cyanhydrins 20 cyclen 316 cyclic - alkyne 95 - peptides 282 cyclization 9 1 - Pd-catalyzed 84 [2 21 cycloaddition 7 1, 73 - diastereoselectivity 73 [2+2+1]-cycloaddition 116 cycloadditions 162 cyclobutanones, synthesis 73 cyclocarbonylation of enynes 118 cyclocondensation 227 cyclodextrin derivates 303 cycloisomerization 2 15 cyclomagnesation, dienes 78 cyclooctane 93 4-cyclopent- I -ene-3-one 16I cyclopentenones 160 - synthesis I16 cyclopeptides 302 cyclophanes 289-300 - alkyne-containing 293, 294 - biphenylophanes 293 -295 - chirality 29 I , 292 - corannulenophane 298 - [nlcyclophanes 289-291 - cyclopropenonophanes 290 - cyclopropenyliophanes 290 - dynamic behavior 291 -293, 298 - in-cyclophanes 294-296 - Kuratowski cyclophane 297, 298 - layered 296, 297 - [ 2.2.]metacyclophanedienes 296 - I I . 1 .]metacyclophans 296 - [ S]metacyclophans 296 - naphthalenophanes 289 - [ 1. I .]paracyclophans 290 - [4]paracyclophans 289, 290 - [5]paracyclophans 289, 290 - [n.n.]paracyclophans 290-293 - pyrenophanes 291 - spheriphanes 296, 297

+

355

- superphanes

293 -295 cyclopropanation 3 - Simmons-Smith 3 cyclopropane 3, 192 cylindrical brushes 309 cytostatics 343 cytotoxicity 269

D (-)-7-deacetoxyalcyonin 272 deconvolution 326 dendrimer fragments 306 - 3 13 dendritic - monomers 306 - polybenzylethers 307 - wedges 307 dendronsldendronized 306 - monomers 306 - polymer chains 309 - side chains 308 (-)-denticulatin 14 deracemisation 40-47 desoxyepothilones 252 desoxyfrenolicin 84 Dess-Martin periodinan 286 desymmetrisation 41, 320 dewar benzenes 289, 290 DHQ-PHAL 333 dialkylzinc compounds 58 diastereofacial selectivity 59 diastereoselectivity - carbomagnesations 80 - in rhodium-mediated intramolecular C-H insertion 130- 133 diazocompounds 4 diazoketones 3 16 diazotation 286 DIBAH 60 dicobalt octacarbonyl 102 Diels-Alder reaction 11, 13, 18, 21, 23, 24, 84, 161, 163, 164 - hetero 24, 26 - intramolecular 207 diethyltartrate 7 diethylzinc 3 17, 3 18 dihydrojasmonate synthesis 116 dihydropyran 13 dihydropyrenes 296

356

Index

dihydrothiopyranes 24 dihydroxylation - asymmetric 284, 331 diiron nonacarbonyl 188 diketides, synthetic 348 1,3-diketonates 329, 330 diketones - P-diketones 195 - unsaturated 199 diols - alcohols 277 - 1,3-anti-diols 58 - Inhoffen-Lythgoe 213 - 1,3-.syn-diol acetonides 58 - unsaturated 200 dipeptide, one pot synthesis 74 1,3-dipolar cycloaddition 106 discodermolide 25 I , 269 dithianes, unsymmetrical bisalkylation 63 dithioacetals 110- 1 1 5 DMAP-analog 176 domino processes 102, 103 Dijtz reaction 75 double bonds, tri- or tetrasubstituted 93 dynamic resolution 40

E electrochemistry I26 electrocyclic ring opening 2 12 eleutherobin 25 1, 268-274 eleuthosides 270 P-elimination 34, 37, 38 elthyl-magnesation 77 - alkenes 77 enamines 11 1 enantiomers - enantiomeric excess 334 - separation 80 enantioselective/enantioselectivity - allylation 208 - approach 60 - carbomagnesations 80 - cyclization 138 - desymmetrization 95 - enzymatic hydrolysis 238 - Heck reactions 136- 143 - hydrosilylation 170 - non-linear 184

145

- reactions 89 - - alkoxypalladations 89 - in rhodium-mediated intramolecular C-H in-

sertion 130- 133 synthesis 106 enol - triflates, palladium-catayzed coupling 2 13 - (Z)-en01 ethers 112 enolate reactions 14, 348 enolization conditions 59 enolsilane 42 enones - n,p-enones 199 - acyclic 184 - cyclic 182- 186 enynes 214 enzymedenzymatic 153, 172- 174, 345 - chemo-enzymatic access 348 - inhibitors 94 - kinetic resolution, enzymatic 320 - resolution 262 ephedrine derivates 182, 183 epothilones 269 - epothilone A 94 - synthesis 25 1-267 epoxidation 21, 108, 162, 190, 255 epoxide 127, 189, 318 (+)-epoxydictymene I20 (+)-eptazocine, synthesis 141 erythromycin - erythromycin A 343, 345, 347 - erythromycin D 348 (+)-esermethol 140 estrone methyl ether, synthesis 133 Et,BOMe/NaBH, 60 ethylmagnesation, enantioselective 8 I eunicellane diterpenoids 273 Evans oxazolidinones 262 -

F face-selective reactions 67 fan- and cone-shaped molecules 307 Felkin-Anh model 27, 60 fenestrane synthesis 120 fermentation 344, 348 ferrocene derivative 178 ferrocenyl diamines ligands 202 Fischrr carbene complexes, photolysis

71 -76

Index fluorotitanium compounds 166- 171 titanium fluoride 167 fluorescence 3 18 fluorous biphasic catalysis concept (FBC) I89 four-component reactions 106 FR-900848 3, 9 frenolicin B, enantioselective total synthesis 84 Friedel-Crafts acylations 105 Friedlander condensation 237 Fries rearrangements 105 fromiamycalin 241 D-fructose-l,6-biphosphatealdolase 153 fucose 276 fungal infections 58 Furukawa procedure 3 -

G galactose 276 gallium 164 Gantrez 335 gene-technological modifications 344 geraniol, hydrogenation 157 glucose 277 GlyCAM-I 278 glycine 103 glycobiology 279 glycopeptide 278, 28 1 glycosyl donors 338 - sulfoxide 339 glycosylation 270, 277, 286 (-)-goniofufuron, synthesis 86 Grignard reagents 13, 77, 182- I84 - Zr-catalyzed carbomagnesation 77 group-selective reactions 67 Grubbs catalyst 254 Grundmanns ketone 2 13 guanidines - guanidine-anion complexes 248 - polycyclic 241 -250

H p-H-elimination 86 haloarene 282 Heck reactions - enantioselective 136- 143 - - BINAP-catalyzed I39

357

intermolecular reactions 137 intramolecular 216, 23.5 Heck-type reactions 2 15 helical polypeptide 329 helix 329 - sense selective polymerisation 329 HEMA (2-hydroxy methacrylate) 333 hemocyanin 187 heterobimetallic catalysis 107, 15 1 N-heterocycles 92 heterocyclic construction by rhodium-mediated intramolecular C-H insertion 130- 133 hetero-Diels-Alder reaction 24, 26 hinokin, synthesis 134 hi sthioureas - diamines 196 - ligands 196 homogenous catalysis 162 o-homologization of aldoses 85 hydroaluminationhodination 2 16 hydroboration 196 hydroformylations 97 - 103 - branched 98- 100 - directed 100 - linear 98-100 hydrogen transfer reaction 69 hydrogenation 98, 192, 194 - asymmetric 194 - cyclic 195 - enantioselective 194 - ketones, aliphatic I94 - transfer 195 hydrolase 173 hydrophosphonylations of imines 162 hydrophosphonylations 107 hydrotris(pyrazoly1)borates 187 hydroxy acids 194 P-hydroxy-enol ether 148 2-hydroxy methacrylate (HEMA) 333 [I-hydroxyketone 1 SO hydroxyketones 106, 195 hydroxylation 188 hydroxymethylation 237 3-hydroxyphosphonic acids 157 --

r ibuprofen 99 ikarugamycin, total synthesis

207-2 I 1

358

Index

imidazolidinone 26 imine 105 - hydrophonylations 162 imino-aldol reactions 105 immobilization 33 1 immunosuppressives 343 indole 125 induced fit 179 industrial process 199 Znhoffen-Lythgoe diol 2 13 inositol- 1,4,5-triphosphate 248 iodine-lithium exchange 235 ion channel 302 irinotecan 233 isonitriles 75 isothermal titration calorimetry 248 isothiocyanate 245 isoxazolines 106 iterative alkylation 58

J Julia-Lythgoe olefination

1 10

K Karasch reaction 2 I ketenes 72 - alkoxy72 -amino- 72 y-keto esters 195 P-ketocarboxylic acids 194 P-ketoester 157, 160 ketones 35, 36, 194 - aliphatic 194 - alkyl 195- I99 - - alkyl-aryl 195 - - alkyl-trifluoromethyl 198 - amino 194 - cyclic 195 - cyclopropyl 200 - diazoketones 3 16 - P-diketones 195 - functionalized 192 - Grundmanns ketone 2 I3 - hydroxyketones 106, 150, 195 - thioketones 195 - a,P-unsaturated 158, 162

- with tripple bonds 195 P-ketophosphonates 157 ketoprofen 99 ketyl radicals 36, 37 kinetic resolution SO, 81, 95, 192, 319 - dihydropyrans 8 I - dynamic 157, 172- 174 - non-enzymatic 17.5- 181 - parallel 177 - propargylic alcohols 178 - secondary alcohols 175- 18 1 - sharpless method 215 Kuratowski cyclophane 297, 298

L labeling experiments 347 LAC (ligand-acceleraded catalysis) 33 1 P-lactam 28 - synthesis 72 P-lactone 220 lanthanide complex 1 SO lanthanum 162 laulimalide 269 LCST (lower critical solution temperature) 335 lectin 339 leucine zipper 303 leukocytes 275 Lewis - acids 104, 144, 147 - - catalysis 147, 180 -bases 104, 148 Lewi.? 278, 279 - Lewisx/selectin 279 - sialyl 278 library 315, 316 - combinatorial 325, 326, 337-342 - oligosaccharide 337 - partial 326 - saccharide 338 - s u b 326 LiCIO, 105 ligands - binaphthyl 155 - 165 - C,-symmetric 189 - C,-symmetric ligands for catalysis 187- 193 - chiral binaphthyl ligand 147 - ferrocenyl diamines 202 - histhioureas 196

Index

LAC (ligand-accelerated catalysis) 182, 186, 33 1 - oxazolines 17 - PennPhos 196 - Ph-ambox 201 - phosphinelphosphite-ligands 99 -smart 334 - trinedate amido ligands 187 - tripodal 187 - tris(oxazo1ine) 191 lignan lactones, synthesis 134 lipase 173 liquid-phase 324 - combinatorial synthesis (LPCS) 324, 325 lithiation 5 1 lithium carbenoids 4 liver esterase, pig 220 loganin aglycon 13 Lombardo reagent 11 1 LPCS (liquid-phase combinatorial synthesis) 324, 325 -

M macroaldolization 254 macrocycles/macrocyclic macrocyclization 52, 253, 254, 282 - Keck method 254 -rings 95 - structures 95 - Yamaguchi method 254 macrolides 343 macromolecules 306 - tree-like 306 magnesium-ene reaction 77 manganese - manganese(I1) 190 - manganese (Mn) 125 - oxydation, manganese-mediated 189 mannose 277 manzamine A 94 mass spectrometry 3 19 McMurry coupling 123 mechanism 5, 91 Meenuein-Porzndo~--rley reduction 173, 236 Meldrums acid 209 membrane reactor 198 MeO-PEG 324 meso-compounds 320

359

metal - alkoxide complexes 107 - complexes, butadiene-Fe(C0)3 complexes 207 - triflates 104 metallacyclobutane 92 metallacyclopentene 117 metallocenes, Pausen-Khand type reactions 117 metallocyclopropane 78 metalloenzymes 187 metastasis 279 metathesis 9 1 methacrolein 162 methane monooxygenase 188 2-methosypropene 150 methyl methacrylate (MMA) 333 2-methylcysteine 2 18 methylene transfer 5 Michael additions 11, 104, 106, 109, 162, 163, 238 - enantioselective 182- 186 microenvironment 329 microscopy, scanning force 3 10 microtubuli 268 migration, stereospecific 61 migratory insertion 83, 84 mimetics 277, 278 mirabazole 2 1 8 - mirabazole C - - Heathcocks synthesis 228 - - Kisos synthesis 229 Mitsunobu reaction 42 MMA (methyl methacrylate) 333 molecular - belts 293, 294, 296, 297 - objects 312 - recognition 246, 304 - ribbons 296, 297 - switches 291, 296 morphine, synthesis I3 1 Mukaiyama aldol - addition 150 - reaction 59, 144, 150, 166, 167 -reagent 239 multi-component - couplings 106 - reactions 53-56 multi-valency mimetics 278

360

Index

N Na+ channel blocker 241 NADPH 347 nanoscale molecules 293, 294, 296-298 nanotechnology 3 I2 nanotubes through self-assembly 301 -305 naphthoquinone antibiotics 84 natural product synthesis 93, 2 I8 -23 I , 25 1 267 - by Rh-mediated intramolecular C-H insertion 130-133 naxoprofen 99 neoglycopeptide derivates 341, 342 neomycin 341 neuraminic acid 276 nitroaldol reactions 107, 162 a-nitroester 31 nitrones 106 nor-sesquiterpene, enantioselective synthesis 141 Nozaki-Hiyarna-Kishi reactions 125 Nozaki-Kishi reactions 271 NSID (non-steroidal inflammatory drugs) 99 - ibuprofen 99 - ketoprofen 99 - naxoprofen 99 nucleophiles - acyl subsitution, nucleophilic 34-38 - addition of nucleophiles to aldehydes 166171 - catalysis, nucleophilic 175, 178 - - acylation 175 - - ferrocene derivative I78 - SN1-nucleophylic subsitution 37, 38 nucleotide-protein interactions 337

0 olefin - metathesis, ring-closing 91 -96 - polymerizations 170 - trans-disubstitued 110 olefination - reaction 110, 123 - Still-Gennari 259 - Wittig 213, 256 oligo(thiazoline), synthesis 2 18 -23 1 oligosaccharide library 337

Oppenauer oxidation 173 Oppolzer sultams 11- 16 organic halides 125 organocerium reagents 236 organocopper reagents I82 organolithium compounds 19 organometallic coupling reactions 239 organozinc reagents 182- I86 - functionalized 184 - 1,4-addition 162 orienticin C 281 ortho-diphenylphosphinylbenzoate 100 ortho-directed lithiation 233, 234 ortho lithiation 51 oxaeunicellane skeleton 268 oxazaborolidines 199 oxazaborolidinone 27 oxazinone 29 oxazole 224 oxazolidinone 29, 222, 281 oxazolines 17- 25 - auxiliaries 17 - chiral 183, 186 - ligands 17 oxepines 93 oxidations 187, 192 oxidative - cyclization 283 - degradation of butyrolactones 61 - desilylation 64 8-oxoester 345 oxydation, manganese-mediated 189 oxygen heterocycles, stereoselective construction 87 oxygenations 187

P paclitaxel 15, 251, 268 palauamine 241 palladium 162, 317 - allylic substitutions 24 - catalysts 56 - - vitamin D a t i v e compounds 212-217 - enolate, mechanism 147 parallel synthesis 318 - strategy 337, 338 Pauson-Khand reaction I 1 6- 122 - with allenes I19

36 I

Index 1 18, 119 -domino 121 - interrupted 119 Puusen-Kharzd-type reactions, metallocenes 117 Pd(I1)-BINAP 138, 147 Pd-catalyzed reactions 83, 136, 2 12 PennPhos, ligand 196 pentalenolactone, synthesis of 130, 131 pentamethyl ether 6 1 peptide 30, 157, 3 15 -3 18 - l3C-labe1led 74 - dipeptide 74 Petasis reagent 111 Peterson olefination 62 a-phellandrene 271 Ph-ambox ligands 201 pharmacophor 233 phase transfer catalysis 3 1 phenol derivatives, synthesis 75 phenyl isonitrile 236 phenylalanine 157 phenyldimethylsilane 10 I (-)-8-phenylmenthol 235 phosphines - chiral - phosphindphosphite-ligands 99 - tripodal 192 phosphites, chiral 186 phosphorus amidites 1 83 - 186 photochemical transformations 7 1 photochromism 296 photolysis of Fischer carbene complexes 71 -76 phthalazine derivate 332 (+)-physostigmine 139 pig liver esterase 220, 228 pinacol coupling 125 pipecolic acid 98 PKS genes 344 plasmid technology 345 platinum 97 polyanions 248 polybinaphthol derivate 334 polycycles 34-38 polyene - macrolide antibiotics 45, 58 - moiety 58 polyenes, tandem cyclizations of, enantioselective 142 - asymmetric

polyethers 343 polyketide origin 58 polyketide - combinatorial biosynthesis 343-349 polyketides 25 1 polyketide-synthase 347 polymer/polymeric 323, 329 - catalysis 328-336 - chains 306-313 - non-stereoregular 329 - polymer-bound regents 105 - polymer-catalyzed reactions 331 - soluble 323 - stereoregular 329 - support, polymeric 323 polypeptide synthesis 324 polypropionate subunits 100 polystyrene 323 precipitation 324 Prins-pinacol condensation rearrangement 272, 273 proline derivatives 182, 183 propargylic alcohols, kinetic resolution I78 prostaglandins, synthesis 133 protein-protein 337 protonation, diastereoselective 74 pseudomonas fluorescens 173 PSGL-I 278 ptilocaulin 24 1 ptilomycalin A 241, 242 PyBOP 227 PyBrOP 228 pylol syntheses 58-66 pyrazolone 106 pyridazine 332 pyrroles 101 2-pyrrolidinemethanol 3 18 pyrrolizidine alkaloids 98

Q QSAR (structure-activity relationship) epothilones 264

-

racemate resolution 29 racemization, palladium-catalyzed

173

264

362

Index

radical - cascade reaction - chemistry 236

236

cyclization 34, 36-38 reactions 15, 239 - - cyclization reaction 68 radio frequencies 320 rare earth metal catalysts 104- 109 reactions - carbonyl addition 35 -37 - p-elimination 34, 37, 38 - nucleophilic acyl subsitution 34-38 - radical cyclization 34, 36-38 - S,1-nucleophylic subsitution 37, 38 reagent-controlled - allyboration 64 - reaction 208 receptor binding 278 reduction 320 - 1,4-reduction 210 - asymmetric 157 - bond formations, reductive 123- 129 - enzymatic 198 - Meerwein-Ponndof- Verley 173 Reformutsky reaction 262 - chromium(I1)-mediated 262 - samarium-mediated 262 - zinc-mediated 262 REMPI (resonance-enhanced muldphoton ionization) 317 resolution 172 - classical 50 resonance-enhanced multiphoton ionization (REMPI) 317 retro-aldol 25 1, 262 retrosynthetic analysis 252 Rh-mediated intramolecular C-H insertion, natural product synthesis 130- 133 rhodium 97, 98 - C-H insertion rhodium-mediated, intramolecular 130- 133 ring closure/ring-closing metathesis 9 1 -96, 102, 114, 254 - diasteroselective 259 - olefin metathesis 91 -96 - multiple ring closure 228 - reaction 254 RNA hydrolysis 247 RNAse modell 248 -

Rut'-diamine complexes, enantioselective transfer hydrogenation 180 ruthenium 97 - carbene complexe 91

-

S saccharid library 338 saccharin 16 Sakuri-Hosomi reaction 166, 167 samarium diiodide 34- 37 Sundmeyer reaction 282 sarcodictyin A 271 Suwada procedure 3 saxitoxin 241 scanning force microscopy 3 10 Schlenk equilibrium 4 Schmidts method 271 Schollkopf synthesis 26 secondary alcohol, non-enzymatic kinetic resolution 175 - 18 1 Seebach synthesis 26 selectin - antagonist 279 - E-selectin 276 - inhibitors 275-280 - L-selectin 276 self-assembly 301 -306 - shape-directed 307 self-replicating peptides 304 sequental - dithiane-epoxide coupling 62 - reactions 34-38 - - anioniclanionic 34-36 - - anionic/radical 34, 36 - - anionic/radical/anionic 36, 37 - - radicallanionic 34, 37 - - radical/cationic 36, 38 sesquiterpenes 93 sharpless - aminohydroxylation 284 - dihydroxylation 236, 285 - method, kinetic resolution 236 sialyl Lewi.? 278 - tetrasaccharide 275 sigmatropic - 1,7-H-shift 212 - [3.3]-sigmatropic rearrangement 64 signal transduction 246

Index

silanes 127 silyl - enol ether 146 - enolates 104 - termination 141 silylformylation 101 silyloxy cope rearrangement 63, 64 Simmons-Smith cycloproanation 3 single-electron-transferring agents 34 - 38 - samarium diiodide 34-37 - tetrafulvalene 34, 37, 38 smart ligands 334 SmI, 126 SmI,/RCHO 60 Sn(OTf), 146 S,Ar - cyclizations 282 - macrocyclization 283 sodium borohydride 195 soft coral 268 solid-phase - strategy 341 - synthesis 105, 272, 314-322, 348 solid support 322 soluble polymers 322-327 solvent effect 86 sonochemical conditions 2 13 spectrometry 3 19 spiro-oxindoles 139 split - synthesis 3 16 - synthetic strategy 337, 338 split-mix 325 (S,S)-diphenylethylenediamine 158 steady state 67-70 Sreglich synthesis 27 stereochemical information 207 stereoconvergent synthesis 67, 69 stereodifferentiation, double 263 stereospecific migration 61 steroid(s) - skeleton 212 - synthesis 133 Stille coupling 265, 271 Still-Gennari olefination 259 Strecker - reaction 319 - synthesis 26, 53, 54 structure-activity relationship (QSAR) 264 - epothilones 264

styrene 99 sulfides 192 sulfinimide 30 sulfone 110 sulfoxides 192 sultam 11 supramolecular chemistry 246, 247 Suzuki coupling 284 synthetic strategy 337, 338

T TADDOLate 168, 170 Takai reagent 111, 112 Takai-Lombard0 reagent 111 Takeda olefination 114 tandem - cyclizations of polyenes, enantioselective 142 - reaction 106 tantazole 2 18 taxol 93, 251 Tebbe reagent 111 tentagel resin beads 339 tert-leucine 3 I8 tetrafulvalene 34, 37, 38 (+)-tetrahydrocerulenin 73 tetrahydropyranes 161 tetralone 202 tetrodotoxin 241 tetronomycin, synthesis 87 thermographic methods 3 17 thermoresponsive catalyst 334, 335 thiangazole 2 I8 - Ehders synthesis 225 - Pattendens synthesis 225, 226 - Wipfs synthesis 229 thiazole A 255 thiazoline 220 thiocarboxylic acid 223 thioketeneacetal 146 three-component - coupling 184 - reactions 104 L-threonine 277 tin hydride 69 titanium 123-125, 318 - catalyst I62 - titanium(1V) complex 146, 191, 192

363

364

Index

W

titanium-alkylidene 110- 115 titanocene 112, 117, 125 tolypothrix conglutinata 61 topoisomerase 1 233 topotecan 233 transfer hydrogenation 196 transition states 67 transmetallation 78 triazacyclononane 187, 189 - 1,4,7-triazacyclononanes 187, 190 triazene method 284 tributylstannane 127 trichloracetimidate 27 1 trimegestone 199 trimethylsilyl cyanide 3 18 trinedate amido ligands 187 tripodal phosphines 192 tris(2-pyridy1)methyl amines 187 tris(oxazo1ine) ligand 191 trisubstitued 1,3-dienes 113 tubulin polymerization 272 tungsten 95 two-center catalysis 107

Wucker - oxidation

84 -process 83 Wilkinsons catalyst 236 Wittig - olefination 213, 256 - reaction 110, 210

X (+)-xestoquinone

Y Yumaguchi method a$-ynones 199

Ugi condensation reaction 53, 54, 341

four-component condensation reaction Ullmunn coupling 20 ultra-filtration 324 urocanic acid 271 Utimoto reagent 112

254

Z

U

-

142

341

valence isomerism 289, 290, 296 vanadium 126 vancomycin aglycon synthesis 28 1-298 (+)-vernolepin, synthesis I38 vitamins - vitamin D 212-217 - - vitamin D-active compounds, palladiumcatalyzed synthesis 212-217 - vitamin E 89

Zimmermann- Truxler model 14, 148, 160 zinc (Zn) 3, 123-125 - carbenoid 3 - enolates 184 zipper concept 243 zirconium(1V) 19 1 Zr-catalysed carbomagnesation of alkenes 7782

Organic Synthesis Highlights V Edited by Hans-Cunther Schmalz and Thomas Wirth

Related Titlesfrom WILEY-VCH

1I

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Organic Synthesis on Solid Phase Second, Completely Revised and Enlarged Edition 2002

ISBN 3-527-30603-X

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Organic Synthesis Workbook II

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NO S::

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Applied Homogeneous Catalysis with Organometallic Compounds Second, Completely Revised and Enlarged Edition 2002

ISBN 3-527-30434-7

Organic Synthesis Highlights V

Edited by Hans-Cunther Schmalz and Thomas Wirth

Prof: Dr. Hans-Gunther Schmolz Institute of Organic Chemistry University of Cologne Greinstrage 4 50939 Koln Germany

This book was carefully produced. Nevertheless, editors, authors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Prof: Dr. Thomas Wirth Cardiff University Department of Chemistry PO Box 912 Cardiff CFlO 3TB United Kingdom

Library of Congress Card No.: applied for A catalogue record for this book is available from the

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Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http:/dnb.ddb.de. 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany. Printed on acid-free paper. Typesetting Asco Typesetters, Hongkong Printing betz-druck gmbh, Darmstadt Bookbinding j. Schaffer GmbH & Co. KG

Griinstadt ISBN 3-527-30611-0

Iv

Contents

Preface xiii List o f Contributors

xu

Part I. Synthetic Methods Direct Conversion o f Sugar Glycosides into Carbocycles Peter 1. Dalko and Pierre Sinai;

1

Synthesis o f Diary1 Ethers: A Long-standing Problem Has Been Solved Fritz Theil

15

Take The Right Catalyst: Palladium-Catalyzed CC-, CN- and CO-Bond Formation on Chloro-Arenes 22 Rainer Stiirmer Alkyne Metathesis i n Natural Product Synthesis Thomas Lindel

27

Transition Metal-Catalyzed Functionalization o f Alkanes Oliver Seitz An Eldorado for Homogeneous Catalysis? Gerald Dyker

36

48

New and Selective Transition Metal Catalyzed Reactions o f Allenes A. Stephen K. Hashmi

56

Controlling Stereoselectivity with the Aid o f a Reagent-Directing Group Bernhard Breit Solvent-Free Organic Syntheses Jiirgen 0. Metzger

82

68

vi

I

Contents

Fluorous Techniques: Progress i n Reaction-Processing and Purification U/f Diederichsen

93

Recent Developments i n Using Ionic Liquids as Solvents and Catalysts for Organic 105 Synthesis Peter Wassencheid Recent Advances on the Sharpless Asymmetric Aminohydroxylation Dmitry Nilov and Oliver Reiser Asymmetric Phase Transfer Catalysis Christabel Carter and Adam Nelson

118

125

Asymmetric Catalytic Aminoalkylations: New Powerful Methods for the Enantioselective 134 Synthesis o f Amino Acid Derivatives, Mannich Bases, and Homoallylic Amines Michael Arend and Xiaojing Wang IBX - New Reactions with an Old Reagent Thomas Wirth Parallel Kinetic Resolutions Jason Eames

144

151

The Asymmetric Baylis-Hillman-Reaction Peter Langer

165

Simple Amino Acids and Short-Chain Peptides as Efficient Metal-free Catalysts in Asymmetric 178 Synthesis Harald Groger, Jorg Wilken, and Albrecht Berkessel Recent Developments i n Catalytic Asymmetric Strecker-Type Reactions

187

Larry Yet Highly Enantioselective or Not? - Chiral Monodentate Monophosphorus Ligands i n the Asymmetric Hydrogenation 193 lgor V. Komarou and Armin Borner Improving Enantioselective Fluorination Reactions: Chiral N-Fluoro Ammonium Salts and Transition Metal Catalysts 201 Kilian Mufiiz Catalytic Asymmetric Olefin Metathesis Amir H . Hoveyda and Richard R. Schrock

210

Contents

Activating Protecting Groups for the Solid Phase Synthesis and Modification o f Peptides, 230 Oligonucleotides and Oligosaccharides Oliver Seitz Traceless Linkers for Solid-Phase Organic Synthesis florencio Zaragoza Donuald

251

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique 265 Andreas Kinchning and Riidiger Wittenberg Polymeric Scavenger Reagents in Organic Synthesis Jason Eames and Michael Watkinson

280

Part II. Applications Total Syntheses o f Vancomycin 297 Lars H. Thoresen and Kevin Burgess Bryostatin and Their Analogues Uf Diederichsen

307

Eleutherobin: Synthesis, Structure/Activity Relationship, and Pharmacophore Uf Diederichsen Total Synthesis o f the Natural Products CP-263,114 and CP-225,917 Ulf Diederichsen and Katrin B. Lorenz Polyene Cyclization t o Adociasulfate 1 Thomas Lindel and Cordula Hopmann

326

342

Sanglifehrin A An Immunosuppressant Natural Product from Malawi Thomas Lindel Short Syntheses o f the Spirotryprostatins Thomas Lindel

360

The Chemical Total Synthesis o f Proteins Oliver Seitz

368

Solid-Phase Synthesis o f Oligosaccharides Ulf Diederichsen and Thomas Wagner

350

384

Polymer-Supported Synthesis o f Non-Oligomeric Natural Products Stefan Sommer, Rolf Breinbauer, and Herbert Waldmann

395

317

I

vii

viii

I

Contents

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions 409 Rudiger Faust

Dendralenes: From a Neglected Class o f Polyenes to Versatile Starting Materials in Organic Synthesis 419 Henning Hopf Fascinating Natural and Artificial Cyclopropane Architectures Riidiger Faust

index

435

428

Development in chemical sciences in general and in organic synthesis in particular has a strong impact on our life. Synthesis as a central position within the field of organic chemistry is contributing to a large variety of different applications. Men’s ability to synthesize complex biologically active or functional molecules has dramatically improved during the past years. However, the art and technology of organic synthesis is still far from being fully developed. Intense research is performed worldwide, and it is important and fascinating to follow the steady development of increasingly powerful methods and tools for organic synthesis. The fifth volume of Organic Synthesis Highlights is divided in two parts. In the first part, recent developments in synthetic methodologies are described and new and improved techniques are highlighted including some general applications of those strategies. The second part of the book is devoted to the total synthesis of natural and non-natural compounds. The complexity and the efficiency of multi-step sequences is still highly challenging and success in this field often has to go hand in hand with the development of new methods. In continuing the tradition of Organic Synthesis Highlights, about 40 articles have been selected from the “Highlights” section of Angewandte Chemie (1998-2001),from the “Concepts” section of Chemistry - A EuropeanJournal(2000-2001), and from the review section of Nachrichten aus der Chemie (1999-2001),the members journal of the GDCh. The articles from the “Synthese im Blickpunkt” have all been carefully translated and updated by the authors ( U . Diederichsen, T. Lindel, 0. Seitz) and we would like to express special thanks to these colleagues and their co-authors. We are also grateful to all the other authors for their excellent contributions and for the good cooperation. We also like to thank the team at Wiley-VCH, especially Dr. E. Westermann, for the excellent and professional support and for the prompt help in all questions. We hope that this volume will stimulate interest in the field of synthesis across a broad range of chemists, from undergraduate students to research group leaders in industry and academia. Cologne and Cardiz September 2002 Hans-Giinther Schmalz and Thomas Wirth

List of Contributors Dr. Michael Arend Fibrogen 225 Gateway Boulevard South San Francisco, CA 94080 USA Professor Dr. Armin Borner Institut fur Organische Katalyseforschung an der Universitat Rostock e. V. Buchbinderstrasse 5/6 18055 Rostock Germany Professor Dr. Bernhard Breit Albert-Ludwigs-Universitat Freiburg Institut fur Organische Chemie und Biochemie Albertstrasse 21 79104 Freiburg Germany Professor Kevin Burgess Department of Chemistry Texas A&M University Box 30012 College Station TX-77842.3012 USA Professor Dr. Ulf Diederichsen Institut fur Organische Chemie Universitat Gottingen Tammannstr. 2 37077 Gottingen Germany Professor Dr. Gerald Dyker Ruhr-Universitat Bochum Fahltat fur Chemie Universitatsstrasse 150 44780 Bochum Germany

Dr. lason Eames Department of Chemistry Queen Mary and Westfield College Mile End Road London E l 4NS U.K. Dr. Rudiger Faust Department of Chemistry Christopher Ingold Laboratories University College London 20 Gordon Street London WClH OAJ U.K. Dr. Harald Groger Project House Biotechnology Degussa AG Rodenbacher Chaussee 4 63457 Hanau Germany Professor Dr. A. Stephen K. Hashmi hstitut fur Organische Chemie Universitat Stuttgart Pfaffenwaldring 55 70569 Stuttgart Germany Professor Henning Hopf Institut fur Organische Chemie Technische Universitat Braunschweig Hagenring 30 38106 Braunschweig Germany Professor Amir H. Hoveyda Boston College Department of Chemistry Merkert Center Chestnut Hill

xii

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List ofcontributors

Massachusetts 02467 USA Professor Dr. Andreas Kirschning Institut fur Organische Chemie Universitat Hannover Schneiderberg 1 B 30167 Hannover Germany Professor Dr. Peter Langer Institut fur Chemie und Biochemie Ernst-Moritz-Arndt Universitat Soldmannstrage 16 17487 Greifswald Germany Professor Dr. Thomas Lindel Department Chemie LudwigMaximilians-Universitat Munchen Butenandtstrasse 5-13 81377 Miinchen Germany Professor Dr. Jurgen 0. Metzger Carl-von-OssietzkyUniversitat Fachbereich Chemie der Universitat Carl-von-Ossietzky-Strasse 9-1 1 26111 Oldenburg Germany

Dr. Oliver Seitz MPI fur Molekulare Physiologie Abteilung Chemische Biologie Otto-Hahn-Strasse 11 44227 Dortmund Germany Dr. Rainer Stiirmer BASF AG Hauptlaboratorium GHF/D, A30 67056 Ludwigshafen Germany Dr. Fritz Theil ASCA Angewandte Synthesesysteme Adlershof GmbH Richard-Willstatter-Strasse 12 12489 Berlin Germany Dr. Peter Wasserscheid Institut fur Technische Chemie und Makromolekulare Chemie Bereich Technische Chemie Worringer Weg 1 52074 Aachen Germany

Dr. Kilian Mufiiz KekulC-Institut fur Organische Chemie und Biochemie Gerhard-Domagk-Strage 1 53121 Bonn Germany

Professor Dr. Herbert Waldmann MPI fur Molekulare Physiologie Otto-Hahn-Strasse 11 44227 Dortmund Germany

Professor Dr. Adam Nelson School of Chemistry University of Leeds Leeds. LS2 9jT U.K.

Professor Thomas Wirth Department of Chemistry Cardiff University P.Q. Box 912 Cardiff CFlO 3TB United Kingdom

Professor Oliver Reiser Institut fur Organische Chemie der Universitat Regensburg Universitatsstrasse 31 93053 Regensburg Germany Prof. Pierre Sinay Ecole Normale Supkrieure DCpartement de Chimie UMR 8642 24, Rue Lhomond 75231 PARIS Cedex 05 France

Dr. Larry Yet Albany Molecular Research, Inc. 21 Corporate Circle P.O. Box 15098 Albany NY 12212-5098 USA Dr. Florencio Zaragoza Dorwald Novo Nordisk A/S Novo Nordisk Park 2760 Milm Denmark

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I’

Direct Conversion of Sugar Clycosides into Carbocycles Peter 1. Dalko and Pierre S h y

Carbocyclic polyols are important constituents of many biologically active molecules. They exhibit far reaching biological effects ranging from cellular regulation, to the selective inhibition of enzymes, which play key roles in living organisms [ 1, 21. Some of the most prominent six membered representatives are cyclohexane hexitols such as inositol derivatives [ 11 or pseudo-sugars [2, 31, such as cyclophellitol [4],or valienamine [ 51. Structural analogues of the latter are constituents of compounds of key pharmacological interest such as acarbose [GI, adiposin [7], trestatin [8], and amylostatin [9]. Together with a growing number of structurally related alkaloids [lo] and purely synthetic compounds Ill], as well as five membered polyol-contain natural products [ 121, these small, but synthetically challenging molecules received growing interest in the last few years. The biological significance and the inherent structural challenge of these molecules have led to the development of a variety of different approaches in optically pure form [13]. To access this class of compounds both (1)a cyclization strategy of alicyclic, polyfunctionalized molecules and (2) transformations of conveniently substituted carbocycles into cyclitols were largely exploited. The former strategy includes Diels-Alder reactions [ 141, Wittigtype olefinations [ 151, radical cyclization approaches [ 161, ring-closing metathesis (RCM) [ 171, and a variety of anionic cyclization/organometallic coupling reactions of advanced polyhydroxylated compounds [ 181. Some of these allow the direct conversion of carbohydrate furanosides and pyranosides to carbocyclic polyols. The tandem fragmentation/Henry-type cyclization reaction provided the first examples in which cyclohexane [ 191 and cyclopentane [ 201 derivatives were obtained from carbohydrate derivatives. Likewise, the elegant application of the Fujimoto-Belleau reaction [21], and the anionic rearrangements of anhydrosugars [ 221 are examples of this transformation. The strategy which includes enantiopure carbocycles as starting materials features transformations of quinic acid 1231, inositols or conduritol derivatives [ 241, desymmetrization of meso cyclohexene derivatives using asymmetric palladium catalyzed hydroxycarboxylation [25], or other enantioselective reactions [ 261, transformation of homochiral carbocycles obtained either by microbial metabolites [ 27, 281, or by some other type of oxidation [29]. At this stage it is important to briefly examine the biosynthesis of carbocyclic polyols, concentrating on six membered rings. Myo-inositol derivatives, for example, are formed from D-glucose6-phosphate 1 by a stereospecific ring-closure under the catalytic influence of inositol cyclase (Scheme 1) [ Ib].

2

I

Direct Conversion of Sugar Clycosides into Carbocycles

@o H

o

b

o

H

-

OH

HO

o a H

o

~

HO

~

~

~

o

~

o

OH

2

1

3

4

myo-inositol 1-phosphate Scheme 1.

Other mechanisms bear strong resemblances to that by which D-glucose is converted into shikimic acid (Scheme 2). This is the biogenetic path in which nature produces the benzoid rings of the aromatic amino acids and an extensive range of other metabolites. At an early stage of this sequence the hemiacetal intermediate Ga undergoes rearrangement and forms the quinic acid derivative 7. As Bartlett and Satake demonstrated, however, the unstable Ga, generated in situ from the 0-nitrobenzyl protected cc-glycoside Gb is rearranged spontaneously to 3-dehydroquinic acid without any specific enzyme [ 301. Moreover, this uncatalyzed reaction gives rise to a single stereoisomer identical to that of the biosynthetic path. This fact suggests the possibility that a key step in cyclitol biosynthesis may also be nonenzymatic.

5

6aR=H 6b R = o-nitrobenzyl

0 H0m.u ~ HO

'OH

0

7 3-dehydroquinic acid Scheme 2.

-

2H

o 8 H ~o ~ ~ 0 2 H HO

8

shikimic acid

Direct Conversion of Sugar Clycosides into Carbocycles

13

Nature found a direct path to perform this tandem fragmentation cyclization reaction in a stereospecific manner and under neutral conditions. Human creativity and luck aimed to uncover synthetic variants, which can compete efficiently with it. With the advent of mild, metal mediated cyclization reactions, the early idea of Grosheinz and Fisher [19a], who converted 6-deoxy-6-nitrohexosesto nitroinositols in a single step, matured to a general strategy of broad interest. The direct conversion of sugar glycosides to a carbocycle can take place either by a domino sequence, or by a concerted reaction. In the former case the reaction combines two distinct steps: an opening step, liberating a highly reactive metal enolate (or equivalent) and electrophile functions (i.e. an aldehyde or oxycarbenium function), which undergo subsequent cyclization. The carbocyclization can proceed with ring contraction providing cyclopentanes and cyclobutanes [31], or alternatively may give rise cyclohexitols, or larger rings. Sugar enol-ethers, which inherently carry both the masked nucleophilic and electrophilic functions, were converted to carbocycles in different reactions. Among the carbocyclization methods the Ferrier (I I) cyclization of hex-5-enopyranosides affording six membered carbocycles in the presence of Hg(11) salts is perhaps the most popular one (Scheme 3) [ 321. This remarkable reaction has provided a practical route to a large variety of bioactive substances such as aminocyclitols [ 331, pseudosugars [34], inositols [35], and other complex hexitols [36].

Hg”

~ BnO ~ 0 %

[

B BnO n

O

OBn

9aR=H 9b R = OAc

-

q +B BnO n

OH OBn

OMe

L

~

OBn

h

O

]

OBn

OMe

10a R = H 10b R = OAc

BnO

O

lla R =H l l b R = OAc

J

Bno BnO

OBn OH

12a R = H (68%) 12b R = OAC(59-72%)

13a R = H (17%) 13b R = OAc (13 %)

Scheme 3.

According to the original protocol the six membered vinyl glycoside such as 9a undergo rearrangement under hydroxymercuration conditions providing cyclohexitols (Schema 3). Among the various conditions proposed for the Ferrier (11) reaction, both catalytic and stoichiometric methods were investigated, which afforded similar but not identical results [ 13, 371. Also, a “nontoxic alternative” consists of using a catalytic amount of palladium(I1) salt [38], instead of mercury(I1) [39]. This modification may alter the selectivity, which is not surprising given the different coordination pattern of the metal in the transition state. A

4

I

Direct Conversion of Sugar tlycosides into Carbocycles

basic feature of this transformation is the loss of the aglycon, for example methanol, and the fragmentation ring-closing aldol reaction. In this cyclization the carbanionic center (C6) attacks the electrophilic carbonyl center (Cl). The stereochemistry of the newly formed asymmetric center is determined by the conformational bias of the molecule, and by the chemical nature of the functions present. The stereoselectivity of the newly formed asymmetric center as well as isolated yields are highly dependent upon the experimental conditions used, however. This fact is mainly due to the preferred conformation of the given sugar derivative in the transition state and also to the formation of a sensitive 8-hydroxy ketone, which may undergo elimination and subsequent aromatization. The scope of the reaction was enlarged by showing that functionalized exocyclic olefins may be converted into carbocycles as well [40]. Accordingly, alkene-bearing oxygen substituents at C6, such as 9b, made from the corresponding aldehyde, were transformed to inosose derivative 121, with high stereoselectivity of each newly formed stereogenic center. Noteworthy, the geometry of the enol acetate of 91, does not affect the stereochemical outcome of the reaction, nor in the Hg(I1) neither in the Pd(I1) salt mediated cases [33c]. The Ferrier (11) reaction is quite efficient to form six membered carbocycles, but is unsuitable to prepare cyclopentitols. Five membered enollactone 14 was converted to the cyclopentanone derivative 16 as a single epimer upon treatment by LiAlH(OtBu)3 (Scheme 4) [41]. Spectroscopic studies established some mechanistic details. Accordingly, the hydride of the reducing agent rapidly added to the carbonyl and formed with the metal a stable aluminate complex. The carbocyclization occurred by protonation followed by fragmentation and aldol type cyclization process.

x-1 14

L

-

\/

1

15

16 (74%)

Scheme 4.

Under particularly mild conditions the triisobutylaluminium (TRIBAL) mediated rearrangement avoided the fragmentation of the “locked’ anomeric substituent in 9a, and even preserved its original configuration with high selectivity (Scheme 5) [42,43]. Lewis acid assisted endo activation, followed by a ring-opening step, generated the zwitterionic enolate intermediate 17 as the hypothesized intermediate of the reaction. The ring closure occurs via an intramolecular 6-em-trig aldol condensation. The “bonus” of the reaction is the stereoselective formation of a hydroxyl, resulting from the final reduction of the keto group probably by an intramolecular hydrogen delivery from the less hindered P-side. The reaction is fairly general and high yielding using a wide array of sugar starting materials. It is worthy to note the good selectivity in conserving the anomeric stereochemical information by retention

Direct Convenion of Sugar Clycosides into Carbocycles

15

18

OMe

OMe

19 (79%)

Scheme 5.

The fact that both the stereochemistry and the substitution pattern of the sugar anomeric center is conserved allowed to realize a direct transformation of a hex-5-enopyranosides of sucrose 20 into a carba-disaccharide analogue 21 (Scheme G), and to achieve cascade rearrangements [45].

OBn

PhMe, 50°C

BnO""

Brio'“‘ OBn

20

21 (34%)

Scheme 6.

No synthetically useful rearrangement occurs, however, by replacing the TRIBAL by DIBAL-H, or by using stronger Lewis acids such as TiC14, Ti(OiPr), or BF3, SnC14, AlC13 under similar conditions [4G].In contrast, slightly modified conditions, by using Ti(OiPr)C13, prepared from TiC14 and Ti(OiPr),, the reaction afforded the rearranged cyclohexanone derivative with retention of the stereochemical information and substitution pattern on the anomeric center [47]. The a-D-glycoside 9a in the presence of Ti(OiPr)C13 provides the expected endo-cleavage of the glycosidic bond and forms the carbocyclic glycoside 23 (Scheme 7). Although the a-glycoside starting material affords nearly quantitative yield, the corresponding I(-glycoside gives rise to a mixture of different products. This Ti'" version

6

I

Direct Conversion of Sugar Glycosides into Carbocycles

Ti(OiPr)C13(1.5 equiv.), BnO

CH2C12, -78"C, 15 min. OMe

9a

OMe

23 (98%) Scheme 7.

involves milder reaction conditions than the triisobutylaluminium mediated rearrangement and does not result in the reduction of the keto function. Vinyl carbohydrate derivatives such as 24 or 27 can be converted to carbocycles 26 and 28 respectively by sequential treatment with "CpzZr" and BF3.0Et, (Scheme 8) [48]. The reaction offers complete cis-selectivitybetween the vinyl groups and the newly formed hydroxyl.

24

"1 * BnO

OBn

26 (65%)

>98% de.

OMe

"Cpzzr"

WoH +

BF3.OEt2 * OBn

27 Scheme 8.

(60%)

"'OBn

OH

*,'

OBn

Direct Conversion ofsugar Clycosides into Carbocycles

Although the major stereoisomer was expected to be trans to the adjacent cc-substituent, the overall selectivity of the reaction depends intimately on the stereochemistry and nature of the substituents present. Despite the difficulty encountered with different derivatives in controlling stereochemistry, the easy access and the seemingly unhindered choice of the vinyl carbohydrate starting materials renders this methodology appealing. Like the in situ generated propargyl-zirconium species, generated from vinyl-carbohydrate derivatives the intramolecular propargylation promoted by SmIz in the presence of a catalytic amount of Pd(0) complexes affords the ring-contracted carbocycle (Scheme 9). The reaction products are usually cyclopentanols and cyclobutanols. The transformation is characterized by high trans selectivity with regard the two newly created stereogenic centers. This procedure represents an extension of the “CpzZr” mediated ring-contraction reaction of vinylfuranosides or pyranosides in a sense that allows also the transformation of alkynylpyranosides [ 491. Like the earlier discussed zirconium mediated ring-contraction reaction the reaction is thought to proceed through the corresponding ally1 or allenylsamarium complexes that undergo cyclization in the presence of the carbonyl of the liberated aldehyde function [SO].

SmI2 (2eq),

OBn

P ~ ( O A C ) ~ . ~(5%) BU~P OBn

OBn

rt

29

30 (82%)

Scheme 9.

Samarium(11) iodide promotes comparable transformations of aldehydo sugar 31 to ring contracted product 34 (Scheme 10) [ 511. The presences of HMPA and tea-butyl alcohol as a proton source are necessary to obtain good conversion to cyclopentane derivatives. The reac-

rBuOH (2 equiv.)

BnO

31

32

OMe

BnO

&

BnO BnO

33 Scheme 10.

H

34 (63%)

8

I

Direct Conversion of Sugar Clycosides into Carbocycles

tion is considered to proceed via the samarium ketyl intermediate, which is reduced to the disamarium species 32 under the reaction conditions. After fragmentation the system is ideally suited for a subsequent aldol cyclization, involving intramolecular nucleophilic attack of the samarium enolate onto the aldehyde through a 5-enol exo-trig process. As expected from the metal linked chelate, the major stereoisomer of the two newly created stereocenters is cis, and trans with regard to the adjacent substituents. A limited number of Sm12-mediated reductive rearrangements affording six membered carbocycles have been reported (Scheme 11) [52a]. The transformation occurs often with high stereoselectivity, and can be explained by assuming a chelation control model. The outcome of the reaction may depend, however, on the stereochemistry of the substitution pattern of the molecule, and the nature of the intramolecular trap. Six membered carbocycles are formed from the ally1 sulfides such as 35, in sharp contrast with a,p-unsaturated methyl esters of sugar pyranosides such as 37, which afford the corresponding five membered carbocycles (38) through a similar SmI2-induced cyclization [ 521. SPh I

b

o

H

Sm12

HOt,/(@H

THF / MeOH

BnO\\\\

'"OBn OBn

5: 1 (83 %)

BnO'"'

""OBn OBn

dr=3: 1

35

36

37

THF / MeOH 15: 1 (91 %)

OBn 38

Scheme 11.

Sugar spiroisoxazolines intermediates such as 40 undergo rearrangement under reductive conditions (Scheme 12) [53]. The starting material can be prepared by an intermolecular [ 3+2] cycloaddition by using pent-4-enofuranosides such as 39 and nitrile oxides. Although this reaction proceeds often in a high facial selectivity, the diastereoselectivity of this transformation is of no importance since the spiro-carbon loses the stereochemical integrity in the following step. The reduction of this intermediate by using Raney Nickel hydrogenation in MeOH-AcOH yield in high diastereoselectivity the corresponding cyclic enaminone 42. The reaction is a result of a selective N - 0 cleavage and a spontaneous aldol-like condensation of the resulted enamine or enone of type 41.This reaction allows the formation of both five and six membered carbocycles respectively. The efficiency of the transformation depends on the substitution pattern of the spiro-isoxazoline moiety.

Direct Conversion of Sugar Clycosides into Carbocycles

eoMe Low,, 2,6-ClzC6H&NO (1.1 equiv.),

-

-:

:

i

-

2,6-C12C~H3

-.-~ --

Y

c

k 0

CH2C12, reflux, 4 h

39

40 (66%)

Raney Ni,

MgS04, H2 (1 atm.)

MeOWCH&OOH, (6: 1) 20 "C, 90 min.

. 41

Scheme 12.

Let's now consider concerted skeletal rearrangements which allow the direct transformation of a sugar structure into a carbocycle. The Claisen rearrangement has been used for the direct conversion of sugar C-glycosides to eight membered carbocycles, respectively. The to reaction has precedents in the transformation of 2-methylene-6-vinyl-tetrahydropyrans cyclooctenone derivatives, a transformation that has been applied in the synthesis of several natural products [ 541. The rearrangement can be promoted by heat [55] or by using TRIBAL [%I. For example, simple heating of a solution of 43 in boiling xylene leads to the eight membered carbocycle 44 in 60% (Scheme 13).

43

44 (60%)

Scheme 13.

The rearrangement of methyl vinylketoside 45 can be accelerated by using TRIBAL. In this case the reaction affords at room temperature the corresponding cyclooctanol derivative 46 with a high preference for a syn-hydrogen delivery compared to the adjacent benzyloxy function (Scheme 14)[57]. An elegant method was devised in preparing pseudo-sugars using thermal [3, 31 sigmatropic rearrangement (Scheme 15) [58]. This methodology is based on the earlier works of Buchi [ 591. Although the generality of this approach using different sugar series remains to be demonstrated, the simplicity is attracting: the vinyl glucal derivative 47 affords the cyclohexene aldehyde 48 by heating. One of the advantages of this transformation is that

19

10

I

Direct Conversion of Sugar Clycosides into Carbocycles

TRIBAL OMe

toluene OBn 45

46 (83%)

Scheme 14.

the formed pseudosugar retains the original configuration of the starting sugar: the D-glucal derivative gives entry to the pseudo-o-glucal series.

240°C

o-dichlorobenzene sealed tube, l h

BnO"" OBn

47

B n ~ " OBn

48 (84%)

Scheme 15.

The intramolecular nitrone cycloaddition (INC) has been used particularly for the synthesis of amino carbasugars [GO, 611. The following scheme illustrates this strategy (Scheme 16) [GO]. The cycloaddition of nitrone derived from lactol 49 and an excess of Nmethylhydroxylamine occurs from the least hindered face affording the isoxazolidine 51 (85% yield). The amino carbasugar 52 was obtained after the cleavage of the N - 0 bond.

F4

O

)"

MeNHOH-HCl, t

>

5

pyridine, rt, 12h,

k 0 49

50

.OH I

Me"\/

\ Scheme 16.

51(85%)

\

52

References and Notes

Conclusion

The easy access to enantiomerically pure carbocyclic polyols from carbohydrate furanosides and pyranosides is an appealing transformation in organic synthesis. New methods made possible to carry out this transformation under mild conditions with high yield and with predictable and high stereoselectivity. Beyond elegance, the compatibility towards a large variety of substituents gives to the discussed rearrangements strategic importance.

References and Notes a) Y. CHAPLEUR (Ed.) Carbohydrate Mimics, Wiley-VCH, Weinheim, 1997; b) D. C. BILLINGTON,The Inositol Phosphates Chemical Syntheses and Biological Sign$cance, VCH, New York, 1993; c) L. C. HUANG,J. LARNER, Adv. Prot. Phosphatases 1993, 7, 373; d) G. ROMERO, Cell. Biol. Int. Rep. 1991, 15, 827; e ) M. J. MCCONVILLE, M. A. J. FERGUSON, Biochem.]. 1993, 294, 305; f ) R. H. MITCHELL, A. H. DRUMMOND, C. P. DOWNES, Inositol Lipids in Cell Signaling, Academic Press, New York, 1989; g) R. KAPELLER,L. C. CANTLEY, BioEssays 1994, 16, 565; h) K. HINTERDING, D. ALONSO-DIAZ, H. WALDMANN, Angew. Chem. Int. Ed. 1998, 37, 668; i) R. I. G . J. WANG,Chem. Rev. HOLLINGSWORTH, 2000, 100, 4267; j) D. C. BILLINGTON, Chem. SOC. Rev. 1989, 18, 83; k) T. HUDLICKY, D. GONZALEZ, D. T. GIBSON, Aldrichim. Acta 1999, 32; 1) B. FRASERREID,Acc. Chem. Res. 1996, 29, 57; m ) B. FRASER-REID, K. TATSUTA, J. T H I E M(Eds) , Glycoscience: Chemistry and Chemical Biology, Vol. 1-111, Springer, Berlin, 2001. 2 a) T. SUAMI,S. OGAWA, Adv. Carbohydr. Chem. Biochem. 1990, 28, 41; b) A. BERCIBAR, C. GRANDJEAN, A. SIRIWARDENA, Chem. Rev. 1999, 99, 779. 3 Pseudosugars are carbohydrate derivatives in which the ring oxygen has been replaced by a methylene group. 4 S. ATSUMI, K. UMEZAWA, H. IINUMA,H. NAGANAWA, H. NAKAMURA, Y. IITAKA, T. Antibiot. 1990, 43, 49. TAKEUCHI,]. 5 T. K. M. SHING,L. H. WAN,Angew. Chem. Int. Ed. Engl. 1995, 34, 1643. 6 D. SCHMIDT, W. FROMMER, B. J U N G E , K. MULLER, W. WINGENDER, E. TRUTSCHEIT, Natunvissenschaften 1977, 64, 536. 1

a) S. OGAWA,Yuki. Gosei Kagaku Kyokai Shi 1985, 43, 26; b) Y. KAMEDA, N. ASANO, M. YOSHIKAWA, K. MABUI,S. HORII, H. FUKAWASE, ]. Antibiot. 1983, 36, 1157. 8 J. ITOH, S. OMOYO, T. SHOMURA, H. OGINO,K. IWAMATSU, S. INOUYE, J . Antibiot. 1981, 34, 1424 and 1429. 9 N. SAKAIRI, H. KUZUHARA, Tetrahedron Lett. 1982, 23, 5327. 10 a) R. L. POLTin Amaryllidaceae Alkaloids with Antitumor Activity, Series Organic Synthesis: 7'heory and Application, Vol. 3 (Ed. T. HUDLTCKY), JAI Press, Greenwich, 1996, pp 109-148; b) P. MAGNUS, I. K. SEBHAT,].Am. Chem. SOC.1998, 120, 5341. 11 S. VORWERK, A. VASELLA, Angew. Chem. Int. Ed. 1998, 37, 1732. 12 M. ISHIBASHI, C. M. ZENG,J. KABAYASHI, ]. Nat. Prod. 1993, 58, 186. 13 a) R. J. FERRIER, S. MIDDLETON, Chem. Rev. 1993, 93, 2779; b) G. D. PRESTWICH, Acc. Chern. Res. 1996, 29, 503; c) P. 1. DALKO, P. SINAY,Angew. Chem. Int. Ed. 1999, 38, 773; d) P. SINAY,Pure Appl. Chem. 1998, 70, 1495. 14 a) S. ALLEMAN, P. VOGEL,Helv. Chim. Acta 1994, 77, 1; b) R. LEUNG-TOUNG, Y. LIU, J. M. MUCHOWSKI, Y.-L. Wu, ]. Org. Chem. 1998, 63, 3235; c) 0. ARJONA, C. BORRALLO,F. IRADIER, R. MEDEL, J. PLUMET, Tetrahedron Lett. 1998, 39, 1977; d) E. ROMAN, M. BANOS,I. I. GUTIERREZ, J . A. SERRANO,].Carbohydrate Chem. 1995, 14, 703; e) S. C. PELLEGRINET, M. T. A. B. BAUMGARTNER, R. A. SPANEVELLO, PIERINI,Tetrahedron 2000, 56, 5311; f ) C. TAILLEFUMIER, Y. CHAPLEUR, Can.]. Chem. 2000, 78, 708; For a general review on the preparation of carbocycles by Diels7

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l1

12

I

Direct Conversion of Sugar Clycosides into Carbocycles Alder chemistry see: g) K. GOTHELF,K. A. )0RGENSEN, Chem. Rev. 1998, 98,863. 15 a) H. PAULSEN, W. VON DEYN,Liebigs Ann. Chem. 1987, 125; b) H. J. M. GITSEN,C. H . WONG,Tetrahedron Lett. 1995, 36, 7057. 16 a) T. V. RAJANBABU, Acc. Chem. Res. 1991, 24, 139. b) A. MARTINEZ-GRAU, 1. MARCOChem. SOC. Rev. 1998, 27, 155; CONTELLES, c) I. MARCO-CONTELLES, C. ALHAMBRA,A. Synlett 1998, 693; d) M. MARTINEZ-GRAU, ADINOLFI, G . BARONE,A. IADONISI,L. MANGONI,Tetrahedon Lett. 1998, 39, 2021; e) J. MARCO-CONTELLES, P. GALLEGO, M. RODRIGUEZ-FERNANDEZ, N. KHIAR,C. DESTABEL, M. BERNABE, A. MARTINEZGRAU,J. L. CHIARA,J . Org. Chem. 1997, 62, 7397; f ) A. M. H O R N E M A N I. ,LUNDT, Synthesis 1999, 317; g) A. M. HORNEMAN, 1. LUNDT,J . Org. Chem. 1998, 63, 1919; h) A. M. HORNEMAN, I. LUNDT,Tetrahedron 1997, 53,6879; i) A. M. HORNEMAN, I. LUNDT,I. SOTOFTE,Synlett 1995, 918; j) A. M. GOMEZ,G. 0. DANELON, E. J. C. LOPEZ,Chem. MORENO,S. VALVERDE, Commun. 1999, 175; k) E. MAUDRU, G. SINGH,R. H. WIGHTMAN,Chem. Commun. 1998,1505; 1) A. M. GOMEZ,G. 0. DANELON, S. VALVERDE, J. C. LOPEZ,J . Org. Chem. 1998, 63, 9626; m) J. C. LOPEZ,A. M. GOMEZ, B. FRASER-REID,Aust.]. Chem. 1995, 48, 333; n) A. M. GOMEZ,S. MANTECON, S. VALVERDE, J. C. LOPEZ,J.Org. Chem. 1997, 62, 6612; 0) K. Y. HSIA, P. WARD,R. B. LAMONT,P. M. D. LILLEY,D. J. WATKIN, G . W. J. FLEET,Tetrahedron Lett. 1994, 35, 4823. 17 a) F. E. ZIEGLER, Y. WANG,J . Org. Chem. 1998, 63, 426; b) D. J. HOLT,W. D.

BARKER, P. R. JENKINS, D. L. DAVIES,S. G A R R A J.~ ,F A W C E D. ~ , R. RUSSELL, S. GHOSH,Angew. Chem. Int. Ed. 1998, 37, P. VAN D E WEGHE!D. 3298; c) 0. SELLIER, LE NOUEN,C. STREHLER, J. EUSTACHE, Tetrahedron Lett. 1999, 40, 853; d) R. N. CONRAD,M. J. GROGAN,C. R. BERTOZZI, Org. Lett. 2002, 4, 1359; e) L. HYLDTOFT,R. MADSEN, J . Am. Chem. SOC.2000, 122, 8444; f ) I. HANNA,L. RICARD,Org. Lett. 2000, 2, 2651; g) P. KAPFERER, F. SARABIA, A. VASELLA, Helu. Chim. Acta 1999, 82, 645; h ) F. D. BOYER,I. HANNA,S. P. NOLAN, J . Org. Chem. 2001, 66, 4094; i) A. KORNIENKO, M. D’ALARCAO, Tetrahedron: AsymmeQ 1999, 10,827.

18 For aldol-type cyclization see: a) D. HAAG,

X. T. C H E N ,B. FRASER-REID, Chem. Commun. 1998, 2577; b) A. J. WOOD,D. J . HOLT,M. C. DOMINGUEZ, P. R. J E N K I N S , J . Org. Chem. 1998, 63, 8522; c) A. J. WOOD,P. R. JENKINS, J. F A W C E D. ~ , R. I. Chem. Soc. Chem. Commun. RUSSELL, 1995, 1567; d) A. H U I , A. J. FAIRBANKS, R. J. NASH,P. M. D E Q. LILLEY,R. STORER,D. J. WATKIN,G. W. J . FLEET, Tetrahedron Lett. 1994, 35, 8895; e) F. CHRETIEN,F. KHALDI,Y. CHAPLEUR, Tetrahedron Lett. 1997, 38, 5977; f ) V. C E R E ,F. PERI,S. POLLICINO,Tetrahedron Lett. 1997, 38, 7797. For related anionic cyclization see: g) A. J. FAIRBANKS, A. HUI,B. M. SKEAD,P. M. DE Q. LILLEY,R. B. LAMONT, R. STORER,J. SAUNDERS, D. J. WATKIN, G. W. J. FLEET,Tetrahedron Lett. 1994, 35, 8891. For Cr/Ni mediated carbocyclization see: h) A. LUBINEAU,I. BILIAUT,J . Org. Chem. 1998, 63, 5668. 19 a) J.M. GROSHEINZ, H. 0. L. F I S C H E R , ~ . Am. Chem. Soc. 1948, 70, 1479; b) for a n intermolecular tandem, ring opening cyclization variant of this reaction see: I . KITAGAWA, A. KADOTA,M. YOSHIKAWA, Chem. Pharm. Bull. 1978, 26, 3825. 20 S. 1. ANGYAL,S. D. GERO,Aust. J . Chem. 1965, 18, 1973. 21 S. MIZRA,L.-P. MOLLEYERES, A. VASELLA, Helu. Chim. Acta 1985, 68, 988. 22 a ) A. KLEMER, M. KOHLA,Liebigs Ann. Chem. 1986,967; b) A. KLEMER, M. KOHLA,Liebigs Ann. Chem. 1987, 683. 23 a) T. K. M. SHING,Y. CUI, Y. TANG,J . Chem. Soc. Chem. Commun. 1991, 754;

b) T. K. M. SHING,Y. TANG,Tetrahedron 1991, 47, 4571.

M. BALCI,Pure Appl. Chem. 1997, G9, 97. B. M. TROST, L. S. CHUPAK,T. LUBBERS, J. Am. Chem. SOC. 1998, 120, 1732. 26 a) Y. LANDAIS, Chimia 1998, 52, 104; b) R. ANGELAUD, Y. LANDAIS,Tetrahedron Lett.

24 25

1997, 51, 8841. 27 For a reviev, see: T. HUDLICKY, D. A.

ENTWISTLE, K. K. PITZER,A. J. THORPE, Chem. Rev. 1996, 96, 1195. 28 a) M. BANWELL, C. DE SAW, K. WATSON, Chem. Commun. 1998, 1189; b) F. YAN, B. V. NGUYEN,C. YORK,T. HUDLICKY, Tetrahedron, 1997, 53, 11541; c) T. HUDLICKY, A. J. THORPE,Chem. Commun. 1996, 1993; d) T . HUDLICKY, K. A.

References and Notes ABBOUD,D. A. ENTWISTLE, R. FAN, R. B. MAURYA,A. J. THORPE,J. BOLONICK, MYERS.Synthesis 1996, 897. 29 A. MARAS,H.SEFEN,Y. SUTBEYAZ, M. BALCI,J . Org. Chem. 1998, 63, 2039. 30 P.A. BARTLETT,K. SATAKE, J . Am. Chem. SOC.1988, 110, 1628. 31 For a highlight on carbohydrate ring contraction reactions see: H . REDLICH, Angew. Chem. Int. Ed. Engl. 1994, 33, 1345. 32 R. J. FERRIER,]. Chem. SOC.Perkin Trans. 1 1979, 1455. 33 a) D.H. R. BARTON,J. CAMARA,P.DALKO, S. D. GERO,B. QUICLET-SIRE, P. STUTZ,J . Org. Chem. 1989, 54, 3764; b) D. J. CLEOPHAX, M. V. DE DUBREUIL, ALMEIDA,C. VERRE-SEBRIE, J. LIAIGRE,G. VASS,S. D. GERO,Tetrahedron 1997, 53, 16747; c) H. TAKAHASHI,H. KITAKA, S. IKEGAMI, J . Org. Chem. 2001, 66, 2705. 34 a) D. H. R. BARTON,S. AUGY-DOREY, J. CAMARA, P. DALKO,J. M. DELAUMENY, S. D. GERO,B. QUICLET-SIRE, P. STUTZ, Tetrahedron 1990, 46, 215; b) S. AUGYDOREY,P. DALKO,S. D. GERO,B. QUICLETSIRE,J. EUSTACHE,P. STUTZ, Tetrahedron 1993, 49, 7997. 35 a) D. J. JENKINS, D. DUBREUIL, B. V. L. POTTER,J . Chern. SOC., Perkin Trans. 1 1996, 1365; b) S. K. CHUNG,S. H . Yu, Y. T. CHANG,J. Carbohydrate Chem. 1998, 17, 385; c) S. K. C H U N G ,S. H. Yu, Bioorg. Med. Chem. Lett. 1996, 6, 1461. 36 a) S. AMANO,N. OGAWA,M. OHTSUKA,S. OGAWA,N. CHIDA,Chem. Commun. 1998. 1263; b) T. MOMOSE,M. SETOGUCHI, T. FUJITA,H. TAMURA,N. CHIDA,Chem. Commun. 2000, 2237; c) S. AMANO,N. TAKEMURA, M. OHTSUKA,S. OGAWA,N. CHIDA,Tetrahedron 1999, 55, 3855; d) S. AMANO,N. OGAWA,M. OHTSUKA,N. CHIDA,Tetrahedron 1999, 55, 2205; e) S. AMANO,N. OGAWA,M. OHTSUKA,S. OGAWA,N. CHIDA,Chem. Commun. 1998, 1263; f ) N. CHIDA,M. JITSUOKA, Y. YAMAMOTO, M. OHTSUKA,S. OGAWA, Heterocycles 1996, 43, 1385; g) N. CHIDA, S. OGAWA,J. Chem. SOC. K. SUGIHARA, Chem. Commun. 1994, 901. 37 C. TAILLEFUMIER, Y. CHAPLEUR, D. BAYEUL,A. AUBRY,J. Chem. SOC.Chem. Commun. 1995,937. 38 a) H. TAKAHASHI, H. KITTAKA,S. IKEGAMI, J. Synth. Org. Chem. Jpn. 2000, 58, 120;

b) H . TAKAHASHI, T. IIMORI,S. IKEGAMI, Tetrahedron Lett. 1998, 39, 6939; c) H. OHTAKE,X. L. LI, M. SHIRO,S. IKEGAMI, Tetrahedron 2000, 56, 7109; d) H . OHTAKE, S. IKEGAMI,Org. Lett. 2000, 2, 457; e) H . TAKAHASHI, H. KITTAKA,S. IKEGAMI, Tetrahedron Lett. 1998, 39, 9703; f ) T. IIMORI,H. TAKAHASHI,S. IKEGAMI, Tetrahedron Lett. 1996, 37, 649. 39 a) S. ADAM,Tetrahedron Lett. 1988, 29, 6589; b) P. LASZLO,A. DUDON,J. Carbohydr. Chem. 1992, 11, 587. 40 a) S. L. BENDER, R. J. BUDHU,J. Am. Chem. SOC.1991, 113, 9883; b) V. A. ESTEVEZ,G. D. PRESTWICH,].Am. Chem. SOC.1991, 113, 9885; c) J. CHEN,L. FENG, Org. Chem. 1998, 63, G. D. PRESTWICH,~. 6511; d) J. CHEN,G . D. PRESTWICH, J . Org. Chem. 1998, 63,430; e) Q. M. Gu, G. D. J. Org. Chem. 1996, 61, 8642; PRESTWICH, f ) A. CHAUDHARY, G. D. PRESTWICH, Bioconjugate Chem. 1997, 8, 680; g) 0. THUM,J. CHEN,G. D. PRESTWICH, Tetrahedron Lett. 1996, 37, 9017; h) J. R. PENG,G. D. PRESTWICH,Tetrahedron Lett. 1998, 39, 3965; i) J. C H E N ,A. A. PROFIT, G. D. PRESTWICH, J . Org. Chem. 1996, 61, 6305; j) J. CHEN,G. DORMAN,G. D. J . Org. Chem. 1996, 61, 393; PRESTWICH, k) G. DORMAN,J. C H E N ,G. D. PRESTWICH, Tetrahedron Lett. 1995, 36, 8719. 41 P. BEIANGER,P. PRASIT,Tetrahedron Lett. 1988, 29, 5521. 42 S. K. DAS, J.-M. MALLET,P.SINAY,Angew. Chem. Int. Ed. Engl. 1997, 36, 493. 43 see also: P. A. V. VAN HOOFT,R. E. J. N. LITJENS,G. A. VAN D E R MAREL,C. A. A. VAN BOECKEL, J. H. VAN BOOM,Org. Lett. 2001, 3, 731. 44 a) M. SOLLOGOUB, A. J. PEARCE, A. HERAULT,P. SINAY, Tetrahedron:Asymmetry 2000, 11, 283; b) M. SOLLOGOUB, J. M. MALLET, P. SINAY.Angew. Chem. Int. Ed. 2000, 39, 362. 45 a) B. D u ROIZEL,A. M. P. HENRIQUES, A. J. PEARCE,P. SINAY,IsraelJ. Chem. 2000, 40, 317; b) A. J. PEARCE,J. M. MALLET,P. SINAY,Heterocycles 2000, 52, 819; c) A. J. PEARCE,R. CHEVALIER, J.-M. MALLET,P. SINAY,Eur. J. Org. Chem. 2000, 2203; d) J. PEARCE,M. SOLLOGOUB, J.-M. MALLET,P. SINAY,Eur.J. Org. Chem. 1999, 3105. 46 For related Lewis acid mediated rearrangements of cyclic vinyl acetals affording

14

I

Direct Conversion of Sugar Clycosides into Carbocycles

47 48

49 50

51

52

53

tetrahydrofuranes o r tetrahydropyranes see: a) N. A. PETASIS,S:P. Lu, /. Am. Chem. SOC. 1995, 117, 6394; b) N. A. PETASIS,S.-P. Lu, Tetrahedron Lett. 1996, 36, 141; c) H.-D. SCHARF,H. FRAUENRATH,Chem. Ber. 1982, 115, 2728; d) R. MENICAGLI, C. MALANGA, M. G U I D I ,L. LARDICCI,Tetrahedron, 1987, 43, 171; e) D. J. DIXON,S. V. LEY,E. W. TATE,/. Chem. SOC., Perkin Trans. I 2000, 2385; f ) R. MENICAGLI, C. MALANGA, L. LARDICCI,J. Org. Chem. 1982, 47. 2288; g) R. MENICAGLI, C. MALANGA, M. DELL’INNOCENTI, L. ~ R D I C C/.I Org. , Chem. 1987, 52, 5700; h) A. B. SMITH, I l l , K. P. MINBIOLE, P. R. VERHOEST,M. /. Am. Chem. SOC.2001, 123, SCHELHAAS, 10942; i) A. B. SMITH,P. R. VERHOEST, K. P. MINBIOLE, J. J. LIM, Org. Lett. 1999, I, 909; j) A. B. SMITH,K. P. MINBIOLE, P. R. VERHOEST, T. J. BEAUCHAMP, Org. Lett. 1999, I, 913 a n d references cited. M. SOLLOGOUB, J.-M. MALLET,P. SINAY, Tetrahedron Lett. 1998, 39, 3471. H. ITO,Y. MOTOKI,T. TAGUCHI,Y. HANZAWA, /. Am. Chem. SOC. 1993, 115, 8835. Y. YOSHIDA, T. NAKAGAWA, F. SATO,Synlett 1996.437. a) J. M. AURRECOECHEA, B. LOPEZ,M. ARRATE,/. Org. Chem. 2000, 65, 6493; b) J. M. AURRECOECHEA, M. ARRATE,B. LOPEZ,Synlett 2001, 872. A. CHENEDB,P. POTHIER,M. SOLLOGOUB, A. J. FAIRBANKS, P. SINAY,J. Chem. SOC. Chem. Commun. 1995, 1373. a) T. KAN,S. NARA,T. OZAWA,H. F. MATSUDA,Angew. Chem. SHIRAHAMA, Int. Ed. 2000, 39, 355; b) F. MATSUDA, /. Synth. Org. Chem. Jpn. 1995, 53, 987; c) J. J. C. GROVE,C. W. HOLZAPFEL, D. B. G. WILLIAMS,Tetrahedron Lett. 1996, 37, 5817; d) 2. H . ZHOU,S. M. BENNETT, Tetrahedron Lett. 1997, 38, 1153; e) J. L. CHIARA,J. MARCO-CONTELLES, N. KHIAR, P. GALLEGO, C. DESTABEL, M. BERNABE,/. Org. Chem. 1995, 60, 6010. a) J. K. GALLOS, T . V. K O F T I S , ~Chem. . SOC. Perkin Trans. 12001, 415; b) J. K. GALLOS,

T. V. KOFTIS,A. E. KOUMBIS,V. I. MOUTSOS,Synlett 1999, 1289; c) J. K. E. E. SPATA,Eur. GALLOS,C. C. DELLIOS, /. Org. Chem. 2001, 1, 79; d) J. K. GALLOS, V. P. XIRAPHAKI,C. C. A. E. KOUMBIS, DELLIOS,E. COUTOULI-ARGYROPOULOU, Tetrahedron 1999, 55, 15167; e) J. K. GALLOS,A. E. KOUMBIS, N. E. APOSTO-

54

55 56

57

58 59 60

61

LAKIS, J. Chem. SOC., Perkin Trans. I 1997, 2457. a ) L. A. PAQUETTE, C. M. G. PHILIPPO, N. H. Vo; Can.J. Chem. 1992. 70, 1356; b) C. M. G. PHILIPPO,N. H. Vo, L. A. J . Am. Chem. 1991, 113, 2762; PAQUETTE, c) L. A. PAQUETTE,D. FRIERICH,R. D. ROGERS, J. Org. Chem. 1991, 56, 3841: M. A. M. FUHRY,A. B. HOLMES,D. R. MARSHALL, /. Chem. SOL., Perkin Trans. I 1993, 2743 a n d references. B. WERSCHKUN, J. THIEM,Angew. Chem. Int. Ed. Engl. 1997, 36, 2793. a ) W. WANG,Y. ZHANG,M. SOLLOGOUB, P. SINAY,Angew. Chem. Int. Ed. 2000, 39, 2466; b) W. WANG,Y. ZHANG,H . Z H O U , Y. BLERIOT,P. SINAY,Eur. J. Org. Chem. 2001, 1053. P. A. V. VAN HOOFT,G. A. VAN D E R MAREL,C. A. A. VAN BOECKEL, J. H. VAN BOOM,Tetrahedron Lett. 2001, 42. 1769. A. V. R. L. SUDHA,M. NAGARAJAN,/. Chem. SOC. Chem. Commun. 1998, 925. G . BUCHI, J. E. POWELL JR.,/. Am. Chem. SOC.1967, 89, 4559. For selected examples see: a) T. K. M. SHING,D. A. ELSLEY, J. G. GILLHOULEY, J. Chem. SOC. Chem. Commun. 1989, 1280; b) S. JIANG,K. J. MCCULLOUGH, B. MEKKI, G. SINGH,R. H . WIGHTMAN,]. Chem. SOC., Perkin Trans. 11997, 1805; c) S. D. JIANG,B. MEKKI,G. SINGH,R. H. WIGHTMAN,Tetrahedron Lett. 1994, 35, 5505; d) R. A. FARR,N. P. PEET,M. S. KANG,Tetrahedron Lett. 1990, 31, 7109; N. P. PEET,E. W. HUBER,R. A. FARR, Tetrahedron 1991, 47, 7537; e) K. VANHESSCHE, C. G. BELLO,M. VANDEWALLE, Synlett 1991, 921. S. JIANG,G. SINGH,A. S. BATSANOV, Tetrahedron:Asymmetty 2000, 1 I, 3873.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Synthesis o f Diary1 Ethers: A Long-standing Problem Has Been Solved Fritz Theil

Until quite recently the synthesis of diaryl ethers has not been an easy task unless the target molecule was not sensitive towards the very harsh reaction conditions employed. The diaryl ether structural unit (Figure 1) is found in natural products such as perrottetines (1) [l],their cyclic analogues [lb], riccardin B (2) 121, and a variety of more complex molecules containing sensitive functional groups and stereogenic centres [ 31 to which for example the cyclic peptides K 13 (3) [ 3 ] and vancomycin [4,51 belong. The diaryl ether formation in cyclic peptides was reviewed by Rama Rao et al. [6] in 1995. Furthermore, poly (aryl ethers) such as 4 are important commercial polymers used as engineering thermoplastics [ 71. Both the synthesis of highly functionalized molecules and the large-scale preparation of polymers are challenging tasks for synthetic organic chemists. However, the classical arylation procedure of phenols with aryl halides under Ullmann conditions [S] using copper powder or copper salts requires harsh reaction conditions as a result of the poor nucleophilicity of the phenoxide and the low reactivity of the aryl halides involved. The reactions have to be carried out in a temperature range of 120-250 "C by using high boiling solvents or neat reagents over an extended period of time. These conditions have been applied to the synthesis of relatively simple diaryl ethers such as riccardin B (2), which lacks sensitive functional groups, by using a copper phenoxide and an aryl bromide in refluxing pyridine for twenty hours. For the preparation of poly (aryl ethers), the most reactive electrophiles towards sodium phenoxides are aryl fluorides and triflates. In a model reaction complete conversion has been achieved at 150 "C in N-methyl-2-pyrrolidinone (NMP) within four hours if both the haloarene and the phenol are activated by a paracarbonyl group (Scheme 1)191. The structural relevance of diaryl ethers and the lack of a convenient, mild and general method for their preparation has resulted in increased efforts towards filling this gap in the synthetic methodology during the past decade. Yamamura et al. [lo] developed a method that encompasses the oxidative coupling of 2,6-dihalophenols with T1(N03)3to afford a 2-substituted quinone, which subsequently is reduced to the corresponding diaryl ether. This procedure has been applied by the Evans group [ 111 for the synthesis of the orienticin C aglycone. Despite the fact that this reaction is conducted under mild conditions, it is nevertheless a two step procedure that requires a

16

I

Synthesis of Diaryl Ethers: A Long-standingProblem Has Been Solved

R'

HO

OH

HO

2

1

HO

Y = S(=O),,

3

c=o 4

Fig. 1. Examples for the diaryl ether function in natural products and synthetic polymers. R', RZ in 1 = H,OH,OMe.

ONa

I

NMP, 150 "C

X = F, OSO,CF, Scheme 1.

Diaryl ether formation from para-carbonyl activated phenolates and arylfluorides or triflates

specific type of substituted phenol and a highly toxic thallium salt. These requirements preclude it from being a general user-friendly method. The recent development directed towards the synthesis of diaryl ethers in a milder and more efficient manner was mainly driven by the synthesis of complex natural products. Eicher and Walter [ 11 introduced an activating ortho-nitro group in their synthesis of diaryl ethers (Scheme 2a), thus increasing the reactivity of aryl halides towards phenoxides s i g nificantly so that a reaction temperature of 125 "C for less than one hour was required. By using this coupling procedure perrottetines (1) [la], and very recently their cyclic analogues

Synthesis ofDiaty/ Ethers: A Long-Standing Problem Has Been Sobed 117

X = CI. F

0 rlJ

0 N I

KN

kN CuBr-SMe,, K,CO,

xR'J (

+

HoQ R2

MeCNIpyridine, 80 "C*

R'

bOQ R'

X = Br, I Diary1 ether formation by orthoactivation. a) Methods of Eicher et al. and Zhu et al., (R' = 4-CHO, 4-C02Me, 4CH2CH(NHBoc)C02Me; R2 = 2-OMe-4-CH0, 2.3(OMe)2-4-C02Me, 4-CH2CH(NH B0c)COzMe), Scheme 2.

b) Method of Nicolaou et al. (R' = 3-Me, 5-Me, 3,5-Me2; R2 = 2-CI, 4 4 , 2-CI-4-Me).1) NaH, DMF, 125 "C (X = CI); 2) NaZCO3 or CsF, DMF, 25 "C (X = F).

[Ib] under even milder conditions, have been synthesized. As reported by Zhu [3], phenoxides react smoothly at room temperature when ortho-nitro fluoro arenes are used as electrophiles. This approach has been applied to the synthesis of a variety of macrocyclic diaryl ethers [ 31 including vancomycin [4a, b] and its subunits [ 12a] or related compounds [ 12b]. However, this method requires subsequent reduction and deamination steps in order to remove the nitro group unless the target molecule bears this functional group. The approach from Nicolaou [ 131 is similarly based on the activation of an aryl halide. Aryl bromides and iodides substituted with ortho-triazene react smoothly with phenols at 80 "C in the presence of KZC03 and CuBr.MezS to afford diaryl ethers in good yields (Scheme 2b). The use of this procedure requires the preformation of the requisite triazenes and the subsequent removal or transformation of this functional group. Alternatively, chloroarenes can be activated via the formation of manganese, chromium, iron or ruthenium n-complexes that react at low temperature with phenoxides to yield diaryl ethers [14]. Higher temperatures (DMF, 90 "C) require the formation of diaryl ethers from iodonium salts and phenoxides [ 151 and the coupling of bromo benzoquinones with phenoxides (DMF, 100-110 "C) followed by a subsequent reduction with dithionite [lG]. Palladium catalyzed couplings between sodium phenoxides and electron deficient aryl bromides have been reported by Hartwig et al. [I71 based on an in-situ-ligand exchange of dibenzylideneacetone (dba) with 1,l'-diphenylphosphinoferrocene(dppf) [ 17a] (Scheme 3a). Further improvements of this methodology have been achieved for unactivated aryl halides by the Hartwig group by using ferrocenyldi-tert-butylphosphine instead of dppf [17b] or the as the palladium ligand [ 17~1. Buchwald group by using 2-(di-tert-butylphosphino)biphenyl The reactions still need relatively high temperatures and long reaction times.

18

I

Synthesis ofDiary1 Ethers: A Long-Standing Problem Has Been Solved

a)

(CuOTf),PhH, EtOAc R2

R'

Cs,CO,,

toluene, 110 "C

X = Br, I Palladium- a n d copper triflate-catalyzed diarylether synthe. sis. a) R' = CN, CHO, COCFj, COPh; R2 = Me, O M e ; b) R' = 4-CI, 4-C02Et. 4-Me, 4431.1, 4-OMe, 4-NMe2, 4-CN, 4-COMe, 2,5-Me2, 3,sMe2; R2 = 2-Me. 4-Me, Z-iPr, 4-CI, 3,4-Me?. Scheme 3.

Another phenoxide activating approach published by Buchwald et al. [ 181 is based on the reaction of cesium phenoxides with aryl bromides or iodides in the presence of catalytic amounts of copper(1) triflate and ethyl acetate in refluxing toluene (Scheme 3b). In certain cases equimolar amounts of 1-naphthoic acid have been added in order to increase the reactivity of the phenoxide. The authors assume the formation of a cuprate-like intermediate of the structure [(Ar0)2Cu]-Csf as the reactive species. In addition, diaryl ether formation between phenols and aryl halides has been achieved using a phosphazene base forming naked phenoxide in the presence of copper bromide in refluxing toluene or 1,4-dioxane [19]. Besides, an enzymatic approach has been developed by Sih and his group by using an oxidative coupling of tyrosine or hydroxyphenylglycine units by hydrogen peroxide in the presence of peroxidases followed by a subsequent reduction step (Scheme 4). Yields in general are moderate and sometimes low. Dependent on the pH of the medium, diaryl ether formation is accompanied by more or less C-C-coupling reactions.

x+x

H,O,.

&:ex pH 4-6

R

CrCI, or NaHSO,

OH

R

R Enzymatic diaryl ether formation. X = F, CI, Br; X' = CI, Br, H; R = C H * C H ( N H A c ) C 0 2 H , (CH?)?NHAc, CH(NHAc)CO2Me.

Scheme 4.

Synthesis o f D i a v / Ethers: A Long-standing Problem Has Been Solved

Finally, the remarkably simple solution came from Evans et al. [2la] and researchers of DuPont [2lb] simultaneously. Their method allows the coupling of structurally and electronically diverse phenols and aryl boronic acids in the presence of copper(11) acetate, triethylamine or pyridine, and molecular sieves at ambient temperature (Scheme 5). Even phenolic amino acid derivatives react smoothly without racemization. The only limitation has been observed when using ortho-heteroatom substituted boronic acids which resulted in lower product yields. The initial step in the proposed pathway (Scheme G) is the transmetallation of the boronic acid residue with the copper salt.

RIW

$2

Copper(l1)-promoted coupling of boronic acids with phenols. R' = 4-Me, 2-CI, 2-1, 2-OMe, ~ - C H ~ C H ( N H B O C ) C O3,s. ~M~, tBu2; R2 = 4-Me, 4-F, 4-OMe, 3-OMe, 3-NO2, 2-Me, 2-OMe, 3-CI-4-F.

Scheme 5.

L

reductive

At-0-

/ Ar'

'OAr'

L Ar/\c$k \OAr' d elimination v e Scheme 6.

Proposed mechanism for the copper(l1)-promoted coupling o f boronic acids with phenols.

The solution of this long-standing problem has been achieved by application of this general method that allows for the coupling of diverse phenols with a variety of aryl boronic acids, many of which are commercially available. It overcomes problems associated with procedures used before and offers significant advantages such as a broad substrate variety, mildness and avoids the use of highly toxic materials. In addition, under the reaction conditions employed N-arylation of different types of Nnucleophiles has been achieved [ 21b]. By using this mild and versatile methodology, symmetrical diaryl ethers have been synthesized in a one-pot, two-step procedure starting from arylboronic acids and their partial conversion to the corresponding phenols by oxidation with hydrogen peroxide and a subsequent coupling of the formed phenols with the remaining arylboronic acids upon addition of copper(I1) acetate, molecular sieves and triethyl amine (Scheme 7) [22]. A much more detailed discussion of the most recent developments in inter- and intramolecular diaryl ether formation can be found in the literature [23].

20

I

Synthesis of Diary/ Ethers; A Long-Standing Problem Has Been Solved 1. HO ,,

CH,CI,

(30%)

-

2.Cu(OAc),, NEt, MS (4A). 25 "C

R

One-pot conversion of arylboronic acids into diary1 ethers. R = 3-NO2, 4-Me, 4-OMe, 4-Ac, 4-F, 4 4 , 4-Br.

Scheme 7.

References 1 a) T. EICHER,M. WALTER,Synthesis 1991,

W. LABADIE, J. L. HEDRICK,M. UEDA, Am. Chem. SOC.Symp. Ser. 1996, 624, 210-

7 J.

469-473; b) T. EICHER,S . FEY,W. PUHL,

2 3

4

5

6

E. BUCHEL,A. SPEICHER, Eur. ]. Org. Chem. 1998, 877-888. M. IYODA,M. SAKAITANI, H. OTSUKA,M. ODA,Tetrahedron Lett. 1985, 26, 4777-4780. a) J. ZHU, Synlett 1997, 133-144, b) A. BIGOT,M. BOIS-CHOUSSY, J. ZHU, Tetrahedron Lett. 2000, 41, 4573-4577. Vancomycin syntheses: a) D. A. EVANS, M. R. WOOD,B. W. T R O ~ E T. R , I. RICHARDSON, J. C. BARROW,J. L. KATZ, Angew. Chem. 1998, 110, 2864-2868; Angew. Chem. Int. Ed. 1998, 37, 27002704; b) D. A. EVANS,C. J. DINSMORE, P. S. WATSON,M. R. WOOD,T. I. RICHARDSON, B. W. TROTTER,J. L. KATZ, Angew. Chem. 1998, 110, 2868-2872, Angew. Chem. Int. Ed. 1998, 37, 2704S. NATARAJAN, 2708; c) K. C. NICOLAOU, H. LI, N. F. JAIN,R. HUGHES,M. E. SOLOMON, J. M. RAMANJULU, C. N. C. BODDY,M. TAKAYANAGI, Angew. Chem. 1998, 110, 2872-2878 Angew. Chem. Int. Ed. 1998, 37, 2708-2714; d) K. C. NICOIAOU,N. F. JAIN,S. NATARAJAN, R. HUGHES,M. E. SOLOMON, H. LI, J. M. RAMANJULU, M. TAKAYANAGI, A. E. KOUMBIS,T. BANDO,Angew. Chem. 1998, 110, 2879-2881, Angew. Chem. Int. Ed. 1998, 37, 2714-2716; e) K. C. NICOLAOU, M. TAKAYANAGI, N. F. JAIN,S. NATARAJAN, A. E. KOUMBIS, T. BANDO,J. M. RAMANJULU, Angew. Chem. 1998, 110, 2881-2883, Angew. Chem. Int. Ed. 1998, 37, 2717-2719. Highlight on the vacomycin syntheses: A. J. ZHANG,K. BURGESS, Angew. Chem. 1999, 11 1, 666-669, Angew. Chem. Int. Ed. 1999, 38, 634-636. A. V. RAMA RAo, M. K. GURJAR,K. L. REDDY,A. S. RAO, Chem. Rev. 1995, 95, 2135-2167.

225. 8 J. LINDLEY, Tetrahedron 1984, 40, 1433-

1456. 9 H. JONSSON, J. L. HEDRICK,J. W. LABADIE,

Polymer Prepnnts 1992, 33, 394-395. H. NODA,M. NIWA,S. YAMAMURA, Tetrahedron Lett. 1981, 22, 3247-3248. For further applications of this methodology by Yamamura's group and others see [ 61. 11 D. E. EVANS,C. J. DINSMORE, A. M. RATZ, D. A. EVRARD,J. C. BARROW,].Am. Chem. SOC.1997, 119,4317-3418. 12 a) D. L. BOGER,R. M. BORZILLERI, S. NUKUI,R. T. BERESIS, /. Org. Chem. 1997, 62, 4721-4736, b) L. NEUVILLE, M. BoisCHOUSSY,J. ZHU, Tetrahedron Lett. 2000, 10

41, 1747-1751. 13

14

15 16

17

K. C. NICOLAOU, C. N. C. BODDY,S. NATARAJAN, T.-Y. YUE, H. LI, S. B R ~ S E , J. M. RAMANJULU, J . Am. Chem. SOC. 1997, 119, 3421-3422. a ) A . J. PEARSON, J. G. PARK,P. Y. ZHU,]. Org. Chem. 1992, 57, 3583-3589; b) A. J. PEARSON, K. LEE,]. Org. Chem. 1994, 59, 2304-2313; c) A. J. PEARSON,P. 0. BELMONT,Tetrahedron Lett. 2000, 41, 1671-1675; d) M. F. SEMMELHACK in Comprehensive Organometallic Chemistry II? Vol. 12 (Ed.: E. W. ABEL,F. G. A. STONE, G. WILKINSON), Pergamon, NY, 1995, p. 979. M. J. CRIMMIN,A. G. BROWN,Tetrahedron Lett. 1990, 31, 2017-2020. B. SIMONEAU, P. BRASSARD,].Chem. SOC. Perkin Trans. 1, 1984, 1507-1510. For further applications of this method see (61. a) G. MANN,J. F. HARTWIG,Tetrahedron Lett. 1997, 38, 8005-8008; b) G . MANN, C. INCARVITO, A. L. RHEINGOLD, J. F. HARTWIG,]. Am. Chem. SOC. 1999, 121, 3224-3225; c) A. ARANYOS, D. W. OLD,

References 121

A. KIYOMORI,1. P. WOLFE,I. P. SADIGHI; S. L. BUCHWALD,]. Am. Chem. SOC.1999, 121, 4369-4378. 18 J.-F. MARCOUX, S. DOYE,S. L. BUCHWALD, I.Am. Chem. SOC. 1997, 119,10539-10540. 19 C. PALOMO, M. OIARBIDE, R. LOPEZ, E. GOMEZ-BENGOA, Chem. Commun. 1998, 2091-2092. 20 a) 2. Guo, G. M. SAIAMONCZYK, K. HAN, K. MACHIYA, C. J. SIH,]. Org. Chem. 1997, 62, 6700-6701; b) 2. G u o , G. M. SAJAMONCZYK, K. HAN,K. MACHIYA, C. J . SIH,J. Org. Chem. 1998,63, 4269-4276;

21

c) I. MALNAR, C. J. SIH, Tetrahedron Lett. 2000, 41, 1907-1911 and references cited therein. a) D. E. EVANS,I. L. KATZ,T. R. WEST, Tetrahedron Lett. 1998,39, 2937-2940; b) D. M. T. CHAN,K. L. MONACO,R.-P.

WANG,M. P. WINTERS,Tetrahedron Lett. 1998,39, 2933-2936. 22 J. SIMON,S. SALZBRUNN, G. K. S. PRAKASH, N. A. PETASIS,G. A. OIAH,]. Org. Chem. 2001, 66, 633-634. 23 J. S. SAWYER, Tetrahedron, 2000, 56, 50455065.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

** I

Take The Right Catalyst: Palladium-catalyzed CC, CN and CO-Bond Formation on Chloro-Arenes Rainer Sturmer

Chlorinated arenes are cheap to manufacture and therefore play a vital role as intermediates in chemical industry. However, in contrast to their - much more expensive - brominated and iodinated counterparts chloroarenes are quite unreactive in subsequent reactions. Classical functionalizations of the C-CI- bond in non-activated arenes usually require harsh conditions and side reactions may produce environmentally hazardous oxygenated chloroarenes. This leads to considerable problems in using these compounds as intermediates in the synthesis of higher functionalized biologically active molecules, e.g. agrochemicals and pharmaceuticals. Due to recent developments in catalysis former problems might be overcome: The groups of S. L. Buchwald, G. C. Fu and J. F. Hartwig among others reported significant improvements on the CC, CN and CO-Bond formation on chloroarenes. For all of these bond formations the right choice of catalyst is crucial for success. In other words: by ligand tuning all three bond forming reactions can be realized by palladium catalysis. The following account focuses on recent work, since the subject has been already reviewed [ 11. Heck and Suzuki type couplings have been described by Fu [2] et al. The reaction of chlorobenzene and styrene in refluxing dioxane in the presence of [Pd2(dba)3]and the electron rich tri-tert.-butyl-phosphane [eq. (a)] gives rise to trans-stilbene in 83% yield. Besides the choice of the ligand - aryl phosphanes, tri-n-butyl-phosphane or tri-cyclohexyl-phosphane show no conversion - the base is also crucial for success. Cesium carbonate gives the best results, although the cheaper potassium phosphate gives comparable yields.

\

*#

1.5 rnol-% [Pd2(dba)3]

(JQ-

/

(a)

6 mol-% P(Wu),

Cs2CO3 Scheme 1.

83 %

Take The Right Catalyst: Palladium-catalyzedCC, CN and CO-Bond Formation on Chloro-Arenes

Under the same conditions the sterically more demanding 2-chlorotoluene is coupled in 70% yield. However longer reaction times are necessary. Acceptor- as well as donorsubstituents are tolerated under these conditions. Tri-tea.-butyl-phosphane is the ligand of choice in Suzuki-couplings [ 31 as well: 2-chlorotoluene reacts with 2-methyl-phenylboronic acid to 2,2'-disubstituted biphenyl in 87% yield [eq. (b)].

B(oH)2

o("'+ 0:

1.5 r n o l - O h [Pd2(dba)3]

* 3.6 rnol-% P ( ~ B u ) ~

f l

(b)

87 Yo Scheme 2.

Another contribution from Fu [4]et al. describes the Stille-coupling of chloroarenes, in which vinyl-, allyl-, phenyl-, and even alkyl groups can be transferred in the presence of cesium fluoride. An improved procedure of Suzuki-couplings was recently described by Buchwald [ 51 et al. By using 0-(di-tert.buty1-phosphin0)-biphenylas ligand, palladium acetate and potassium carbonate couplings are facilitated at room temperature [eq. (c)].

B(OH)z OMe

1 mol-% Pd(OAc)2 >

(c)

2 mol-%

95 Yo

RT Scheme 3.

Catalyst concentrations may be kept quite low in the range of 0.02-0.05 mol%. In a similar context Hartwig [GI et al. published a screening method aiming at the rapid identification of efficient ligands in Heck-type couplings based on a fluorescence assay. Arylations of ketones and malonates with aryl chlorides have been recently published [eq. (d)] by the same research group [7]. Electron rich phosphanes are used to secure good conversions.

( ~ c +l /

6

2 mol-% Pd(0Ac)p

50'C, 12 h Scheme 4.

(a

2 mob% P ( C Y ) ~

93 %

I

23

24

I

Take The Right Catalyst: Palladium-catalyzed CC,

CN and CO-Bond Formation on Chloro-Arenes

0-(Di-tert.-buty1phosphino)biphenyl has been used by Buchwald IS] et al. as the most efficient ligand in the Pd-catalyzed amination of aryl chlorides. 2-Chloro-4-methyl-toluene can be aminated with pyrrolidine in 98% yield using sodium-tert.-butoxide [eq. (e)].

98 %

RT Scheme 5.

These reactions went to completion at room temperature within 15-20 hours; donor- and acceptor-substituents are tolerated. Pd-catalyzed CO- bond forming reactions were performed by Buchwald [ 8 ] et al. with 2-dimethylamino-2’-di-(tert.-butyl)-biphenyl as ligand. 3,4-Dimethylphenol can be arylated smoothly with 2-chloro-4-methyl-toluenein the presence of sodium hydride [eq. (f)].

1 mob% Pd(OAc),

*

2 mol-% P(m2

&p

(f)

78 %

Me2N Scheme 6.

Hartwig [91 et al. developed a novel ferrocene-based dialkyl-phosphine-ligand for this arylation: 2-methoxy-4-methyl-phenolis arylated with 2-chloro-pxylene in 81% yield [eq. (g)].

a:+ *no& (9)

OMe 2 mob% [Pd2(dba)s] 4 mol-% FcP(tBu)2

81 % Scheme 7.

Recent work from Lipshutz [lo] et al. even shows at least in CC-bond formations the replacement of the rather expensive palladium with nickel. Chloroarenes are coupled with organo zink compounds under nickel(0) catalysis.

References 125

After the original publication of this highlight in 1999 more than 300 related papers have appeared in the field. A complete coverage is well beyond the scope of this book. Therefore only an update on some selected developments is given. Carbonylations [ 111 and Cyanations [ 121 of chloroarenes have been described by Beller et al. Several new catalysts have been introduced during the past two years; especially noteworthy are nucleophilic carbene-ligand based catalysts developed [ 131 by Herrmann’s group among others. A saturated variant has been established by Hartwig et al. Related work with donor-substituted carbenes has been published [ 151 by McGuiness and Cavell. Several detailed mechanistic papers have been published by Hartwig [ 161 et al. Palladacycles [ 171 have been established as important class of catalysts, an unusual phosphine-free sulfur containing catalyst was introduced by Zim [ 181 et al. A phosphinite based palladacycle [ 191 proved to be very efficient in Suzuki coupling reactions. An N,P-Ligand type was synthesized by Kocovsky [20] et al. Tridentate pincer ligands [21] have been proved useful in the Heck reaction. Recent developments regarding Heck 1221 and Suzuki [23] reactions have been reviewed by Fu and Littke. A new catalyst especially suitable for Heck couplings has been introduced by Beller [24] et al. Carbene [25] - as well as phosphine [26] ligands have been attached to polymer supports and proved to be recyclable catalysts in the Heck reaction. With special regard to CO-bond formation including intra-molecular examples two papers by Buchwald [27] have been published. Recent advances in amination chemistry was highlighted by Buchwald [28] and Hartwig [29]. Besides palladium nickel [ 301 evolved as a suitable metal for several coupling reactions. For quite a long time chloroarenes were considered as too unreative for catalysis. However the significant improvements in various coupling reactions of chloroarenes by the use of electron rich phosphanes have rendered this statement as no longer valid. The use of these cheap intermediates as coupling partners in the synthesis of higher functionalized molecules of industrial relevance is now within reach. Since some of these ligands are already commercially available it’s probably only a question of time when we will see the first industrial applications of these improved procedures.

References a) M. BELLER, T. H. RIERMEIERin Transition Metals for Organic Synthesis, Vol. 1 (Hrsg.: M. BELLER, C. BOLM): Wiley-VCH, Weinheim, 1998, S. 184-193; M. BELLER, T. H. RIERMEIER, G. STARKibid. S. 208Angew. Chem. 1998, 236; b) J. F. HARTWIG, 110, 2154-2177, Angew. Chem. Int. Ed. 1998, 37, 2046-2067; c) B. H. YANG, S. L. BUCHWALD, 1. Organomet. Chem. 1999, 576, 125-146. z A. F. LITTKE,G. C. Fu,J. Org. Chem. 1999, 64, 10-11. 3 A. F. LITTKE,G. C. Fu, Angew. Chem. 1998,

1

110, 3586-3587, Angew. Chem. Int. Ed. 1998, 37, 3387-3388. 4 A. F. LIITKE,G. C. Fu, Angew. Chem. 1999, 111, 2568-2570; Angew. Chem. Int. Ed. 1999, 38, 2411-2413. 5 a) J. P. WOLFE, S. L. BUCHWALD,Angew. Chem. 1999, 111, 2570-2573; Angew. Chem. Int. Ed. 1999, 38, 2413-2416; b) R. A. SINGER, S. L. BUCHWALD,Tetrahedron Lett. 1999, 40, 1095-1098. 6 K. H. SHAUGNESSY, P. KIM, J. F. HARTWIG, J . Am. Chem. Soc. 1999, 121, 2123-2132.

26

I

Take The Right Catalyst: Palladium-catalyzedCC, CN and CO-Bond Formation on Chloro-Arenes 7

8

9

10

11 12

13

14

15 16

17 18

M. KAWATSURA, J. F. HARTWIG,/. Am. Chem. SOC.1999, 121, 1473-1478. A. ARANYOS, D. W. OLD,A. KIYOMORI, J. P. WOLFE,J . P. SADIGHI,S. L. BUCHWALD,/.Am. Chem. SOC.1999, 121, 43694378. G. MANN,C. INCARVITO, A. L. RHEINGOLD, J. F. HARTWIG,/.Am. Chem. SOC.1999, 121, 3224-3225. a) B. H. LIPSHUTZ, P. A. BLOMGREN, /. Am. Chem. SOC.1999, 121, 5819-5820; b) B. H. LIPSHUTZ, T. TOMIOKA, P. A. J. A. SCLAFANI, Inorg. Chim. BLOMGREN, Acta 1999, 296, 164-169. M. BELLER, A. F. INDOLESE, Chimiu 2001, 55, 684-687. M. SUNDERMEIER, A. ZAPF,M. BELLER,J. SANS,Tetrahedron Lett. 2001, 42, 67076710. a) W. A. HERRMANN, V. P. W. BOHM, C. W. K. GSTOITMAYR, M. GROSCHE, C. P. REISINGER,T. WESKAMP, /. Orgunomet. Chem. 2001, 617, 616-628; b) T. WESKAMP,V. P. W. BOHM,W. A. HERRMANN, J . Organomet. Chem. 1999, 585, 348-352; c) C. ZHANG,J. HUANG, M. L. TRUDELL, S. P. NOLAN,/.Org. Chem. 1999, 64, 3804-3805. S. R. STAUFFER,S. W. LEE, J. P. STAMBULI, S. I. HAUCK,J. F. HARTWIG, Org. Lett. 2000, 2, 1423-1426. D. S. MCGUINNESS, K. J. CAVELL, Orgunometallics 2000, 19, 741-748. a) L. M. ALCAZAR-ROMAN, J. F. HARTWIG, A. L. RHEINGOLD,L. M. LIABLE-SANDS, I. A. GUZEI,/. Am. Chem. SOC.2000, 122, 4618-4630; b) A. H. ROY, J. F. HARTWIG, /. Am. Chem. SOC. 2001, 123, 12321233. V. P. W. BOHM, W. A. HERRMANN, Chem. Eur. /. 2001, 7,4191-4197. D. ZIM,A. S. GRUBER, G . EBELING, J.

19 20

21 22 23 24 25

26 27

28

29

30

DUPONT,A. L. MONTEIRO, Org. Lett. 2000, 2, 2881-2884. R. B. BEDFORD,S. L. WELCH,Chem. Commun. 2001, 129-130. P. KOCOVSKY, S. VYSKOCIL, I. CISAROVA, J. SEJBAL, 1. TISLEROVA, M. SMRCINA, G . C. LLOYD-JONES,S. C. STEPHEN, C. P. Burrs, M. MURRAY,V. LANGER,]. Am. Chem. SOC. 1999, 121, 7714-7715. D. E. BERGBREITER, P. L. OSBURN, Y.-S. LIU. J. Am. Chem. SOC.1999, 121,9531-9538. A. F. LITTKE, G. C. Fu,/. Am. Chem. SOC. 2001, 123, 6989-7000. A. F. LITTKE, G. C. Fu,]. Am. Chem. SOC. 2001, 123, 2719-2724. A. EHRENTRAUT,A. ZAPF,M. BELLER, Synlett 2000, 1589-1592. J. SCHWARZ, V. P. W. BOHM, M. G. GARDINER, M. GROSCHE, W. A. H E R R M A N W. N , HIERINGER, G. RAUDASCHL-SIEBER, Chem. Eur. /. 2000, 6, 1773-1780. C. A. PARRISH, S. L. BUCHWALD,/. Org. Chem. 2001, 66, 3820-3827. a) S. KUWABE, K. E. TORRACA, S. L. BUCHWALD, /. Am. Chem. Soc. 2001, 123, X. H . 12202-12206; b) K. E. TORRACA, H U A N GC. , A. PARRISH, S. L. BUCHWALD, /. Am. Chem. SOC.2001, 123, 10770-10771. J. P. WOLFE,H. TOMORI;J. P. SADIGHI; J. J. Y I N , S. L. BUCHWALD, 1. Org. Chem. 2000, 65, 1158-1174. J. F. HARTWIG,M. KAWATSURA, S. I. HAUCK,K. H. SHAUGHNESSY, L. M. ALCAZAR-ROMAN, /. Org. Chem. 1999, 64, 5575-5580. a) D. ZIM,V. R. LANDO, J. DUPONT,A. L. MONTEIRO, Org. Lett. 2001, 3, 3049-3051; b) V. P. W. BOHM,T. WESKAMP, C. W. K. GSTOTTMAYR, W. A. HERRMANN, Angew. Chem. 2000, 112, 1672-1674; Angew. Chem. h t . Ed. 2000, 39, 1602.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Alkyne Metathesis in Natural Product Synthesis Thomas Lindel

The application of alkene [ 11 - and, more recently, enyne [ 21 and alkyne - metathesis to the synthesis of natural products has been triggered by the development of powerful catalysts that allow metathesis reactions to be carried out under mild conditions. Scheme 1 outlines two important cases of alkene and alkyne metathesis of particular interest to the synthesis of natural products (together with the general scheme of enyne metathesis, not discussed in this review). The metathesis products can be obtained in high yields, since ethene/2-butyne are formed as volatile products. After the alkene/alkyne metathesis, the substituents (R) of the alkenes/alkynes are located on the same multiple bond. Enyne metathesis can be considered as the more general case of alkene metathesis, because two new double bonds are again formed, albeit now connected by a single bond.

p== f+ II cat.

alkene metathesis

R

+

R

enyne metathesis

alkyne metathesis

Scheme 1 .

1

+

,(I k

cat.

R

111

+

111

R

Alkene, enyne, and alkyne metathesis.

This short review focuses on the application of alkyne metathesis in the field of natural product synthesis, which is central for the evaluation and ranking of synthetic methods. Natural products are often complex, with the simultaneous presence of different functional groups and novel molecular architecture. If a method works for chemicals bought from the

28

I

Alkyne Metathesis in Natural Product Synthesis

catalog, this does not necessarily mean that it works for important cases of application. After about four years of alkyne metathesis in total synthesis, the problems tackled have already become quite demanding and relevant. Alkyne metathesis reactions have considerable potential for the synthesis of novel polymers, not covered in this article. For a leading reference, see Bunz [ 31. Scheme 2 shows two pioneering experiments. The first homogeneously catalyzed alkyne metathesis was achieved in 1974, by Mortreux and Blanchard. In a sealed flask, 4-methyland resorcin, resulting in the tolane (1)was heated in the presence of 10 mol% of MO(CO)~ formation of the metathesis products tolane (2) and 4,4'-dimethyltolane (3) [4]. After three hours the statistical equilibrium was reached. The mechanism of the molybdenum-catalyzed alkyne metathesis is still unknown. In 1981, Schrock et al. reported the capability of tungsten alkylidyne complexes to catalyze alkyne metathesis [ Sa]. With the complex 4, the equilibrium of 1, 2, and 3 was reached under milder reaction conditions and with shorter reaction times than had been obtained with the Mortreux catalyst. As early as 1975, Katz and McGinnis had proposed metallacyclobutadienes as intermediates of alkyne metathesis [ 61. In 1984, Schrock et al. were successful in obtaining a crystal structure of the catalytically active triaryloxytungstate complex 5, and thereby proved the earlier hypothesis [ Sb]. The geometry of the planar four-ring, with an approximately trigonal bipyramidal-coordinated tungsten, is shown in Scheme 2. It should be mentioned that the metathesis of terminal alkynes, unlike the analogous reaction of terminal alkenes, is inhibited, due to the formation of catalytically inactive, deprotonated tungsten cyclobutadiene complexes [ Sc]. Hence, alkyne metathesis liberating acetylene instead of 2-butyne has no use in synthesis.

Mortreux and Blanchard, 1974 10 mol-% [MO(CO)~]/ resorcin (1:6), 160'C, 3 h

2 or 4 - t ~ ~ 4 mol-% [ ( t ~ ~ ~ ) 3] ~ toluene, rt, 1 h Schrock et al., 1981 1

2

3

5

Pioneering experiments by Mortreux et al. (1974) and Schrock et al. (1981). Geometry o f the tungstacyclobutadiene 5 in the crystal (OAr = 0-2,6-diisopropyIphenyl; bond lengths in pm).

Scheme 2.

A major drawback of alkene metathesis is lack of control over the stereochemistry of the newly formed double bond. For unstrained systems, E/Z ratios are virtually unpredictable. Alkyne metathesis, on the other hand, can always be combined with subsequent Lindlar hydrogenation, thereby giving access to stereochemically pure Z-olefins. In 1998, Fiirstner and Seidel were the first to report a ring-closing alkyne metathesis [7]. Under high-dilution conditions (0.02 M) and reduced pressure (20 mbar, removal of 2-butyne, solvent 1,2,4trichlorobenzene (b.p. 214 "C)) the Schrock catalyst was applied to assemble macrocyclic

Alkyne Metathesis in Natural Product Synthesis

lactones, lactams, and cyclic silyl ethers. Soon, various olfactory macrolides, such as the mint-scented yuzu lactone (7) or the strongly musk-scented ambrettolide (9), became synthetic targets, pioneered by Furstner et al. Scheme 3 gives the syntheses, both starting with 9-undecyn-1-01,using the "instant" Mortreux catalyst for ring-closing alkyne metathesis of 6 and 8 under high-dilution conditions, and finishing with Lindlar hydrogenation. The sim(civetone) has been obtained in a similar ple macrocyclic musk (Z)-cycloheptadec-9-en-1-one manner [8]by use either of the Schrock catalyst or of the quite harsh Mortreux conditions (5 mol% Mo(CO)~,p-trifluoromethylphenol, chlorobenzene, 140 "C, 7 h), as optimized by Bunz et al. [9].

68 Yo

6

1. 5 mol% MO(CO)~, 1 eq. pchlorophenol chlorobenzene. 14O'C 2. HP, Lindlar cat.

-~

8

c: 7 : yuzu lactone

-

-

9: ambrettolide

Scheme 3. Simple examples of natural products synthesis by alkyne metathesis with the Mortreux catalyst.

The Mortreux and Schrock catalysts have a somewhat different scope. In particular, secondary amides and silyl ether groups are not compatible with the Mortreux conditions. The high temperatures (140-150 "C) are also not desirable for complex, multifunctional natural products. Scheme 4 gives the key steps of the syntheses of several nitrogen-containing macrocycles, of which motuporamine (13) from the marine sponge Xestospongia exigua [ 101, and epilachnene (16) and homoepilachnene (17), defense secretions of the pupae of the Mexican beetle Epilachnar uariuestis [ 111, are natural products [ 121. In all cases the amino functions had to be protected as carbamates (Boc or Fmoc) prior to alkyne metathesis. The secondary amide present in the metathesis product 18, however, did not have to be protected for use of the Schrock catalyst at 80 "C. In the key reaction of the eight-step synthesis of motuporamine C (13), the open-chain, Nprotected bisalkyne 10 was exposed to Mortreux and to Schrock conditions [13]. The yields (67% vs. 71%) of the macrocycle 11 were comparable, but the reaction temperature (140 "C vs. 80 "C) and the reaction times (30 h vs. 1 h) clearly favor the Schrock conditions. Epi-

30

I

Alkyne Metathesis in Natural Product Synthesis

5 rnol% MO(CO)~, 1 eq. pchlorophenol chlorobenzene, 140aC,30 h, 67 Yo or: 10 rnol% (‘BuO)~WCCM~~, chlorobenzene 80‘C, 1 h, 65 Yo

e F;J

Frnoc

10

-~

Z 3 steps

H2 Lindlar cat., quinoline

Frnoc

Frnoc 11

-

Q L

12

N H

w NH,

13: rnotuporarnine C

1 . Mortreux cond., 67 %

or: 1. Schrock cond., 71 % 14: n=l; 15: n=2

-~

*

-

G

H

16: epilachnene (n=l) 17: hornoepilachnene (n=2)

2. H2, Lindlar cat., 94 % 3. TBAF, H20, 62 %

- O Z s S :I: 0 : a\ 18

cry;H

19: nakadornarin A

1. ‘BuC(NH)CCI3, BF3.Et20, CH2CI2, rt, 8 h, 83 % 2. Schrock cond., 66 % 3. Hz, Pd/C, MeOH, rt, 12 h 4. Frnoc-OSu, dioxane, O‘C, 76 %

*

h N H 0 20 Scheme 4.

BocHN

I l F r n o c ‘BuO~C 21

Alkyne metathesis affording nitrogen-containing natural products or synthetic intermediates.

Alkyne Metathesis in Natural Product Synthesis

I

31

lachnene (16) and its homologue 17 were obtained by starting from the homologous precursors 14 and 15 ( 6 2 4 9 % macrocyclization yields) [12]. For the structurally more complex molecule 18, only the Schrock conditions worked. Compound 18 has been synthesized as a synthetic precursor of the marine alkaloid nakadomarin A (19 [14]) from the marine sponge Amphimedon sp. Nakadomarin A (19) belongs to the manzamine alkaloids, which are also targets of biomimetic syntheses [15]. For both strategies, there is still some distance to go. Diaminosuberic acid (21, protected form) is used as a dicarba isostere of cystine in peptides to provide stable analogues of disulfide bridges. Occasionally, the conformational flexibility of diaminosuberic acid is a disadvantage and conformationally restricted cystine isosteres are desired. Rutjes, van Boom, et al. report the application of alkyne metathesis to the synthesis of analogues containing Z-alkene or alkyne functionalities [ 161. Moreover, orthogonal protection is frequently needed. Scheme 4 gives the synthesis of N’-Boc-N-Fmocdiaminosuberic acid mono-tert-butyl ester (21) (see also [ 171) starting from the open-chain bisalkyne 20. The established tungsten catalyst 4 ( G mol%) in chlorobenzene was used, affording macrocyclization in 66% yield. Alkyne metathesis can also be employed to synthesize open-chain natural products through intermolecular reactions. Fiirstner and Dierkes reported the total synthesis of the natural product (S,S)-(+)-dehydrohomoancepsenolide (24) from the gorgonian Pterogorgia citrina, to which it contributes to chemical defense (Scheme 5) [18]. The synthesis features both alkene and alkyne metatheses. The butenolide unit 23 was assembled first, by alkene metathesis starting from the open-chain precursor 22, in the presence of Grubbs’ catalyst [ 191. Interestingly, competing enyne metathesis was not observed. Subsequent alkyne metathesis with the Schrock catalyst and Lindlar hydrogenation successfully provided 24 from 23.

16 mob% (PCy&ClzRu=CHPh,

c

CH2C12, A, 24 h, 70 % 22

1. l o mol-% [(‘Bu0)3W-‘Bu] toluene, 100 ‘C, 10 h, 75 %

23

.

2. H P , Lindlar cat., quinoline, hexane/EtOH, rt, 30 min, 96 YO

0

24: (S,S)-(+)-dehydrohomoancepsenolide Scheme 5. Combined application of alkene and alkyne metathesis, affording the open-chain natural product 24.

32

I

Alkyne Metathesis in Natural Product Synthesis

It is of key importance for the success of a synthetic method that it be compatible with the greatest possible variety of functional groups. The tungstacyclobutadiene 5, for example, is ring-opened by pyridine and looses its catalytic activity [20]. In 1999, Fiirstner et al. found a new molybdenum catalyst with wider scope (Scheme 6) [21]. Dissolution of the trisamidomolybdenum complex 25 12.21 in dichloromethane results in the endothermic formation of the chloride 26, The catalytic activity of 26 was demonstrated with the alkyne metathesis of the pyridine-2,3-dicarboxylatediester 27 in toluene, affording the macrocyclic alkyne 28 in the very good yield of 88%. The new catalyst 26 has several advantages, including the tolerance of basic nitrogen functional groups, thioethers, and polyether chains. The probable reason for this is the steric hindrance of the Lewis acidic molybdenum center. Complex 26 is not compatible with substrates containing acidic protons, such as secondary amides, which are tolerated by the Schrock system. Despite intensive studies, no X-ray structures of reactive intermediates composed of both molybdenum and alkyne components have so far been obtained, and the mechanism of catalysis is still unknown. Fiirstner et al. give a detailed account of their work on trisamidomolybdenum complexes of the general type [Mo(('Bu)(Ar)N}3]in ref. [23].

10 mol% of 26 toluene, 80'C

88 % 27 Scheme 6.

28 Furstner's new molybdenum catalyst 26.

There are already advanced applications of the new catalyst to the synthesis of natural products. Scheme 7 gives the metathesis steps towards, and the structures of, the target molecules prostaglandin Ez methyl ester (31), its lactone 33 from the nudibranch Trtetys Jimbria [24], and the structures of the glycolipid sophorolipid lactone (34) from the yeast Candida bombicola [25] and of the microtubule-stabilizing epothilone C (35)from the myxobacterium Sorangium cellulosum 1261. To obtain the open-chain prostaglandin Ez methyl ester (31), the symmetrical Cl0 alkyne 30 was employed as the source of the Cs unit to be introduced into the starting material 29 (Scheme 7). The yield of this less symmetrical alkyne metathesis was 51% [27]. The macro-

Alkyne Metathesis in Natural Product Synthesis

I

33

1. 10 mol% [MO(N(~BU)(A~)}~], CH2C12,toluene, 80'C, 51 % 2. Hz, Lindlar cat. quinoline, hexane, rt, 87 %

3. aq. HF, THF, rt, 1 h , 88 %

HO 31 : PGE2 methyl ester

Ar = 3,5-dimethylphenyl

1:

1. 7.5 mol% [Mo(N('Bu)(Ar)J3],

CH2C12,toluene, 80'C, 16 h, 70 % 2. HP,Lindlar cat. quinoline, hexane, rt, 2 h, 86 % 3. aq. HF, MeCN, rt, 1 h , 88 %

HO 33: PGE2 lactone

'*m 13

U 34: sophorolipid lactone Scheme 7.

35: epothilone C

The most complex natural products so far obtained by alkyne metathesis.

cyclization of the bisalkyne 32 to the analogous lactone 33 proceeded in the higher yield of 70% [28]. The molybdenum catalyst 26 is compatible with esters, ethers, silyl ethers, tertiary amides, thioethers, pyridines, and ketones. Sophorolipid lactone (34) was obtained from an open-chain bisalkyne precursor (concomitant formation of 2-butyne) in a macrocyclization yield of 78% [29]. The epothilones have been obtained through non-stereoselective alkene metathesis [ 2Gd], making them worthwhile targets for the combination alkyne metathesis/Lindlar hydrogenation to assemble the C12-Cl3 Z double bond. Furthermore, epothilone C (35) shows the most complex array of functional groups among the substrates of alkyne metathesis. The macrocyclization yield, starting from the expected OTBS-protected precursor (not shown) was 81% 123, 301. Neither

34

I

Alkyne Metathesis in Natural Product Synthesis

the basic nitrogen not the sulfur of the thiazole ring interfered with the catalyst. The labile aldol and the already present alkene double bond stayed intact. Only the OH group had to be protected, as a TBS ether. Epothilone C (35)can be epoxidized stereoselectivelyto epothilone A by dimethyldioxirane [ 311. In summary, alkyne metathesis seems about to become one of the key reactions frequently employed in the synthesis of increasingly complex natural products. Recently, Trost et al. and Furstner et al. reported new hydrosilylation protocols for the convenient, chemoselective transformation of alkynes to E alkenes which will extend the value of alkyne metathesis for natural product synthesis [32].

References A. FURSTNER, Angew. Chem. 2000, 112, 3140-3172; Angew. Chem. Int. Ed. 2000, 39, 3012-3043; b) R. H. GRUBBS,S. CHANG,Tetrahedron 1998, 54, 4413-4450; c) M. SCHUSTER, S. BLECHERT, Angew. Chem. 1997, 109, 2124-2145; Angew. Chem. Int. Ed. 1997. 36, 2037-2056.

1 Reviews o n alkene metathesis: a)

2 Examples o f enyne metathesis in natural products synthesis: a) S. C. SCHURER,

S. BLECHERT, Synlett 1999, 1879-1882; b) B. M. TROST,G. A. DOHERTY,J. Am. Chem. SOC. 2000, 122, 3801-3810; c) D. BANTI,M. NORTH,Tetrahedron Lett. 2002, 43, 1561-1564 d) J. S. CLARK,F.

3

4

5

6

ELUSTONDO, G. P. TREVITT,et al., Tetrahedron 2002, 58, 1973-1982. e) M. MORI,K. TONOGAKI, N. NISHIGUCHI, J. Org. Chem. 2002, 67, 224-226. a) U. H. F. BUNZ,ACC.Chem. Res. 2001, 34, 998-1010.17) U. H. F. BUNZ,L. KLOPPENBURG, Angew. Chem. 1999, 111, 503-505; Angew. Chem. Int. Ed. Engl. 1999, 38, 478-481. A. MORTREUX, M. BLANCHARD, J . Chem. SOC.Chem. Commun. 1974, 786-787. a) J. H. WENGROVIUS, J. SANCHO,R. R. SCHROCK,].Am. Chem. SOC.1981, 103, 3932-3934; b) M. R. CHURCHILL, J. W. ZILLER,J. H. FREUDENBERGER, et al., Organometallics 1984. 3, 1554-1562; c) L. G . MCCULLOUGH, M. L. LISTERMANN, R. R. SCHROCK, et al., /. Am. Chem. SOC. 1983, 105, 6729-6730; d) Summary: R. R. SCHROCK,Polyhedron 1995, 14, 31773195. T. J. KATz, J. MCGINNIS,J.Am. Chem. SOC. 1975, 97, 1592-1594.

7 A. FURSTNER,G. SEIDEL,Angew. Chem.

8 9

10

11

12

13 14 15

16

17 18 19

20

1998, 110, 1758-1760; Angew. Chem. Int. Ed. Engl. 1998, 37, 1734-1736. A. FURSTNER,G. SEIDEL, J . Organomet. Chem. 2000, 606,75-78. L. KLOPPENBURG, D. SONG,U. H. F. BUNZ,I. Am. Chem. SOC.1998, 120,79737974. D. E. WILLIAMS, P. LASSOTA,R. J. ANDERSEN,J. Org. Chem. 1998, 63,48384841. A. B. ATIYGALLE, K. D. MCCORMICK, C. L. BLANKESPOOR, et al., Proc. Natl. Acad. Sci. USA 1993, 90, 5204. A. FURSTNER, 0. GUTH,A. RUMBO,et al., / . A m . Chem. SOC.1999, 121, 11,10811,113. A. FURSTNER, A. RUMBO,J . Org. Chem. 2000, 65, 2608-2611. J. KOBAYASHI, D. WATANABE, N.KAWASAKI, et al., /. Org. Chem. 1997, 62, 9236-9239. a) J. E. BALDWIN, R. C. WHITEHEAD, Tetrahedron Lett. 1992, 33, 2059-2062; b) J. E. BALDWIN, T. D. W. CIARIDGE,A. J. CULSHAW, et al., Angew. Chem. 1998, 110, 2806-2808; Angew. Chem. Int. Ed. Engl. 1998, 37, 2661-2663. B. AGUILERA, L. B. WOLF,P. NIECZYPOR. et al., /. Org. Chem. 2001, 66, 35843589. R. M. WILLIAMS? J. LIU,J. Org. Chem. 1998, 63, 2130-2132. A. FURSTNER, T. DIERKES, Org. Lett. 2000, 2, 2463-2465. P. SCHWAB,R. H. GRUBBS,J. W. ZILLER,/. Am. Chem. SOC.1996, 118, 100-110. M. L. LISTERMANN, R. R. SCHROCK, Organometallics 1985, 4, 74-83.

References I 3 5 21

22 23

24 25 26

A. FURSTNER,C. MATHES, C. W. LEHMANN,].Am. Chem. Soc. 1999, 121, 9453-9454. C. C. CUMMINS, Chem. Commun. 1998, 1777-1 786. A. FURSTNER, C. MATHES, C. W. Chem. Eur.]. 2001, 7, 5299LEHMANN, 5317. G. CIMINO, A. SPINELLA, G. SODANO, Tetrahedron Lett. 1989, 30, 3589-3592. A. P. TULLOCH, A. HILL,J. F. T. SPENCER, Can.]. Chem. 1968, 46, 3337. (a) G . HOFLE,N. BEDORF, K. GERTH,et al. (GBF Braunschweig), Ger. Offen. DE 4138042 A1 19930527,1993 [ Chem. Abstr. 1994, 120, P526411; (b) D. M. BOLLAG, P. A. MCQUEENEY, J. ZHU, et al., Cancer Res. 1995, 55, 2325-2333; (c) G . HOFLE, N. BEDORF, H. STEINMETZ, et al., Angew. Chem. 1996, 108,1671-1673; Angew. Chem. Int. Ed. Engl. 1996, 35, 1567-1569; (d) see also L. A. WESSJOHANN, G. SCHEIDin

Organic Synthesis Highlights Iy H.-G. (Ed.), Wiley-VCH, 2000, p. 251SCHMALZ 267. 27 A. FURSTNER, C. MATHES,Org. Lett. 2001, 3, 221-223. 28 a) A. FURSTNER, K. GRELA, Angew. Chem. 2000, 112, 1292-1294; Angew. Chem. Int. Ed. Engl. 2000, 39, 1234-1236; b) A. FURSTNER, K. GRELA, C. MATHES, et af., /. Am. Chem. SOC.2000, 122, 11,799-11,805. 29 A. FURSTNER, K. ~ D K O W S K J. I , GRABOWSKI, et al.,]. Org. Chem. 2000, GS, 8758-8762. 30 A. FURSTNER, C. MATHES,K. GRELA, Chem. Commun. 2001, 1057-1059. 31 D. MENG,P. BERTINATO,A. BALOG, et al.,j. Am. Chem. SOC.1997, 119, 10,073-10,092. 32 (a) B. M. TROST,2. T. BALL, T. JOGE, I. Am. Chem. SOC.2002, 124, 7922-7923; b) A. FURSTNER, K. RADKOWSKI,Chem. Commun. 2002, 2182-2183.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Transition Metal-catalyzed Functionalization o f Alkanes Oliver Seitz Introduction

Alkanes, which are the principal components of natural gas and crude oil, are still the preferred energy source of our society. In regard to the prime importance of alkanes as feedstock for the chemical industry, it appears a waste of resources “simply” to burn these precious raw materials. Unfortunately, attempts to transform alkanes into more valuable products are hampered by their low reactivity, as best illustrated by the use of alkanes as inert solvents. For example, the cracking process requires temperatures of about 1000 “C in order to convert long-chain alkanes into short-chain alkanes. Controlled conversion of hydrocarbons is difficult to achieve and limited to partial oxidations, such as the conversion of butane into acetic acid. It is obvious that processes that would enable efficient functionalization to occur at low temperature would have enormous potential application. Achievements towards this goal will almost certainly rely on the use of catalysts, which will have to activate the stable C-H bond (375-440 kJ mol-’) in order to induce its scission. C-H activation reactions can be induced by one-electron or two-electron transfer processes. Radical chain reactions, which operate in many alkane oxidations, belong to the first category (Scheme 1). In a “conventional” oxidation reaction, molecular oxygen effects the initiation and the propagation of the radical chain. Metals, transition metals in particular, are able to accelerate the cleavage of the formed hydroperoxides, thereby catalyzing the ratelimiting radical chain initiation. With a few exceptions, radical reactions of alkanes proceed relatively unselectively, but with tertiary C-H bonds being preferred [l].This is due to the high reactivity of radicals such as the hydroxyl radical and the differences in the C-H bond strengths (tea CH < sec CH < primary CH < CH3-H). In contrast, homogenous transition metal systems, which proceed by - for example - oxidative addition, show higher reactivity for primary C---Hbonds than for secondary and tertiary C-~Hbonds. The latter process is much more attractive when aiming for functionalization of linear alkanes. For this reason, this “account” focuses on transition metal-catalyzed two-electron processes. It is not intended to present a comprehensive overview, but to highlight some instructive examples for the generally interested reader, with a strong emphasis on newly developed catalysts. For a more detailed coverage the reader is referred to the review literature [ 2-51.

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

37

One-electron transfer

Contribution of the metal: ROzH + M"

+

M"+'

+ RO- + OH.

Two-electron transfer M+RH

1

[M-RH]

2

Scheme 1.

-

A

0R

(%

M+RX+H2

H 3

4

C-H activation reactions proceed by transfer of one or two electrons

Alkane Functionalization with Homogenous Transition Metal Catalysts

To unlock its full potential, C-H activation has to be coupled with a functionalization event (e.g., 3-4). For instance, a hydride elimination occurring after the formation of metal complexes such as 3 furnishes olefins, versatile intermediates for further modification reactions. Transition metal-catalyzed atom- or atom group-transfer reactions that permit the introduction of oxygen-, carbon-, and boron-containing groups are also presented. The development of catalytic C-H activation reactions is one of the most challenging enterprises in organic chemistry. The only complexes able to activate C-H bonds by oxidative addition are coordinatively unsaturated at the metal center. The lifetimes of these highly reactive metal species, however, are usually very short. A key issue is therefore the development of stabilizing metal ligands. In addition, it is desirable that the ligands should confer a selectivity to the functionalization reaction, such that repeated functionalization can be prevented. Oxygenation

The most widespread efforts made towards the achievement of selective oxidation of alkanes are targeted on methane, a principal constituent of natural gas 16-81. Activation of the very stable C-H bond of methane is a particularly demanding problem. One example in which this has been achieved on industrial scales is the Degussa process "91. Methane is coupled to ammonia by heterogeneous catalysis in order to produce HCN, an important fundamental material for industrial chemistry. An unsolved problem is the selective oxidation of methane to methanol: a reaction that would convert the methane gas into a transportable liquid. In nature, monooxygenases have evolved. These are able to activate molecular oxygen and to

38

I

Transition Metal-catalyzed Functionalization of Alkanes

insert one oxygen atom into a C-H bond of an alkane. This process has inspired many efforts devoted to the development of biomimetic chemical model systems [ l o , 111. The most important catalysts for achieving selective hydroxylation of methane by two-electron transfer are based on the so-called Shilov system. Shilov and Shteinman reported a Pt(1v)mediated C-H activation as early as 1972 [12, 131. Typically, these reactions are performed under oxidative and highly acidic conditions, which results in the separation of a metal precipitate. This precipitation promotes the decomposition of the formed methanol and reduces the lifetime of the catalytically active species. Complexation with stabilizing ligands can substantially increase the lifetime of the catalyst. Periana and co-workers identified 2,2'bispyrimidine as a suitable ligand [14]. A solution of the bispyrimidine-Pt(I1) complex 5 in 20% oleum remained homogeneous even after 50 h at 200 "C, and no formation of insoluble platinum complexes such as (PtC12),or metal precipitates was observed (Scheme 2). The fact that metallic platinum dissolves upon treatment with a solution of bispyrimidine in 96% sulfuric acid is testimony to the remarkable affinity of the bispyrimidine ligand for platinum. It is this astonishing stability that renders the Pt(I1) complex functional under the drastic conditions of methane hydroxylation. At a temperature of 220 "C in concentrated sulfuric acid, complex 5 catalyzed more than 500 conversion cycles of methane to sulfuric acid methyl ester 6. The only liquid products detectable were sulfuric acid methyl ester 6 and methanol, which were formed in 73% yield and with 81% selectivity (based on methane). A mechanism similar to the Shilov process has been suggested [15]. According to this, acid treatment of the bispyrimidine-Pt(Ir) complex 5 results in the formation of the coordinatively unsaturated 14-electron complex 7. Subsequently, C-H activation proceeds by oxidative addition of methane to furnish complex 8. Periana and co-workers recognized the oxidation to the Pt(~ vcomplex ) 9 as the rate-limiting step. Finally, reductive elimination ejects methyl sulfate 6 and regenerates the active species 7. Recently, Sames and co-workers showed an interesting application, in which it was demonstrated that the Shilov chemistry permits heteroatom-directed functionalization of polyfunctional molecules [ 161. The amino acid valine (10) was allowed to react in an aqueous solution of the oxidation catalyst K2PtC14 and CU(11) chloride as stoichiometric oxidant (Scheme 3). At temperatures >130 "C a catalytic reaction was observed, and a regioselective C-H functionalization delivered the hydroxyvaline lactone 11 as a 3:l mixture of antilsyn isomers. It was noted that the hydroxylation of amino acid substrates occurred with a regioselectivity different from those for simple aliphatic amines and carboxylic acids. The authors therefore proposed that the amino acid functionalization proceeded through a chelate-directed C-H activation. Dehydrogenation

Specific dehydrogenation at the terminal positions of alkanes is a reaction that would be of high utility. The 1-alkenes obtained by such a reaction are the basis of a variety of additional products. Felkin and co-workers discovered that metal complexes are able to mediate the transfer of hydrogen from alkanes 13 to olefins 14 (Scheme 4) [ 171. The specific advantages of a transition metal catalyst can be applied to the benefit of the chemoselectivity of this reaction. In a kinetically controlled process, it is predominantly primary C-H bonds that add to the metal complex. A subsequent /?-hydride elimination affords the terminal alkenes

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

39

5

CH4

+

2H2S04

+

CHBOSO~H

2H20

+

SO2

220’C,73%

6

+ X

N

X

ld

7

X = CI, HS04

-

\

HX

X

S o p + HpO

Scheme 2.

SO3 + 2 HX

Efficient Pt-catalyzed oxidation of methane

1 5 (R’ = R 2 = H). Successive isomerization reactions, which begin to dominate after a very short period of time, complicate the preparative usefulness of this reaction. A remarkable selectivity for the formation of cc-olefins has been reported by Jensen, Goldman, and co-workers [18].The iridium “pincer” complexes 20a and 20b were compared in the dehydrogenation of octane 17 (Scheme 5). When norbornene (Ma) was used as acceptor

40

I

Transition Metal-catalyzed Functionalization of Alkanes

5 mol% KpPtC14, 7 eq. CuCIp, 160’C, H20

1) BOQO 2) AcOH

NH2

NH-BOC

NH2

12

11

10

27 % (isolated yield)

56 % (crude in mixture with starting material) Scheme 3.

H

Pt-catalyzed oxidation o f amino acids.

R1#R3 R2 R4

13 Scheme 4.

metalcatalyst

R5

H

+ R6

Ra

-

14

H

R’

+ R2

R4

15

H

R5*R7 R6 Ra 16

Metal-catalyzed transfer (de) hydrogenation.

olefin, the highest cc-selectivities were obtained with the iPr complex 20a. After 5 minutes (12 turnovers) the 1-octene 21 had been formed with 91% selectivity. At prolonged reaction times and increased turnover the isomerization reaction began to dominate, and after 30 minutes (132 turnovers) 1-octene constituted only 30% of the product mixture. The use of a more reactive hydrogen acceptor such as 1-decene (18b) in combination with the sterically demanding tBu complex 201, enhanced the r-selectivity, particularly at prolonged reaction time. For instance, 1-octene was formed with 95% selectivity after 15 minutes (13 turnovers). After 90 minutes (111 turnovers) the product mixture still contained 84% of 1-octene and only 16% of the isomerization product 2-octene 22. The proposed mechanism involves a hydrogen transfer from the hydrido-iridium complex 20 to the alkene 18 as the first step. The formed complex 23 undergoes /3-hydride elimination. The coordinatively unsaturated iridium species 24 causes the oxidative oxidation of octane (24125). This C-H activation step is then followed by a reductive elimination, which gives rise to the formation of the dehydrogenation product 21. Recently, a new type of “pincer” complex has been introduced [19]. The “anthraphos” ligand confers a thermal stabilization on the iridium complex 26 (Figure 1). Hence, dehydrogenation reactions can be performed at temperatures (>200 “C) that would normally result in complete decomposition of the pincer complexes 20. Reluctant reactions, the kinetics and/or the thermodynamics of which require high temperatures, can therefore succeed. In spite of the remarkable improvement upon previously existing methodology, there is one disadvantage that remains. For the synthesis of an olefin, a second olefin has to be sacrificed. It is obvious that a process that would enable dehydrogenation to occur in the absence of sacrificial reagents would be highly desirable. Moreover, the selectivities that can be obtained at high turnovers are still too low for practical applications. Neither turnover frequencies nor turnover numbers of the catalysis are sufficient to be useful for industrial processes. These limitations are less of an issue in total synthesis, provided that the “quality” of the metal-mediated reaction justifies the use of stoichiometric processes.

Alkane Functionalization with Homogenous Transition Metal Catalysts

b

18a

catalyst 20a

5 rnin (TON = 12): 91% 21, 9% 22 30 min (TON = 132): 30% 21,67% 22

18b

catalyst 20b

15 min (TON = 13): >95% 21, 0% 22 90 min (TON = 1 11): 84% 21, 16% 22

mC8H1,

k

A

r( H

(PCP)lr,

23

H

mC6H13 CHz 17

I Scheme 5.

- CH3

(PCP)lr 24

H

H

19

A dehydrogenation with high a-selectivity (PCP = C G H ~ ( C H ~ P R ~ ) ~ ) .

I

41

42

I

Transition Metal-catalyzed Functionalization of Alkanes

H H Fig. 1.

A thermally stable pincer complex.

Such an example has been demonstrated by Johnson and Sames, who chose a platinummediated dehydrogenation as a key step in the synthesis of the antimitotic rhazinilam 33 (Scheme 6) [20]. The key intermediate 27 was converted into the imine 28, which was allowed to react with [ MezPt(,u-SMez)]z to afford the platinum complex 29. Subsequent treatment with triflic acid resulted in elimination of methane and furnished the cationic complex 30. Upon thermolysis in trifluoroethanol, the complex lost a second methane molecule, which resulted in the activation of the ethyl group. A subsequent P-hydride elimination gave the hydrido-Pt(I1) complex 31. Treatment with aqueous KCN followed by hydroxylamine removed the platinum and yielded the liberated amine 32. Johnson and Sames added a homologization and a macrolactamization and completed the total synthesis of rhazinilam (33) by removal of the carboxyl group.

c- C-Coupling Reactions that combine C-H activation with a C-C bond-forming event are invaluable synthetic tools, allowing concise construction of carbon frameworks. Rhodium( I ) catalysts have been shown to catalyze alkane carbonylation [ 211. Recently, Sakakura and co-workers succeeded in subjecting methane to a catalytic acetaldehyde synthesis [22]. They found that, in dense carbon dioxide, the complex [ RhC1(PMe3)3]catalyzed the carbonylation of methane with 77 turnovers. One problem that occurs when this class of catalysts is used is a concomitant dehydrogenation. To achieve a selective carbonylation, Murai and co-workers used substrates in which the metal complex was coordinated by a directing group, thereby placing the active metal center in close proximity to the C-H bond to be cleaved. This tactic was applied to the carbonylation of alkylamines (Scheme 7) [ 231. In the presence of ethylene, the rhodiumcyclooctadienyl complex 35 catalyzed the conversion of the pyrrolidines 34 into the saturated ketones 36. Different pyridine substituents were examined in terms of their suitability to support the rhodium-catalyzed carbonylation reaction. Electron-donating groups at the 5position (34, R = 5-Me) increased product formation. In the absence of the pyridine ring the reaction failed to take place. The introduction of electron-withdrawing (34, R = 5-CF3) or sterically demanding groups (34, R = 6-Me), reducing the basicity or accessibility of the pyridine nitrogen, gave decreased product yields. Murai and co-workers also explored the use of acyclic amines such as 36. Carbonylation to 37 and 38 proceeded, albeit in low yields. It is noteworthy that a preference for the sterically less demanding primary C-H bond (-37) as

Alkane Functionalization with Homogenous Transition Metal Catalysts

I

43

0

COOMe

27

phx 30

0

J

CF3CH20H, 70'C, 60h, 90%

& -

/

a) KCN, H20, 60% from 29 ~)%~OH,MeOH, ___)

/

phw N-Pt'H

II

NH2

\

/

32

31

33

Scheme 6.

@ -

fl 0

Pt-mediated dehydrogenation in the total synthesis of rhazinilam.

opposed to the energetically favored benzylic C-H bonds ( 1 3 8 ) was observed. Interestingly, the use of the ruthenium catalyst 39 allowed the introduction of ethyl groups [24]. Cyclic amines were more reactive than acyclic ones. For example, double alkylation occurred with the pyrrolidine 34, whereas monoalkylation was possible when the acyclic alkylamine 41 was

44

I

Transition Metal-catalyzed functionalization of Alkanes

d R=

R

34

H

36

40h

3-Me 60h

4-Me 60h

5-Me 40h

6-Me 60h

5-CF3 60h

68%

73%

73%

84%

12%

15%

Ph

CO, H2C=CHp

iPrOH, 160’C 36

37

18% (9:l)

34

Ph

41 Scheme 7.

38

40

Ph

42 (8%)

Ph

43 (20%)

Directed C-H activation for the carbonylation and alkylation of alkylamines.

Ph

44 (12%)

Alkane Functionalization with Homogenous Transition Metal Catalysts

employed as substrate. It is also interesting to note that the use of the ruthenium catalyst 39 changed the selectivity. The complex predominantly activated the benzylic C-H bond (+43) rather than the primary C-H bond ( 1 4 2 ) preferred when the C-H activation was catalyzed by the rhodium complex 35. At first glance, the requirement for the use of already functionalized alkanes seems to limit the applicability of the directed C-H activation approach. However, the utility of such a method is obvious for chemists familiar with the use of auxiliary groups during stereoselective synthesis (neighboring group participation was also applied in the total synthesis shown in Scheme 6). Borylation

The formation of carbon-boron bonds is one of the most versatile tools for the functionalization of hydrocarbons. The repertoire of functional group conversions in which organoboranes are transformed into alcohols, amines, ketones, alkenes, etc. is rich and characterized by broad applicability. Hartwig and co-workers recognized that the combination of a C-H activation with an alkane borylation can afford an exothermic process. Hence, the development of a catalytic alkane borylation seemed attainable. Hartwig's group first elaborated a photochemical means of alkane borylation [25]. Another impressive example of this hypothesis was also reported by Hartwig and co-workers, who described a thermal process for transition metal-catalyzed functionalization of alkanes [2G]. As an example, 5 mol% of the rhodium-bisethylene complex 46 catalyzed the reaction between n-octane (17) and the dioxaborolane 45 (Scheme 8). Complete conversion of the diborane 45 was achieved after 1 h at 150 "C. The n-octylborane 47 was formed in 84% yield after an additional 4 h reaction time. It has to be emphasized that both boron atoms of dioxoborolane 45 were transferred by the rhodium complex. Hartwig and co-workers showed that the pinacolborane 48 formed upon conversion of 45 is also a substrate and supports the catalytic octane borylation. The C-H activation was highly selective towards the primary position, GC-MS analysis attesting that n-octylborane was the only octylborane formed. Nevertheless, various ethylborane products were detected. Ethylborane formation seemed to be associated with a dissociation of ethylene ligands from rhodium complex 46a. Indeed, the use of the hexamethylbenzene complex 46b, which would dissociate by liberation of unreactive hexamethylbenzene, led to increased product yields. The driving force for this remarkably efficient alkane functionalization seems to be provided by the unusual thermodynamic properties of boron reagents. In the initial stage of the reaction, one octane C-H (412 kJ mol-') and one B-B bond (437 kJ mol-') are broken, while one B-C (470 kJ mol-') and one B-H bond (466kJ mol-') are formed. In total, an energy of 87 kJ mol-' is released. Analogously, conversion of the borane 48 gives rise to the formation of Hz (H-H bond: 437 kJ mol-') thereby releasing an overall bond energy of 29 kJ mol-'. This thermodynamic peculiarity enables C-H activation to occur even in absence of a catalyst. For instance, Knochel and co-workers showed that a thermal reaction can induce the activation of remote C-H bonds of acyclic tertiary alkylboranes to afford cyclic organoboranes [ 271. A theoretical study has suggested that even intermolecular C-H activation reactions such as direct methane borylation could succeed [28].

I

45

46

I

Transition Metal-catalyzed functionalization of Alkanes

46a =

46b =

Scheme 8.

* Rh

5 mol% Cat, 84% (5h); 1 mol% Cat, 64% (1 10h)

5 mol% Cat, 88% (25h); 1 mol% Cat, 72% (80h)

Thermal, catalyzed functionalization of alkanes t o organoboranes.

Conclusion

The first activation of an alkane C-H bond was described in 1969 [29]. Three decades were to pass until the development of the current catalytic procedures for dehydrogenation and G O , C-C, and C-B bond-forming reactions. Progress has been slow. Nevertheless, significant advances in catalyst research were achieved in the 1990s, aided by the development of improved metal ligands and the increased understanding of the mechanism of transition metal-catalyzed C-H activation reactions. Further improvements of catalytic cycles are nec-

Literature 1 4 7

essary, especially for the goal of application in economically useful industrial processes. As far as chemoselectivity is concerned, modern alkane functionalization reactions seem to suit the needs of laboratory practice, with the promise of a concise means of carbon framework synthesis. The examples presented here suggest that the goal of achieving both high catalytic efficiency and high chemoselectivity might be within reach. In particular, the thermally catalyzed alkane borylation indicates that C-H activation reactions present new opportunities and increase the repertoire of organic synthesis. It thus seems conceivable that alkanes will find a place not only as a source of energy but also as valuable building blocks in chemical synthesis. Literature

J. M. THOMAS,R. RAJA, G. SANKAR, et al., Acc. Chem. Res. 2001, 34, 191-200. 2 A. E. SHILOV, G. B. SHULPIN, Chem. Reti 1997, 97, 2879-2932. 3 G. DYKER, Angew. Chem. 1999, 111, 18081822; Angew. Chem. Int. Ed. 1999, 38, 1699-1712. 4 C. G . JIA, T. KITAMURA,Y. FUTIWARA, ACC. Chew. Res. 2001, 34, 633-639. 5 R. H. CRABTREE,J. Chem. SOC.,Dalton Trans. 2001, 2437-2450. 6 R. H. CRABTREE, Chem. Rev. 1995, 95, 987-1007. 7 S. S. STAHL,J. A. LABINGER, J. E. BERCAW, Angew. Chem. 1998, 110, 2298-2311; Angew. Chem. Int. Ed. 1998,37,2181-2192. 8 J. H. LUNSFORD,Catal. Today 2000, 63, 165-174. 9 For a mechanistic investigation: M. DIEFENBACH, M. BRONSTRUP, M. ASCHI,et al., J. Am. Chem. SOC.1999, 121, 10,61410,625. 10 An overview of mechanistic aspects: A. E. SHILOV,A. A. SHTEINMAN, Acc. Chem. Res. 1999, 32, 763-771. I 1 For an overview of the scope of enzymatic alkane hydroxylation: H. L. HOLLAND, Curr. Opin. Chem. Biol. 1999, 3, 22-27. 12 N. F. GOL’DSHLEGER, V. V. ES’KOVA,A. E. SHILOV, et al., Zh. Fiz. Khim. 1972, 46, 1353. 13 A. E. SHILOV, A. A. SHTEINMAN, Coord. Chem. Reu. 1977, 24, 97-143. 14 R. A. PERIANA, D. J. TAUBE,S. GAMBLE, et al., Science 1998, 280, 560-564. 15 M. W. HOLTCAMP, J. A. LABINGER,J. E. BERCAW,J . Am. Chem. SOC.1997, 119, 848-849. 1

16 17

18 19

20 21

22

23

24

25 26

27

28

29

B. D. DANGEL, J. A. JOHNSON, D. SAMES, J . Am. Chem. SOC.2001, 123, 8149-8150. D. BAUDRY,M. EPHRITIKINE, H. FELKIN, et al., J . Chem. SOC.,Chem. Commun. 1983, 788-789. F. C. LIU, E. B. PAK,B. SINGH,etal., J. Am. Chem. SOC.1999, 121,4086-4087. M. W. HAENEL, S. OEVERS, K. ANGERMUND, et al., Angew. Chem. 2001, 113, 3708-3712; Angew. Chem. Int. Ed. 2001, 40, 3596-3600. J. A. J O H N S O N , D. SAMES, J . Am. Chem. SOC. 2000, 122, 6321-6322. T. SAKAKURA, T. SODEYAMA, K. SASAKI,et al., J. Am. Chm. SOC.1990, 112, 72217229. J. C. CHOI,Y. KOBAYASHI,T. SAKAKURA, J. Org. Chem. 2001, 66, 5262-5263. N. CHATANI, T. ASAUMI,T. IKEDA, et al., J . Am. Chem. SOC.2000, 122, 12,88212,883. N. CHATANI,T. ASAUMI,S. YORIMITSU,et al., J. Am. Chem. SOC.2001, 123, 10,93510,941. K. M. WALTZ,J. F. HARTWIG,Science 1997, 277, 211-213. H. Y. C H E N ,S. SCHLECHT, T. C. SEMPLE, et al., Science 2000, 287, 1995-1997. H. LAAZIRI, L. 0. BROMM, F. LHERMIITE, et al., J . Am. Chem. SOC.1999, 121, 69406941. B. GOLDFUSS, P. KNOCHEL, L. 0. BROMM, et al., Angew. Chem. 2000, 112, 4299-4302; Angew. Chem. Int. Ed. 2000, 39, 41364139. N. F. GOL’DSHLEGER, M. B. TYABIN, A. E. SHILOV, et al., Zh. Fiz. Khim. 1969, 43, 2174.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

An Eldorado for Homogeneous Catalysis? Gerald Dyker

Gold has always been the embodiment of something extremely valuable and evidently holds a fascination deeply rooted in the cultural history of mankind. As is generally known, the endeavour to produce gold synthetically played a significant role in the development of chemistry over a long period [2]. Concerning the search for catalysts gold has until recently lived in the shadows, which perhaps has its reason in the preconceived opinion that gold is expensive and inert. Indeed, gold is the most precious metal and was considered for a long time to be extremely chemically inert particularly in reactions with nonmetals such as hydrogen, carbon, and oxygen [3]. Through successes in heterogeneous catalysis, which are also of economic significance, this assessment has fundamentally changed [4a]: tetrachloroauric acid on active charcoal is currently the best catalyst for the hydrochlorination of ethyne, and gold clusters (diameter 2-5 nm) on iron oxide are particularly active for the oxidation of carbon monoxide [4b]. Other possible applications in environmentally relevant fields are the oxidative decomposition of halogenated hydrocarbons and the reduction of nitrogen monoxide with carbon monoxide and hydrogen to give nitrogen, carbon dioxide, and water [4c, 4d, 51. Surprisingly, gold can also catalyze skeletal rearrangements of hydrocarbons: for instance, the isomerization of 2,2-dimethylbutane to n-hexane has been achieved by Schmid with the aid of Auss clusters on titanium dioxide [4c, 61 and the aromatization of the dispirocycle 1 to tetrahydronaphthalene 2 was achieved by de Meijere et al. in a reactor with gold surface at 100 "C in a few seconds (Scheme 1) [ 7 ] .

Au-surface helium 100 O C . 10 s 1 Scheme 1.

2 (> 90%) Gold-catalyzed skeletal rearrangement of a strained hydrocarbon.

An Eldorado for Homogeneous Catalysis?

In the field of homogeneous catalysis only a few gold-catalyzed processes are known to date, which, however, are characterized by the need for extremely small amounts of gold salts. In view of the high catalytic activity of gold salts the higher price for gold is relativized in comparison to that for the corresponding palladium and ruthenium compounds. Recent developments in gold chloride catalyzed C-C and C-0 coupling reactions provide a fitting opportunity to highlight the current status [8] of homogeneous catalysis with gold salts and to show the potential for further developments. A first landmark in gold catalysis was made by Ito and Hayashi when they carried out an asymmetric aldol reaction in 1986 [9]: aldehydes 3 were treated with isocyanoacetate 4 to give oxazolines 5 (Scheme 2). The active catalyst is a ferrocenylphosphane-gold(I) complex (structure G sketches the complex with coordinatively bound reactants). In general, nearly quantitative yields and diastereo- and enantioselectivities of greater than 90% in favor of the 4S,SR-configurated trans-product 5 are achieved in this reaction. For instance, this method facilitates a two-step synthesis of the naturally occurring amino acid threo-3-hydroxylysine from 4-phthalimidylbutanal as the aldehyde component 3 [ 9d]. cat. 6

R-CHO

. (1 mol-%)

+

CHZC12 25 O C , 20 h

yo C

3

O v N

5

4

r

Me Me Me. Ph?

1

/

6 Scheme 2.

Synthesis o f oxazolines by a gold-catalyzed asymmetric aldol reaction.

Also in the activation of alkynes for nucleophilic attack, gold salts prove to be soft, exceptionally carbophilic Lewis acids, as confirmed by the examples shown in Scheme 3 [lo]. According to Utimoto and Fukuda both the addition of water as well as of amines to alkynes are catalyzed by gold(111) salts, in particular by sodium tetrachloroaurate; ketones such as 8 and imines such as the ant toxin 10 are obtained as products in excellent yields [loa-el. In the cyclization reaction giving the 1,4-dioxane 12 developed by Teles et al.,

I

49

50

I

An Eldoradofor Homogeneous Catalysis?

Au"'-cat. (2 mol-%)

MeOHiHzO reflux, 1 h

7

8 (929'0)

Ill

Au -cat.

(5 mol-%,)

MeCN

reflux, I h

10 (900/)

cfL

H', Au'-cat. (0.001 mol-%)

MeOjt,,

McOH

Me

55 O C , 20 h

\ L 13 Scheme 3.

12 (93%)

-3T.r Au 111-cat. ( 5 mol-%)

MeN02, H N 0 3 , N a N 0 2 , 50 'C

Gold-catalyzed additions t o alkynes; Ac

'0

14 (35%) =

acetyl.

the short reaction time and use of extremely small amounts of catalyst, in this case methyl(triphenylphosphane)gold(I), are particularly impressive [ 1Od-el. In the isoxazole synthesis according to Gasparrini et al., gold salts catalyze the addition of H N 0 3 to alkynes; under the oxidative reaction conditions nitrile oxides are formed, which undergo a cycloaddition to give final products such as 14 [ 1Of 1. In the gold-catalyzed carbonylation of olefins according to Xu et al., gold(I) carbonyl complexes are considered as active catalysts; this reaction proceeds already at room temperature in concentrated sulfuric acid at a CO pressure of 1 atm and leads after acid-catalyzedskeletal rearrangement to tertiary carboxylic acids such as 16, 18, and 19 (Scheme 4) [ll]. In a more recent publication Hashmi et al. reported that propargyl ketones such as 20 and allenyl ketones such as 21 can be cyclized to furans such as 22 in reactions catalyzed by gold(II1) chloride (Scheme 5) [12]. This type of reaction had already been described as a

An Eldorado for Homogeneous Catalysis?

I

51

Ab.03 (10 mol%) H2S04, 1 atm CO A,2h 15

16 (56%)

AU203 (10 mol%) H2SO4, 1 atm CO A.2h

18 (53%)

17 Scheme 4.

19 (25%)

Cold-catalyzed carbonylation of alkenes.

silver(I)-catalyzed process by Marshall et al. (typical reaction conditions: 20% catalyst and a reaction time of several hours) [13]; obviously. gold salts are the significantly more active catalysts, which is confirmed by the fact that quantitative yields are obtained after a few minutes at room temperature using only 1 mol% of the catalyst.

'0

20

or

AuC13 (1 mol-%) MeCN

E t q E t

20 T

22 (quant.)

Et 0

21

-

R

AuC13 (1 mol-%)

23 Scheme 5.

MeCN 2 0 OC R = CHZ-~-(TBDMSO)C~H~

R

24 (42%)

New gold-catalyzed C-C and C - 0 coupling reactions; TBDMS = tea-butyldimethylsilyl.

52

I

An Eldorado for Homogeneous Catalysis?

Of particular interest is the observation that in certain cases products such as 24 resulting from domino processes are obtained: After the formation of the furan, evidently a double Michael-type addition of these intermediates to the remaining starting material 23 can take place at the unsubstituted 5-position. Preliminary experiments to investigate scope and limitations of such addition reactions in the presence of gold salts also confirm the applicability to the functionalization of other electron-rich arenes (Scheme 6 ) : Besides furans, azulene 28 and di- and trialkoxybenzene are suitable as nucleophiles for the reaction with unsaturated carbonyl compounds [ 141. For instance, 2-methylfuran (25) reacts at the reactive 5-position with methyl vinyl ketone 26 to give the addition product 27, and with azulene 28 a twofold

20 OC, 40 min 25

26

27 (91%)

aAuC13 (1 mol-%)

+ 26 (3 equiv.)

\ \

MeCN, 20 OC 28

29 (49%)

Pd"-cat.

PhCOgBu 25

31 (67%)

30

Pd"-cat.

~

p C 0 2 E t

(1 mol-%)

OCH3 32

H 33

CF3C02H 25 'C, 45 h

OCH3 34 (78%)

Gold and palladium-catalyzed Michael-type additions o f electron-rich arenes to *,,&unsaturated carbonyl compounds.

Scheme 6.

An Eldorado for Homogeneous Catalysis?

alkylation occurs to give 29. In contrast to the catalysis of these reactions with hydrochloric acid and other protic and Lewis acids [15], gold(II1) chloride in acetonitrile guarantees sufficiently mild reaction conditions; the otherwise typical decomposition and polymerization reactions, particularly in the case of furans, are suppressed. On the basis of the results obtained so far, the acidic hydrate of gold(II1) chloride or tetrachloroauric acid works as a protic catalyst [14]. It is important to note that similar products are obtained from palladium-catalyzed reactions, but presumably through a different mechanism. In this case the reaction sequence clearly starts with an electrophilic metalation of the electron-rich arene, followed by intermolecular carbornetalation of the olefinic coupling component, a reaction sequence that by far is a domain of palladium and ruthenium catalysis [16, 171. As shown by the coupling reaction of 2-methylfuran (25) with the acrylate 30 developed by Tsuji and Nagashima [18], owing to the pronounced tendency of alkylpalladium intermediates for /I-H elimination the unsaturated product 31 is obtained; the generally associated reduction of the active palladium(11) catalyst necessitates the addition of an oxidizing agent such as a peroxy acid ester. Very recently Fujiwara et al. [ 191 reported that correponding coupling reactions with alkynes such as 33 in trifluoroacetic acid as solvent proceed already at room temperature with reaction times of several hours. Whether gold salts can also directly metalate electron-rich arenes under C-H activation in analogy to palladium and ruthenium catalysts will require detailed reactivity studies.

35

36 (95%)

Ar

AuCI~ (3 mol-%)

37

+ AAr

r

CH3CN

W

80 OC, 1 h

Ar

Ar

Ar = 4-anisyl 39 (43%)

38 Scheme 7.

Additional examples of protic catalysis provided by gold(ll1) chloride.

I

53

54

I

An Eldorado for Homogeneous Catalysis?

However, the ability of gold(111) chloride to provide protic catalysis under exceptionally mild conditions is further demonstated by two recent examples: the hydroxyallene 35 bearing a silyl protecting group is efficiently cyclyzed to give the 2,s-dihydrofuran 36 without deprotection [20]; other acidic catalysts which in principle sufficiently promote this type of cyclization - such as HCI gas or Amberlyst 15 resin - are of course much less compatible with acid sensitive functionalities. Also for the formation of macrocycle 39 gold(111) chloride turned out to be the catalyst of choice [21]. A new chapter for gold catalysis was opened up by Hashmi et al. when they found a highly selective gold catalyzed arene synthesis [ 221: the efficient formation of the annulated phenol 41 from furan 40 with a terminal alkyne in the side chain is certainly not a simple intramolecular cycloaddition reaction followed by rearomatization, since the oxygen atom obviously migrates during the transformation. According to a recent mechanistic suggestion even gold carbene complexes have to be taken into account as reactive intermediates [ 231. Clearly, it has been shown that gold salts display considerable catalytic activity under moderate conditions and gold catalysis will likely provide for some more surprises. Thus, an extensive development of gold catalysis with numerous new applications is anticipated.

AuC13 (2 mol%)

"3C

/

~

CH3CN 20 OC

40

H3C

OH 41 (94%)

Scheme 8.

References 1

2

An appeal to catalyst research from Faust 11: Man grefe nun nach.. . . Gold, dem Greijeenden ist meist Fortuna hold. a) 0. K R ~ T Z ,7000Jahre Chemie, Nikol Verlagsgesellschaft, Hamburg 1999; b) H. SCHMIDBAUR, Natunv. Rdsch. 1995, 48, 443-451; c) A. GROHMANN, H. SCHMIDBAUR, Organogold Chemistry in: Comprehensive Organometallic Chemistry rr, E. w. ABEL,F. G. A. STONE; G. WILKINSON (Edts.), Pergamon Press Ltd., Oxford, UK, 1994, 1-56; d) H. SCHMIDBAUR, Gold: Organometallic Chemistry in: Encyclopedia of Inorganic Chemistry, John Wiley & Sons, Ltd., Chichester, 1994, 1226-1234; e) H. SCHMIDBAUR, Chem. SOC.Rev. 1995, 24, 391-401; f ) H. SCHMIDBAUR (Ed.), Gold -

Progress in Chemistry, Biochemistry and Technology, John Wiley & Sons, Inc., New York, 1999. 3 L. JAENICKE, Chemie in unserer Zeit 1995. 29, 272-273. 4 a) J. SCHWANK, Gold Bulletin 1985, 18, 210; b) D. THOMPSON, Gold Bulletin 1998, 31, 111-118; c) D. THOMPSON, Gold Bulletin 1999, 32, 12-19; d) G. C. BOND, D. THOMPSON, Catal. Rev.-Sci. Eng. 1999, 41, 319-388. 5 a) T. AIDA,R. HIGUCHI, H. NIIYAMA, Chem. Lett. 1990, 2247-2250; b) T. M. SALAMA, T. SHIDO,R. OHNISHI,M. ICHIKAWA, J. Chem. Soc., Chem. Commun. 1994, 2749-2750. 6 G. SCHMID,Progress in the Science and Technology of Gold, Hanau, June 1996, see Gold Bulletin 1996, 29, 105.

References I 5 5

7 L.-U. MEYER, A. D E MEIJERE,Tetrahedron

Lett. 1976, 497-500. 8 For some special gold( I)-catalyzed processes, see: a) boration of vinylarenes: R. T. BAKER; P. NGUYEN, T. B. MARDER, S. A. WESTCOTT, Angew. Chem. 1995, 107, 1451-1452; Angav. Chem. Int. Ed. Engl. 1995, 34, 1336-1338; b) dehydrogenative dimerization of trialkyltin compounds: H. ITO, T. YAJIMA, J. TATEIWA, A. HOSOMI,Tetrahedron Lett. 1999, 40, 78077810. 9 a) Y. ITO, M. SAWAMURA, T. HAYASHI,]. Am. Chem. SOC. 1986, 108, 6405-6406; b) T. HAYASHI, M. SAWAMURA, Y. ITO, Tetrahedron 1992, 48, 1999-2012; c) A. TOGNI,S. D. PASTOR, J . Org. Chem. 1990, 55, 1649-1664; d) P. F. HUGHES,S. H. SMITH,J. T. OLSON, J. Org. Chem. 1994, 59, 5799-5802. 10 a) Y. FUKUDA, K. UTIMOTO, J. Org. Chem. 1991, 56, 3729-3713; b) Y. FUKUDA, K. UTIMOTO,Bull. Chem. SOC.Jpn. 1991, 64, 2013-2015; c) Y. FUKUDA, K. UTIMOTO, Synthesis 1991, 975-978; d) J. H. TELES,S. BRODE,M. CHABANAS, Angav. Chem. 1998, 110, 1475-1478; Angew. Chem. lnt. Ed. Engl. 1998; 37, 1415-1418; e) J. H. TELES, M. SCHULZ(BASF AG), WO 97/21648 (CA 127:121499u); f ) F. GASPARRINI, M. GIOVANNOLI, D. MISITI,G. NATILE,G. PALMIERI, L. MARESCA,J. Org. Chem. 1993, 115,4401-4402. 11 Q. Xu, Y. IMAMURA, M. FUJIWARA, Y. SOUMA, J. Org. Chem. 1997, 62, 15941598. 12 A. S. K. HASHMI,L. SCHWARZ; J.-H. CHOI, T. M. FROST,Angew. Chem. 2000, 112, 2382-2385; Angew. Chem. Int. Ed. Engl. 2000, 39, 2285-2288.

J. A. MARSHALL, G. S. BARTLEY, J. Org. Chem. 1994, 59, 7169-7171. 14 A. S. K. HASHMI,G. DYKER, E. MUTH, unpublished results. 15 a) K. ALDER, C.-H. SCHMIDT,Chem. Ber. 1943, 76, 183-205; b) M. CATTALINI, S. Cossu, F. FABRIS,0. DE LUCCHI, Synth. Commun. 1996, 26, 637-647; c) M. YAMAGUCHI,M. SHIROTA, T. WATANABE, Heterocycles 1990, 31, 1699-1704; d) C. ROGERS,B. A. KEAY, Can.J. Chem. 1993, 71, 611-622. 16 G. DYKER, Angav. Chem. 1999, 111, 18081822; Angew. Chem. Int. Ed. Engl. 1999, 38, 1698-1 7 12. 17 The addition of carbonyl-functionalized arenes to electron-rich alkenes and alkenes is achieved under ruthenium catalysis (Murai reaction): S. MURAI,F. KAKIUCHI, S. SEKINE,Y. TANAKA, A. KAMATANI, M. SONODA, N. CHATANI,Nature 1993, 366, 529-531. 18 J . TSKJJI, H . NAGASHIMA, Tetrahedron 1984, 40, 2699-2702. 19 C . J I A , D.PIAO,J. OYAMADA, W. Lu, T. KITAMURA, Y. FUJIWARA, Science 2000, 287, 1992-1995. 20 A. HOFFMANN-RODER, N. KRAUSE,Organic Lett. 2001, 3, 2537-2538. 21 G. DYKER, J. LIKJ,unpublished results. 22 a) A. S. K. HASHMI,T. M. FROST,J. W. BATS,]. Am. Chem. SOC.2000, 122, 1155311554; b) A. S. K. HASHMI,T. M. FROST, J. W. BATS,Org. Letters 2001, 3, 3769-3771; c) A. S. K. HASHMI,T. M. FROST,J. W. BATS, Catalysis Today 2002, 72, 19-27. 23 B. MARTIN-MATUTE, D. J. CARDENAS, A. M. ECHAVARREN, Angew. Chem. 2001, 113, 4890-4893; Angew. Chem. Int. Ed. Engl. 2001, 40,4754-4757.

13

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

New and Selective Transition Metal Catalyzed Reactions of Allenes A. Stephen K. Hashmi

Among the most popular organic substrates for transition metal catalyzed reactions are alkenes A and alkynes B. Allenes C have received much less attention. This is easily explained by increasing selectivity problems when we proceed from A to C. While in A we face the question of regioselectivity (Markovnikov versus anti-Markovnikov orientation leading to constitutional isomers, Scheme 1)and stereoselectivity of an addition reaction (cis- or trans-addition at possibly enantiotopic or diastereotopic faces of the double-bond leading to stereoisomers), in B we have to cope with the problem of chemoselectivity (single or double addition leading to different products) and for each addition the regio- and stereoselectivity problems apply as discussed for A. In C the situation is even more complicated: as with the alkynes chemo-, regio- and stereoselectivity are significant, but furthermore we face the question of positional selectivity (which of the two orthogonal double bonds will react in the case of a single addition, thus again leading to constitutional isomers).

R’

dR2 R’ = R2

regioselectivity

regioselectivity

regioselectivity

regioselectivity

stereoselectivity

stereoselectivity

stereoselectivity

stereoselectivity

chemoselectivity

chemoselectivity positional selectivity

A Scheme 1.

B

C

Selectivity problems in different types of unsaturated substrates A-C.

In early investigation of the reactions of allenes with transition metals, the conversions proceeded quite unselectively due to the enhanced reactiuity of the allenes [ 11. This observation led to the neglect of allenes as substrates in such reactions for a long time. In the past

Cyclopropyl Allenes

decade allenes have reemerged as interesting compounds for scientist working in the field of transition metal catalysis. Three major principles were used to overcome the selectivity problem: (1) In intermolecular reactions, the positional selectivity was often controlled by steric hindrance, that is, by substituents on only one of the double-bonds. (2) Intramolecularization of the reactions, usually by placing the reacting groups in such a distance that five- or six-membered rings are formed, automatically solved the positional selectivity problem. (3) Allenes bearing functional groups on the carbon atom next to the allene allowed to control the selectivity by both geometrical restrictions and electronic differentiation of the two cumulated double bonds of the allene, not only in intramolecular but also in intermolecular reactions. While approach ( 1) has allowed some very interesting transformations and numerous mechanistic details could be investigated [ 21, the substituents used to provide steric hindrance also limited the synthetic potential. Principle (2) seems to have a higher potential for organic synthesis [ 31. Principle (3), in paticular, seems to provide some interesting and truly new transformations, which shall be summarized here. The following section is organized along the different types of substrates that all belong to principle (3). If nothing else is mentioned, the reactions proceed with 0.5-5 mol% of catalyst. Vinyl Allenes

As mentioned in the introduction [Ic], no selectivity was observed in early dimerization experiments of 1. But when other partners were offered, the corresponding crossdimerizations were quite selective. Probably methylene metallacyclopentenes 2 [4], which could be isolated, are intermediates that then react with the other partners. Generally, the related 1,3-dienes are less reactive than 1 with its reactive allenic double-bond and do not react in a similar manner [4a]. Rh-catalyzed [4+1] cycloadditions with CO as a second reaction partner led to alkylidene cyclopentenones 3 and 4 [4, 51, while in Pd-catalyzed reactions where 1 was generated in situ and a base was present, only 4 [GI was formed. When Pt(0) was used instead of Rh(I) in the carbonylation reaction, both in the presence of the (R,R)DuPHOS-ligand, opposite enantiomers of 3 were obtained [ Sb]. This observation still needs a precise explanation. [ Fe(CO)5]-mediated reactions of diallenes form dialkylidene cyclopentenones 7 (Scheme 2, here 10 mol-% of catalyst are needed) [7]. Other partners like alkynes in Rh- or 1,3-dienes in Pd-catalyzed reaction led to arenes 5 [8] or vinyl alkylidene cyclohexenes 6 [9]. Since these [4+2] cycloadditions take place between two electronically quite similar partners, a direct Diels-Alder reaction is not feasible. With a certain substitution pattern even [4+4+1] cycloadditions that deliver ninemembered rings 8 [ 101 could be achieved (Scheme 3). With Rh' the very same substrate delivers 3. Cyclopropyl Allenes

Substrates 9 can be regarded as homoolefinic derivatives of 1. Here also the analogous vinyl cyclopropanes don't react similarly to 9, the allenic unit makes 9 more reactive [ll].In Ir'catalyzed reactions with CO the sixmembered analoges of 3, the cyclohexenones 11 [ll], were formed in a [ 5+1] cycloaddition (Scheme 4).

I

57

58

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

R3

R'

R

R3

M"Lm

1

R4

-

y

i

M"+~L,,, R4

2

M"orPto = Rh'

co

Z 68-99%

+ HC=CR5

R3@Ri

* R4

R3

64-82%

3

R3xR R4

4

R'

4

8596%

5 (regioselective! for R4 = H) 15-94%

Scheme 2.

Reactions of vinyl allenes 1.

-@ R

2

R q o 4

Pdo

co R R = Ph, CH=CHZ Scheme 3.

61-8770

Formation of nine-membered rings from vinyl allenes and CO

On the other hand, Rh' in the absence of CO leads to 12 [12] formed via a vinyl cyclopropane/cyclopentene rearrangement. Such a rearrangement without a catalyst would require temperatures between 300 and 400 "C! Again one suspects metallacycles 10 as intermediates that either insert CO or undergo a reductive elimination immediately. With [ CozCOe] 1-hydroxycyclopropyl allenes 13 can be transformed into hydroquinones 14 and the corresponding diacetates 15, respectively, under mild conditions [ 131. This methodology can be used in the synthesis of vitamine E and K analogues (Scheme 5).

Allenes with Neighbouring OH- or NH-groups

I

59

co

9 10

I

Scheme 4.

11 28~83% M" = Rhl

Reactions of cyclopropyl allenes 9.

R'

14

13

15 51-90% over two steps

Scheme 5.

Formation of dihydroquinones from cyclopropyl allenes 13

Allenes with Neighbouring OH- or NH-groups

The addition of hydroxy groups to the distal double bond of the allene, mediated by Hg" or Ag' and leading to dihydrofurans, has been known for quite a while [14]. Quite recently Krause et al. could show that Au"' is also able to catalyze such a reaction with complete axis to center chirality transfer, even with substrates that possess additional alcohol groups or silyl ethers therefore were notoriously difficult [ 151. Marshall et al. very successfully applied this principle to the synthesis of natural products and extended it to allenyl carboxylic acids like 16 [16], which can lead to lactones like 17 (Scheme 6).

HOAO

16 (-)-Kallolide B 68%

Scheme 6.

Silver-catalyzed lactonization i n Marshall's synthesis of (-)-Kallolide B (17)

60

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

Further targets were analogues of pseudopteranes [ 171 and of (-)-deoxypukalide [ 181. comparable lactones 19 can be synthesized from allenyl alcohols 18 by a rutheniumcatalyzed carbonylative cyclization [ 191 and an extension of this procedure to the synthesis of lactames 21 has also been reported [ 20). In these examples with one more carbon atom between the allene and the OH or NH group, the corresponding sixmembered compounds could be obtained. With substrates 22 additional C-C bonds can be formed in Pd-catalyzed reactions with aryl halides as reaction partners (Scheme 7) [ 211. With enantiomerically pure bis(oxazoline) ligands ee-values up to 53% could be observed in such reactions [22].

RU3(CO)I2

p,4>**R2

R'

OH

R5

NEt,, dioxane 10 atm. CO,100°C

18

R4

R5

19

RU3(CO)12

R1<*=

NEt,, dioxane 20 atm. CO,100°C

NHR~

20 Scheme 7.

Carbonylative cyclization o f hydroxymethyl allenes 18 and aminomethyl allenes 20.

In the case of Pd-catalyzed reactions of aryl halides with allenyl carbinols 24, enones 27 [23] were obtained (Scheme 8). R

+

Ar-X

OH

22 Scheme 8.

X=Br, I

K2C03

59-79%

23

Combination o f C-C-bond formation and lactonization.

Interestingly, in DMF as solvent and with C032-, for 24 a cyclization leading to the corresponding vinyl epoxides 26 [24] could be achieved! Simple treatment of 24 with Ag' delivers 25. The silver(1)-catalystsshow significant lower reactivity, thus usually 20 mol% or even more are applied. Similar developments were possible for the amines 28, which either formed dihydropyrroles 29 or vinyl aziridines 30 (Scheme 8) [ 251. Here also the reaction heavily depends on the solvent, but no explanation has been provided so far. On the other hand, in the presence of a Pd-catalyst and CO, tertiary amines 31, which cannot form another C-N bond, gave a-vinyl acrylamides 32 (Scheme 9) [26].

Allenes with Neighbouring OH- or NH-groups

I

61

24

25 T R

l PPhl d oor Ph,l+BF;

i

h

l

DMF/CO:-

'

R-S

R d p h

0 27 (HZ-mixtures)

::-65?!0

54~88%

I

1

Mts

28 29

50%

!Zxane

a

30 [cis:trans = 82:18)

,ph

77-83%

1

Mts

Reactions of allenyl carbinols 24 and related amines 28. Mts = 2,4,6-trimethylbenzenesulfonyl.

Scheme 9.

R' R

p

R2

N-R3

R

R3'

Pdo

* R2

'

1 mol% pTsOH

31

At?:

co

R'

R~ R'

32 59-84 Yo

Scheme 10.

Formation of vinylacrylamides 32. p-TsOH = para-toluenesulphonic acid

An alkylative version of the dihydrofuran-synthesis, leading to 35, was developed by Ma et al. [27]. Recently Trost et al. reported that in vanadium-catalyzed additions of allenic alcohols 36 and aldehydes 37 aldol-type products 38 can be obtained in an atom economic manner [28]. Backvall et al. utilized a stereoconvergent palladium-catalyzed S N ~ reaction ' of cc-allenic acetates 39 for the synthesis of (Z,E)-2-bromo-l,3-dienes40 [29]. With different allenylcarbinols 41 a nickel-catalyzedliving polymerization was possible, but no regioselectivity of the C-C bond formation was observed (40% reaction of the @-double bond, 60% reaction at the P-double bond in 42) [ 301.

62

I

wR4

New and Selective Transition Metal Catalyzed Reactions of Allenes

+

R2>*=

R'

" c , R4 r

PdCI,

R2

DMA rt

R'

P

OH

33

34

35 57-86%

Scheme 11. Alkylative cyclization o f hydroxymethyl allenes 33.

R

+

Ph--(F*& OH

VO(OSiPh,),

LRI

-

CH2CI2, rt

36 Scheme 12.

0

37

0

OH

Ph+R' R 6O-88% usually syn preferred

38

Aldol-like products 38 from hydroxymethyl allenes 36.

R2

Pd(0AC)p R'-(=*&

R

'

b

OAc

39 Scheme 13.

2.5 eqs LiBr AcOH/acetone, 40°C

v

R Br

2

40 77-94%, de 86-99%

(E,Z)-Configurated 2-bromo-l,3-dienes 40 from 39.

1.. N!

WCF3 PPh3

/=*=

R

41 R = CH20H, CHMeOH, CMe,OH

Scheme 14.

42

M, = 9.6.103 M,/M,=1.13

Polymerization of hydroxymethyl allenes 41.

Allenyl Ketones

Here also a diversity of reactions was developed. With y,y-disubstituted derivatives 43 and [ Fe(C0)5] (again 10 mol-%), the lactones 44 were formed (Scheme 10) [ 311. Rh' or Ag' cause the cycloisomerization of 45 to the corresponding furan 46 [32]. Again this principle was used in the synthesis of natural products like the enantiomer of the furanocembrane rubifolide [ 331. Even greater is the diversity of substrates 47. Pd" leads to the formation of dimer 48 [ 341, Au"' to a constitutional isomer of 48, the dimer 50.When the latter reaction was performed in the presence of Michael acceptors, the addition products 49 were formed [35]. Finally, in the case of alkoxy-substituted allenyl benzyl ketones 51, the spirocycles 52 are obtained (Scheme 11) [ 361.

Allenyl Carboxylic Esters and Related Substrates R’

43

44 54-89%

45

46 72-99%

21-91Yo

50 24-51% 49 46-7470 Scheme 15.

Transition metal-catalyzed reactions o f allenyl ketones 43, 45 and 47

RO

Q

a=

+

ROH

0

51

80~84%

Scheme 16.

Hg(ll)-catalyzed formation o f spiro[4,5]decanes 52 from p-alkoxy allenyl ketones 51.

Allenyl Carboxylic Esters and Related Substrates

In Nickel(0)-catalyzed reactions these substrates 53 selectively delivered the head-to-head [ 2+2] dimers 54 [ 371.

2

=* dEWG 10 mol% Ni(PPh,), 53

toluene

EWG = COpR, CONRp, SOpPh, COR Scheme 17.

[2+2] Cycloaddition o f 53.

f EWG

54 33-81Yo

I

63

64

I

New and Selective Transition Metal Catalyzed Reactions of Allenes

Transition Metal Catalysis for the Synthesis o f Allenes with Neighboring Functional Groups

The last chapters might have led to the conclusion that transition metals will always react with allenes bearing functional groups in the direct neighborhood. But this is not automatically the case, such substrates can often be prepared by transition metal catalysis without reacting to another product in situ. For example, the copper catalyzed addition of Grignard compounds to alkynyl substituted p-lactones 55 delivers p-allenic acids 56 in high yields [ 381, During these reactions, the central chirality of one of the stereogenic centers of the p-lactone is transferred to the axial chirality of the allene. R3-MgBr

C02H

* 10 mol% CuBr or CuCN.2 LiBr " THF, -78°C

55

56 79-94?0 '

Copper-mediated ring-opening of 55.

Scheme 18.

Amino allenes of type 58 can be prepared by palladium-catalyzed reduction 57 [ 391.

N PG

Br 2 eqs EtJn THF, rt

57

80 - 90%

PG = MTS or Boc Palladium-catalyzed reduction o f amino allenes 58. Mts = 2,4,6-trimethylbenzenesulfonyl.

Scheme 19.

Ma et al. demonstrated that the palladium-catalyzed coupling of vinyl halides GO and allenyl/propargyl metal species 59 can deliver vinyl allenes 61 [40]. R'

Ph

+JR1

Ph+(

59

M

M

R' Pd(O)

b

R2?Od

R4

4-

R2

60 Scheme 20.

R3

xR4

x

X=Br, I

R3

61

5 - 77%

Vinyl allenes 61 by palladium-catalyzed cross-coupling.

2-Bromo-l,3-butadienes 62 can be coupled with nucleophiles to deliver allenylcarbinols and the related amines and phosphanes 63 [41]. In some cases even chloroprene can be used [421.

Conclusion I 6 5

T:

M-NU

R

62

-

[rr-allylPdCI],

R3 Nu

THF

63

M-NU= NaOPh, KN(Boc),, LiPPh,

Scheme 21.

Palladium-catalyzed allylic substitution at 62.

Palladium catalysts rearrange chiral 2-alkynyl sulfinates 64 into chiral allenyl sulfones 65

WI.

65

(Ss,S)-64 Scheme 22.

39-89% 60-89% ee

Palladium-catalyzed isornerization of 64.

The iron-catalyzed reaction of propargyl sulfides 66 and trimethylsilyldiazomethane 67 delivers allenyl cc-silyl sulfides 68 [44].

DCE, 83°C

66 Scheme 23.

67

d’ 68 48-90%

Iron-catalyzed synthesis o f 68.

The Latest Highlight: Selective Reactions between Two Allenes

As mentioned in the introduction, the reactivity of the allenes is high. Therefore the oxidative and cyclizative cross dimerization of two different allenic substrates just recently reported by Ma et al. can be considered to be a milestone in this field! They discovered that one equivalent of 2,3-dienoic acids 69 and five equivalents of allenyl ketones 70 with the simple PdC12(MeCN)2catalyst can deliver up to 92% of the cross dimerization product 71

PSI. Conclusion

The recent investigation in many groups made selective and synthetically interesting transformations of allenes available, one important motive for this achievement is the presence

66

I

New and Selective Transition Metal Catalyzed Reactions ofAllenes

.=

R.<

69 PdCI,(MeCN),

+ R*

R'

+{ HO

MeCN, rt * ''-H*"

ko

R4

0

70

71

61-92°/o

Scheme 24. Cyclizative cross-dimerization of two different allenic substrates 69 and 70

on fuctional groups in the direct proximity of the allene. Still, often the unique chemoselectivity still lacks explanation. A deeper mechanistic understanding of these selectivities might be the key for future developments of even more exciting and synthetically fruitful reactions. References a) B. L. SHAW,A. J. STRINGER, Inorg. Chem. Acta Rev. 1973, 7, 1-10; b) F. L. BOWDEN,R. GILES,Coord. Chem. Rev. 1976, 20, 81-106; for further efforts, see: c) H . SIEGEL,H. HOPF,A. GERMER,P. BINGER,Chem. Ber. 1978, 111, 3112-3118; d) G. ERKER,Methoden Org. Chem. (Houben-Weyl)4th ed, 1952-, Vol. E18, 1986, pp. 870-873 and 882-883. 2 For selected examples and additional references, see: L. BESSON,I. G o R ~B. , CAZES,Tetrahedron Lett. 1995, 36, 3853H . ALPER, 3856; W.-J. XIAO,G. VASAPOLLO, J . Org. Chem. 1998, 63, 2609-2612; R. C. LAROCK, Y. H E , W. W. LEONG,X. HAN, M. D. REFVIK,J. M. Z E N N E RJ,. Org. Chem. 1998, 63, 2154-2160; T. SUDO,N. ASAO,V. GEVORGYAN, Y. YAMAMOTO, J . Org. Chem. 1999; 64, 2494-2499; S. KACKER, A. S E N ,J. Am. Chem. SOC.1997, 119, 10028-10033; B. M. TROST,A. B. PINKERTON, J . Am. Chem. SOC.1999, 121, 10842-10843; D. HIDEURA,H. URABE,F. SATO,J . Chem. SOC.,Chem. Commun. 1998, 271-272. 3 For selected examples and additional references, see: V. M. ARREDONDO, S. TIAN,F. E. MCDONALD, T. J. MARKS,J . Am. Chem. SOC.1999, 121, 3633-3639; R. D. WALKUP,G. PARK,J . Am. Chem. SOC. 1990, 112, 1597-1603; R. GRIGG,J.M. SANSANO, Tetrahedron 1996, 52, 1344113454; C. JONASSON, J.-E. BACKVALL, Tetrahedron Lett. 1998, 39, 3601-3604; 1

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5

6

7 8

9

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References I 6 7 10 M. MURAKAMI, K. ITAMI,Y. ITO, Angav.

Chem. 1998, 110, 3616-3619; Angew. Chem. Int. Ed. 1998, 37, 3418-3420. 11 M. MURAKAMI, K. ITAMI,M. UBUKATA,I. TSUJI,Y. ITO,J. Org. Chem. 1998, 63, 4-5. 12 M. HAYASHI, T. OHMATSU,Y.-P. MENG,K. SAIGO,Angav. Chem. 1998, 110, 877-879. 13 Y. OWADA,T. MATSUO,N. IWASAWA, Tetrahedron 1997, 53, 11069-11086. 14 L.-I. OLSSON, A. CLAESSON, Synthesis 1979, 743-745. 15 A. HOFFMANN-RODER, N. KRAUSE,Org. Lett. 2001, 3, 2537-2538. 16 J. A. MARSHALL, K. G. PINNEY,J. Org. Chem. 1993, 58, 7180-7184; J. A. G. S. BARTLEY, E. M. WALLACE, MARSHALL, J. Org. Chem. 1996, Gl, 5729-5735. 17 J. A. MARSHALL, L. M. MCNULTY, D. Zou, J. Org. Chem. 1999, 64, 5193-5200. 18 j. A. MARSHALL, E. A. VAN D E V E N D E R , ~ . Org. Chem. 2001, 66, 8037-8041. 19 E. YONEDA,T. KANEKO,S.-W. ZHANG,K. ONITSUKA,S. TAKAHASHI,Org. Lett. 2000, 2,441-443. 20 S.-K. KANG, K.-J. KIM, C.-M. Yu, J.-W. HWANG,Y.-K. Do, Org. Lett. 2001, 3, 2851-2853. 21 S. MA, Z. S H I ,J. Org. Chem. 1998, 63, 6387-6389. 22 S. MA, Z. SHI, S. W u , Tetrahedron: Asymmetry 2001, 12, 193-195. 23 I. SHIMIZU,T. SUGIURA, J. TsurI, J. Org. Chem. 1985, 50, 537-539. 24 S.-K. KANG,T. YAMAGUCHI, S:J. PYUN, Y.-T. LEE,T.-G. BAIK,Tetrahedron Lett. 1998, 39, 2127-2130; S. MA, S. ZHAO,J. Am. Chem. Sac. 1999, 121, 7943-7944. 25 H. OHNO,M. ANZAI,A. TODA,s. O H I S H I , N. FUJII,T. TANAKA, Y. TAKEMOTO, T. IBUKA,]. Org. Chem. 2001, 66,4904-4914. H. OHNO,A. TODA,Y. MIWA,T. TAGA,E. N. FUJII,T. IBUKA,]. OSAWA,Y. YAMAOKA, Org. Chem. 1999, 64, 2992-2993; See also A. CLAESSON, C. SAHLBERG, K. LUTHMAN, Acta Chem. Scand. B 1979, 33, 309-310. 26 Y. IMADA,G . VASAPOLLO, H . ALPER,J. Org. Chem. 1996, 61, 7982-7983. 27 S. MA, W. GAO, Tetrahedron Lett. 2001, 41, 8933-8936. 28 B. M. TROST,C. JONASSON, M. WUCHRER, J. Am. Chern. Soc. 2001, 123, 1273612737. 29 A. H O R V ~ T H j.-E. , BACKVALL, J. Org. Chem. 2001, 66,8120-8126. 30 M. TAGUCHI,I. TOMITA,T. ENDO,Angav.

Chem. 2000, 112, 3813-3815; Angau. Chem. Int. Ed. 2000, 39, 3667-3669. 31 M. S. SIGMAN,C. E. KERR,B. E. EATON,]. Am. Chem. Soc. 1993, 115, 7545-7546; M. S. SIGMAN,B. E. EATON,J. D. HEISE, C. P. KUBIAK,Organometallics 1996, 15, 2829-2832; For the analogous allenyl imines, see: M. S. SIGMAN,B. E. EATON,J. Org. Chem. 1994, 59, 7488-7491. 32 J. A. MARSHALL, E. D. ROBINSON, J. Org. Chem. 1990, 55, 3450-3451; J. A. X. WANG,J. Org. Chem. 1991, MARSHALL, 56, 960; j. A. MARSHALL, X. WANG,J. Org. Chem. 1992, 57, 3387; J. A. MARSHALL, G . S. BARTLEY, J. Org. Chem. 1994, 59, E. M. WALLACE, 7169-7171; j. A. MARSHALL, P. S. COAN,J. Org. Chem. 1995, GO, 796; J. A. MARSHALL, C. A. SEHON,J.Org. Chem. 1995, 60, 5966; J. A. MARSHALL, j. LIAO,J. Org. Chem. 1998, 63, 5962. 33 j. A. MARSHALL, C. A. SEHON,]. Org. Chem. 1997, 62,4313-4320. 34 A. S. K. HASHMI,Angew. Chem. 1995, 107, 1749-1751; Angew. Chem. Int. Ed. Engl. 1995, 34, 1581-1583; A. S. K. HASHMI, T. L. RUPPERT,T. KNOFEL,J. W. BATS,J. Org. Chem. 1997, 62, 7295-7304. 35 A. S. K. HASHMI,L. SCHWARZ,j.-H. CHOI, T. M. FROST,Angew. Chem. 2000, 112, 2382-2385; Angew. Chem. Int. Ed. Engl. 2000, 39, 2285-2288. 36 A. S. K. HASHMI,L. SCHWARZ, M. BOLTE, Tetrahedron Lett. 1998, 39, 8969-8972. 37 S. SAITO,K. HIRAYAMA, C . KABUTO,Y. YAMAMOTO, J. Am. Chem. Soc. 2000, 122, 10776-10780. 38 Z. WAN, S. G. NELSON,J.Am. Chem. SOL. 2000, 122, 10470-10471. 39 H . O H N O ,A. TODA,S. OISHI,T. TANAKA, Y. TAKEMOTO, N. FUJII, T. IBUKA,Tetrahedron Lett. 2000, 41, 5131-5134. 40 S.-M. MA, A,-B. ZHANG,Pure Appl. Chem. 2001, 73, 337-341. 41 M. OGASAWARA, H . IKEDA,T. HAYASHI, Angew. Chem. 2000, 112, 1084-1086; Angew. Chem. Int. Ed. 2000,39,1042-1044. 42 M. OGASAWARA, H. IKEDA,T. NAGANO,T. HAYASHI,Org. Lett. 2001, 3, 2615-2617. 43 K. HIROI, F. KATO,Tetrahedron 2001, 57, 1543-1550. 44 R. PRABHARASUTH, D. L. VANVRANKEN,]. Org. Chem. 2001, 66, 5256-5258. 45 S. MA, Z. Yu, Angew. Chem. 2002, 114, 1853-1856; Angew. Chem. Int. Ed. 2002, 41, 177551778,

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I

Controlling Stereoselectivity with the Aid o f a Reagent-Dir e dng Croup Bernhard Breit

Introduction

Substrate control can be a useful tool to allow for high levels of selectivity in organic reactions. This is particularly valid for reactions in which the reacting substrate is equipped with a functionality suitable to allow for a precoordination of the reagent followed by an intramolecular reagent delivery. This type of reactions, named according to Evans et al. as substrate directable reactions, is of great synthetic value as proven in numerous total syntheses [ 11. However, known substrate directable reactions rely on the nature of the coordinating functionality present in a particular substrate. This clearly defines limitations to the set of reagents potentially directable by a specific functional group. A way to overcome such an intrinsic limitation may provide a specifically introduced reagent-directing group into an organic substrate (see Scheme 1).

Reagent Directing Group via precoordination

Concept of a specifically introduced reagent-directing group into an organic substrate as a selectivity control instrument.

Scheme 1.

Such a specifically introduced functionality should have the ability to precoordinate the desired reagent which would result in an intramolecular pathway for the desired chemical reaction with a corresponding reactive functional group within the substrate. By choosing the appropriate point of attachment of the directing functionality, as well as by choosing the appropriate geometry of this group, one should have complete control of the trajectory of a particular reagent, which of course should be the ideal basis to control any type of selectivity for a given chemical reaction.

Discussion I 6 9

Such an approach necessitates two additional synthetic operations: introduction as well as removal of the reagent-directing group. However, such a disadvantage at first sight should be acceptable if one could solve a selectivity problem for a synthetically valuable reaction which is otherwise not susceptible to stereocontrol. In this context transition metal catalyzed addition reactions have gained importance as a consequence of their intrinsic atom economy and efficiency which may be beneficial for enviromental and economic grounds [ 21. An example is the rhodium catalyzed hydroformylation reaction, which is an industrially important homogenous catalytic process [ 3 ] . In contrast, it is amazing that such an important transition-metal catalyzed CjC bond-forming process has been employed only rarely in organic synthesis [4]. Part of the reason stems from the difficulty in controlling stereoselectivity. Even though some recently developed chiral rhodium catalysts allow for enantio- and diastereoselective hydroformylation of certain specific classes of alkenes [ 5, 61, only little is known about the diastereoselective hydroformylation of acyclic olefins [ 7, 81. Discussion

The difficulty of this task became obvious in an attempt to achieve a diastereoselective hydroformylation of a simple methallylic alcohol system. It was expected that in analogy to the known substrate-directed rhodium-catalyzed hydrogenation reaction, substrate direction via the hydroxyl substituent would control diastereoselectivity in the course of the hydroformylation reaction [91. However, a completely stereorandom hydroformylation product formation was observed (1+3) [lo, 111.

1

2

3 syn : anti 50 : 50

Reagents and conditions (a) 0.35 mol% [Rh(CO)~acac], 7 mol% PPh,, 20 bar H 2 / C 0 (l:l),toluene, 90 "C, 6-24 h (83-95%); (b) PCC on A1203, CH2C12, 25 "C, 16 h (95%).

Scheme 2.

In contrast to the rhodium-catalyzed hydrogenation reactions, the hydroxyl group does not operate as an efficient catalyst-directing group in the rhodium catalyzed hydroformylation. This may be primarilly due to the carbon monoxide, itself an excellent ligand for rhodium(I), which is present in large excess under hydroformylation conditions. Hence, the hydroformylation reaction is an ideal first-test case for the concept of a specifically introduced catalyst-directing functionality with respect to its potential to control diastereoselectivity in the course of the hydroformylation reaction. Therefore, a specific catalyst-directing group needed to be designed, which itself had to (a) function as a good ligand for rhodium under hydroformylation conditions, (b) provide reversible coordination of the catalytically active rhodium

70

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

species to allow for turnover, (c) enable facile introduction into the substrate as well as removal from the product and (d) allow for a highly ordered cyclic transition state for the stereochemistry defining step of the hydroformylation reaction.

(c-DPPBA) 4

Scheme 3. Design o f a catalyst-directing group for the control of diastereoselectivity upon hydroformylation of acyclic methallylic alcohols.

As an ideal catalyst-directing group for that particular problem the ortho-diphenylphosphino benzoate system (0-DPPB) was introduced [lo]. With the aid of the o-DPPB functionality a substrate-directed diastereoselective hydroformylation of methallylic alcohol derivatives could be achieved with high levels of acyclic stereocontrol to provide the syn-aldehydes6 as the major diastereomers [ 101.

5

syn-6

up to

96

anti-6 4

Scheme 4. o-DPPB-directed stereoselective hydroformylation o f methallylic alcohol derivates. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 mol% [P(OPh)3], 20 bar Hz/CO ( l : l ) , toluene, 90 "C, 24 h (63-99%).

Support for the role of the o-DPPB substituent as a catalyst-directing group was provided in a control experiment with the benzoate 7. Thus, exchanging the phosphorus of the oDPPB group with a CH moiety, itself not able to coordinate to the catalytically active rhodium center, caused a complete loss of stereoselectivity in the hydroformylation reaction [lo].

Discussion

F X P . 2

P

h

Rh-Cat. H&O

q

0 p X P h 2

P

h

h

0 2 X P ~ 2

+

Ph% CH3 0

CH3 0

CH3

TOF [h-'1 X = P:

5a

21

syn-6a

92

:

a

anti-6a

X=CH:

7

1.4

syn-8

50

:

50

anti-8

Reagents and conditions (a) 0.7 mol% (Rh(CO)lacac], 2.8 mol% [P(OPh),], 20 bar H?/CO ( l : l ) , toluene (0.1 M), 90 "C, 2 h Scheme 5.

The o-DPPB-directedhydroformylation of methallylic alcohol derivatives could be applied for the construction of stereotriads - central building blocks of the polyketide class of natural products. Thus, starting from the methallylic o-DPPB esters 9, 11 the anti-syn and all-syn stereotriad building blocks 10 and 12 could be obtained in good yields and diastereoselectivities [ 121.

+

OTr

O(o-DPPB)

Rh-Cat. H$CO (a)

+

OTr

*

O(o-DPPB)

anti-syn

CH3 CH3 0

CH3 CH3

dr b 96 : 4 9

OPiv O(eDPPB)

YY

CH3 CH3

* 10

Rh-Cat. H$CO (b)

OPiv O(eDPPB) t

all-syn

CH3 CH3 0

dr 95 : 5

11

12

Scheme 6. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 mol% [P(OPh),], 20 bar H 2 / C 0 ( l : l ) , toluene, 90 "C, 24 h (91%), (b) same as (a) (70%).

Interestingly, the same concept involving a catalyst-directing group allowed also to make efficient use of 1,3 asymmetric induction. This, of course, is a much more difficult situation, since additional degrees of freedom have to be controlled in the course of the stereo-

I

71

72

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

chemistry defining step of the hydroformylation reaction. However, homomethallylic oDPPB esters 13 were reacted to give the anti-aldehydes 14 as the major diastereomer in selectivities of ca. 91:s) [13]. Rh-Cat.

13

anti-14

syn-14

o-DPPB-directed stereoselective hydroformylation of homomethallylic alcohol derivates. Reagents and conditions (a) 0.7 mol% [Rh(CO)~acac],2.8 mol% [P(OPh),], 20 bar H2/CO ( l : l ) , toluene, 3O-5O0C, 24 h (72-90%).

Scheme 7.

In these cases, the interplay of a preferred substrate conformation as well as catalyst delivery via the catalyst-directing group form the basis for the diastereoselectivity observed ~31. Removal of the Reagent Directing Group

After successful hydroformylation one may decide to remove the catalyst-directing o-DPPB group, which may be achieved by simple alkaline hydrolysis (syn-Gaisyn-3) [lo] or via hydride reduction after transferring the aldehyde e.g. to an alkene via Wittig olefination (syn-6b+syn-23) [14]. OH

0

syn-2

syn-3 (92 : 8)

4

0

(*)-syn-sa (92 : 8)

O(eDPPB)

O(eDPPB) i-Pr

CH3 0

(+)-sy1~6b (96 : 4)

CH3

syn-15 (96 : 4)

Reagents and conditions (a) KOH, T H F / M e O H / H 2 0 (2:2:1), 50 "C,2.5 h (99%); (b) 2 equiv. PCC on A1203,25 "C, 16 h (95%); (c) Ph3P = CH2, THF, -78"+0 "C (89%); (d) LiAIH4, ether, 0 "C (95%). Scheme 8.

CH3

syn-16 (96 : 4)

Multiple Use of One Reagent-Directing Croup: Towards a RDC-Controlled Organic Synthesis

I

73

Multiple Use of One Reagent-Directing Group: Towards a RDC-Controlled Organic Synthesis

To increase the efficiency of a specifically introduced directing functionality one should make use of that functionality as often as possible to control selectivity in further skeletonconstructing processes (see Scheme 9). In an ideal scenario each reaction would generate the functionality required for a subsequent transformation. Hence, at the end an organic synthesis could be the result in which one reagent-directing group (RDG) would control the selectivity of each single reaction step.

8-9 Reagenta

R

reaction i

@ Scheme 9.

R-A

Reagentb

Reagent c

____)

reaction ii

R-A-B

reaction iii

8

R-A-B-C

Reagent-Directing Group: Controls selectivity of reaction i-iii

R

Organic Substrate

A

Via reaction 1 and reagent a introduced modification

Multiple use of a reagent-directing group - towards an RDC-controlled organic synthesis.

Towards this goal, the potential of the o-DPPB group to control diastereoselectivity in a carbon carbon bond forming reaction, following the hydroformylation step was explored [15]. Enoates 17, were chosen as the test substrates since the stereoselective 1,4-addition of a methyl would provide a structural building block found in biologically important natural products of the polyketide class (e.g. antitumor agent dictyostatin 1 and the ionophore calcimycin).

conjugate addition

Scheme 10. Working hypothesis for the o-DPPB group t o act as an organometallic reagent directing group for the conjugate addition of Cilman cuprates t o acyclic enoates.

The enoates 17 were obtained in good yield and diastereoselectivity by subjecting the crude hydroformylation products 6 to Horner-Wadsworth-Emmons olefination conditions (HWE). Reaction of enoates 17 with dialkyl Gilman cuprates gave the anti 1,4-addition

74

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group

product 18 in good yield as the major diastereomer (dr 2 95:s with respect to the newly formed stereogenic center) [ 151. Rh-Cat. H&O

O(o-DPPB)

O(o-DPPB)

HWEolefination

(b)

(a)

R?

R +

CH3 5

*

CH3 0 6

17

18 dr 595:5

dr294:6 E:Z > 95:5 Sequential use o f t h e reagent directing o-DPPB group t o control stereoselectivity in the course o f hydroformylation and subsequent conjugate addition with organocuprates. Reagents and conditions (a) 0.7 mol% [Rh(CO)zacac], 2.8 Scheme 11.

mol% [P(OPh)j], 20 bar H2/CO ( l : l ) ,toluene, 90 "C;(b) (EtO)z(O)PCH2CO,Et, n-BuLi, DME, 20 "C (71-83% both steps); (c) 1.5 equiv. R'ZCuLi, ether, -78"+0 "C (61-93%).

Thus, combining o-DPPB-directed hydroformylation with the o-DPPB-directed cuprate addition afforded building blocks with up to four stereogenic centers (19-21). (?(o-DPPB)

OPiv O(o-DPPB) *OE' CH3 CH3 CH3 0 19

20

dr 8 5 : 15

dr 95 : 5

/--7

O(o-DPPB)

'UN

I 2o

-i-Pr

CH3 CH3 CH3 0 21 dr 95 : 5

lonophore A-23187 (Calcimycin)

Interestingly 1,4-addition product 21 is equipped with the same relative and absolute configuration of the four stereogenic centers found in the ionophore calcimycin.

o-DPPB-directed Hydroformylation as Part of Sequential Transformations

I

75

o-DPPB-directed Hydroformylation as Part o f Sequential Transformations

One may improve efficiency of an o-DPPB directed hydroformylation by incorporating this reaction into sequential transformations (domino reactions) [ 161. The hydroformylation itself should be ideally suited for such a purpose, since this reaction provides under fairly mild reaction conditions access to the synthetically valuable aldehyde functionality. The aldehyde itself should be ideally suited to allow for further skeleton-constructing reactions. One type of sequential transformations employing the hydroformylation reaction as a key step is the hydroaminomethylation of olefins originally discovered by Reppe [ 171. However, efficient control of diastereoselectivity in the course of this hydroaminomethylation reaction was unknown [18, 191. Employing the same concept and catalyst-directing o-DPPB group enabled the development of a substrate-directed diastereoselective hydroaminomethylation of acyclic methallylic alcohol derivatives 5 to give in diastereoselectivities of greater 94% the corresponding amines 22 [20]. This process allows, in one step, the formation of a C~-Cbond, a C-heteroatom bond, introduction of the ubiquitous amine functionality, and, additionally, generates a new stereogenic center with high levels of acyclic stereocontrol. The mechanism of this sequential transformation involves presumably three steps. First o-DPPB directed stereoselective hydroformylation of the methallylic o-DPPB esters 5 provides the aldehyde 6 . Enamine formation ( 1 2 3 ) with the secondary amine present and subsequent rhodium catalyzed hydrogenation finishes the sequence of reactions, and affords the saturated amines 22.

+

HNR'z

O(eDPPB)

Q(eDPPB)

Rh-cat; CO/Hp t

CH3

syn/anti> 94 : 6 22

5

I

enamine hydrogenation

hydroformylation

I

'

6

2

3

Scheme 12. o-DPPB-directed hydroaminomethylation with secondary arnines. Reagents and conditions: 1.5 Equiv. HNR'?, 0.7 mol% [Rh(CO)?acac], 2.8 mol% [P(OPh)3], 20-80 bar H 2 / C 0 ( l : l ) , toluene, 90"-120 "C (40-65%).

In addition to secondary amines, primary amines could be employed furnishing the corresponding secondary amine derivatives as the final products in equally high diastereoselectivity.

76

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing Group HzNR'

Rh-cat; CO/H2D

O(c-DPPB) R+NHR 1

CH3 syn/anfi 2 94 : 6 24

5

I

imine

hydroformylation

2

6

5

Scheme 13. o-DPPB-directed hydroaminomethylation with primary arnines. Reagents and conditions: 1.5 Equiv. HINR', 0.7 mol% [Rh(CO)2acac], 2.8 mol% [P(OPh)3], 20+80 bar H2/CO ( l : l ) , toluene, 90"-120 "C (40-46%).

In these cases, the reaction sequence must have proceeded through an imine intermediate 25 followed by a rhodium catalyzed imine reduction. This appeared surprising, since known hydroaminomethylation attempts starting from primary amines and alkenes, employing similar rhodium-catalysts, under similar reaction conditions were found to stop generally at the stage of the imine [21]. Hence, a special situation may be given for o-DPPB derivatives 5. A plausible explanation for the increased reactivity towards imine hydrogenation may take into account the presence of the catalyst-directing o-DPPB group.

Catalyst-Directing Group (CDG)

[mine-Hydrogenation Scheme 14.

Possible role of the o-DPPB group in the course of the imine hydrogenatlon step.

Thus, it is likely, that after imine formation a second catalyst precoordination occurs and an intramolecular imine hydrogenation takes place. Such an intramolecular process should be kinetically favored compared to a corresponding intermolecular reaction pathway. Hence, the catalyst-directing o-DPPB group may be acting within one sequential transformation in

o-DPPB-directed Hydroformylation as Part of5equential Transformations

two different ways. Firstly, the CDG controls diastereoselectivity in the hydroformylation step and secondly controls chemoselectivity in the course of the imine reduction. Other sequential transformations employing the hydroformylation as the key step may be realized if other nucleophiles such as e.g. carbon nucleophiles are offered in the course of the hydroformylation reaction. A resulting domino reaction would approach an ideal synthetic method as defined by Hendrickson [21]. Thus, according to his definition, only skeleton-constructing reactions are inevitable and consequently an efficient synthesis should consist only of framework elaborating steps. Furthermore, if a particular target contains stereogenic centers the most efficient synthetic steps are according to Corey those which in addition to carbon skeleton construction allow for the generation of new stereogenic centers selectively [22]. A reaction in agreement with these efficiency criteria would be a domino stereoselectivehydroformylation-Wittig olefination process. This would require that the hydroformylation reaction be compatible with the presence of a Wittig ylid throughout the course of the reaction. Reacting both methallylic and homomethallylic alkenic substrates under hydroformylation conditions in the presence of stabilized Wittig ylids gave the corresponding domino hydroformylation products 26 in good yields and diastereoselectivities [24]. Whereas in the case of the disubstituted stabilized Wittig ylids the reaction stopped at the stage of the trisubstituted olefin 26, in the case of monosubstituted ylids a further hydrogenation reaction of the @'unsaturated carbonyl functionalities occurred and provided the corresponding saturated derivatives 27. Control of diastereoselectivity was provided via the catalyst-directing o-DPPB group making use of both 1,2- and 1,3-asymmetric induction. O(PDPPB)

Ph3P=CMeCOR' Rh-Cat.; H2/C0 *

R+

CH3

O(@DPPB) CH3 ++R

0

CH3

synhnfi 5

up to 96 : 4 26

Scheme IS. Domino hydroformylation-Wittig olefination. Reagents and conditions: 1.1 Equiv. Ph,P = CMeCOR'. 0.7 mol% [Rh(CO)zacac],2.8 mol% [P(OPh)p], 20 bar H2/C0 ( l : l ) , toluene, 90 "C (60-78%). R' = Me, OEt.

This domino reaction enables in one step the construction of two carbon carbon single bonds and additionally, generates a new stereogenic center with high levels of acyclic stereocontrol. Through the substituents R and R' this domino reaction may potentially be used as a fragment coupling step in the course of a convergent synthetic strategy. However, although synthetically useful, in terms of atom economy the Wittig olefination suffers from the stoichiometric loss of phosphane oxide as the byproduct. This deficiency of the above Domino protocol could be overcome employing the Knoevenagel condensation as the key olefination step. Thus, when methallylic o-DPPB esters were subjected to hydroformylation conditions

I

77

78

I

Controlling Stereoselectivity with the Aid ofa Reagent-Directing

O(oDPPB)

Ph3P=CHCOR', Rh-Cat.; H$CO R' = Alkyl, OEt

R+

Group O(oDPPB)

*

R R +8

0 CH3 syn/anfi 2 90 : 10 27

CH3 5

+

hydroforrnylation

hydrogenation

1 I

[

wittig olefination

.D

[

R*Rt]

CH3 6

28

Domino hydroformylation-Wittig olefination-hydrogenation Reagents and conditions: 1.5 Equiv. PhlP = CMeCOR', 0.7 mol% [Rh(CO)2acac],2.8 mol% [P(OPh),], 20 bar Hz/CO (l:l), toluene, 90 "C (60-82%). R' = Me, OEt.

Scheme 16.

O(oDPPB)

JY

.EWG ( EWG

O(oDPPB) EWG R

Rh-Cat.; H$CO D EWG = COR', C02R'

CH3

W

W

G

CH3 syn/ani 2 92 : 8 29

5

hydroforrnylation

hydrogenation

t

[ 4-31

E

1 I

Knoevenagel

D

[

R%R\]

6

CH3

30

Domino hydroformylation-Knoevenagel condensationhydrogenation. Reagents and conditions: 1.1 Equiv. CH2EWC2, 1.2 equiv. piperidinium acetate, 0.7 mol% [Rh(CO)2acac], 2.8 mol% [P(OPh)3], 20 bar H*/CO (1:1), toluene, 90 "C (51-71%). Scheme 17.

in the presence of catalytic amounts of piperidinium acetate and 1.1 equivalent of a CHacidic compound (e.g. malonates, 8-ketoesters, 1,3-diketones) a Domino hydroformylationKnoevenagel condensation-hydrogenation reaction occured to furnish the saturated derivatives 29 in good yields and with excellent diastereoselectivities [ 2 5 ] .

Conclusion 179

o-DPPB-directed Allylic Substitution with Organocopper Reagents

When looking for a process to remove the reagent-directing o-DPPB group with concomitant formation of a new carbon skeleton bond, allylic substitution with organocopper reagents appeared to be a synthetically appealing candidate.

O(eDPPB) H

3

C

e

p

h

symaddition mol% CuBr.SMe2/ 1.1 equiv. MeMgl

CH3

*

H

3

(-)-31

C

d

P

h

(+)-32

€:Z>99:1 ee > 99 %

mol% CuBr.SMe2 €:Z

yield

2 98:2

95:5 > 9 9 % >99% 92 Yo 85 %

t Scheme 18.

o-DPPB-directed allylic substitution with organocopper reagents.

Interestingly, the o-DPPB group was found to serve as an efficient reagent-directing leaving group for copper mediated and catalyzed allylic substitution with Grignard reagents [ 261. The o-DPPB group provided almost perfect control over regioselectivity, alkene geometry and 1,3 chirality transfer, and could be recovered as the corresponding o-DPPB acid almost quantitatively. Conclusion

The introduction of an appropriately designed reagent-directing group allowed the development of a substrate-directed, stereoselective hydroformylation reaction of acyclic methallylic and homomethallylic alcohol derivatives. The potentially multifunctional character of the introduced reagent-directing o-DPPB group was explored in the course of a stereoselective addition of Gilman cuprates to acyclic enoates. Thus, by combining both o-DPPB-directed hydroformylation and o-DPPB-directedcuprate addition a short and efficient synthesis of the building blocks for polyketide synthesis were devised. Incorporating the o-DPPB-directed hydroformylation as part of sequential transformations allowed a further increase of synthetic efficiency. An efficient way to remove the o-DPPB group from the organic substrate, with concomitant extension of the carbon skeleton, was found to be its use as a reagentdirecting leaving group for allylic substitution. Thus, complete control over all issues of selectivity in the course of allylic substitution with organocopper reagents was obtained.

80

I

Controlling Stereoselectivity with the Aid o f a Reagent-Directing Group References 1

2

3

4

5

6

A. H. HOVEYDA, D. A. EVANS, G. C. Fu, Chem. Rev. 1993, 93, 1307-1370. a) B. M. TROST,Angew. Chem. 1995, 107, 285-307; Angew. Chem. Int. Ed. Engl. 1995, 34. 259: b) B. M. TROST,Science 1991, 254, 1471-1477. For recent reviews see: a) J. A. MOULIJN, P. W. N. M. VAN LEEUWEN,R. A. VAN SAUTEN, Catalysis - A n Integrated Approach to Homogenous, Heterogenous and Industrial Catalysis, Elsevier, Amsterdam 1995, S. 199-248; b) C. D. FROHNING,C. W. KOHLPAINTNER in Applied Homogeneous Catalysis with Organometallic Compounds, (Eds.: B. CORNILS, W. A. HERRMANN), VCH, Weinheim 1996, Kap. 2.1.1, S. 29104; c) M. BELLER,B. CORNILS, C. D. FROHNING,C. W. K O H L P A I N T N EMol. R,~. Cat. A 1995, 104, 17-85; d) J. K. STILLEin Comprehensiue Organic Synthesis, (Eds.: B. M. TROST,I. FLEMING),Pergamon, Oxford 1991, Vol. 4, pp 913-959; e) F. AGBOSSOU,J.-F. CARPENTIER, A. MORTREUX, Chem. Rev. 1995, 95, J. C. BAYON, 2485-2506; f ) S. GLADIALI, C. CIAVER,Tetrahedron Asymrn. 1995, 6, 1453-1474. For exceptions see: S . D. BURK, J. E. COBB, K. TAKEUCHI, /. Org. Chem. 1990, 55, 2138-2151; T. TAKAHASHI, K. MACHIDA, Y. KIDO,K. NAGASHIMA, S. EBATA, T. DOI, Chem. Lett. 1997, 1291-1292; B. BREIT, S. K. ZAHN,Tetrahedron Lett. 1998, 39, 1901-1904; I. OTIMA, E. s. V I D A L ,Am. ~. Chem. SOC.1998, 63, 7999-8003. N. SAKAI, S. MANO,K. NOZAKI,H. TAKAYA, 1.Am. Chew SOC.1993, 115, 7033-7034: N. SAKAI, K. NOZAKI,H. TAKAYA,].Chem. SOC.,Chem. Commun. 1994, 395-396; K. NOZAKI,N. SAKAI, T. NANNO,T. HIGASHIJIMA, S. MANO,T. HORIUCHI, H. TAKAYA, /. Am. Chem. SOC.1997, 119, 4413-4423; T. HORIUCHI, T. OHTA,E. SHIRAKAWA, K. NOZAKI,H. TAKAYA, Tetrahedron 1997, 5, 7795-7804; K. NOZAKI, W. LI, T. HORIUCHI, H. TAKAYA, Tetrahedron Lett. 1997, 38, 4611-4614; T. HORIUCHI, T. OHTA,E. SHIRAKAWA, K. NOZAKI,H. TAKAYA, 1.Org. Chem. 1997, 62,4285-4292. J. E. BABIN, G. T. TODD(Union Carbide) IPN: W093/03839.

7 For a review on stereoselective hydrofor-

8

9

10

11 12 13

14

15

16

17

18

mylations see P. EILBRACHTin HoubenWeyl, Methods of Organic Synthesis, E 21, Stereoselective Synthesis, (Eds.:G. HELMCHEN, R. W. HOFFMANN, J. MULZER, E. SCHAUM A N N ) , Thieme, Stuttgart, 1995, p. 24882557. For substrate-directed diastereoselective hydroformylation of cyclic systems see S. D. BURKE,J. E. COBB,Tetrahedron Lett. 1986, 27, 4237-4240; W. R. JACKSON, P. PERLMUTTER, E. E. TASDELEN, J. Chem. SOC.Chem. Commun. 1990, 763-764. For a review see J. M. BROWN, Angew. Chem. 1987, 99, 169-182; Angew. Chem. Int. ed. engl. 1987, 26, 190-203. - See also ref. [l]pp 1331-1340. a) B. BREIT,Angew. Chem. 1996, 108, 3021-3023; Angew. Chem. Int. Ed. Engl. 1996, 35, 2835-2837; b) B. BREIT, Liebigs Ann. 1997, 1841-1851. T. DOI,H. KOMATSU, K. YAMAMOTO, Tetrahedron Lett. 1996, 37, 6877-6880. B. BREIT, M. DAUBER, K. HARMS,Chem. Eur. /. 1999, 5, in press. B. BREIT,/. Chem. SOC.,Chem. Commun. 1997, 591-592; B. BREIT, Eur. 1.Org. Chem. 1998, 1123-1134. B. BREIT, unpublished results. B. BREIT, Angew. Chem. 1998, 110, 535538; Angew. Chem. Int. Ed. Engl. 1998, 37, 525-527. For the concept of domino reactions in organic synthesis see a) L. F. TIETZE, Chem. Rev. 1996, 96, 115-136; b) L. F. TIETZE,U. BEIFUSS, Angew. Chem. 1993, 105, 137-170; Angew. Chem. Int. Ed. Engl. 1993, 32, 131-163; c) T. L. Ho, Tandem Organic Reactions, Wiley, New York 1992 d) H. M. R. HOFFMANN, Angew. Chem. 1992, 104, 1361-1363; Angew. Chem. Int. Ed. Engl. 1992, 31, 1332-1334. a) W. REPPE,Experientia, 1949, 5, 93; b) W. REPPE, H. KINDLER,Liebigs Ann. Chem. 1953, 582, 133. a) A. F. M. IQBAL, Helv. Chim. Acta 1971, 45, 1440; b) R. M. LINE, J. Org. Chem. 1980, 45, 3370; c) K. MURATA, A. MATSUDA, T. MATSUDA, 1.Mol. Cat. 1984, 23, 121; d) F. JACHIMOWICZ (W. R. Grace and Co.) Belgian Patent 887630 (1980); Chem. Abstr. 1981, 95, 152491; e) F.

References I 8 1 JACHIMOWICZ, P. MANSON (W. R. Grace and Co.) Canadian Patent 1231199 (1984); Chem. Abstr. 1988, 109, 38485; f ) F. JACHIMOWICZ, J. W. RAKSIS, /. Org. Chem. 1982, 47, 445; g) E. E. MACENTIRE, J. F. KNIFTON (Texaco Development Corp.) European Patent 240193 (1987); Chem. Abstr. 1989, 110, 134785; h) S. TOROS,I. GEMES-PESCI, B. HEIL,S. MAHo, Z. /. Chem. SOC., Chem. Commun. TUBER, 1992, 858; i) E. DRENT,A. J. M. BREED (Shell Int. Res. M) European Patent 457386 (1992); Chem Abstr. 1992, 11 6, 83212; j) M. D. J O N E S , J . Organomet. Chem. 1989, 366, 403; k) T. IMAI (Uop Inc) US Patent 4220764 (1978); Chem. Abstr. 1980, 93, 239429; 1) G. DIEKHAUS, D. KAMPMANN.C. KNIEP, T. MULLER,I. WALTER, J. WEBER(Hoechst AG) German Patent DE 4334809 (1993); Chem. Abstr.

1995, 122, 314160. 19

For recent results on efficient hydroaminomethylation of functionalized derivatives see T. RISCHE, P. EILBRACHT, Synthesis 1997, 1331-1337; C. L. KRANEMANN, P. EILBRACHT,Synthesis 1998. 71-77.

20

B. BREIT,Tetrahedron Lett. 1998, 39, 51635166.

21

a) T. BAIG,P. KALCK,/. Chem. SOC.,Chem. Commun. 1992, 1373; b) T. BAIG,J. P. KALCK, /. Organomet. Chem. MOLINIER, 1993, 455, 219; c) A. L. JAPIDUS, A. P. RODIN, L. Y . BREZHNEV, I . G. PRUIDZE, B. I. UGRAK,Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 1448; Chem. Abstr. 1990, 113,

22

a) J.B. HENDRICKSON,/. Am. Chem. SOC. 1975, 97, 5784-5800; b) ibid. 1977, 99, 5439-5450; c) J. B. HENDRICKSON, Angew. Chem. 1990, 102, 1328-1338; Angew. Chem. Int. Ed. Engl. 1990, 29,

171812.

1286-1295. 23 E. J. COREY, X.-M. CHENG,The Logic of Chemical Synthesis,Wiley, New York 1989, Chapter 4, pp 47-57. 24 B. BREIT, S. K. ZAHN,Angew. Chem. 1999, 1 1 1 , 1022-1024; Angew. Chem. Int. Ed. Engl. 1999, 38,969-971. 25 B. BREIT,S. K. ZAHN,Angew. Chem. 2001, 113, 1964-1967; Angew. Chem. Int. Ed. Engl. 2001,40, 1910-1973. 26 B. BREIT,P. DEMEL, Ado. Synth. Cat. 2001, 343,429-432.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

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I

Solvent-Free Organic Syntheses Jiirgen 0. Metzger

A consequence of the necessity to minimize the amount of toxic waste and by-products from

chemical processes is a need for the development of new, more environmentally friendly and resource-saving synthetic methods in which fewer toxic substances are used. Nowadays in the development of new syntheses, ecological points of view must also be taken into consideration and apportioned due importance in the assessment of viability [l,21. In this process the solvents are especially important, as they are generally used in large quantities. Many organic solvents are ecologically harmful, and their use should therefore be minimized as far as possible or even avoided altogether [ 2 ] . In industry they are of course recycled wherever possible. However, in practice this is only rarely accomplished with complete efficiency, which means that some organic solvent from chemical production will inevitably escape and severely pollute the environment. Alternatives under investigation as solvents for organic reactions are water [ 31 and supercritical gases, in particular COz [ 41. The best solvent from an ecological point of view is without doubt no solvent. There are many great reactions that can already be carried out in the absence of a solvent, for example numerous industrially important gas-phase reactions and many polymerizations. Diels-Alder and other pericyclic reactions are also often carried out without solvents. Reports on solventfree reactions have, however, become increasingly frequent and specialized over the past few years. Areas of growth include reactions between solids [S], between gases and solids [GI, and on supported inorganic materials [ 71, which in many cases are accelerated or even made possible through microwave irradiation [ 81. Some most important solvent-free routes for selective oxidations of hydrocarbons and aromatics [ 91, hydrogenations [ 101, and for a one step production of ecaprolactam from cyclohexanone with a mixture of air and ammonia using porous heterogeneous catalysts have been reported, in which the active sites have been atomically engineered [ 111.There are also reactions in which at least one reactant is liquid under the conditions employed, which means the solvent normally used can simply be left out. To begin with, two industrially important examples are discussed, which confirm that a reaction process that is more environmentally friendly can also be economically very acceptable. This is followed by some recent examples of solvent-free reactions covering a remarkably broad range of reaction types in which the term “solvent-free” refers solely to the reaction itself. On the other hand, workup processes, except for a few examples, invariably involve the use of solvent. The

Polymer Syntheses

examples show that these reactions proceed with similar and in many cases even higher yield and/or selectivity and, because of the higher concentration of the reactants, with a larger rate of reaction. Polymer Syntheses

The method for the manufacture of polypropylene by the Ziegler-Natta process, which has been in widespread use for several decades, involved some years ago a polymerization in a relatively volatile solvent, for example a light petroleum fraction. That was the drawback of this process, since in the separation and subsequent drying of the polymer formed the solvent could not be completely recovered. Problems are thus experienced in fulfilling environmental protection requirements. An additional obstacle was the large volume of aqueous waste that is generated during workup of the polymer suspension. The new polypropylene processes do not require solvents because of a new and highly efficient catalyst [12].Therefore, there are also no solvent emissions in the exhaust gases. Small amounts of gaseous hydrocarbons that are formed are incinerated. In the manufacture of the polymer the amount of aqueous wastewater accumulated is much smaller, since the amount of catalyst used can be reduced to such low levels that it no longer needs to be washed after the reaction. Comparable results have also been achieved in the manufacture of high-density polyethylene. Polycarbonates are amorphous polymers with excellent handling properties. Their spectrum of applications ranges from baby bottles to compact discs. Most of the polycarbonate produced is generated by the polycondensation of bisphenol A with phosgene in a biphasic system (sodium hydroxide/dichloromethane). The solution of the polycarbonate product in dichloromethane is washed with water to remove the by-product NaC1. However, in this washing process some 20 g . L-' of the dichloromethane ends up dissolved in the aqueous phase. The dichloromethane must also be removed from the polycarbonate, which is not easy. This means that the polycarbonate will invariably contain some chlorinated impurities, which adversely affects the properties of the polymer. Komiya et al. [ 131 recently introduced the novel, environmentally friendly process from Asahi Chemical Industry Co. for the production of polycarbonates, which requires neither phosgene nor solvent (Scheme 1). In this process bisphenol A undergoes a prepolymerization with diphenyl carbonate in the melt. A simple crystallization of the prepolymer is fol-

1

Scheme 1.

Solvent-free synthesis of polycarbonate from bisphenol A and diphenyl carbonate [lo].

I

83

84

I

Solvent-Free Organic Syntheses

lowed by a solid-state polymerization to a polycarbonate of high molecular weight. Its quality is superior to the product of the phosgene process, and the production costs appear to be similar. A variety of strategies for reducing or eliminating the use of traditional organic solvents in polymer synthesis and processing have been discussed recently [ 141. Radical Additions

For some time, intermolecular radical additions have been an integral part of the methodological arsenal of preparative organic chemistry. However, from an ecological point of view the methods that have been used to date suffer from a number of drawbacks that present obstacles to their broad-based industrial application. This applies particularly to the commonly used organotin compounds. Transition metal complexes and salts which initiate radical reactions through electron transfer processes are a highly promising alternative, and some recent examples even do not require the use of solvents [ 15, lG]. Thus, cc-iodo esters undergo addition to alkenes through an electron transfer initiated by metallic copper [15]. The reaction procedure is very simple: The alkene, iodo compound, and commercial copper powder are mixed together without any pretreatment and heated to 130 "C under an inert atmosphere (Scheme 2). After a simple workup the products were obtained in good yield; the entire reaction was carried out in the complete absence of solvent, as the product was distilled off directly from the reaction mixture. The iodo compound could be replaced by the corresponding, more easily accessible bromo compound; in this case an equimolar quantity of sodium iodide is added. The iodo compound is formed initially as an intermediate by a solvent-free Finkelstein reaction.

Scheme 2.

Copper-initiated radical addition of methyl 2-iodopropionate to methyl 10-undecenoate [15].

cc-Iodonitrile [ 151 and perfluoroalkyl iodides [ 161 underwent addition to alkenes in a completely analogous solvent-free reaction. Additional points in favor of these solvent-free radical additions are that the yields are generally better than with the conventional methodology and that they also permit additions to 1,2-disubstituted alkenes. Enzyme-Catalyzed Reactions

The selective enzyme-catalyzed acylation of carbohydrates is of great interest, as of carbohydrates fatty acid esters of carbohydrates have important applications in detergents, cosmetics, foodstuff, and pharmaceuticals because of their surface-active properties. Monoacylated sugars have been synthesized by lipase-catalyzed transesterifications of activated esters in pyridine and by protease-catalyzed esterifications in DMF. A most remarkable new development

Enzyme-Catalyzed Reactions

is the use of immobilized lipases for the selective acylation of I-0-ethyl glucopyranoside with free carboxylic acids in the absence of solvent. This afforded G-0-acyl glucopyranosides in 8 5 9 0 % yield [ 171, with small amounts of the 2,G-O,O-diacylglucopyranosides being formed as by-products. This reaction can also be carried out without problems on a large scale. Thus, 8 kg of glucose was allowed to react with ethanol in the presence of an ion-exchange resin to form 1-0-ethyl glucopyranoside. After removal of the ion exchange resin and the residual ethanol 12.7 kg of coconut oil fatty acids were added to the crude 1-0-ethylglucopyranoside, and the mixture was heated to 70 "C. Then 400 g of immobilized lipase from Candida antarctica was added, and the water of reaction that formed was removed under vacuum. After 28 h a conversion of greater than 90% was achieved. After the enzyme was filtered off, a crude product was obtained which contained 70% of the 6-0-monoester.After removal of the excess fatty acid (21%) by distillation, the final product had a 6-0-monoester content of greater than 85% (Scheme 3). HO

RC02H

RCO2

Lipase, 70"C, 24h .OEt

H

O

85 - 90%

OH

O

H

E

t

OH

Lipase-catalyzed acylation o f 1-0-ethyl glucopyranoside with carboxylic acids t o 6-0-acyl glucopyranosides (R = n-C7H15, n-CgH19, nCII H23, n-C13H27, n-C15H31, n-Cl7H35) [171. Scheme 3.

In another solvent-free process with the same lipase as above, trimethylene carbonate underwent an almost quantitative ring-opening polymerization in 120 h at 70 "C to form poly(trimethy1ene carbonate) [ 181. No decarboxylation was detected (Scheme 4). wPentadecalactone was likewise polymerized with lipases in the absence of a solvent to form polyesters of high molecular weight [ 191. 0

II

0

O A O

70°C,48h Scheme 4. Lipase-catalyzed ring-opening polymerization of trimethylene carbonate t o linear poly(trimethy1ene carbonate) [18]

The latter two successful processes were combined in the solvent-free lipase-catalyzed reaction of 1-0-ethyl glucoside with trimethylene carbonate or c-caprolactone to form amphiphilic oligomers and polymers [ 201. The products are biodegradable polycarbonates and polyesters that are formed regioselectively by reaction with the primary hydroxyl group of the sugar moiety. Lipase catalyzed esterifications were performed favorably solvent-free [21] and were applied also to bulk polymerization for polyester synthesis [ 221.

86

I

Solvent-Free Organic Syntheses

Homogeneous Catalysis

Oxidations are of great importance, and it would be highly desirable to carry them out with environmentally friendly oxidants such as atmospheric oxygen and hydrogen peroxide -30% H202 if possible. Ideally such reactions should also be carried out without the need for any additional organic solvent. Noyori et al. [23] recently reported an efficient oxidation of secondary alcohols to ketones with sodium tungstate as catalyst and methyltrioctylammonium hydrogen sulfate as phase-transfer catalyst (Scheme 5). The yield in the case of 2-octanol was approximately 95%. Primary alcohols are four to five times less reactive and were generally oxidized to carboxylic acids. More remarkably, unsaturated secondary alcohols, including even allylic alcohols, were oxidized with high selectivity to the corresponding ketones. Moreover, using the same catalyst, cyclohexene was efficiently oxidized to give adipic acid [ 241. However, if a catalytic quantity of arninomethylphosphonic acid was added, an efficient epoxidation catalyst was obtained, and terminal alkenes could be oxidized to the epoxides in greater than 90% yield using 30% H 2 0 2(Scheme 6) [25].

Scheme 5.

Oxidation of secondary alcohols to ketones with 30%

H202

[23]

Scheme 6. Epoxidation of 1-alkenes with 30% H 2 0 2by addition o f aminomethylphosphonic acid t o the catalytic oxidation system shown i n Scheme 5 [25].

The chiral Cr"' - salen complex 1 is a highly efficient catalyst for the enantioselective ring opening of epoxides with Me3SiN3 [26]. For example, cyclohexene oxide underwent ring opening with 2% of 1 and MejSiNj in the complete absence of solvent - the product was removed by short-path distillations under reduced pressure from the reaction mixture - in 90% yield and with 84-88% ee (Scheme 7). The catalyst was easily recovered and could be reused without any loss of activity. The yield and enantioselectivity were similarly high as for the corresponding reaction in diethyl ether. Palladium complexes with phosphinooxazoline ligands such as 2 have been proven to be very efficient catalysts for the coupling of alkynes to enynes in solvent-free reactions (Scheme 8) and provided an efficient tool for regiocontrolled cross-coupling reactions between mono- and disubstituted alkynes [ 271. The neat Ru-catalyzed hydroesterification of 3,3-dimethyl-l-propene with 2-pyridylmethyl formates afforded exclusively a linear ester in 89% isolated yield using only 0.2 mol%

Homogeneous Catalysis

187

2% (R,R)-l, 20h D 91%,88% ee

+ Me3SiN3

(RR1-1 Catalytic enantioselective ring opening of cyclohexene oxide with trimethylsilyl azide using the chiral Cr(lll) - salen complex 1 1261. Scheme 7.

2

H13C6

Pd(0Ac)zi 2

2

*

C6H1 3

H13C6

'tBu

2 Scheme 8.

Pd-catalyzed coupling of 1-octyne 1271

Ru3( C0)12 [ 281. Furthermore, the Pd-catalyzed solvent free arsination of aryl triflates (Scheme 9) [ 291, and the hydroamination of phenylacetylene with aniline in the presence of [ Ru3(C0)12]/NH4PF6 proceeds with high regioselectivity giving the product by simple distillation with greater than 99% purity in 92% yield (Scheme 10) [ 301. Pd(OAc)Z P ~ ~ A115°C s,

Fn

40 - 50%

Fn

0

AsPh;!

-

Fn = COOMe, COMe, CHO, CN, NOz, OMe Scheme 9.

Pd-catalyzed arsination of aryltriflates with triphenylarsine (291.

88

I

Solvent-Free Organic Syntheses

Scheme 10.

Catalytic hydroamination of phenylacetylene with aniline [30]

Lewis Acid and Base Catalyzed Reactions

Several examples have been described on Lewis acid and base catalyzed Michael addiacid ethylester was added at room temperature to methyl tions. Cyclopentanone-2-carboxylic vinyl ketone using 2 mol% FeC13.G HzO as catalyst yielding > 90% of the addition product (Scheme 11) [31]. Cerium(II1) chloride in the presence of sodium iodide [32] and trifluoromethanesulfonic acid have been used as catalysts as well [ 331.

d

M0

e

2 mol% >FeC13 90%

- 6 H20*

W

C02Et M

e

I

Scheme 11. FeCI3-catalyzed Michael-addition of cyclopentanone-2carboxylic acid ethyl ester with methylvinylketone [31].

Modified guanidines 3 efficiently catalyzed the asymmetric Michael addition of a prochiral glycine derivatives with acrylate, acrylonitrile and methyl vinyl ketone under simple and mild conditions. Remarkably, both product formation and enantioselectivity were dramatically improved using solvent-free conditions (Scheme 12) [34]. The addition of alcohols to methyl propiolate was performed using fluorous phosphines such as P[(CH2)2(CFZ),CF3I3 and again better yields of 99% have been obtained under solvent-free conditions. Toluene was added to efficiently separate the product from the solid catalyst, which was then reused without loss of activity [ 351. Ph2C=NCH2COOtBu

+ //'\cooE~

+ 3(0.2 eq)

*

20"C, 3d, 87%, 97% ee

MeN

K

NMe

Ph

Ph 3

Scheme 12. Cuanidine-catalyzed asymmetric Michael-addition of tert-butyl diphenyliminoacetate with ethyl acrylate [34].

Ph2C=N Y O t B u COOEt

Reactions Using Organometallic Reagents

The indium trichloride-catalyzed Mukaiyama aldol reaction of 3-aminoketoesters with various silylenolethers gave under solvent-free conditions 1,3-amino alcohols with high stereoselectivity [ 361. Several Robinson annelation reactions have been carried out enantioselectively using (S)-proline as a chiral catalyst [ 371. Remarkably, the enantioselectivity was distinctly higher in the absence of solvent than in DMSO. The ytterbium triflate catalyzed Biginelli reaction of aldehydes, ethyl acetoacetate and urea to give in a one-pot synthesis dihydropyrimidones was performed again in higher yields without any solvent (Scheme 13) [ 381.

OEt

5mol% Yb(OTf)3 w

IOO'C, 20 tnin., 98%

Me H

Scheme 13.

Ytterbium triflate catalyzed Biginelli reaction [38].

The same Lewis acid has been applied also as a catalyst for the syntheses of 2J-dihydro1H-1,s-benzodiazepines in very good yields from o-phenylenendiamine and ketones [ 391.

Solvent-free coumarin [40] and porphyrin syntheses have also been reported [41]. The Baylis-Hillman reaction of aldehydes with methyl methacrylate can be catalyzed with tetramethylguanidine (TMG) whereby the activity of the catalyst is decreased when solvents are used in the reaction (Scheme 14) [42].

1,

Ph

+

fiCOOMe

5%TMG 20"C, 6h, 58%

Scheme 14. Tetramethylguanidine ( T M C ) is an efficient catalyst for the solvent-free Baylis-Hillman reaction [42].

A catalytic amount of aluminum chloride hexahydrate enables solvent-free tetrahydropyranylation of alcohols and phenols at moderate temperatures and a simple addition of methanol helps to regenerate the corresponding alcohols and phenols [43]. Reactions Using Organornetallic Reagents

Solvent-free enantioselective additions of diethylzinc to aldehydes and to N-diphenylphosphinoylimines using p-amino alcohols as chiral catalysts afforded chiral sec-alcohols and N-

90

I

Solvent-Free Organic Syntheses

diphenylphosphinoylamines, respectively, with high enantiomeric excess, and is faster than using organic solvents in these reactions (Scheme 15) [44]. Ph

EtZZn, 4 (1 eq.) phv,N, ,Ph ;lPh

O'C, 76%, 84% ee

0

*

0

phMMe

HO

4

c-

Scheme 15.

Catalytic enantioselective addition of diethylzinc to N-diphenylphosphinoylimines [44b].

Indium mediated Barbier-type cross coupling between carbonyl compounds and allyl halides proceed efficiently under solvent-free conditions. No apparent competing pinacolcoupling or homo-coupling of the allyl halide was observed. The reactions were found to be mediated also by zinc, tin, bismut and copper [45]. Cycloadditions

The solvent-free asymmetric Hetero-Diels-Alder reaction of 14 different aldehydes with Danishefsky's diene was carried out with 0.1-0.005 mol% of chiral titanium complexes to afford dihydropyrones with up to quantitative yields and 99.8% ee. A library of chiral metal complexes was generated by combining one or two different chiral diol ligands e.g. 5 (13 different diols were applied) with titanium isopropylate (Scheme 16) [46]. OMe Ti-2.5 99%E

Me3Si-0

5 Scheme 16.

Asymmetric Hetero-Diels-Alder reaction of benzaldehyde w i t h Danishefsky's d i m e [46].

References I 9 1

+

[2 2lCycloadditions of cyclic ketene trimethylsilyl acetals with ethyl propynoate and other electrophilic alkines were run at room temperature, without a catalyst and solvent-free (47). Nucleophilic Substitutions and /I-eliminations

As has already been pointed out, the Finkelstein reaction can be conducted in situ in the absence of solvents. For example, alkylations of purine and pyrimidine bases with alkyl halides and dimethyl sulfate have been carried out by solid/liquid phase-transfer catalysis in the absence of any additional solvent [48], as have cyanation of haloalkanes [49] and peliminations [SO]. Noteworthy is the synthesis of glycosyl isothiocyanates by the reaction of potassium thiocyanate with molten glycosyl bromide at 190 "C [Sl]. To summarize, solvent-free reactions are not only of increasing interest from an ecological viewpoint, but in many cases also offer considerable synthetic advantages in terms of yield, selectivity, and simplicity of the reaction procedure. References 1

2

3 4

5

6

7

8

P. T. ANASTAS, T. C. WILLIAMSON in Green Chemistry, Designing Chemistry for the T. C. Environments (Eds.: P. T. ANASTAS, WrLLrAMsoN), American Chemical Society, Washington DC, 1996, pp. 1-17. M. EISSEN,J. 0. METZGER, E. SCHMIDT, U. SCHNEIDEWIND, Angew. Chem. 2002, 114, 402-425, Angew. Chem. Int. Ed. 2002, 41, 414-436. C.-J. LI, T.-H. CHAN,Organic Reactions in Aqueous Media, Wiley, Chichester, 1997. P. G. JESSOP, W. LEITNER (eds.), Chemical Synthesis Using Supercritical Fluids, WileyVCH, Weinheim, 1999. a) F. TODA,Acc. Chem. Res. 1995, 28, 480A N D F. TODA,Chem. 486; b) K. TANAKA Rev. 2000, 100, 1025-1074; c) G. W. V. J. L. SCOTT,Chew. CAVE,C. L. RASTON, Commun. 2001, 2159-2169. a) G. KAUPP, J. SCHMEYERS, Angew. Chem. 1993, 105, 1656-1658; Angew. Chem. Int. Ed. Engl. 1993, 32, 1587-1589; b) G. KAUPP, J. S C H M E Y E R Org. S , ~ .Chem. 199.5, 60, 5494-5503; c) G. KAUPP,Andreas Herrmann, lens Schmeyers, Chem. Eur. I. 2002, 8, 1395-1406, and references therein. J. H. CLARK, Catalysis oforganic Reactions by Supported Inorganic Reagents, VCH, New York, 1994. a) R. S. VARMA,Clean Prod. Proc. 1999, 1, 132-147; b) R. S. VARMA, Green Chew. 1999, 1, 43-55; c) A. LOUPY, Top. Curr. Chem. 1999. 206, 153-208.

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J. M. THOMAS, R. RAJA,G. SANKAR, B. F. G. J O H N S O N , D. W. LEWIS, Chem. Eur. /. 2001, 7, 2973-2978. S. HERMANS, R. RAJA,J. M. THOMAS, B. F. G. J O H N S O N , G . SANKAR, D. GLEESON, Angew. Chem. 2001, 113, 12511255; Angew. Chem. Int. Ed. 2001, 40, 1211-1215. R. RAJAQ, G. SANKAR, J. M. THOMAS,J. Am. Chem. Soc. 2001, 123, 8153-8154. a) J. HORNKE; R. LIPPHARDT, R. MELDTin Produktionsintegrierter Umweltschutz in der chemischen Industrie (Ed.: J. WIESNER) DECHEMA, Frankfurt/Main, 1990, pp. 17-18; b) A. N. THAYER, Chew. Eng. News 1995, 73(37), 15-20. K. KOMIYA,S. FUKUOKA,M. AMINAKA, K. HASEGAWA, H. HACHIYA, H. OKAMOTO, T. WATANABE, H. YONEDA, J. FUKAWA,T. DOZONO in Green Chemistry, Designing Chemistryfor the Environment (Eds.: P. T. ANASTAS, T. C. WILLIAMSON), American Chemical Society, Washington DC, 1996, p. 20-32. T. E. LONG, M. 0. HUNT,Solvent-Free Polymerizations and Processes, ACS Symposium Series 1999, 713. a) J. 0. METZGER, R. MAHLER, Angew. Chem. 1995, 107, 1013-1015; Angew. Chem. Int. Ed. Engl. 1995, 34, 902-904; b) J. 0. METZGER, R. MAHLER, G. FRANCKE, Liebigs Ann. 1997; 2303-2313. a) 2.-Y. YANG,B. V. NGUYEN,D. J.

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SON,R. A. GROSS,D. L. KAPLAN,G. SWIFT, Macromolecules 1997, 30, 7735-7742. 19 K. S. BISHT,L. A. HENDERSON, R. A. GROSS,D. L. KAPLAN,G. SWIFT,Macromolecules 1997, 30, 2705-2711. 20 K. S. BISHT, F. DENG,R. A. GROSS,D. L. KAPLAN,G. SWIFT,]. Am. Chem. Soc. 1999, 119, 1363-1367.

35 36 31

38 39

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21 a) J. M. S. ROCHA,M. H. GIL, F. A. P.

GARCIA,1.Chem. Techn. Biotechnol. 1999, 74, 607-612; b) N. WEBER,P. WEITKAMP, K. D. MUKHERJEE, J . Agnc. Food Chem.

110-111.

2. GRVSS,N. GALILI,1. SALTSMAN, Angew. Chem. 1999, 111, 1530-1533; Angew. Chem. Int. Ed. 1999, 38, 14271429; b) 2. GROSS,N. GALILI,L. SIMKHVVICH, I. SALTSMAN, M. BVTOSHANSKY, D. B L ~ S E RR., BOESE,I. GOLDBERG, Org. Lett. 1999, 1, 599-602; c) M. G. WARNER, G. L. SUCCAW, J. E. HUTCHISVN,Green Chem. 2001, 3, 267-

A. K. CHAUDHARY, J. LOPEZ,E. J. BECKMAN, A. J. RUSSELL, Biotechnol. Prog. 1997, 13, 318-325.

K. SATO,M. AOKI,J. TAKAGI,R. NVYVRI,]. Am. Chem. SOC.1997, 119, 12386-12387. 24 K. SATV,M . AVKI,R. NOYORI,Science 23

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a) K. SATO,M. AOKI,M. OGAWA,T. HASHIMOTO,R. NVYVRI,]. Org. Chem. 1996, 61, 8310-8311; b) K. SATV,M. AOKI, M. OGAWA,T. HASHIMOTO, D. PANYELLA, R. NOYORI,Bull. Chem. Soc.]pn. 1997, 70,

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2002, 124, 750-751.

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F. Y. KWVNG,c . w. h I , K. s. CHAN,]. Am. Chem. SOC.2001, 123, 886443865, M. TOKUNAGA, M . ECKERT,Y. WAKATSUKI, Angew. Chem. 1999, 111, 3416-3419; Angew, Chem. lnt. Ed. 1999,38,3222-3225. a) J. CHRISTOFFERS, Org. Synth. 2000, 78, 249-253; b) I. CHRISTVFFERS, J . Chem. Soc., Perkin Trans. 11997, 3141-3149. G. BARTOLI,M. Bosco, M. C. BELUCCI, E. MARCANTONI, L. SAMBRI,E. TVRREGIANI, Eur.]. Org. Chem. 1999, 617-620. H. KVTSUKI,K. ARIMURA, T. OHISHI,R. MARUZASA, I. Org. Chem. 1999, 64, 37703773.

34

T. ISHIKAWA, Y. ARAKI,T. KUMAMOTO, H.

N. E. LEADBEATER, c . VAN DER PVL,]. Chem. Soc., Perkin Trans. 12001, 28312835.

905-9 15.

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T. SUGINO,I. TANAKA, Chem. Lett. 2001,

41 a)

2001, 49, 5210-5216. 22

SEKI,K. FUKUDA,T. ISOBE,Chem. Commun. 2001, 245-246. M. WENDE,R. MEIER,J. A. GLADYSZ,]. Am. Chem. SOC.2001, 123, 11490-11491. T.-P. LOH, J.-M. HUANG,S.-H. GVH, J. J. VITTAL, Org. Lett. 2000, 2, 1291-1294. D. RAJAGOPAL, K. RAJAGOPALAN, S. SWAMINATHAN,Tetrahedron:Asymmetry 1996, 7, 2189-2190. Y. MA, C. QIAN, L. WANG,M. YANG,]. Org. Chem. 2000, 65, 3864-3868. M. CURINI,F. EPIFANV,M. C. MARCVTULLIV, 0. ROSATI,Tetrahedron Lett.

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V. V. NAMBVVDIRI, R. S. VARMA, Tetrahedron Lett. 2002, 43, 1143-1146. a) I. SATV,T. SAITO,K. SOAI, Chem. Commun. 2000, 2471-2472; b) I. SATO,R. KVDAKA,K. SOAI,J . Chem. Soc., Perkin Trans. 12001, 2912-2914. a) X.-H. YI, J. X. HABERMAN, C.-J. LI, Synth. Commun. 1998, 28, 2999-3009; b) P. C. ANDREWS, A. C. PEATT,C. L. RASTON, Green Chem. 2001, 3, 313-315. J. LONG,J. H u , X. SHEN,B. J I , K. D I N G , J . Am. Chem. Soc. 2002, 124, 10-11. M. MIESCH,F. WENDLING, Eur.]. Org. Chem. 2000, 3381-3392. G. BRAM,G . DECODTS,Synthesis 1985, 543-545.

Y.-Q. CAO,B.-H. C H E M ,B.-G. PEI, Synth. Commun. 2001, 31, 2203-2207. 50 a) J. BARRY,G . BUM, G. DECODTS, A. LVUPY,P. PIGEON,J. SANSONLET,].Org. Chem. 1984, 49, 1138-1140; b) P. VINCZER,S. SZTRUHAR, L. NOVAK,C. SZANTAY, Org. Prep. Proced. lnt. 1992, 24,

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540-543. 51

T. K. LINDHVRST,C. KIEBURG, Synthesis 1995, 1128-1130.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

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93

Fluorous Techniques: Progress in ReactionProcessing and Purification Ulf Diederichsen

Fluorous solvents contain perfluorinated or very highly fluorinated alkanes. They have been developed within the last decade as an interesting alternative to classical organic solvents [I31. They are inert, thermally stable, non-polar, immiscible with water and most organic solvents, and non-toxic. The ecological reservations against fluorine hydrocarbons can be met by using higher perfluorinated alkanes with lower vapor pressure. Perfluorinated solvents provide a third liquid phase next to water and organic solvents; this can be advantageous both during reaction-processing and for purification procedures. As is known from phasetransfer catalysis, the distribution of starting materials, products, and reagents in triphasic systems extends the possibilities for planning of syntheses and separation strategies. Provided that they are not modified with fluorous tags, neither salts nor organic compounds are found in the fluorous phase. The heavier fluorous phase can easily be separated from the organic phase or water solution by simple phase-separation techniques. The biphasic system of fluorous phase and organic solvent is especially interesting, since the partition coefficient is temperature-dependent: while phase separation is suitable for successful extraction at room temperature, at temperatures higher than GO "C the phases form a homogeneous solution. Hence, reaction processes in homogeneous solution at higher temperatures can be combined advantageously with workup by extraction at room temperature. There are two main applications for fluorous-phase chemistry in organic synthesis. First of all, catalytic reactions can take advantage of thermoregulation of the two-phase systems, especially when the catalyst is soluble in the fluorous phase. On the other hand, the fluorous phase gives an additional dimension to traditional organic chemistry and parallel synthesis. For reactions, partially fluorinated solvents are usually preferred over perfluorinated solvents. Perfluorinated solvents are often not polar enough for many organic reagents, and this phase is therefore applied only for the workup procedure. Fluorous Biphasic Catalysis

Catalysts immobilized on resins are quite often used for catalytic reactions. Phase-transfer conditions, guaranteeing separation and recovery of the catalysts by use of water/organic solvent biphasic systems, are another possibility. Unlike homogeneous processes, these kind of catalytic processes take account of product loss and substrate selectivity. Furthermore,

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Fluorous Techniques: Progress in Reaction-Processing and Purification

catalysts that are sensitive to hydrolysis cannot be used. In this respect, solvation of the catalyst in the fluorous phase offers an interesting alternative. The catalyst can be separated from the organic phase at room temperature, whereas at higher temperatures a homogeneous reaction mixture is provided. In order for the catalyst to be soluble in the fluorous phase, it needs to be modified at the ligands with perfluoroalkyl chains, the length of which (C6F13-C8F17)is decisive for the distribution between the fluorous phase and the organic solvent. The option of tailoring the partition coefficient provides conditions similar to those created by slow addition of reaction partners [4]. The fluoroalkyl groups are electronwithdrawing because of the high electronegativity of fluorine. In order to avoid influencing the catalytic activity, the fluorous tags are usually linked to the catalyst ligands through an ethylene, propylene, or CHzCHzSiMe spacer. To date, the following catalytic processes have been carried out within biphasic systems, taking advantage of the fluorous phase: hydroformylation of olefins [ 51, hydroboration [GI, hydrogenation of alkenes [ 71, hydrosilylation of ketones [8], oligomerization of ethylene [O],cyclopropanation [ 101, transesterification [ 111, various oxidations [ 12-18], asymmetric reduction of ketones [ 191, cross-coupling of organozinc bromides with aryl iodides [ 201, palladium allylic alkylation [ 211, the Heck reaction [22], Suzuki coupling [23], and asymmetric alkylation of aromatic aldehydes [24], as well as Friedel-Crafts acylation and Diels-Alder reactions (Figures 1 and 2) [ 25, 261. An application of the fluorous two-phase system to catalytic reactions is the hydroformylation of terminal olefins with CO and H2 [S]. Aldehydes 1 can be isolated, together with the branched side products 2. In the C6FI1CF3/toluene solvent mixture, the catalyst [HRh(CO){P[CH2CHz(CF2)5cF,]3}3]is obtained in situ. It acts in the hydroformylation reaction at 100 "C and can be separated afterwards in the fluorous phase. In this process, however, approximately 0.5% of the catalyst remains in the organic phase. Furthermore, the lower solubility of CO and Hz in the fluorous phase produces a lower catalyst activity. Accordingly, the hydroformylation of ethene can be conducted in a continuous process in an autoclave. The use of the fluorous analogue of the Wilkinson catalyst [RhCl{P[ CHzCH2(CF2)5CF3]3}3](3) is advantageous for hydroboration, because cleaning of the often inflammable organoborane is facilitated and destruction of the catalyst by the commonly used oxidative workup (H202/NaOH) is avoided [GI. In this case, the heterogeF ~ catecholborane 5 has even proven neous hydroboration of norbornene (4) in C ~ F I I C with to be better than the fluorous two-phase system. The organoborane can be extracted with THF, and the C6FllCF3 mother liquor containing the catalyst can be used for further synthesis cycles. Turnover numbers (TONS)higher than 10,000 are reached. For a practical transesterification reaction, next to high yields, an equimolar ratio of the reactants is desirable. The catalyst should be neutral and easily separable, and no special technology for alcohol removal should be needed [ 111.These requirements are fulfilled by the fluorous tagged distannoxane catalyst 6 . Transesterification yields are quantitative and the FC-72 solution (FC-72 and FC-75 are commercially available mixtures of perfluoroalkanes) of the catalyst can be reused. Asymmetric alkylation of benzaldehyde can be performed in a toluene/FC-72 biphasic system with Ti(O-iPr)4and the fluorous BINOL ligand 7 (Figure 2) with reasonable yield and enantioselectivity [241. The asymmetric hydrogen-transfer reduction of ketones works fairly

Fluomus Biphasic Catalysis

I

95

Hydroformylation

+

H

R

CH3

2 Hydroboration

5

Transesterification

-

MeOH I FC 72

+

*

CI C2H4-C6F13 C H -C6F13 .**' C6Fl,-C,H4,,, -c HjSn-O-Sn-CI 6 13 2 4 I I I I gCzH4-C6F~3

I

\

6 Fig. 1. Fluorous biphasic catalysis part I: hydroformylation, hydroboration, and transesterification with fluorous tagged catalysts.

similarly [ 191, hydrogen transfer taking place in a mixture of perfluoroalkane and isopropanol with iridium complexes in association with the chiral perfluorosalen ligand 8. Oxidation of aldehyde 9 can be accomplished at 64 "C with oxygen and a catalytic amount of nickel derivative 10 in a homogeneous phase consisting of the toluene/perfluorodecalin solvent mixture [12]. After phase separation at room temperature, the catalyst is kept in the fluorous phase by its fluoroalkyl chains and can easily be separated from the product, which remains in the organic phase. The catalyst can be used again, still yielding 70% of the oxidation product after six reaction cycles. No leaching of the catalyst was observed. Esters, chlorides, and silyl ethers are functional groups that are tolerated in this reaction. The high solubility of Oz in fluorinated solvents is of special advantage for this oxidation reaction. In analogous systems, sulfides can be oxidized to sulfoxides or sulfones in the presence of isobutyraldehyde, while epoxides are selectively obtained from substituted olefins [ 121. Further catalysts that take advantage of the fluorous phase and are used for alkene epoxidation are

EtOH

96

I

Fluorous Techniques: Progress i n Reaction-Processing and Purification Asymmetric alkylation

+

&H

Ti(0i-Pr), FC-72IToluene

Et,Zn

*

0""

3::

(C,F,,CH,CH,)3Si

\

/

(C,F,3CHzCH,)3Si 7 Reduction [Ir(COD)CI], i-PrOH/C,F,8/KOH

ph+dph F17c8

+OH tBu

a

tBu

Oxidation

10 (3 Mol.%)

AcO J y H

9

0, (1 atm) Toluene / Perfluorodecalin

AcO &OH

Cross coupling

Fig. 2. Fluorous biphasic catalysis part II: asymmetric alkylation, reduction, oxidation, and cross-coupling reactions with fluorous tagged catalysts.

Fluorous-Phase Strategy for lmprouing Separation Eficiency

I

97

a cobalt complex of a tetraarylporphyrin, an optically active (sa1en)Mn"' complex, and a catalyst generated in situ from a bipyridine, RuC13, and NaI04 [13]. In addition, M ~ ( O A C ) ~ . ~ H2O in a heterogeneous mixture with pivalaldehyde catalyzes aerobic epoxidation in FC-75 as a solvent [27]. Olefins are epoxidized with 5 mol-% perfluoroheptadecan-9-one and H z 0 2 in boiling CH2C12, in which the catalyst is not wholly soluble. Up to 92% of the catalyst can be recycled by crystallization at 0 "C. In addition, the Wacker oxidation of an olefin to the respective ketone can be successfully performed in the two-phase system of benzene and bromoperfluorooctane with tert-BuOOH and a catalyst similar to 10, with palladium as the metal [28]. The palladium-catalyzed cross-coupling of an aryl, alkenyl, or benzylzinc bromide 11 with aryl iodide 12 succeeds with 0.15 mol-% [ Pd{ P ( C G H ~ C ~ F in ~ ~toluene/l-bromo)~}~] perfluorooctane, taking advantage of variable miscibility through thermoregulation [20]. In this case the electron-deficiencyof the phosphanes, due to the perfluorinated side chains, appears to influence the reductive elimination step in the cross-coupling reactions. Finally, 10 mol-% of the lanthanide perfluoroalkylsulfone amide complex in CGH~CF3 catalyzes both Friedel-Crafts acylation and the Diels-Alder Yb(N( S02C4F9)2)3 reaction [ 261. The high Lewis acidity of the metal complexes seems to be crucial. Fluorous-Phase Strategy for Improving Separation Efficiency

Apart from its use for solvation and separation of catalysts, the fluorous phase can also be used advantageously for separation processes during workup. Strategic synthesis planning is facilitated by tagging with fluorous residues to overcome the frequently limiting recovery and purification difficulties [ 11. As in solid-phase syntheses, an excess of components can be used to drive the reactions to completion. Side products can easily be separated if, for example. only the product is tagged with fluorous alkyl residues and therefore precipitates from the reaction mixture or is extracted with the fluorous phase. Isoxazoline 13 is obtained by 1,3-dipolar cycloaddition of nitrile oxide tBuCNO to olefin 14, labeled with a fluorous alkyl residue, with CH2C12 or C6H5CF3 as the solvent (Figure 3) [29]. Since these solvents are partially halogenated, all substrates appear to dissolve fully. After extraction with benzene, the fluorous-labeled product 13 remains. Cleavage of the fluorous alkyl tag from the product allows extraction into the organic phase by a three-phase extraction procedure (water, CH2C12,FC-72).The problem with this 'one-phase' reaction procedure is that phase separation does not distinguish between substrate 14 and product 13. An excess of reagents and reactants is required to overcome this problem and to drive the reaction to completion. Another way of avoiding the one-phase problem is to conduct a phase switch, as illustrated for Grignard addition to aldehyde 15. Acetaldehyde is soluble in the organic phase and is transferred into the fluorous phase during the course of the reaction, as the generated hydroxyl group is immediately silylated with a fluorous tag. Separation of derivative 16 from remaining starting material is therefore facilitated. Subsequent cleavage of the fluorous label lets alcohol 17 switch into the organic phase and thus facilitates efficient separation from both reactants and side products. In a fluorous variant of the Ugi and Biginelli multicomponent reactions, it has been

98

I

Fhorous Techniques: Progress in Reaction-Processing and Purification

One-phase reaction process 1. t-BUCNO. c6H5cF3

N

OSi(CHzCHzC6F13)3

-

2. extraction

14

OSi(CH2CH,C6Fl3), t-Bu 13

Reaction with phase change 1. PhMgBr 2. BrSi(CH2CH,C6F13)3

Si(CH2CH2C6F13)3 1. CsF

*

H3C 15 Fig. 3.

3. extraction in the fluorous phase

16

'h H3CP

2. extraction in the organic phase

"7

I I

Fluorous-phase reactions: single-phase reaction versus reaction with phase changes.

shown that larger molecules, with molecular weights of about 450, can also be synthesized through the advantages of fluorous-phase separation. The desired condensation products are obtained in good yields, even though only 6 weight-% of the reaction mixture belongs to the products [30]. At this point, atom economy [31] becomes an obvious problem of fluorousphase chemistry, with regard both to the starting material/product relationship and to fluorous labeling ((CloF21-C2H4)3-Sitags). This is particularly the case with rising polarity and size of the substrates, since an even higher degree of fluorination is needed. If protecting groups are required for synthetic transformations, fluorous tagging reagents can be introduced directly for the protection of functional groups, thereby meeting two needs without additional steps [ 321. After application of the fluorous benzyl protecting group Bnf, glucal 18 is converted by an excess of diacetone galactose 19 into the disaccharide 20, which, despite its relatively high polarity, is extracted into the FC-72 fluorous phase (Figure 4). Fluorous tags are also interesting as scavengers for an excess of starting material or of one of the reagents. Compounds that are not entirely converted after the reaction can be quenched with molecules bearing an alkyl fluorous group and can then be removed by fluorous-phase extraction [ 331. This principle has been applied, for example, to an excess of ~CH~CH~]~N isocyanate, which was quenched with the amine [ ( C ~ F ~ S C H ~ C H ~ ) ~ S ~ C H and then extracted into the fluorous phase. Although tin hydride is widely used as a reagent in ionic and radical reactions, it is prone to problems regarding its complete removal and its toxicity. The fluorous reagent tris[2(perfluorohexyl)ethyl]tin hydride ( ( C ~ F I ~ C H ~ C H ~21) ) ~has S ~normal H; tin hydride reactivity and can be completely extracted with perfluoromethylcyclohexane [34]. It can be used

Fluorous-Phase Strategy for lmproving Separation Eficiency

I

99

OH

p

OBnf I

I

'""0 (10 equiv.)

BnfO"' OH Br

9BnfBr

OBnf 18

OBnf

+

extraction in the FC-72 phase Fig. 4.

excess in the MeOH phase

Fluorous protecting group (Bnf): simultaneous function as protecting group and as fluorous tag.

advantageously in reactions carried out in a partially fluorinated solvent such as C ~ H S C F ~ , which provides a homogeneous reaction mixture. The rate constants for radical trapping by the fluorous tin hydride reagent 21 are about twice those of the reaction between Bu3SnH and the primary radical 22 [35]. This implies a convenient application of fluorous tin hydride reagents that can closely mimic tributyltin hydride in preparative chemistry (Figure 5). Another application of fluorous chemistry is offered by palladium-catalyzed Stille crosscoupling between fluorous aryltin reactants and organic halides or triflates [ 361. This reaction is catalyzed by [PdC12(PPh3)2] and carried out in a DMF/THF/C~FSCF~ solvent mixture, with LiCl as an additive. Workup is by extraction from the three-phase system of water, CH2C12,and FC-72. As an example, coupling of the heteroaryl tin derivative 23 with aryl triflate 24 (Figure 5) indicates the broad applicability of the fluorous Stille reaction. This fluorous variant of Stille coupling can be achieved in only two minutes (as opposed to 24 hours) by use of microwave irradiation in DMF. The fluorous allyltin reagent 25 is also valuable in the radical allylation of alkyl or aryl halides [ 371 and in a radical four-component carbonylation reaction (Figure 5) [ 381. Fluorous allyltin reagent 25 reacts with the acrylic ester 26 and the alkyl iodide 27 in the presence of CO (90 atm) in the partially fluorinated solvent C6HSCF3.The product 28 resulting from a radical tandem sequence is extracted from the two-phase mixture CH3CN/FC-72.The chainpropagating abilities of fluorous allyltin reagents have been found to be slightly weaker than those of conventional allyltin reagents.

100

I

Fluorous Techniques: Progress in Reaction-Processing and Pur$cation

Trapping of a primary radical (c6F1 3CH2CH2)3SnH u

p

h

d

I

P

21

h

kT

*

dPh @Ph

Stille cross coupling

eTfo& mo A

U

M~ PdC12(PPh& *

(C6F13CH2CH2)3Sn

\ I +I

23

/ \

LiCI, DMF

OMe

Radical allylation

+

&Br

(C6F13CH2CH2CH2)3Sn 25 (C6F1,CH2CH2CH2),Sn Br

Fluoroallylation in a four-component coupling

+

25

EtO

+

&COOMe 26

Ll

+

co

-

EtO*

0

COOMe

27

28 Fig. 5.

Reactions that have been performed with the aid o f the fluorous-phase approach.

Fluorous Reversed-Phase Silica Gel I 1 0 1

+

-

FH3

coz

(~FI3CH,CH,),SnH

I

21

Cbz

+

(C6Fl,CH,CH,)3Snl

\

Cbz

0

Fig. 6.

Radical cyclization in supercritical COz.

Reactions in Supercritical C 0 2

Although supercritical C02 is interesting as a reaction medium from the toxicological and environmental points of view, its use is limited because of the poor solubility of polar molecules. Organofluorine compounds are well known to be highly soluble in supercritical C02; this greatly extends synthetic possibilities in this medium [ 391. This is particularly the case for radical reactions, which require neither nucleophiles nor electrophiles and do not involve charged intermediates during the course of the reaction. Indeed, the fluorous alkyltin hydride 22 can be used for radical cyclizations in supercritical CO2 at moderate pressure. The formation of tin formate 29 (a side product often encountered in tributyltin hydride reactions in COz) is completely suppressed (Figure 6). The use of highly COz-soluble fluorous reagents, catalysts, and protecting groups should prove to be a valuable strategy for transportation of other reactions into supercritical CO2. In the long run, COZ should thereby serve as both the reaction and the separation solvent. Fluorous Reversed-Phase Silica Gel

A silica gel with a fluorocarbon bonded phase was first introduced in 1978 [40].It is ~C~FI~ commercially available with either of two residues, - S ~ ( M ~ ) ~ C H ~ C Hor -Si(Me)2CH2CH2CH2C(CF3)zCFzCFzCF3, attached to silica gel. These solid-phase materials retain fluorinated molecules with an affinity defined primarily by fluorine content [41-431. Fluorous solid-phase extractions are a first application of this material. As an alternative to liquid-liquid extractions, it is possible to extract fluorous products, catalysts, or reagents into the solid phase. Organic products are eluted with CH3CN, whereas various mobile phases of differing eluting power (hexanes, THF, partially fluorinated solvents, fluorocarbon solvents) are used afterwards to elute the fluorinated compounds from the silica gel. Another application is in fluorous chromatography: separation of fluorous compounds from other fluorous compounds on the basis of their respective fluorine content is possible. This chromatographic separation is quite sensitive, as shown by the following example of a small library synthesis of 100 mappicine analogues [44]. Starting with a mixture of pyridines 30, in which each residue R1 corresponds to a defined fluorous tag Rf, a series of cascade transformations and radical annulations is performed as indicated in Figure 7. Finally, a mixture

102

I

Fluorous Techniques: Progress in Reaction-Processing and Purijication OMe

A

-

,Me

2. BBr,

*a* TMS 30

I

0-Si(iPr),CH,CH,-

I

Rf

0-Si(iPr),CH,CH,-

Rf Five propargyl halides

Four pyridine derivatives

31 I 0-Si(iPr),CH,CH;

Rf- CH,CH,Si(iPr),-0

Rf

100 tagged mappicines R1

R2

H TBS Et H tBu H Bn H Ph Et

R3 Me iPr iPr iPr iPr

Rf (tag)

retention time (min)

C,H,, C,F, C,F,, C,F,, C,,F,,

2 11 16 24 30

Fig. 7. Synthesis of a library containing 100 rnappicine derivatives with fluorous tags (Rf): efficient separation on fluorous reversed-phase silica gel is possible on the basis of the fluorine content of the tag [44].

of tagged mappicines 31 is obtained, and these can be separated and deconvoluted on the basis of their fluorous tags. Separation is very efficient, as shown by the retention times of five derivatives. In fluorous synthesis, the possibility for separation on a fluorous solid phase allows for reduction of the fluorine content in the tags. Fluorous resins offer a way to confront the high molecular weight problem resulting from fluorous tagging and therefore the problem of atom economy in fluorous-phase chemistry.

References 1 a) B. CORNILS, Angew. Chem. Int.

Ed. Engl.

1997, 36, 2057-2059; b) D. P. CURRAN, Angew. Chem. Int. Ed. 1998, 37, 11751196; c) E. D E WOLF,G. VAN KOTEN,B.-J. DEELMAN, Chem. SOC.Rev. 1999, 28, 37-41. 2 M. VOGT; Ph.D. thesis, RWTH Aachen, 1991.

of fluorous phase chemistry see the following internet pages: http://www.fluorous.com and

3 For commercial use

http://www.ict-inter.net. TAKEUCHI, Y. NAKAMURA, Y. OHGO, et al., Tetrahedron Lett. 1998, 39, 86918694.

4 S.

References I103

I. T. H O R V ~ T HJ. , R ~ B A IScience , 1994, 266,72-75;b) I. T.H O R V ~ T G. H , Kiss, R. A. COOK,et a]., J . Am. Chem. SOL.1998, 120.3133-3143;c) S. KAINZ. D. KOCH. W. BAUMANN,et al., Angew. Chem. Int. Ed. Engl. 1997, 36,1628-1630. 6 a) J. J. J. JULIETTE, I. T. H O R V ~ T H J. ,A. GLADYSZ, Angew. Chem. Int. Ed. Engl. 1997, 36.1610-1612;b) J. J. J. JULIETTE, D. RUTHERFORD,I. T. H O R V ~ T Het H ,al., /. Am. Chem. SOC.1999, 121,2696-2704. 7 a) D.RUTHERFORD,J. J. J. JULIETTE, C. ROCABOY, et al., Catal. Today 1998, 42, 381-388;b) C. M. HAAR,J. HUANG,S. P. NOLAN, et al.. Organometallics 1998, 17, 5018-5024;c) B. RICHTER,A. L. SPEK,G. VAN KOTEN,et al., /. Am. Chem. SOC.2000, 122,3945-3951. 8 L. V. DINH,J. A. GLADYSZ, Tetrahedron Lett. 1999, 40,8995-8998. 9 W. KEIM,M. VOGT,P. WASSERSCHEID, et al., /. Mol. Catal. A : Chem. 1999, 139,1715 a)

175. 10 A. ENDRES,G. MAAS,Tetrahedron Lett.

1999, 40,6365-6368. 1 1 J.XIANG,S. TOYOSHIMA, A. ORITA,et al.,

Angew. Chem. Int. Ed. 2001, 40,3670-3672. I. KLEMENT, H. LUTJENS, P. KNOCHEL, Angew. Chem. Int. Ed. Engl. 1997, 36, 1454-1456. a) G. POZZI,F. MONTANARI, S. QUICI. Chem. Commun. 1997, 69-70;b) G. POZZI, F. CINATO,F. MONTANARI, et al., Chem. Commun. 1998, 877-878;c) G. POZZI,M. CAVAZZINI, F. CINATO,et al., Eur. /. Org. Chem. 1999, 8,1947-1955;d) S.QUICI,M. CAVAZZINI, S. CERAGIOLI, et al., Tetrahedron Lett. 1999, 40,3647-3650;e) G. POZZI,M. CAVAZZINI, S. QUICI,et al., Tetrahedron Lett. 1997, 38.7605-7608. K. S. RAVIKUMAR, F. BARBIER,J:P. BBcuB, et al., Tetrahedron 1998, 54,7447-7464. T. NISHIMURA, Y. MAEDA,N. KAKIUCHI. et al., J . Chem. Soc., Perkin Trans. 1 2000, 4301-4305. B. BETZEMEIER, M. CACAZZINI, S. QUICI, et al., Tetrahedron Lett. 2000,41,43434346. B. BETZEMEIER,P. KNOCHEL,in ‘Peroxide Chemistry’ (Ed. W. ADAM),Wiley-VCH 2000,454-468. J.-M. VINCENT, A. RABION,V. K. YACHANDRA, et al., Angew. Chem. lnt. Ed. Engl. 1997, 36,2346-2349.

12 a)

13

14 15

16

17

18

19 D. MAILLARD, C. NGUEFACK, G. POZZI,S.

QUICI,B. VALADE, D. S I N O UTetrahedron , Asymmetry 2000, 1 I , 2881-2884. 20 B. BETZEMEIER, P. KNOCHEL,Angew. Chem. Int. Ed. Engl. 1997, 36,26232624. 21 R. KLING, D. SINOU,G. P o z z ~ et , al., Tetrahedron Lett. 1998, 39,9439-9442. 22 J. MOINEAU, G. POZZI,S. QUICI,eta].: Tetrahedron Lett. 1999, 40,7683-7686. 23 S. SCHNEIDER, W. BANNWARTH,Hela Chim. Acta 2001, 84,735-742. 24 Y. NAKAMURA, S. TAKEUCHI, Y. OHGO,et al., Tetrahedron Lett. 2000,41, 57-GO. 25 K. MIKAMI,Y. MIKAMI, Y. MATSUMOTO, et al., Tetrahedron Lett. 2001, 42,289-292. 26 J. NISHIKIDO, H. NAKAJIMA, T. SAEKI,et al., Synlett 1998, 1347-1348. 27 M. c. A. VAN VLIET, I. w. c. E. ARENDS, R. A. SHELDON, Chem. Commun. 1999, 263-264. 28 B. BETZEMEIER,F. LHERMITE, P. KNOCHEL, Tetrahedron Lett. 1998, 39, 6667-6670. 29 a) A. STUDER,S. HADIDA, R. FERRITTO, et al., Science 1997, 275,823-826;b) A. STUDER,D. P. CURRAN,Tetrahedron 1997, 53,6681-6696. 30 A. STUDER. P. J E G E R , P. WIPF. et a]., /. Org. Chem. 1997, 62,2917-2924. 31 B. M.TROST,Angew. Chem. Int. Ed. Engl. 1995, 34,259-281. 32 a) D.P. CURRAN, R. FERRITTO,Y. HUA, Tetrahedron Lett. 1998, 39,4937-4940;b) T. MIURA,Y. HIROSE,M. OHMAE,eta]., Org. Lett. 2001, 3,3947-3950. 33 B. LINCLAU,A. K. SING,D. P. CURRAN,]. Org. Chem. 1999, 64,2835-2842. 34 D. P.CURRAN, S. HADIDA, /. Am. Chem. SOC.1996, 118,2531-2532. 35 J. H. HORNER, F. N. MARTINEZ, M. NEWCOMB, et al., Tetrahedron Lett. 1997, 38,2783-2786. 36 a) D.P. CURRAN, M. HOSHINO,J.Org. Chem. 1996, 61,6480-6481;b) M. LARHED, M. HOSHINO,S. HADIDA, et al., /. Org. Chem. 1997, 62,5583-5587;c) M. HOSHINO,P. DEGENKOLB, D. P.CURRAN, J . Org. Chem. 1997, 62,8341-8349. 37 D.P. CURRAN, Z. Luo, P. DEGENKOLB, Bioorg. Med. Chem. Lett. 1998, 8,24032408. 38 I. RYU, T. NIGUMA,S. MINAKATA, et al., Tetrahedron Lett. 1999, 40,2367-2370.

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Fluorous Techniques: Progress in Reaction-Processing and Purification 39 a) S. KAINZ, D. KOCH, W. BAUMANN,

et al., Angew. Chem. Int. Ed. Engl. 1997, 36, 1628-1630; b) S. HADIDA,M. S. SUPER,E. J. BECKMAN,et a!.,]. Am. Chem. SOC.1997, 119, 7406-7407; c) J. S. KEIPER, R. SIMHAN, J. M. DESIMONE, et al., J . Am. Chem. SOC.2002, 124, 18341835. 40 G. E. BERENDSEN, L. D. GALAN,].Liquid Chromatop. 1978, I , 403. 41 D. E. BERGBREITER,J. G. FRANCHINA, Chem. Commurz. 1997, 1531-1532.

a) D. P. CURRAN, S . HADIDA, M. HE,]. Org. Chem. 1997, 62, 6714-6715; b) S . KAINZ, 2. Luo, D. P. CURRAN, et al., Synthesis 1998, 1425-1427; c) D. P. CURRAN, Z. Y. Luo,]. Am. Chem. SOC. 1999, 121, 9069-9072; d) D. P. CURRAN, Synlett 2001, 1488-1496. 43 W. ZHANG,D. P. CURRAN, C. H.-T. CHEN, Tetrahedron 2002, 58, 3871-3875. Issue 20 is a special issue on fluorous chemistry. 44 Z. Luo, Q. ZHANG,Y. ODERAOTOSHI, et a!., Science 2001, 291, 1766-1769. 42

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I105

Recent Developments in Using lonic Liquids as Solvents and Catalysts for Organic Synthesis Peter Wasserscheid Introduction

An ionic liquid is a liquid that consists only of ions and has a melting point below 100 “C. The apparently somewhat arbitrary line drawn between molten salts and ionic liquids at a melting temperature of 100 “C is justified by the possibility to replace water and organic solvents in synthetic applications with salts melting below this temperature. Research in ionic liquids and in organic synthesis using ionic liquids as solvents and/or as catalysts is attracting a lot of interest today. More than 300 citations in the SciFinder database looking for the keyword “ionic liquid(s)” in 2001 clearly indicate this. However, the big interest in ionic liquid methodology has only developed quite recently. In the years before 1997, less than 10 publications per year referred to the progress in this research field. What are the reasons for this rapidly growing interest? As far as I can see, there are three main contributions which will be briefly summarised in the following sub-chapters. Availability of Hydrolysis Stable lonic Liquids

So far the historical development of ionic liquids has mainly been driven by combining imidazolium, pyridinium, ammonium and phosphonium cations with different classes of anions. Chloroaluminate ionic liquids were the first more detailed studied ionic liquids. As early as 1948 they were synthesized by Hurley and Wier at the Rice Institute in Texas as bath solutions for electroplating aluminum [ 11. Later in the seventies and eighties, these systems were further developed by the groups of Osteryoung [2], Wilkes [3], Hussey [4] and Seddon [4c, 51. Due to their chemical nature, chloroaluminate ionic liquids must be classified as extremely hygroscopic and labile towards hydrolysis. In 1992, Wilkes and Zaworotko described the synthesis of the first imidazolium tetrafluoroborate ionic liquids [GI. These systems together with the slightly later published [7] hexafluorophosphate analogues are the “working horses” of the actual research with ionic liquid. However, their use in many technical applications is still limited by their relatively high sensitivity versus hydrolysis. The tendency of anion hydrolysis is of course much less pronounced than for the chloroaluminate melts but still existent. The [PF,j- anion of 1butyl-3-methylimidazolium ([ BMIM]) hexafluorophosphate - for example - has been found in our laboratories to completely hydrolyse after addition of excess water when the sample

106

I

Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

Tab. 1. Comparison of some properties of well-established ionic liquid systems with the l-ethyl-3methyimidazolium ([EMIM]) ion

ionic liquid

phasetransition

viscosity‘ fCPl

density‘ fgWl

tendencyfor hydrolysis

ref:

7 (mp)

18

1.240

very high

10

[EMIM] [ B F4] [EMIM][CF3SO,]

6 kP) -3 (mp)

34

1.240

relatively low

11

45

1.390

very low

9

[EMIM][(CF~SWZNI

-9 (mp)

31

1.518

very low

12

“Cl ~

[ EMIM][ AIC14]

4 a t 25 ” C ; mp = melting point: gp = glass point

was kept for 8 h at 100 “C. HF (toxic and highly corrosive) and phosphoric acid was formed. Under the same conditions hydrolysis of the tetrafluoroborate ion of [BMIM][BF4] was observed as well, however to a much smaller extend [8]. Consequently, the application of tetrafluoroborate and hexafluorophosphate ionic liquids is effectively restricted - at least under a technical scenario - to those applications where water-free conditions can be realised at acceptable costs. In 1996, Gratzel, BonhBte and coworkers published synthesis and properties of ionic liquids with anions containing CF3-groupsand other fluorinated alkyl groups [9].These do not show the same sensitivity towards hydrolysis than [BF4]- and [PF6]- containing systems. In fact, heating [BMIM][CF3S02),N] with excess of water to 100 “C for 24 h did not reveal any hint for anion hydrolysis [8]. In addition to their hydrolysis stability, a number of other very suitable properties of imidazolium salts with [ CF3S02)2N]-anion should be mentioned here. In comparison to other well established ionic liquids they combine low melting points and low viscosity with high thermal stability (for a comparison of some physico-chemical data see Table 1). Moreover, they can be easily prepared in high quality due to their miscibility gap with water. Commercial Availability

Historically, the know-how to synthesise and handle ionic liquids has been treated somehow like a “holy grail”. Indeed, only a small number of specialised industrial and academic research groups were able to prepare and handle the highly hygroscopic chloroaluminate ionic liquids which were the only ionic liquid systems available in larger amounts up to the mid-nineties. The first publication describing the synthesis of tetrafluoroborate and hexafluorophosphate ionic liquids by metathesis reaction from the corresponding alkali salts [ 131 opened up the way towards a commercial ionic liquid production. Nowadays, a number of commercial suppliers offer ionic liquids even in large quantities [14]. Moreover, the availability of many ionic liquids on a rapid delivery basis has been established through internationally operating distributors [ 151. Without any doubt the improved commercial availability of ionic liquids is a key factor for the strongly increasing interest in this new class of liquid materials. In fact, a synthetic

Progress in lonic Liquid Design and Synthesis

chemist searching for the ideal solvent for his specific application usually takes solvents which are ready for use on the shelf of his laboratory. The additional effort of synthesising a new special solvent can be rarely justified especially in industrial research. Green Chemistry

For good reasons, ionic liquids are often discussed as solvents for a “Greener Chemistry” [lG]. In contrast to volatile organic solvents and extraction media, they have no measurable vapour pressure. Therefore there is no loss of solvent through evaporation. Environmental and safety problems arising through the use of volatile organic solvents can be avoided. For catalytic application where a transition metal catalyst is dissolved in the ionic liquid or the ionic liquid itself acts as the catalyst two additional aspects are of interest. Firstly, the special solubility properties of the ionic liquid enables a biphasic reaction mode in many cases. Exploitation of the miscibility gap between the ionic catalyst phase and the products allows, in this case, the catalyst to be isolated effectively from the product and reused many times. Secondly, the non-volatile nature of ionic liquids enables a more effective product isolation by distillation. Again, the possibility arises to reuse the isolated ionic catalyst phase. In both cases, the total reactivity of the applied catalysts is increased and catalyst consumption relative to the generated product is reduced. For example, all these advantages have been convincingly demonstrated for the transition metal catalysed hydroformylation [ 171. Therefore, the general trend towards a “greener” and more sustainable chemistry has contributed substantially to the growing interest in using ionic liquids for synthetic applications. Following the large number of original publications describing the use of ionic liquids in synthetic applications an extensive reviewing practise about this topic has developed over the last three years. Olivier-Bourbigouand Magna [18], Sheldon [19] and Gordon [20] published three excellent reviews presenting a comprehensive overview of the actual work carried out on catalysis involving ionic liquids with slightly different emphasis. All three up-date earlier published reviews by the author and Keim [21], Welton [22] and Seddon and Holbrey [23] on the same topic. Moreover, a whole book has been dedicated to the application of ionic liquids in synthetic applications [ 241. Obviously, it can not be the aim of this contribution to repeat or summarise the above mentioned reviews again. In contrast, a few selected recent developments in different areas of ionic liquid research should be highlighted which are believed to be of some general relevance for the future development of ionic liquids and their application in synthetic chemistry. Progress in Ionic Liquid Design and Synthesis

In the last two years, an interesting process could be observed in the research aiming for the development of new ionic liquids. Depending on the complexity of the combination of properties required and on the amount of ionic liquid consumed for a given application, the recently developed ionic liquids can be divided in two groups: The first group falls under the definition of “bulk ionic liquids”. This means a class of ionic liquids that is designed to be produced, used and somehow consumed in larger quan-

I

107

108

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

r-

Fig. 1.

1

Examples for “bulk ionic liquids” developed in the last three years.

tities. Applications for these ionic liquids are expected to be solvents for organic reactions, homogeneous catalysis, biocatalysis and other synthetic applications with some ionic liquid consumption as well as non synthetic applications such as the application as heat carriers, lubricants, additives, surfactants, phase transfer catalysts, extraction solvents, solvents for extractive distillation, antistatics etc. Cation and anion of these “bulk ionic liquids” are chosen to make a relatively cheap (expected price on a multi-hundred litre scale: ca 30 (€/litre), halogen-free (e.g. for easy disposal of spent ionic liquid by thermal treatment) and toxologically well-characterized liquid (a preliminary study about the acute toxicity of a nonchloroaluminate ionic liquid has been recently published [25]). It can be expected that from all ionic liquids meeting these requirements only a very limited number of candidates will be selected for an industrial use on larger scale. However, these candidates will become well characterised and - due to their larger production quantities - readily available. Promising examples for this type of “bulk ionic liquids” include benzenesulfonate [ 261, toluenesulfonate [ 271, octylsulfate [ 281 and hydrogensulfate [ 291 ionic liquids. Some examples are given in Figure 1. On the other hand several research groups are active in developing highly specialised, task-specific ionic liquids that - of course - will be used in much smaller quantities. Fields of applications for the latter are expected to be special solvents for organic synthesis, homogeneous catalysis, biocatalysis and all other synthetic applications with very low ionic liquid consumption (e.g. due to very efficient multiphasic operation). Non-synthetic applications for these materials are analytic applications (stationary or mobile phases for chromatography, matrixes for MS etc.), sensors, batteries etc. These ionic liquids are designed and optimised for the best performance in high-value-adding applications. Consequently, in future research only the scientist’s fantasy will limit the number of used ionic liquids in this group. Interesting recently published examples include ionic liquids with fluorinated [ 301. functionalized [31] and chiral cations [32] and anions (331. Advanced Acidic Ionic Liquids

Acidic chloroaluminate ionic liquids were used as reaction media for Friedel-Craftsreactions as early as 1976 [ 341. Systematic investigations into Friedel-Crafts alkylations of benzene with the same acidic systems followed in 1986 by Wilkes et al. [35]. The alkylation of benzene with alkenes in acidic imidazolium chloroaluminate melts was disclosed in a patent by BP Chemicals in 1994 [36]. Here, as advantages over the reaction with aluminum trichloride in organic solvents, claims are made regarding the easy isolation of the product, the practically total reusability of the liquid catalyst and the better selectivity to the desired products.

Advanced Acidic fonic Liquids

Fig. 2.

Examples for task specific ionic liquids developed in the last three years.

Following up this initial work a large number of reactions have been published by academic and industrial groups wherein a Lewis-acidic chloroaluminate ionic liquid is used as the acidic catalyst. A comprehensive overview on these research activities can be found in several reviews on this topic and the literature cited therein [18, 22, 371. However, acidic systems based on chloroaluminate ionic liquids have some serious limitations. They are extremely oxophilic thus forming adducts with C-0 functionalities. This makes their catalytic use difficult if the substrate or product of the reaction under investigation contains such a functional group. Often, it is necessary in these cases to hydrolyse the ionic liquid prior to product isolation including complete loss of the acidic ionic liquid catalyst. Moreover, chloroaluminate ionic liquids are difficult to handle since they react irreversibly with traces of water to form HC1 and Al-oxides. In this chapter alternative acidic ionic liquids systems will be briefly presented that have been recently developed as alternatives to chloroaluminate ionic liquids. In spite of this selection, it should be noted that chloroaluminate ionic liquids may still be attractive catalyst phases in reactions where their tuneable acidity and solubility properties offer advantage over AlC13 in organic solvents. Non-chloroalurninate Lewis Acidic Ionic Liquids

Seddon and co-workers described the Friedel-Crafts acylation reaction of benzene with acetylchloride using acidic chloroferrate ionic liquids as catalysts [38]. In contrast to the same reaction in presence of acidic chloroaluminate systems the ketone product could be separated from the ionic liquid by solvent extraction, provided that the molar ratio of FeC13 is in the range 0.51-0.55 in the applied ionic liquid catalyst (Scheme 1).

Scheme 1.

Friedel-Crafts acetylation using an acidic chloroferrate ionic liquid

I

109

110

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis Examples for non-chloroaluminate ionic liquids formed by the reaction of a halide salt with a Lewis acid.

Tab. 2.

ionic liquid

anion species

references

[cation] Cl/FeClj [cation] CI/AlEtC12 [cation] CI/BCl, [cation] Cl/CuCI [cation] Cl/SnC12 [cation] X/SbF, [cation] CI/ZnC12

C1-, [FeC14][AlEtCl,] , [A12Et2Cls]-, [AlzEtC16]Cl-, [BC14][CuC12]-, [Cu2C1,]-, [Cu3C14][SnCI,]-, [Sn,Cl,]e.g. [SbFSXIe.g. [ZnC13]

38 39

cation

= pyridinium,

40 41

42 43 44

imidazolium, ammonium.

This simple example may illustrate that in general the reaction of an organic halide salt [cation]X with an excess of a Lewis-acid MX, can result in new catalytic materials even if other Lewis-acidsare applied than AlC13. In contrast, the use of other Lewis-acidsto form the ionic liquid of type [cation][MX,+l] + excess MX, (the excess of MX, may be dissolved in the neutral ionic liquid or may form acidic anionic species such as e.g. [M2X2y+l]-)gives access to new combinations of properties (e.g. a liquid, less oxophilic, Lewis-acidic catalyst with defined solubility and acidity properties). In Table 2 other examples of ionic liquids are presented which are formed by the reaction of an organic halide salt with different Lewis-acids. All these systems should be in principle useful acidic catalysts for synthetic organic chemistry even if not all displayed examples have been already discribed in the literature for this application. However, the formation of Lewis-acidic ionic liquids is not restricted to those systems obtained by reaction of an organic halide salt with an excess of Lewis-acid. For example, Kitazume and Zulfiqar have investigated the scandium(111) trifluoromethanesulfonate catalyzed Claisen rearrangement of several aromatic ally1 ethers in a neutral trifluoromethanesulfonate ionic liquids [45]. The reaction initially gave the 2-allylphenol but this reacted further to give 2-methyl-2,3-dihydrobenzo[b]furan (Scheme 2). The yields in this reaction were highly dependant on the ionic liquid chosen, with [EDBU][OTf] giving the best yields (e.g. 91% for R = G-CH3).

6 Sc(OTf)3 "JL"

R

Scheme 2.

PH

'J \

R

- \

R

Claisen rearrangement catalysed by Sc(OTf)3 in .a trifluoromethansulfonate ionic liquid

Conceptsfor Transition Metal Catalysis Using lonic Liquids

Brmsted-acidic lonic Liquids

The easiest way to create a Brensted acidic ionic liquid is to dissolve a strong Brernsted acid in an ionic liquid. Already in 1989, Smith and coworkers described that mixtures of HC1 and acidic chloroaluminate ionic liquids result in the formation of superacidic Brensted acids (more acidic than 100% sulfuric acid). This is due to the reaction of HC1 with the acidic anions (e.g. [AlzC17]-) of the melt forming a proton with extremely low solvation and therefore very high acidity [46]. A more recent - but much less acidic example - was presented by Raston et al. who converted 3,4-dimethoxyphenylmethanolto cyclotriveratrylene using mixtures of tributylhex] [ ( C F ~and phosylammonium bis(trifluoromethanesulfony1)amide [ N B u ~ ( C ~ H ~ ~ )S02)2N] phoric or ptoluenesulfonic acid (Scheme 3) [47]. H3C0

OCH3

L4

OCH3 I

H3c0&0H H3COH3CO

OCH3

Scheme 3.

The cyclisation of 3,4-dimethoxyphenylmethanol catalyzed by phosphoric acid dissolved in a neutral ionic liquid.

The synthesis of several hydrogensulphate and tetrakis(hydrogensu1phato)borate ionic liquids has been described by our group [29]. Mixtures of these ionic liquids with sulphuric acid were used as non-volatile acidic phases with tuneable solubility properties for catalytic applications such as e.g. the alkylation of benzene with 1-decene. The results demonstrate that hydrogensulfate and tetrakis(hydrogensu1fato)borate ionic liquids are highly interesting additives to mineral acids to form new, highly Brensted-acidic catalysts. For example, it was found that a mixtures of sulphuric acid with only 2.2 mol% of [ OMIM][B( HS04)4] ionic liquid yielded 90% more monoalkylbenzene product than the neat sulphuric acid catalyst under identical reaction conditions. This and related results are explained by an interplay of solubility and acidity effects caused by the ionic liquid additive. Concepts for Transition Metal Catalysis Using Ionic Liquids

In the following sub-chapters two selected examples will be presented to illustrate general concepts for transition metal catalysis in ionic liquids. In both examples the role of the ionic liquid is different being alternatively used mainly in its function as ligand precursor or selective extraction solvent respectively.

I

111

112

I

Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis lonic Liquid as Reactive Catalyst Phase Forming in-situ Transition Metal Carbene Complexes Exempl8ed for the Pd-catalysed Heck Reaction in Ionic Liquids

The Heck reaction and other related transformations for selective C-C-couplings are receiving a great deal of attention among synthetic chemists due to their versatility for fine chemical synthesis. However, these reactions suffer in many cases from the instability of the Pdcatalysts used, leading to high catalyst consumption and difficult processing. Starting from the early work by Kaufmann and al. in 1996 [48], many groups have investigated Heck-reactions in ionic liquids (for detailed reviews see [49, 20, 211). However, as has been demonstrated by Xiao et al. [SO] and Welton et al. [51],the use of imidazolium based ionic liquids in Pd-catalysed Heck reaction always bears the possibility of an in-situ formation of Pd-carbene complexes. The reason for this originates from the well-known relatively high acidity of the H atom in the 2-position of the imidazolium ion [ 521. Xiao and coworkers demonstrated that a Pd imidazolylidene complex is formed when Pd(OAc)2 was heated in presence of [BMIMIBr. The isolated Pd carbene complex was found to be active and stable in Heck coupling reactions. Welton et al. were later able to characterize an isolated Pd-carbene complex obtained in this way by X-ray spectroscopy. The reaction pathway to form the Pd-carbene in presence of a base is displayed in Scheme 4.

w Formation of a Pd-carbene complex by deprotonation o f the imidazolium cation.

Scheme 4.

It should be noted here that the abstraction of the acidic proton in 2-position of the imidazolium ring by a base is not the only possibility to form a metal carbene complex. Cave11 and co-worker have observed the in-situ metal carbene complex formation in an ionic liquid by direct oxidative addition of the imidazolium cation on a metal centre in a low oxidation state (Scheme 5) [53]. However, the Pt-carbene complex formed can decompose by reductive elimination.

[

N

~

1

/ v \

Scheme 5.

N[BF,I-

Pt(PPh314

Formation of a Pt-carbene complex by oxidative addition o f 1,3-dimethylimidazolium ion,

Conclusions and Outlook I 1 1 3

In the light of these results, it is very important to check catalytic results obtained from imidazolium ionic liquid for a possible influence of in-situ formed carbene species. This can be done especially by testing a given reaction as well in ionic liquids which do not form carbene complexes e.g. in pyridinium based ionic liquids. lonic Liquid as lnert Catalyst Phase Preventing Product lnhibition by Selective Extraction Exernplifiedfor the Pd-catalyzed Dirnerisation of Methylacrylate in lonic Liquids

-

Recently, our group described in collaboration with Tkatchenko et al. the Pd-catalyzed dimerisation of methylacrylate(MA) using a tetrafluoroborate ionic liquid as catalyst solvent (Scheme 6) [ 541.

2 / T O

OMe

Pd(acac)2/ [HOEt2][BF4] ligand, H[BF4]

-

PMIM"F41

-

'0

OMe selectivity > 92 %

Scheme 6. Pd-catalyzed dirnerisation of methylacrylate u s i n g a tetrafluoroborate ionic liquid as catalyst solvent.

However, in batch mode all dimerisation reaction (with and without added IL) were found to stop at a maximum MA conversion of about 80%. By adding fresh feedstock (and by some other experiments) we could reveal that the reaction suffers at this conversion from a product inhibition effect. To overcome this limitation we decided to carry out the reaction in a continuous biphasic mode using [BMIM][BF4]/tolueneas the solvent mixture. For the continuous experiment, a mixture of substrate and toluene was pumped into a glass tube containing the ionic liquid catalyst phase [Pd(acac)2,H[BF4] and an ionic phosphine ligand]. Driven by its lower density the feed rose in the tube and the organic phase - a mixture of product/substrate and organic solvent - was removed at the top of the reactor. Using this method a continuous experiment over 50 h could be carried out obtaining an overall TON of 4000 mol MA converted per rnol of Pd. Our results clearly demonstrated that the product inhibition problem could be efficiently solved by the continuous extraction of the MA dimer from the ionic catalyst solution. In general, this type of highly specialised liquid-liquid biphasic operations can be regarded as an ideal field for the application of ionic liquids. Due to their tuneable solubility properties (by proper cation/anion choice) an efficient optimisation of those combined reaction/ in-situ extraction systems becomes possible. Conclusions and Outlook

Obviously, there are many good reasons to study ionic liquids as alternative solvents in synthetic organic chemistry and particularly in catalytic reactions. Besides the engineering

114

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Recent Developments in Using Ionic Liquids as Solvents and Catalystsfor Organic Synthesis

advantage of their non-volatile nature, the investigation of new biphasic reactions with an ionic catalyst phase is of special interest. The possibility to adjust solubility properties by different cation/anion Combinations has already been mentioned. Moreover, the application of an ionic liquid catalyst layer often enables a biphasic operation even in those cases where this is not possible using water or polar organic solvents (e.g. due to incompatibility with the catalyst or due to problems with substrate solubility). In this context, recent developments to apply ionic liquids in combination with biocatalysts should be mentioned here. After pioneering studies by Magnuson et al. [55] this new research area was developed by Kragl et al. [56] and others [57]. The first promising results, namely the fact that the use of ionic liquid in biocatalysis can help to overcome common problems observed in aqueous media (such as e.g. product and substrate hydrolysis or low substrate solubility) led to a busy research activity in this field (comprehensive reviews describing these activities have been published by Kragl et al. [ 581 and Sheldon [ 191). However, research on catalytic reactions in ionic liquids should not focus only on the question how to make some specific products more economical or ecological by using a new solvent and presumably a new multiphasic process. By bridging in a novel and highly attractive manner the gap between homogeneous and heterogeneous catalysis, the application of ionic liquids in catalysis gives rise to more fundamental questions. In fact, in many respects catalysis in ionic liquids is better regarded as heterogeneous catalysis with a liquid catalyst support than as conventional homogeneous catalysis in an organic solvent. As for heterogeneous catalysis, support-catalyst interactions are known in ionic liquids and can lead to catalyst activation. Product separation from an ionic catalyst layer is often easy (at least if the products are relatively unpolar and have low boiling points) like in classical heterogeneous catalysis. However, mass transfer limitation problems (when the chemical kinetics are fast) and some uncertainty concerning the exact microenvironment around the catalytically active centre represent common limitations for transition metal catalysis in ionic liquids and in heterogeneous catalysis. Of course, the use of a liquid catalyst immobilisation phase still makes some very important differences in comparison to classical heterogeneous supports. Obviously, by using a liquid ionic catalyst support it is possible to integrate some classical features of traditional homogenous catalysis into this type of “heterogeneous” catalysis. For example, a defined transition metal complex can be introduced and immobilised in an ionic liquid giving access to the chance to optimise the selectivity of a transition metal catalyzed reaction by ligand variation, which is a typical approach in homogeneous catalysis. Catalytic reactions in ionic liquids proceed under similar mild conditions as are typical for homogenous catalysis. Analysis of the active catalyst in an ionic liquid immobilisation phase is in principle possible by using the same methods developed for homogeneous catalysis which should enable a more rational catalyst design in the future. In comparison to traditional biphasic catalysis using water, fluorous phases or polar organic solvents, catalysis in ionic liquids represents a new and advanced way to combine the specific advantages of homogeneous and heterogeneous catalysis. In many applications the use of a defined transition metal complex immobilised on a liquid ionic “support” has already shown its unique potential. To identify new exciting examples for the use of ionic liquids in synthetic and catalytic reactions, it is probably the most promising way to start from a detailed understanding of

References

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115

the special properties of the ionic liquid material and to identify from this point attractive targets for this methodology. Two successful examples from the past should illustrate this approach in more detail. The fact that ionic liquids with weakly-coordinating anions can combine in a unique manner relatively high polarity with low nucleophilicity allows for the first time biphasic catalysis with highly electrophilic, cationic Ni-complexes [ 591. The wide electrochemical window of ionic liquids in combination with their ability to serve as solvents for transition metal catalysts opens up new fascinating ways for a combination of electrochemistry and transition metal catalysis. A first very exiting example has been recently published by Bedioui et al. [GO]. Without any doubt, a lot of exciting chemistry is still to be done in ionic liquids! References 1

2

3 4

5

6 7

8 9

10

a) F. H. HURLEY, U.S. Patent 2,446,331, 1948 [Chem. Abstr. 1949,43, P7645bl; b) F. H. HURLEY, T. P. WIER,JR.,]. Electrochem. SOC.1951, 98, 207. a) H. L. CHUM,V. R. KOCH,L. L. MILLER, R. A. OSTERYOUNG, 1.Am. Chem. SOC. 1975, 97, 3264; b) J. ROBINSON, R. A. OSTERYOUNG,]. Am. Chem. SOC. 1979, 101, 323. J. S. WILKES, J. A. LEVISKY; R. A. WILSON, Inorg. Chem. 1982, 21, 1263. C. L. HUSSEY, a) T. M. LAHER, C. L. HUSSEY, lnorg. Chem. 1983, 22, 3247; b) T. B. SCHEFFLER, Znorg. Chem. 1984, 23, 1926; C. L. HUSSEY, c) D. APPLEBY,C. L. HUSSEY, K. R. SEDDON, J. E. TURP,Nature 1986, 323, 614. a) P. B. HITCHCOCK, T. J. MOHAMMED, K. R. SEDDON, j. A. ZORA,C. L. HUSSEY, E. H. WARD,Znorg. Chim. Acta 1986, 113, L25. J. S. WILKES, M. J. ZAWOROTKO,]. Chem. SOC.Chem. Commun. 1992, 965. J. FULLER,R. T. CARLIN, H. C. D E LONG, D. HAWORTH,].Chem. SOC. Chem. Commun. 1994,299. A. BOSMANN, P. WASSERSCHEID, unpublished results. P. BONHBTE, A,-P. DIAS,N. K. KALYANASUNDARAM, PAPAGEORGIOU, M. GFL~TZEL, h r g . Chem. 1996, 35, 1168. a) J. S. WILKES, j. A. LEVISKY,R. A. WILSON, C. L. HUSSEY, Znorg. Chem. 1982, 21, 1263; b) A. A. FANNIN J R . , D. A. FLOREANI, L. A. KING, J. S. LANDERS,B. J. PIERSMA, D. J. STECH,R. J. VAUGHN, J. S. WILKES, J. L. WILLIAMS,]. Phys. Chem. 1984, 88, 2614.

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J. FULLER, R. T. CARLIN, R. A. 1.Electrochem. SOC.1997, OSTERYOUNG,

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M. L. M. ELLIS,P. K. G. HODGSON, MORGAN,K. R. SEDDON, WO 9521806 (to BP Chemicals Ltd, UK) 1995 [ Chem. Abstr. 1995, 124, 83811. 37 M. EARLEi n P. WASSERSCHEID, T. WELTON (Eds.) “Ionic Liquids in Synthesis”, WileyVCH, Weinheim, 2002, pp. 174-213. 38 P. N. DAVEY, M. J. EARLE,C. P. NEWMAN, K. R. SEDDON, WO 9919288 [to Quest International B.V., Neth.), 1999 [Chem. Abstr. 1999, 130, 2818711. 39 a) Y. CHAUVIN, S. EINLOFY,H. OLIVIER, Ind. Eng. Chem. Res. 1995, 34, 1149; b) B. GILBERT, Y. CHAUVIN, H. OLIVIER, F. DI MARCO-VAN TIGGELEN,].Chem. SOC. Dalton Trans. 1995, 3867. 40 S . D. WILLIAMS, J. P. SCHOEBRECHTS, J. C. G. MAMANTOV,]. Am. Chem. SOC. SELKIRK, 1987, 109, 2218. 41 Y. CHAUVIN, H. OLIVIER-BOURBIGOU, CHEMTECH 1995, 25, 26. 42 a) G . LING, N. KOURA, Denki Kagaku Oyobi Kogyo Butsuri Kagaku 1997, 65, H. WAFFEN149; b) P. WASSERSCHEID, SCHMIDT,].Mol. Cataf. A: Chem. 2000, 164( 1-2), 61. 43 P. BONNET, E. LACROIX, J.-P. SCHIRMANN, WO 0181353 (to Atofina, France) 2001 [Chem. Abstr. 2001. 135, 3384831. 44 A. P. ABBOTT,D. L. DAVIES, WO 0056700 (to University of Leicester, UK) 2000 [ Chem. Abstr. 2000, 133, 2690581. 45 F. ZULFIQAR, T.KITAZUME, Green Chem. 2000, 2, 296. 46 a) G . P. SMITH,A. S. DWORKIN, R. M. PAGNI,S. P. ZINGG,]. A m . Chem. SOC. 1989, 111, 525; b) M. MA, K. E. JOHNSON, J. Am. Chem. Soc. 1995, 117, 1508. 47 J. L. SCOTT,D. R. MACFARUN, C. L. RASTON, C. M. TEOH,Green Chem. 2000, 2, 123. 48 D. E. KAUFMANN.M. NOUROOZIAN, H. HENZE,Synlett 1996, 1091. 49 a) P. WASSERSCHEID in P. WASSERSCHEID, T. WELTON(Eds.) “Ionic liquids in synthesis”, Wiley-VCH, Weinheim, 2002, pp. 213-257 50 L. Xu. W. CHEN,J. XIAO,Organometallics 2000, 19, 1123. 51 C. J. MATHEWS, P. J. SMITH,T. WELTON, A. J. P. WHITE,Organometallics, 2001, 20( 18), 3848. 52 a) A. J. ARDUENGO, R. L. HARLOW, M.

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HARLOW, J . Am. Chem. SOC.1992, 114, 9th 5530; c) G. T. CHEEK,J. A. SPENCER, Int. Symp. on Molten salts, (Hrsg.: C. L. HUSSEY, D. S. NEWMAN, G. MAMANTOV, Y. ITO),The Electrochem. Soc., Inc., New York, 1994,426; d) W. A. HERRMANN, M. ELISON, J. FISCHER, C. KOECHER, G. R. J. ARTUS,Angew. Chem., Int. Ed. Engl. 1995, 34, 2371; e) D. BOURISSOU, 0. GUERRET, Chem. Rev. F. P. GABBAI,G. BERTRAND, 2000, zoo, 39. D. S. MCGUINNESS, K. J. CAVELL, B. F. YATES,Chem. Commun. 2001, 355. P. WASSERSCHEID, J. ZIMMERMANN, I. TKATCHENKO, S. STUTZMANN, Chem. Commun. 2002, 760. D. K. MAGNUSON, J. W. BODLEY,D. F. J . Solution Chem. 1984, 13, 583 EVANS, S. SCHOFER, N. KAFTZIK,P.

WASSERSCHEID, U. KRAGL, Chem. Commun. 2001,425. 57 a) S. G. CULL,1. D. HOLBREY, V. VARGASMORA,K. R. SEDDON, G. J . LYE, Biotechnol. Bioeng. 2000, 69, 227; b) M. ERBELDINGER, A. J. MESIANO, A. j. RUSSEL, Biotechnol. Prog. 2000, 16, 1131; c) R. MADEIRA JAW, F. VAN RANTWIJK,K. R. SEDDON, R. A. SHELDON, Org. Lett. 2000, 2, 4189. 58 U. KRAGL, N. KAFTZIK, S. H. SCHOFER,M. ECKSTEIN, P. WASSERSCHEID, C. HILGERS, C H I M I C A OGGI/Chemistry Today 2001, 7/8, 22; b) U. KRAGL, M. ECKSTEIN, N. KAFTZIK in P. WASSERSCHEID, T. WELTON (Eds.) “Ionic liquids in Synthesis”, Weinheim, Wiley-VCH, pp. 336-347. 59 P. WASSERSCHEID, C. M. GORDON,C. HILGERS: M. J. MALDOON; I. R. DUNKIN; Chem. Commun. 2001, 1186. 60 L. GAILLON, F. BEDIOUI, Chem. Commun. 2001, 1458.

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Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Recent Advances on the Sharpless Asymmetric Am inohyd roxyIation Drnitry Nilov and Oliver Reiser

Introduction

The asymmetric aminohydroxylation (AA), although only discovered [ 11 by B. Sharpless et al. in 1996, has rapidly become an invaluable synthetic tool in organic chemistry. Its great value is given in the possibility of enantioselectively introducing a 1,2-amino alcohol functionality, being most important for the construction of biologically active compounds and chiral ligands, from readily available alkenes. Although initially only a N-tosyl protected amino group could be transferred, quite rapidly other nitrogen sources transferring the amino group with standard protecting groups such as BOC [2] (tert-butoxycarbonyl) or Cbz [3] (benzyloxycarbonyl)were discovered, broadening greatly the utility of the AA. Moreover, by appropriate choice of the ligands or substrates, the regioselectivity of the reaction can be XNClNa or AcNBrLi K ~ O S O ~ ( O(1 H-4mol%) )~ DHQ2PHAL (1.25-5 mol%)

Rl/\\/R2

*

NHX Rl+R2

+

OH R 1 k R 2

OH

ROH I H20 O'C or room temp

NHX

X = Ts, Ms, Cbz. Boc, TeoC, Ac

OAlk'

OAlk* PHAL

OAlk*

0 AQN OAlk*

0

IND Scheme 1.

OAlk'

I

.

WoMe DHQD

OAlk* PY D

Overview of the Sharpless asymmetric aminohydroxylation (AA)

New Substrates and Applications

I

119

controlled either way quite efficiently (41, a strategy that has been further improved during the last three years [S]. There have been already a number of reviews [GI about the AA, but nevertheless, rapid progress in this area is still being made, so that a comprehensive compilation of all contributions towards the AA is beyond the scope of this article. New Substrates and Applications

The most amenable substrates for the AA have been so far cc,p-unsaturated carboxylic esters and styrenes, and quite a number of publications have been reported that further demonstrate this trend [7]. Especially useful appears the possibility to use Baylis-Hillman adducts 1 as starting materials, giving syn-2 with good preference over the diastereomer anti-2 without the need of adding the chiral ligands of the AA [8].The amino group is exclusively introduced at the terminal end of the alkene, however, it is interesting to note that the ligands of the AA does not seem to influence the course of the reaction at all: In the presence of (DHQ)zPHAL the products were obtained racemically, i.e. no kinetic resolution seems to have taken place, with the hydroxy group in 1 obviously acting as a directing group. OH

0

OH

0

R ’HO Y O / R 2 no AA ligand * R’ . y U ‘ . OOH NR2+ 65-88% 1

NHTs

HNTs

syn-2

R’= H, Me, Et, i-Pr, cyclohexyl, Ph &Me, Et, i-Pr, cyclohexyl, t-Bu

anfi-2

syn/anfi: 86:14 up to 99:l

Asymmetric arninohydroxylation o f Baylis-Hillrnan adducts.

Scheme 2.

The excellent results being usually obtained with cinnamates can be also used to arrive at acyclic saturated compounds as demonstrated in the synthesis of a precursor 5 of Ramoplanin A2 [9]. The para-methoxy phenyl group in 4 can be readily degraded to an ester group by oxidation with RuC13/NaI04. NHCbz

rcooM -

Me0

(DHQD)2PHAL AA

MeO

64%

3

299% ee

4

-

Fmoc , NH 0 BnO#N,Ttl

0

OH 5

Scheme 3.

Application of the AA toward the synthesis o f Rarnoplanin A2.

120

I

Recent Advances on the Sharpless Asymmetric Aminohydroxylation

Changing the ester to a related phosphonate group allows the synthesis of biologically important [ 101 2-amino-1-hydroxyphosphonic esters 7. However, the selectivities and especially the yields are significantly lower compared to the corresponding acrylates [ 111. NHR'O

O

Ar-?-OR

AA

OR

P-OR \OR OH

* Ar? (DHQ)2PHAL

21-53% 42-98% ee

R = Me, Et, 'Pr R' = Ts, COOEt

6 Scheme 4.

7 Synthesis of 2-amino-1-hydroxy phosphonic esters via the AA.

In the synthesis of manzamine alkaloids, the AA of 8 proceeded with remarkable selectivity, given the fact that the double bond is electronically not differentiated [12]. The formation of 9 as the exclusive product can be understood by a transfer of the nitrogen group via the least hindered trajectory to the alkene, i.e. the less-substituted position of the double and equatorial approach.

mBnmBn H

U

AA * N (DHQD)zPHAL BOC'

N

Boc'

H

76%

a Scheme 5.

H

>99% de

OH NHTS

9

Application of the AA toward the synthesis of manzarnine alkaloids,

Heteroaromatic alkenes have been found to be especially useful substrates for the AA, since they offer a considerable potential for further synthetic transformations. Thus, in a most elegant application the product 12 obtained from vinylfurane (10) via the AA was used for the synthesis of azasugars like 13 as precursors toward deoxymannojirimycin [ 131.

21 % (86% ee)

10

11

(1:2)

12

13 Scheme 6.

Application o f the AA toward the synthesis of deoxyrnannojirimycin.

N e w Nitrogen Sources I 1 2 1

While acrylates being substituted with a furan, thiophene, or indole moiety serve as excellent substrates in the AA [ 141, pyrrole and pyridine substituted acrylates fail in the title reaction [ 14al. However, the corresponding pyridine-N-oxides 16 can be used alternatively in the AA and subsequently reduced, thus providing an indirect solution to access aminohydroxylated products 14 or 15 of pyridine substituted acrylates [14a]. It was interesting to note that the major regioisomer 17 was formed with good enantioselectivity,while the minor 18 was obtained virtually racemic. This approach was used for the synthesis of the pyridyl analog of the side chain of taxol, which had been demonstrated to yield a considerable more potent taxol derivative than the natural product itself [ 151.

14

15

i 0-

0-

63-79% ee

17

16 Scheme 7.

(2.3-2.8: 1)

18

Indirect AA of pyridinyl acrylates via the corresponding N-oxides.

A quite remarkable desymmetrization of 19 was achieved using the AA: 20 was obtained with complete regioselectivity, indicating a strong directing effect of the silyl group due to its p-effect [ 161. SiMepOH AA

75% >98% ds, 68% ee

20

19 Scheme 8.

Desyrnmetrization of cyclohexa-l,4-dienes via the AA.

New Nitrogen Sources

There were a number of new nitrogen sources for the AA introduced, such as tertbutylsulphonamide [ 171, primary amides [ 181 and N-bromobenzamide [ 191. The combination of urethanes as the nitrogen and 1,3-dichloro-5,5-dimethyl hydantoin as a co-oxidant/

122

I

Recent Advances on the Sharpless Asymmetric Aminohydroxylation

chlorine source could be utilized in a one-pot procedure of chiral oxazolidin-2-ones 24 and 25, being most valuable chiral auxiliaries 1201. AA / Urethane 1,3-dichlor0-5,5-dimethyl hydantoin

Ar\=\

"kR ArxoH

HN

b-OEt

(DHQ)zPHAL 28-81Yo L

21

OH+HO

22

NH

Et0-d '0 23

0

0 81-98% ee 24

4-5:l

25

Ar = Ph, 4-MeO-C&l6,4-02NC6H4 R =Me, Ph, COOEt Scheme 9.

A one pot synthesis o f oxazolidones via the AA.

Similarly, an intramolecular variant utilizing carbamates 26 derived from allylic alcohols has been developed using an amine like Hunigs base (ethyl diisopropylamine) as additive 1211. The products were obtained with complete regio- and diastereocontrol, but surprisingly, only in racemic form when chiral ligands like (DHQ)zPHAL, being established for the AA, were employed. 0

(DHQ)2PHAL orkPr2NEt 41 -61Yo

R

R--(

OH

R = H, Ph, Pr, CH,CH=C-

(rac)-27

26 Scheme 10.

An intramolecular variant of the AA

New Ligands and Catalysts

Based on the established alkaloid ligands, a number of modifications have been reported which have led to alternative ligands and catalysts for the AA [7c, 221. Conceptually interesting is the discovery that products obtained by the aminohydroxylation itself can serve as ligands 1231. Thus, the AA of styrenes 28 proceeds in high yields to the regioisomeric amino alcohols 29 and 30 in the presence of catalytic amounts of 31, being the AA product of cinnamic acid, with moderate, nevertheless significant enantioselectivity.

References NHTs

AA

7

PhWR

Ph-R

4-

OH

29 (30-59% ee)

28

NHTs

1 . 2

30 (24-55%ee)

NHTs ph*CooH

OH 31 Scheme 11.

AA adducts o f cinnamic acid serve as ligands for the AA

Related to the previous example is the report that the AA of carboxylic acids [24] - as well as of carboxylic amides [25] or pinenes and camphenes [2G] - proceeds well in the absence of any ligand. It can be assumed that the reaction is autocatalytic, however, no definite experimental evidence has been provided to prove this speculation. While osmium is the metal of choice for the AA, there has been a recent report of the copper(1)-catalyzed intramolecular aminohydroxylation starting from hydroxylamines [ 271. The mechanism of this reaction is distinctively different, involving radicals as intermediates. Conclusion

There remain still quite a few conceptual advances to be discovered in the asymmetric aminohydroxylation, broadening further the scope and limitations of this process. On the other hand, the utility of the AA is demonstrated in many applications now, giving ample proof that this reaction has become an indispensable tool in organic synthesis. References G. LI, H.-T. CHANG,K. B. SHARPLESS, Angew. Chem. Int. Ed. 1996, 35, 451-454. 2 (a) K. L. REDDY,K. B. SHARPLESS,]. Am. Chem. SOC.1998, 120, 1207-1217. (b) P. O’BRIEN,S. A. OSBORNE, D. D. PARKER, Tetrahedron Lett. 1998; 39, 4099-4102. (c) P. O’BRIEN, S. A. OSBORNE, D. D. ]. Chem. Soc., Perkin Trans. 1 1998, PARKER, 1

2519-2526. 3 G . LI, H. H. ANGERT, K. B. SHARPLESS, 4

Angew. Chem. Int. Ed. 1996,35,2813-2817. (a) B. TAO,G . SCHLINGHOFF, K. B. SHARPLESS, Tetrahedron Lett. 1998, 39, C. E. 2507-2510. (b) A. I. MORGAN, MASSE,J. S. PANEK, Org. Lett. 1999, I, 783-786.

5 (a) C.-Y. CHUANG, V. C. VASSAR, 2 . MA, R.

GENEY, I. OJIMA,Chirality 2002, 14, 151162. (b) R. M. DAVEY, M. A. BRIMBLE, M. D. MCLEOD,Tetrahedron Lett. 2000, 41, 5141-5145. (c) H. HAN,C.-W. CHO, K. D. JANDA: Chem. Eur. 1999, 5; 1565-1569. (d) C. E. MASSE,A. J. MORGAN, J. S. PANEK, Org. Lett. 2000, 2, 2571-2573. 6 (a) G. SCHLINGLOFF, K. B. SHARPLESS in Asymmetric Oxidations Reactions: A Practical Approach (Ed.: T. KATSUKI), Oxford University Press, Oxford 2001. (b) H. C. KOLB, K. B. SHARPLESS in Transition Metals for Fine Chemicals and Organic Synthesis, Vol. 2 (Eds.: M. BELLER, C. BOLM),WileyVCH, Weinheim, 1998, pp. 243-260.

I.

I

123

124

I

Recent Advances on the Sharpless Asymmetric Arninohydroxylation

7

8 9

10 11 12

13

14

(c) P. O’BRIEN,Angew. Chem. Int. Ed. 1999, 38, 326-329. (d) 0. REISER,Angew. Chem. Int. Ed. Engl. 1996, 35, 1308-1309. (a) C. E. SONG,C. R. OH, E. J. ROH, S. LEE,J. H . CHOI, Tetrahedron: Asymmetry 1999, 10, 671-674. (b) S. H. K. REDDY,S. LEE,A. DATTA,G. I. GEORG;]. Org. Chem. 2001, 66, 8211-8214. (c) A. MANDOLI,D. PINI, A. AGOSTINI,P. SALVADORI, Tetrahedron: Asymmetry 2000, 11, 4039-4042. (d) S.-H. LEE,J. YOON,S.-H. CHUNG, Y . 4 . LEE,Tetrahedron 2001, 57, 2139-2145. (e) H. PARK,B. CAO,M. M. JOULLIE,]. Org. Chem. 2001, 66, 7223-7226. ( f ) I. H. KIM, K. L. KIRK, Tetrahedron Lett. 2001, 42, 8401-8403. (8) R. N. ATKINSON, L. MOORE,J. TOBIN,S. B. KING,1.Org. Chem. 1999, 64, 3467-3475. W. PRINGLE,K. B. SHARPLESS, Tetrahedron Lett. 1999, 40, 5151-5154. D. L. BOGER,R. J. LEE,P.-Y. BOUNAUD, P. MEIER,J . Org. Chem. 2000, 65, 6770-6772. Review: H . GROGER,B. HAMMER,Chem. Eur. 1.2000, 6, 943-948. A. A. THOMAS,K. B. SHARPLESS,].Org. Chem. 1999, 64,8379-8385. J. S. CLARK,R. J. TOWNSEND, A. J. BLAKE, S. J. TEAT,A. JOHNS,Tetrahedron Lett. 2001, 42, 3235-3238. (a) M. L. BUSHEY,M. H. HAUKAAS,G . A. O’DOHERTY, ]. Org. Chem. 1999, 64, 2984-2985. (b) M. H. HAUKAAS,G. A. O’DOHERTI, Org. Lett. 2001, 3,401-404. See also (c) N. XI, M. A. CIUFOLINI, Tetrahedron Lett. 1995, 36, 6595-6598. (d) C. F. YANG,Y. M. Xu, L. X. LIAO, W.4. ZHOU, Tetrahedron Lett. 1998, 39, 9227-9228. (a) D. RAATZ,C. INNERTSBERGER, 0. REISER,Synktt 1999, 1907-1910. (b) H.

15

16

17 18 19

20

21

22

23

24 25

26

27

ZHANG,P. XIA, W. ZHOU,Tetrahedron: Asymmetry 2000, 11, 3439-3447. See: G . I. GEORG,G . C. B. HARRIMAN, M. HEPPERLE, J. S. CLOWERS, D. G. V. VELDE, R. H. HIMES,]. Org. Chem. 1996, 61, 2664-2676. R. ANGELAUD; 0. BABOT,T. CHARVAT, Y. LANDAIS,].Org. Chem. 1999, 64, 9613-9624. A. V. GONTCHAROV, H. LIU, K. B. Org. Lett. 1999, I , 1949-1952. SHARPLESS, 2. P. DEMKO,M. BARTSCH,K. B. SHARPLESS, Org. Lett. 2000. 2, 2221-2223. C. E. SONG,C. R. O H , E. J. ROH, S. LEE, J. H. C H O I ,Tetrahedron: Asymmetry 1999. 10, 671-674. N. S. BARTA,D. R. SIDLER,K. B. SOMMERVILLE, S. A. WEISSMAN, R. D. LARSEN,P. J. RIEDER,Org. Lett. 2000, 2, 2821-2824. T. J. DONOHOE,P. D. J O H N S O N , M. HELLIWELL, M. KEENAN,Chem. Commun. 2001, 2078-2079. R. M. DAVEY,M. A. BRIMBLE,M. D. MCLEOD,Tetrahedron Lett. 2000, 41, 5141-5 145. M. A. ANDERSON,R. EPPLE,V. V. FOKIN, K. B. SHARPLESS, Angew. Chem. Int. Ed. 2002, 41, 472-475. V. V. FOKIN,K. B. SHARPLESS, Angew. Chem. Int. Ed. 2001, 40, 3455-3457. A. V. GONTCHAROV, H. LIU, K. B. SHARPLESS, Org. Lett. 1999, I , 19491952. S. PINHEIRO,S. F. PEDRAZA,F. M. C. FARIAS,A. S. GONCALVES, P. R. R. COSTA, Tetrahedron: Asymmetry 2000, 11, 3845-3848. M. NOACK,R. G O ~ L I C HChem. , Commun. 2002, 536-537.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I125

Asymmetric Phase Transfer Catalysis Christabel Carter and Adam Nelson Introduction

Phase transfer catalysis is a powerful method for the acceleration and control of the selectivity of chemical reactions. An important development has been the use of chiral phase transfer catalysts to induce asymmetry in reactions involving anionic intermediates [ 11. The efficient transfer of stereochemical information between contacting ions is a challenging goal; nonetheless, some isolated examples of highly enantioselective phase-transfer catalysed reactions have been known for many years [ 2 ] . Recently, however, the structural features of cinchonidinium (1) and cinchoninium (2) salts which are necessary for effective asymmetric phase transfer catalysis have been unravelled [ 31. These salts have proved to be extremely versatile reagents for controlling the enantioselectivity of a wide range of synthetically important transformations.

1

2

a; R’ = Ph, R2 = H; X = CI b; R’ = 9-anthracenyl; R2 = allyl; X = Br c; R’ = 9-anthracenyl, R2 = H; X = CI d; R’ = 9-anthracenyl; R2 = Ph; X = Br e; R’ = 9-anthracenyl, R2 = H; X = Br f; R’ = p-CF3C&-, R2 = H; X = Br

Asymmetric Alkylation of Clycine Derivatives

Asymmetric alkylations of the glycine derivative 3 have become the standard by which chiral phase transfer catalysts are judged, and enable the preparation of a wide range of unnatural

126

I

Asymmetric Phase Transfer Catalysk 0

0

conditions BnBr

Ph

3

4

Scheme 1.

a-amino acids. A key discovery has been the realisation that the size of the R1 substituent of salts 1 and 2 has a profound effect on the enantioselectivity of alkylation of the glycine derivative 3 (Scheme 1, Table 1). The benzyl cinchoninium salt 2a induces a modest level of enantioselectivity in the reaction of 3 with benzyl bromide (entry 2, Table 1) [4]. Corey [3] and Lygo [5] have found that by changing the quaternary ammonium substituent to the bulkier 9-anthracenylmethyl group, good to excellent levels of enantioselectivity can be obtained, using either solid-organic or aqueous-organic biphasic systems (entries 3-5, Table 1). An important feature of this methodology is that the cinchonidinium salts 1 and the cinchoninium salts 2 induce almost equal levels and opposite senses of enantioselectivity (compare entries 1-2 and 4-5, Table 1). The symmetrical quaternary ammonium salts 5-6 have also been shown to be effective reagents for the enantioselective alkylation of the Schiff base 3 under mild phase-transfer conditions [6]. Although results with the Cz-symmetrical quaternary ammonium salt 5 were disappointing (entry 6, Table l),the more rigid spiro ammonium salts G were much more effective catalysts. The rate and enantioselectivity of the benzylation of 3 was found to depend critically on the substituent R. With the ammonium salt Gc (R = P-Np), the reaction was complete within 30 min at 0 "C (entry 9, Table 1) and gave the amino acid derivative 4 with 95% ee, whereas the unsubstituted catalyst Ga ( R = H) required a longer reaction time and gave 4 in only 79% ee (entry 7, Table 1).

Tab. 1. Asymmetric PTC alkylation of 3 with benzyl bromide

Entry

catalyst

mol%

1

la

10

2

2a

3

Temp, Time

Reagents

Solvent

Product

ee@)

Yield(%)

Ref:

25 "C, 9 hr

NaOH

CHzCl2H2O

(R)-2

66

75

4

10

25 "C, 9 hr

NaOH

CHzCl2~H20

(S)-2

64

85

4

lb

10

-78 "C, 23 hr

CH2C12

(R)-2

94

87

3

4

lc

10

25 "C, 18 h r

CsOH. H20 KOH

HzO-PhMe

(R)-2

89

63

5

5

2c

10

25"C, 1 8 h r

KOH

HzO-PhMe

(S)-2

91

68

5

6

5a

1

O0C,6hr

KOH

H2O-PhMe

(R)-2

21

34

6

7

Ga

1

O0C,6hr

KOH

HZO-PhMe

(R)-2

79

73

6

8

6b

1

0"C,0.5 hr

KOH

H2O-PhMe

(R)-2

89

81

6

9

Gc

1

0 " C , 0 . 5 hr

KOH

H20-PhMe

(R)-2

96

95

6

Introduction I 1 2 7

a&@% \

\

\

\

5a; R = Ph 5b; R = a-Np

/

R

B

r

\

/

\

6a; R = H 6b; R = Ph 6 ~R ;= P-Np 6d; R = 3,4,5-F~-Ph

Synthesis of Unnatural Amino Acid Derivatives by Asymmetric Alkylation

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the Cz-symmetrical quaternary ammonium salt 6d, have been reported: these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of u,a-dialkyl a-amino acids [8, 91. For example, benzylation of the Schiff base 10 gave the r-methyl phenylalanine derivative 11 in 92% ee (Scheme 3 ) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give u,cc-dialkyl a-amino acids in good enantiomeric excess [ 101.

1 mol% 6d CsOH.H20 ____)

toluene, -1 0 "C Me

8, 91% ee

7 BOC 70% Scheme 2.

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-cc-amino acids (Scheme 4) [ 111. Bis-amino acids, such as rneso-diaminopimelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. Asymmetric Alkylation of Other Enolates

The asymmetric alkylation of other prochiral enolates has also been studied, and good results have been obtained provided that the intermediate enolate is stabilised by conjugation. For example, the extended enolate derived from 15 has been trapped with a range of alkylating agents to give cc-alkylated esters such as 16 in 98% ee (Scheme 5) [ 121.

128

I

Asymmetric Phase Transfer Catalysis

1 mol% 9

0

CsOH.Hz0

Ph+N

OiPr

BnBr

Me

71Yo

Ph 11, 92% ee

10 Scheme 3.

KOH, 10 mol% l e

0

H20-PhMe ______)

Ph r"31,,,u Ph

tBuO

Br

0

3

Ph

14, >95% ee diast. ratio: 86:14

55%

Scheme 4.

10 mol% 3d M

e

2

N

v

O

t

B

u

P CsOH.Hz0 c

/

~

e

2

N

-~

$

/

\

NMep

15

81o/o

Ph \ I Me2N 16; 98% ee

Scheme 5.

Phh,,/OH

9

12

HO-Ph

17

u

Application Asymmetric Phase Transfer Catalysis t o Other important Reactions

Manabe has prepared the chiral quaternary phosphonium salt 17 with a multiple hydrogen bonding site; this salt accelerates the alkylation of the ketoester 18, giving products such as 19 with ca. 40% ee at room temperature (Scheme 6) [ 131.

-

0.2 mol% 17, BnBr

n

18

19; 40% ee

Scheme 6.

Application Asymmetric Phase Transfer Catalysis to Other Important Reactions

Chiral phase transfer catalysts have been exploited in a wide range of reactions which involve anionic intermediates. Remarkably, quaternary ammonium salts of 1 and 2 have been shown to induce asymmetry in many different synthetic reactions, and the cinchona alkaloids appear to be a “charmed’ template for the design of effective phase transfer catalysts [ 141. Asymmetric Michael Reactions

The enolate derived from the Schiff base 3 has been added to a$-unsaturated esters and ketones with a high level of enantioselectivity. For example, in the presence of 10 mol% lb, the enolate of the glycine derivative 3 was added to cyclohexenone with excellent diastereoselectivity to give the ketoester 20 with >99% ee (Scheme 7) [ 151. Promising results have also been obtained in the Michael additions of malonates to chalcone deriviatives [16]. The novel cinchonidinium bromide Ig was found to be the most effective catalyst for this transformation, yielding the Michael adduct 21 with 70% ee (Scheme 8).

CsOH.H20,3 10 mol% l b

b

O

tBu

CH2C12, -78 “C 88% Ph

20; 99% ee, 25:l d.r. Scheme 7.

P

h

d

P

h

21; 70% ee Scheme 8.

I

129

130

I

Asymmetric Phase Transfer Catalysis

Asymmetric Epoxidation Reactions

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [ 171. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [IS]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the cc,p-epoxyketone 28 in >99.5% ee (Scheme 10).

22

23

R = 9-Anthracenyl

24

(+)-25: 95%, 89% ee (cat. 22) (-)-25: 93%, 86% ee (cat. 23)

Scheme 9.

NHBOC

‘BuOOH, NaOH 25% 0

27

28, >99.5% ee

0 HO

Manumycin C, 26 Scheme 10.

A complementary approach to similar products involved the asymmetric Darzens reaction of cc-chloro ketones such as 29 with aldehydes. The cinchoninium salt 2f allowed the epoxide 30 to be prepared with reasonably high enantiomeric excess (Scheme 11) [ 191.

Application Asymmetric Phase Transfer Catalysis to Other lmportant Reactions

'BuCHO, LiOH.HzO " d p h

10 mol% 2f

29

BuzO, 4 "C 73%

-Ph

30,69% ee

Scheme 11.

Asymmetric Cyclopropanation Reactions

The enantio-determining step of nucleophilic additions to cc-bromo-cc,p-unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [ 2 0 ] . The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an cc-cyanosulfone [ 201.

32 Scheme 12.

Asymmetric Oxidative Cyclisation of 7,5-dienes

An exciting addition to the armoury of asymmetric phase transfer catalysed reactions has been the oxidative cyclisation of 1,s-dienes (Scheme 13) [21]. This tandem reaction process leads to the formation of tetrahydrofurans such as 35 in a single step from the open chain dienes 34. The step which determines the sense of asymmetry is the initial attack of permanganate anion, and this chiral information is efficiently relayed in the cyclisation to give products with three new stereogenic centres. For example, oxidation of the dienone 34 with potassium permanganate, catalysed by the salt 36, gave the tetrahydrofuran 35 in 72% ee.

KMn04, AcOH 10 mol% 36 F - H CHPCIZ,-30 "C 34

50%

35, 72% ee 36

Scheme 13.

I

131

132

I

Asymmetric Phase Transfer Catalysis

/-

alkvla tion

37

-lb

Fig. 1.

Rationalisation o f the Mechanism of Transfer of Stereochemical Information

Corey studied the X-ray crystal structures of cinchonidinium salts and has formulated a model which explains the highly enantioselective alkylation of the enolate of 3 [ 3 ] . This model accounts for the sense of asymmetric induction in this process and the importance of the size of the R' substituent in the salts 1 and 2; the model can be used to rationalise other phase transfer catalysed processes involving similar catalysts. The enolate 37 is thought to be in close contact with the least hindered face of the tetrahedron formed by the four atoms surrounding the quaternary nitrogen atom (the rear face of this tetrahedron is blocked by the bulky 9-anthracenylmethyl group). Alkylation of the less hindered face of 37 leads to the observed enantiomer of the product (see Figure 1). Summary

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantioselectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. References A. NELSON, Angew. Chemie., Int. Ed. Engl. 1999, 38, 1583-1585. 2 E. V. DEHMLOW, P. SINGH,J. HEIDER,]. Chem. Res. Synop. 1981, 292-293, and 1

3 4

references therein. E. J. COREY,F. Xu, M. C. NoE,]. Am. Chem. SOC.1997, 119, 12414-12415. M. J. O'DONNELL, W. D. BENNETT, S. Wu, ]. Am. Chem. SOC.1989, I 1I, 23532355.

B. LYGO, P. G. WAINWRIGHT, Tetrahedron Lett. 1997, 38, 8595-8598. 6 T. 001,M. KAMEDA, K. MARUOKA,]. Am. Chem. SOC.1999, 121, 65196520. 7 T. 001,M. TAKEUCHI, M. KAMEDA, K. MARUOKA,].Am. Chem. SOC.2000, 122, 5228-5229. a Y. N. BELOKON, M. NORTH,v. s. KUBLITSKI,N. S. IKONNIKOV, P. E. KRASIK, 5

References I133 V. I. MALEEV,Tetrahedron Lett. 1999,40, 6105-6108. 9 Y. N. BELOKON, R. G. DAVIES,M. NORTH, Tetrahedron Lett. 2000,41, 7245-7248. 10 Y. N. BELOKON, K. A. KOCHETKOV, T. D. A. A. CHURKINA, N. S. IKONNIKOV, 0. V. LARIONOV, V. S. CHESNOKOV, PARMAR,R. KUMAR,H. B. KAGAN, Tetrahedron: Asymmetry 1998,9, 851-857. 1 1 B. LYGO,J. CROSBY, J. A. PETERSON, Tetrahedron, 2001,57, 6447-6453. 12 E. J. COREY, Y. Bo, J. BUSCH-PETER SEN,^. Am. Chem. SOC.1998,120, 13000-13001. 13 K. MANABE,Tetrahedron Lett. 1998,39, 5807-5810. 14 K. KACPRZAK, J.GAWRONSKI. Synthesis, 2001,961-998.

15

16 17 18

19 20

21

E. J. COREY,M. C. NOE, F. Xu. Tetrahedron Lett. 1998,39, 5347-5350. D. Y. KIM, S. C. H U H , S. M. KIM, Tetrahedron Lett. 2001,42, 6299-6301. B. LYGO,P. G. WAINWRIGHT, Tetrahedron Lett. 1998,39, 1599-1602. L. ALCARAZ, G . MACDONALD, J. RAGOT, N. J. LEWIS,R. J. K. TAYLOR,Tetrahedron 1999, 55, 3707-3716. S . ARAI, T. SHIOIRI,Tetrahedron Lett. 1998, 39, 2145-2148. S. ARAI,K. NAKAYAMA, T. ISHIDA,T. SHIOIRI,Tetrahedron Lett. 1999,40, 4215-4218. R. C. D. BROWN,I. F. KELLY,Angew. Chem., Int. Ed. Engl. 2001,40, 44964498.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Asymmetric Catalytic Aminoalkylations: New Powerful Methods for the Enantioselective Synthesis o f Amino Acid Derivatives, Mannich Bases, and Homoall y k Am ines Michael Arend and Xiaojing Wang

The economical importance of enantiomerically pure compounds has grown considerably during the last years and will increase even further [ 11. Therefore, the development of efficient asymmetric syntheses using chiral catalysts is a main focus of modern industrial and basic research. As a result, there are meanwhile powerful asymmetric catalytic variants for many essential reactions [2]. However, until recently this did not include the important class of aminoalkylation reactions [ 31, if one leaves aside aminoalkylations of organometallic compounds such as Grignard, organolithium, or organozinc reagents catalyzed by chiral ligands (Lewis bases) [3c-d, 4, 51. Analogous attempts to activate and to chirally modify other nucleophiles such as ester enolates with chiral ligands (e.g., diether or aminodiether) [ 61, and to aminoalkylate them enantioselectively were only partly successful. These methods either require stoichiometric amounts of the chiral ligand or provide good enantioselectivities solely in special cases. However, the potential of chiral organocatalysts (i.e., metal-free catalysts) [ 71, for asymmetric aminoalkylation reactions is definitely not exhausted yet. Impressive examples are asymmetric variants of the Mannich reaction [S, 91 employing the cheap and readily available (S)-proline or related compounds as chiral catalysts [ 101. This approach provides among other things an easy and convenient access to the enantioselective synthesis of b-amino ketones 2 (Scheme 1) from acetone (large excess), various aldehydes 1 ( R = alkyl, aryl), and p-anisidine (1.1eq) [Sa]. The methodology also proved to be suitable for the regio-, diastereoand enantioselective aminoalkylation of ketones other than acetone furnishing Mannich bases such as 3 which can serve as valuable synthetic building blocks (Scheme 1) [Sa]. It is assumed that an (E)-enamine from (S)-prolineand the ketone and an (E)-imine from the aldehyde and p-anisidine are formed in situ. The enamine then selectively attacks the si-face of the imine (access to the corresponding re-face is limited by unfavorable steric interactions between the pyrrolidine and the aromatic ring) to allow protonation of its lone pair as shown in the transition state 4 depicted in Scheme 1 (i.e., proline activates both, the nucleophile and the electrophile: it hence acts as a bifunctional catalyst) [10a, l l a ] . Despite the fact that the method requires 35 mol% of the catalyst and a large excess of the ketone [Ilb], these results are quite remarkable. A modification of this methodology using the preformed, highly electrophilic imine 5 as the aminoalkylating agent [9] casts additional light on the scope and limitations of this approach. On the one hand, various aldehydes (1.5 eq)

Asymmetric Catalytic Aminoalkylations n

12-48 h, rt

I

1

2 R = alkyl, aryl 35-SO%, 70-96% ee n

Ty

OH

3 57%, dr = 17:1, 65% ee

4

5

Diastereo- and/or enantioselective aminoalkylation of ketones catalyzed by a chiral bifunctional organocatalyst [gal.

Scheme 1.

could be successfully aminoalkylated with imine 5 in the presence of 5 mol% proline (rt, dioxane, 2-24 h) furnishing the corresponding [{-amino aldehydes in good yields, excellent syn-diastereoselectivities (mostly 219:l) and enantioselectivities (mostly 299% ee) [ 9b]. However, on the other hand, in order to achieve similar results in the aminoalkylation of the less reactive ketones with imine 5 (rt, 2-24 h) [gal, a large excess of the ketone (the reactions were performed in DMSO/ketone = 4:l) and 20 mol% of the proline catalyst were used. Chiral organocatalysts also proved to be highly useful for the development of various asymmetric catalytic variants of the Strecker reaction [12, 131. An especially efficient and broadly applicable methodology is the aminoalkylation of HCN with N-ally1 or N-benzyl imines G in the presence of the imino peptide catalyst 7a [ 12d] developed by combinatorial methods (Scheme 2; for a closely related earlier publication, see: [12b]). The resulting aamino nitriles 8 were formed quantitatively with no detectable byproducts. However, losses occurred upon product isolation as a result of the need to separate the catalyst chromatographically. In order to avoid product losses the reaction was also performed using the polymer-supported imino peptide catalyst 7b, which could easily be removed by filtration and was recycled nine times without any significant loss of reactivity or product enantioselectivity. However, the ee values obtained with the polymer-supported catalyst 71, were about 2-4% lower compared to the use of the soluble catalyst 7a. Catalyst 7a was, among other

I

135

136

I

Asymmetric Catalytic Aminoalkylations

1) 2 mol% catalyst 7 , toluene, -70 "C, 20 h 2) ( c F 3 c O ) ~ o

N. R'

)I

+

R

6

0 F3

HCN

R = alkyl, aryl; R' = allyl, benzyl

cJy' R

CN

8

65-99%, 77-97% ee

Scheme 2.

Enantioselective variant of the Strecker reaction catalyzed by chiral organocatalysts [I Zd].

uses, also applied successfully in the aminoalkylation of N-benzyl ketimines (ArCOMe and tert-BuCOMe derivatives) employing similar reaction conditions ( 2 mol% catalyst, toluene, -75 "C, 15-90 h) to give the corresponding N-benzyl-a-amino nitriles in excellent yields (generally 297%) and good enantioselectivities (in most cases 290% ee, examples are given for enantioselectivities 299.9% ee after recrystallization) [ 12el. These are really noteworthy findings taking into account all the difficulties that usually occur in the construction of N-substituted quaternary carbon atoms by 1,2-addition of nucleophiles to ketimines [ 141. Attempts to aminoalkylate Me3SiCN or HCN with an imine derived from acetophenone and benzylamine employing chirally modified Lewis acids (10 mol%) as the catalyst generally gave lower ee values [ 151. Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [ 3b-d, 161. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be aminoalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., x-amino nitriles, a- or b-amino acid derivatives, homoallylic amines or p-amino ketones) [ 3b-d]. 9 (R = alkyl, aryl) together with chiral zirconium For example, N-(2-hydroxyphenyl)imines catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [ 171, the diastereo- and/or enantioselective synthesis of homoallylic amines [ 181, the enantioselective synthesis of simple p-amino acid derivatives [ 191, the diastereo- and enantioselective preparation of a-hydroxy-b-aminoacid derivatives [ 201 or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans,a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserinehydrochloride (10)

Asymmetric Catalytic Aminoalkylations

10 mol%

R’

OTB:S

9

-78 “C, 20 h, PhCH3

OTBS R = Ph

10

loo%, 95% ds, 94% ee

88%

Scheme 3.

Asymmetric catalytic aminoalkylation a s key step in the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10) [20]. TBS = tea-butyldimethylsilyl, L = 1,2dimethylimidazole, CAN = cerium ammonium nitrate.

depicted in Scheme 3 [20]. The advantages of the methodology include good yields and stereoselectivities, a broad scope, and also the fact that the N-(2-methoxyphenyl)-moiety is easily removed by oxidation with cerium ammonium nitrate (CAN). It should be noted however, that generally low reaction temperatures and/or relatively large amounts of the catalyst (often up to 10 mol%, in some cases up to 20 mol%) were required to achieve the aforementioned results [ 17-21]. Nevertheless, it has been shown impressively that these problems can be solved in principle by the design of improved chiral ligands and N-aryl moieties. An interesting example is the asymmetric synthesis of /I-amino esters 11 (Scheme 4) [22] with the key step performed highly enantioselectively at 100 “C in the presence of 2 mol% of a chiral (R)-VAPOL zirconium catalyst (the catalyst was generated from = (R)-VAPOL, and N-methyl Zr(OiPr).+, (R)-2,2’-Diphenyl-[3,3/]biphenanthrenyl-4,4’-diol imidazole = NMI). Additional related methods are direct asymmetric Strecker reactions employing aliphatic or aromatic aldehydes and 2-amino-3-methyl-phenol instead of the preformed imines 9 [ 17b-c], and enantioselective aminoalkylations of ketene acetals with N-4-trifluoromethylbenzoyl hydrazones [ 231. The imines 12 (X = 4-CH3-C6H4-S02(Ts), Ar, C 0 2 R , COR, etc.) preformed or generated in situ from N,O- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24]. A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b]. Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [ 24h, 251, and the diastereo- and/or enantioselective aminoalkyla-

I

137

138

I

Asymmetric Catalytic Aminoalkylations

OSiMe3

2 mol% Zr-catalyst

toluene, 100 "C, 5-24 h

HN

Ar 83-95%, 93.0-99.8% ee

lc

Ph Ph

AN

NH2

(4-VAPOL

11 59-79%0

Asymmetric catalytic aminoalkylation as key step i n t h e enantioselective synthesis of the p - a m i n o esters 11 [22]. CAN = cerium a m m o n i u m nitrate. Scheme 4.

"&(i X.

Ar

re3+ N

5 mol%, ML = CuC104

k.CO2Et

R

0

NHTs

RU C 0 2 E t 14

THF, 0 "C, 24 h

12

65-93%, 90-98% e e

Rk +

R'

15

R 2 C T s

13 0.1-1 mol%, ML = CuPF,

12

b

CH2CI2,0 "C, 22-60 h

R'

I

r C02Et

62-82%, 78-98% ee

Enantioselective catalytic aminoalkylation of silyl enol ethers [24b] and alkenes [24h, 251 w i t h imines 12 (X = Ts) a n d BINAP catalysts 13 (Ar = 4-MeC6H4). Scheme 5.

tion of numerous other nucleophiles such as allyl silanes [24c, 24h, 261, allyl stannanes [26], ketones [ 271, electron-rich aromatic compounds [ 281, trimethylsilyl nitronates [2Gb-c, 29a], nitroalkanes [ 2Gb, 29b], and alkyl radicals [ 301. The aforementioned aminoalkylations catalyzed by chirally modified Lewis acids employ special imino compounds such as 9 and 12 that can act as bidentate ligands and form

Asymmetric Catalytic Aminoalkylations

chelate complexes with the chiral Lewis acid catalysts. On the other hand, simple Mannich reagents usually furnish significantly lower enantioselectivities [ 24a, 311. One can easily explain this by the restriction of the configurational diversity in chelate complexes favoring a stereochemically uniform course of the reaction. However, it could be shown that in principle simple imines can be used successfully as well for asymmetric aminoalkylation reactions catalyzed by chiral Lewis acids. The asymmetric allylation of simple imines 16 with allyltributylstannane (Scheme 6) catalyzed by the /I-pinene derivative 17 [32a], for example furnished comparatively good results (for related asymmetric catalytic allylations of simple imines, see: [ 32b-d]). Moreover, it was demonstrated on the basis of several Strecker-typesyntheses [33-351 that catalysts such as the chiral aluminum complex 18 (Scheme 6) [ 33a-b] are also well suited for enantioselective aminoalkylations with simple imines. The mechanism indicated in Scheme 6 shows that the

DMF, 0 "C, 62-173 h

Ar

*

ArM

\

R = Pr, CH2Ar'

16

30-74%, 61-81% ee

CI

HN 20 mol% PhOH CH2CI2, -40 "C, 24-68 h 66-97%, 70-96% ee

8 Ph

19 Asymmetric catalytic arninoalkylation of allyltributylstannane [32a] and M e s S i C N [33a-b] with simple irnines.

Scheme 6.

I

139

140

I

Asymmetric Catalytic Aminoalkylotions

catalyst 18 acts in a bifunctional way (i.e., catalyst 18 activates both, the imine and the nucleophile) has been proposed to explain the selectivity and the broad scope of this method (the imines used in this study were derivatives of aromatic, heteroaromatic, aliphatic or qBunsaturated aldehydes). Additional interesting examples are the diastereo- and/or enantioselective aminoalkylation of nitroalkanes with N-phosphinoylimines catalyzed by chiral heterobimetallic complexes [ 361 and the asymmetric arylation of aromatic [ 37a], or qpunsaturated N-sulfonylimines [ 371 with arylstannanes catalyzed by chiral rhodium complexes. During the past few years impressive progress has been made in the field of catalytic asymmetric aminoalkylation. For example, the development of powerful bifunctional catalysts mimicking enzymes by activating both, nucleophile and electrophile and in addition controlling their orientation (e.g., see: 4 and 19; see also: [ 10, 12c, 33d, 34~1).Nevertheless, this chemistry is still in its infancy. An important reason for this is that the common techniques (even if they have been applied successfully to formally closely related reactions such as aldol additions) in many cases are only imperfectly or not at all applicable to aminoalkylations (e.g., see: [31]). Hence, the hitherto known methods for asymmetric aminoalkylation are mostly limited to special cases. Furthermore, they often require low reaction temperatures, relatively large amounts of the catalyst or long reaction times to give good yields or ee values. However, it can be assumed that in future both scope and efficiency of enantioselective aminoalkylations can be enhanced considerably by the development of more advanced tailor-made catalysts. There is no doubt that modern methodologies such as the design of chiral catalysts using combinatorial and evolution-based techniques will play a key role in this process [ 381. References and Notes For reviews, see: a) Chirality in Industry: The Commercial Manufacture and Applications of Optically Active Compounds (Eds.: A. N. COLLINS, G. N. SHELDRAKE, J. CROSBY), Wiley, Chichester, 1992; b) Chirality in Industry 11: Developments in the Commercial Manufacture and Applications of Optically Active Compounds (Eds.: A. N. COLLINS, G . N. SHELDRAKE, J. CROSBY), Wiley, Chichester, 1997; c) S. C. STINSON, Chem. Eng. News 2001, 79(40), 79. 2 For reviews, see: a) Comprehensive Asymmetric Catalysis (Eds.: E. N. J A C O B S E N , A. PFALTZ,H. YAMAMOTO), Springer, Berlin, 1999; b) Catalytic Asymmetric Synthesis (Ed.: I. OTmA), 2nd ed., Wiley-VCH, New York, 2000; c) H. TYE,J . Chem. Soc., Perkin Trans. 1 2000, 275; d) H. TYE,P. J. COMINA, J . Chem. Soc., Perkin Trans. 1 2001, 1729. 3 For reviews, see: a) M. AREND, B. WESTERMANN, N. RISCH, Angew. Chem. 1

1998, 110, 1097; Angew. Chem. Int. Ed. Engl. 1998, 37, 1045; b) M. AREND, Angew. Chem. 1999, 11 I, 3047; Angew. Chem. Int. Ed. Engl. 1999, 38, 2873; c) S. KOBAYASHI, H. ISHITANI, Chem. Rev. 1999, 99, 1069; d) S. E. DENMARK, 0. I.-C. NICAISEin Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN, A. PFALTZ, H. YAMAMOTO),Springer, Heidelberg, 1999, p. 923. 4 For reviews, see: a) N. RISCH, M. AREND, Methoden Org. Chem. (Houben- Weyl) 4th ed. 1952-, Vol. E21b 1995, p. 1833; b) S . E. DENMARK, 0. J.-C. NICAISE, Chem. Commun. 1996, 999; c) D. ENDERS,U. REINHOLD,Tetrahedron: Asymmetry 1997, 8, 1895; d) R. BLOCH,Chem. Rev. 1998, 98, 1407. 5 For two recent examples of asymmetric catalytic aminoalkylations of Reformatskytype reagents, see: a) Y. UKAJI,Y. YOSHIDA, K. INOMATA, Tetrahedron:

References and Notes

6

7

8

9

10

11

12

Asymmetry 2000, 11, 733; b) Y. UKAJI,S. TAKENAKA, Y. HORITA,K. INOMATA, Chem. Lett. 2001, 254. a) H. FUJIEDA, M. KANAI,T.KAMBARA, A. IIDA,K. TOMIOKA,].Am. Chem. SOC.1997, 119, 2060 b) T. KAMBARA, M. A. HUSSEIN, A. IIDA,K. TOMIOKA, TetraH. FUJIEDA, hedron Lett. 1998, 39, 9055; c) T. KAMBARA, K. TOMIOKA,).Org. Chem. 1999, 64, 9282; d) K. TOMIOKA, H. FUTIEDA, S. HAYASHI, M. A. HUSSEIN, T. KAMBARA, Y. NOMURA,M. KANAI,K. KOGA, Chem. Commun. 1999, 715; e) T. KAMBARA, K. TOMIOKA, Chem. Pharm. Bull. 1999,47,720; f ) M. A. HUSSEIN,A. IIDA,K. TOMIOKA, Tetrahedron 1999, 55,11219; g) T. KAMBARA, K. TOMIOKA, Chem. Pharm. Bull. 2000, 48, 1577. For a general review on asymmetric organocatalysis, see: P. I. DALKO,L. MOISAN,Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. Engl. 2001, 40, 372G. a) B. LIST,]. Am. Chem. SOC.2000, 122, 9336; for a closely related method using among other things the penicillamine derivative 5,5-dirnethylthiazolidine-4carboxylic acid as a chiral catalyst, see: b) W. NOTZ,K. SAKTHIVEL, T. BUI, C. ZHONG,C. F. BARBAS111, Tetrahedron Lett. 2001, 42, 199. a) A. CORDOVA, W. NOTZ,G. ZHONG,J. M. C. F. BARBAS 111,). Am. Chem. BETANCORT, SOC.2002, 124, 1842; b) A. CORDOVA, S. WATANABE, F. TANAKA, W. NOTZ, C. F. BARBAS111, J. Am. Chem. SOC.2002, 124, 1866. For reviews on the use of proline and related compounds as chiral catalysts for asymmetric syntheses, see: a) B. LIST, Synlett 2001, 1675; b) H. GROGER,J . WILKEN, Angew. Chem. 2001, 113, 545; Angew. Chem. Int. Ed. 2001, 40, 529. a) The transition state 4 depicted in Scheme 1 [ lOa] differs from the transition states postulating (2)-imineintermediates [8al proposed in the original publication; b) The reactions were performed in DMSO/ketone or CHC13/ketone = 4:l or the ketone was used as the solvent. a) M. S. IYER, K. M. GIGSTAD, N. D. NAMDEV, M. LIPTON,]. Am. Chem. SOC. 1996, 118,4910; b) M. S. SIGMAN,E. N. JACOBSEN,]. Am. Chem. SOC.1998, 120,

13

14

15

16

17

18

19

20 zi

4901; c) E. J. COREY,M. J. CROGAN, Org. P. Lett. 1999, 1, 157; d) M. S. SIGMAN, VACHAL, E. N. JACOBSEN, Angew. Chem. 2000, 112, 1336; Angew. Chem. In#. Ed. 2000, 39, 1279; e) P. VACHAL, E. N. Org. Lett. 2000, 2, 867; f ) B. JACOBSEN, LIU, X. FENG,F. C H E N G. , ZHANG,X. CUI, Y. JIANG,Synlett 2001, 1551. For recent reviews on modern variants of the Strecker reaction, see: a) D. ENDERS,J. P. SHIVLOCK, Chem. SOC. Rev. 2000, 29, 359; b) L. YET, Angew. Chem. 2001, 113, 900; Angew. Chem. Int. Ed. 2001, 40, 875. For a review, see: A. G. STEINIG, D. M. SPERO,Org. Prep. Proced. In#.2000, 32, 205. a) J. J. BYRNE, M. CHAVAROT, P.-Y. CHAVANT, Y. V A L L ~Tetrahedron E, Lett. 2000, 41,873; b) M. CHAVAROT, J. J. BYRNE,P. Y. CHAVANT, Y. V A L L ~ E , Tetrahedron:Asymmetry 2001, 12, 1147. For early publications on enantioselective aminoalkylations mediated by stoichiometric amounts of chiral Lewis acids, C. P. DECICCO,R. C. see: a) E. J. COREY, Tetrahedron Lett. 1991, 32, 5287; NEWBOLD, b) K. ISHIHARA, M. MIYATA,K. HATTORI, Am. Chem. SOC. T. TADA,H . YAMAMOTO,]. 1994, 116, 10520. a) H. ISHITANI,S. KOMIYAMA, S. KOBAYASHI, Angew. Chem. 1998, 110, 3369; Angew. Chem. In#. Ed. Engl. 1998, 37, 3186; b) H. ISHITANI,S. KOMIYAMA,Y. HASEGAWA, S. KOBAYASHI,]. Am. Chem. SOC.2000, 122, 762; c) S. KOBAYASHI, H. ISHITANI,Chirality 2000, 12, 540. T. GASTNER, H. ISHITANI, R. AKIYAMA, S. KOBAYASHI, Angew. Chem. 2001, 113, 1949; Angew. Chem. Int. Ed. 2001, 40, 1896. a) H. ISHITANI, M. UENO,S. KOBAYASHI,J. Am. Chem. SOC.1997, 119, 7153; b) H. ISHITANI, T. KITAZAWA, S. KOBAYASHI, Tetrahedron Lett. 1999, 40, 2161; c) S. KOBAYASHI,K. KUSAKABE,J . Org. Chem. 1999, 64, 4220; d) H . ISHITANI, M. UENO, S. KOBAYASHI.J. Am. Chem. SOC.2000, 122, 8180; e) S. KOBAYASHI, H. ISHITANI, Y. YAMASHITA,M. UENO,H. SHIMIZU, Tetrahedron 2001, 57, 861. S. KOBAYASHI, H. ISHITANI,M. UENO,]. Am. Chem. SOC. 1998, 120,431. S. F. MARTIN,0. D. LOPEZ,Tetrahedron Lett. 1999, 40, 8949.

I

141

142

I

Asymmetric Catalytic Aminoalkylations XUE,S. Yu, Y. DENG,W. D. WULFF, Angew. Chem. 2001, 113, 2331; Angau. Chem. Int. Ed. 2001, 40, 2271. S. KOBAYASHI, Y. HASEGAWA, H. ISHITANI, Chem. Lett. 1998, 1131. a) E. HAGIWARA, A. FUJII,M. SODEOKA,]. Am. Chem. SOC.1998, 120, 2474; b) D. FERRARIS, B. YOUNG, T. DUDDING,T. LECTKA,]. Am. Chem. SOC.1998, 120, 4548; c) D. FERRARIS, T. DUDDING, B. YOUNG, W. J. DRURY111, T. LECTKA,].Org. Chem. 1999, 64, 2168; d) D. FERRARIS, B. YOUNG, C. Cox, W. J. DRURY111, T. DUDDING, T. LECTKA,]. Org. Chem. 1998, 63, 6090; e) A. FUJII,E. HAGIWARA, M. SODEOKA,]. Am. Chem. SOC.1999, 121, 5450; for an example using polymer supported BINAP derived palladium catalysts, see: f ) A. FUJII,M. SODEOKA, Tetrahedron Lett. 1999, 40, 8011; g) D. FERRARIS. B. YOUNG,T. DUDDING, W. J. DRURY,T. LECTKA, Tetrahedron 1999, 55, 8869; h) D. FERRARIS, B. W. J. YOUNG, C. Cox, T. DUDDING, DRURY111, L. RYZHKOV, A. E. TAGGI,T. LECTKA,]. Am. Chem. SOC.2002, 124, 67; for an example using chiral copper complexes derived either from xylyl-BINAP or chiral diamines, see: i) S. KOBAYASHI, R. MATSUBARA, H. KITAGAWA,Org. Lett. 2002, 4, 143. a) W. J. DRURY111, D. FERRARIS, C. Cox, B. YOUNG, T. LECTKA,]. Am. Chem. SOC. 1998, 120, 11006; b) S . YAO, X. FANG, K. A. J B R G E N S E N , Chem. b n m U n . 1998, 2547. a) X. M. FANG,M. J O H A N N S E N , S. L. YAO, N. GATHERGOOD, R. G. HAZELL, K. A. JBRGENSEN, /. erg. Chem. 1999, 64, 4844; 17) Cl-symmetric bisoxazoline copper catalysts were used; c) a BINAP derived catalyst proved to be less suitable. K. JUHL, N. GATHERGOOD, K. A. J B R G E N S E N , Angew. Chem. 2001, 113, 3083; Angew. Chem. Int. Ed. 2001, 40, 2995. a) M. J O H A N N S E N , Chem. Commun. 1999, 2233; b) S. SAABY, X. FANG,N. GATHERGOOD, K. A. J B R G E N S E N , Angew. Chem. 2000, 112, 4280; Angew. Chem. Int. Ed. 2000, 39, 4114. a) K. R. KNUDSEN, T. RISGAARD, N. NISHIWAKI, K. V. GOTHELF, K. A. JBRGENSEN,]. Am. Chem. SOC. 2001, 123, K. R. K N U D S E N , 5843; b) N. NISHIWAKI,

22 S.

23 24

25

26

27

28

29

30 31

32

33

34

35

K. v. GOTHELF,K. A. JBRGENSEN, Angew. Chem. 2001, 113, 3080, Angew. Chem. rnt. Ed. 2001, 40, 2992. N. HALLAND, K. A. J B R G E N S E N , I. Chem. SOC.,Perkin Trans. 12001, 1290. a) S. YAMASAKI,T. IIDA,M. SHIBASAKI, Tetrahedron Lett. 1999, 40, 307; b) S . YAMASAKI, T. IIDA,M. SHIBASAKI, Tetrahedron 1999, 55, 8857. a) H. NAKAMURA, K. NAKAMURA, Y. YAMAMOTO,J. Am. Chem. SOC. 1998, 120. 4242; for a closely related method using H. allylsilanes, see: b) K. NAKAMURA, NAKAMURA, Y. YAMAMOTO,J . Org. Chem. 1999, 64, 2614; for intramolecular diastereo- and enantioselective asymmetric catalytic allylations of imines, see: c) J. Y. PARK,I. KADOTA, Y. YAMAMOTO,]. Org. Chem. 1999, 64, 4901; for the application of a polymer-supported chiral n-allylpalladium catalyst for the allylation of imines. Y. see: d) M. BAO, H. NAKAMURA, YAMAMOTO,Tetrahedron Lett. 2000, 41, 131. a) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI,M. SHIBASAKI, Angew. Chem. 2000, 112, 1716; Angew. Chem. Int. Ed. Engl. 2000, 39, 1650; b) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI, M. SHIBASAKI, Chem. Pham. Bull. 2000, 48, 1586; for enantioselective Strecker-type reactions promoted by related polymer supported bifunctional catalysts, see: M. KANAI, c) H. NOGAMI,S. MATSUNAGA, M. SHIBASAKI, Tetrahedron Lett. 2001, 42, 279; for a review on multifunctional asymmetric catalysis covering related M. examples, see: d) M. SHIBASAKI, KANAI, Chem. Pharm. Bull. 2001, 49, 511. For the use of bifunctional chiral imino peptide titanium catalysts identified by screening of parallel libraries, see: a) C. A. KRUEGER,K. W. KUNTZ,C. D. DZIERBA, W. G. WIRSCHUN, J. D. GLEASON, M. L. SNAPPER, A. H. HOVEYDA,].Am. Chem. SOC.1999, 121,4284; b) J. R. PORTER, W. K. W. KUNTZ, M. L. G. WIRSCHUN, SNAPPER, A. H. HOVEYDA, J . Am. Chem. SOC.2000, 122, 2657; c) N. S. J O S E P H S O H N , K. W. KUNTZ, M. L. SNAPPER, A. H. HOVEYDAJ.Am. Chem. SOC. 2001, 123, 11594. For the use of a chiral aluminum salen complex, see: M. S. SIGMAN,E. N.

References and Notes I 1 4 3 JACOBSEN, J .

Am. Chem. Soc. 1998, 120,

5315. 36 a) K. YAMADA,S. J. HARWOOD, H. GROGER,

M. SHIBASAKI, Angew. Chem. 1999, 111, 3713; Angew. Chem. Int. Ed. 1999,38, 3504; b) K. YAMADA,M. SHIBASAKI, Synlett 2001,980.

37

a) T. HAYASHI, M. ISHIGEDANI, J . Am. Chem. SOC.2000, 122, 976; b) T. HAYASHI, M. ISHIGEDANI, Tetrahedron 2001, 57,

2589. 38 For a general review, see: M. T. REETZ, Angew. Chem. 2001, 113, 292; Angew. Chem. Int. Ed. Engl. 2001,40, 284.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

IBX - New Reactions with an Old Reagent Thomas Wirth

Hypervalent iodine reagents have attracted increasing interest during the last decade because of their selective, mild, and environmentally friendly properties as oxidizing agents in organic synthesis [ 11. 2-Iodoxybenzoic acid (IBX, l-hydroxy-1,2-benziodoxol-3( lH)-one 1-oxide 1)was first reported in 1893 [2] but has been rarely used in reactions, probably due to its insolubility in most organic solvents [3]. Dess and Martin transformed IBX (1) into the much more soluble Dess - Martin periodinane (DMP, l,l,l-triacetoxy-l,l-dihydro-1,2benziodoxol-3(lH)-one 2) [ 3, 41, which has received much attention. Improved procedures for the synthesis of reagents 1 and 2 have been disclosed recently [ 51.

1 (IBX)

2 (DMP)

Fig. 1.

The broad functional group tolerance of these reagents and high-yielding reactions without over-oxidation have made DMP (2) very prominent for the oxidation of alcohols to the corresponding carbonyl compounds. But IBX (1)in DMSO was also found to be a highly efficient reagent for the clean oxidation of alcohols 3 to carbonyl compounds 4 even in the presence of thioethers or amines [6, 71 (the number of reported examples are given below the arrows here and in the following). It is also possible to selectively oxidize 1,2-diols to 1,2diketo derivatives without oxidative cleavage of the glycol C-C bond [ 6, 81. The selective oxidation of 1,4-diols 5 to the corresponding y-lactols 6 can also be realized [9]. Recently, the research groups of Giannis and Rademacher have published independently polymer-supported IBX-reagents of type 7 [lo, 11).These reagents on solid support can be used with similar efficiencies to IBX for the oxidations of alcohols, but other functionaliza-

ISX

1 (IBX)

OH

A-

DMSO

A

R k 0 I - l

78-98% 15 examples

DMSO 1 (IBX)

60-93%

5

5 examples

7

Reactions with an Old Reagent

.

.

6

8

Scheme 1.

tions highlighted later in this article can be achieved only with much lower yields. The synthesis of a water soluble IBX derivative 8 has been reported as well [ 121. This reagent is able to perform the alcohol to carbonyl conversion in pure water or in aqueous solvent mixtures with very good yields. The first step in these oxidation reactions is a fast pre-equilibrium, which can be formally considered as ligand exchange (hydroxy - alkyloxy) on the iodine atom. The product 9 then disproportionates to the carbonyl derivative 4 and the iodosoarene 10 (IBA) [ 8).

3

1 (IBX)

9

A 4

I

-.RoH

- New

+ 10 (IBA)

Scheme 2.

The known paths for the oxidation of alcohols have been extended by recent reports utilizing IBX (1)and DMP (2) [13] in other transformations. The introduction of an cc,jl-double bond into carbonyl compounds is sometimes a challenging transformation, which is pre-

145

146

I

IBX

- New Reactions with an Old Reagent

dominantly performed by using selenium or palladium reagents. A ligand exchange on IBX with the ketone-enolate might be involved as a key step and a subsequent SET is postulated in the mechanism of this new and general procedure. Although the reaction proceeds only at elevated temperatures (65-85 "C, conditions l), even acid-labile carbonyl compounds can be employed in the process, from which derivatives 11are obtained in good yields [14]. Recently it was found that the reactivity profile of IBX can be modulated by ligand complexation. Various IBX ligand adducts are known and used for different transformations. The IBX. NMO (NMO: N-methylmorpholine-N-oxide) adduct can be used for the dehydrogenation of aldehydes and ketones to the a$-unsaturated carbonyl compounds 11 at room temperature (conditions 2) [ 151. A reaction employing the corresponding trimethylsilylenol ethers as substrates has been published recently [ 161.

0

;? .--. '\.

*

0

+

[q '.--.' ,

<

11

'\

'---*'

*

,

'---*'

*

conditions 11141 1 (IBX), to1uene:DMSO 2:l 65-85"C, 3-72 h 40-89%, 29 examples conditions 2 [15]: IBX . NMO, DMSO 25"C, 15-48 h 43-96%, 17 examples

conditions I1 61: IBX . NMO, DMSO 25"C, 0.3-6 h 43-96%, 13 examples

11 Scheme 3.

Even alcohols can be converted to a$-unsaturated carbonyl compounds directly by using an excess of IBX (l),as shown in the oxidation of the phenylalanine derivative 12 to 13. The involvement of an aldehyde-enolate as a ligand on IBX has also been postulated in a first oxidative C-C bond cleavage reaction using IBX. N-Protected amino alcohols 14 have been oxidized with IBX in DMSO to the corresponding imides 15 [17]. Although hypervalent iodine compounds are often used as oxidants and sometimes as electrophilic reagents, the cyclization of aryl-substituted unsaturated amines to heterocycles 19 is started by a single-electron transfer (SET) reaction. Either 1 or an IBX THF adduct serves as the oxidant to initiate the heterocyclization by a SET process. The subsequently generated N-centered radical will then cyclize in a 5-exo-trig manner to yield, after hydrogen abstraction from the solvent, heterocycles of type 19. The cyclization of amides to y-lactams offers the possibility to synthesize even a variety of annelated heterocyclic compounds. The IBX-mediated cyclization of (thio)carbamates and ureas to (thio)oxazolidinones and cyclic ureas can be followed by hydrolysis to synthesize, for example, 1,2-aminoalcohols of type 20 [MI.The fast access to the carbamate starting materials by adding allylic alcohols to isocyanates allows the rapid generation of compound libraries [ 191.

ISX

PhyC02Me

2.5 eq. 1 (IBX)

- New Reactions with an Old Reagent

phyCoPMe

65 "C, 12 h 86%

12

%,\ ,

13

NHBoc

2 eq. 1 (IBX) DMSO

R

75 "C, 5 h 63-68%, 3 examples

14

15

Scheme 4.

The mechanism of this transformation has been investigated in detail. Although amide radicals have already been employed in cyclization reactions [20], their involvement in the IBX-mediated reaction has been proven by a detailed analysis [18b]. It was concluded that the irreversible SET from the aryl moiety to the IBX . THF adduct is the rate-determining step of the reaction and can only proceed with a free ortho-position in the substrate as shown in the mesomeric structures 17 and 18.

,: H N Ar'

1 (IBX) THF:DMSO

, .

,,--

< - -

,

%

I

hydrolysis

(1O:l)

H

9O"C, 24h

16

J

NH OH

X

y0

Scheme 5.

Ar/

(x=CHZ,0,NR~ Ar"y

0 70-95% 29 examples

1. l*THF (SET) 2. -H+

-

Y

19

t

1. cyclisation 2. Ha -abstraction

20

I

147

148

I

IBX - N e w Reactions with an Old Reagent

On the basis of this reaction mechanism, a process for the oxidation of the benzylic position has been developed. This reaction is quite general and proceeds with an excess of 1 at higher temperatures. Over-oxidation of compounds 21 with R' = H to the corresponding carboxylic acids was not observed, and the yields of ketones or aldehydes 22 even with labile substrates were generally quite high [ 211.

6 7.

R

21

1 (IBX) DMSO

52-95% 22 examples

R

22

(R' = H, alkyl)

Scheme 6.

To show the selectivity and controllability of these IBX-mediated reactions, substrate 23 was synthesized and converted in a series of steps to compound 27. The cyclization reaction 26 + 27 must not necessarily be the last step in the sequence.

HO

24

23

3 eq. 1

DMSO 90 "C,2 h 76%

0

OHC

2.2 eq. 1 THF:DMSO(10:1)

,j

OHC

26 Scheme 7.

25

27

References I 1 4 9

IBX can also be used to oxidize phenols to ortho-quinones at room temperature. A variety of phenols 28 has been converted to the corresponding ortho-quinones 29 in good yields [22]. 1 eq. 1 (IBX) CDCl3 or d7-DMF X

Y

1.5-53 h, 16-99% 11 examples

--&. X

28

Y

29

Scheme 8.

AS shown recently in the hydrolysis of phosphonofluoridates, 1 can also be used as a catalyst with oxone being the stoichiometric oxidant [23]. IBX (1) is able to oxidize thiols selectively to the corresponding disulfides [24]. It can also be used as a versatile reagent for the cleavage of oximes and tosylhydrazones to the corresponding carbonyl compounds [ 251. The first attempts to synthesize chiral reagents derived from IBX have appeared, although the selectivities obtained in the sulfide oxidation are low (up to 16% ee) [26]. The further development of electronically modified IBX reagents [ 271 to tune electron transfer processes, their application to new reactions, and the synthesis of efficient polymer-bound IBX [28] for rapid combinatorial chemistry will undoubtedly be reported in literature in the near future.

References 1 a) A. VARVOGLIS, Hypervalent Iodine in

Organic Synthesis, Academic Press, London, 1997 b) T. WIRTH, U. H. HIRT, Synthesis 1999, 1271-1287. 2 C. HARTMANN, V. MEYER,Chem. Ber. 1893, 26, 1727-1732. 3 D. B. DESS,J. C. MARTIN,J. Am. Chem. SOC. 1991, 113, 7277-7278. 4 D. B. DESS,J. C. MARTIN,]. Org. Chem. 1983, 48,4155-4156. 5 IBX: a) M. FRIGERIO,M. SANTACOSTINO, S. SPUTORE, J. Org. Chem. 1999, 64,4537L. J. LIU, J . 4538;DMP: b) R. E. IRELAND, Org. Chem. 1993, 58,2899;c) S. D. MEYER, S. L. SCHREIBER, /. Org. Chem. 1994, 59, 7549-7552;Caution! IBX and DMP are explosive under impact or heating >200 "C: d) J. B. PLUMB,D. J. HARPER, Chem. Eng. News 1990, 68(29),3. 6 M. FRIGERIO, M. SANTAGOSTINO, Tetrahedron Lett. 1994, 35, 8019-8022. 7 M. FRIGERIO, M. SANTACOSTINO, S.

SPUTORE,G. PALMISANO, J. Org. Chem. 1995, 60, 7272-7276. 8 With DMP 1,2-diolsare cleaved at the C-C bond: S. DE MUNARI,M. FRIGERIO,M. SANTAGOSTINO, I. Org. Chem. 1996, 61,

9272-9279. a) E. J. COREY,A. PALANI,Tetrahedron Lett. 1995, 36, 3485-3488;b) E. J.COREY,A. PALANI,Tetrahedron Lett. 1995, 36, 79457948;1,5-Diols can also be converted to lactols: c) J. M. BUENO,J. M. COTERON, J. L. CHIARA,A. FERN~NDEZ-MAYORALAS, j. M. FIANDOR,N. VALLE,Tetrahedron Lett. 2000, 41,4379-4382;d) J. ROELS,P. METZ, Synlett 2001, 789-790. 10 M. MULBAIER, A. GIANNIS,Angew. Chem. 2001, 113,4530-4532;Angew. Chem. Int. Ed, 2001, 40,4393-4394. 11 G. SORG,A. MENGEL, G. JUNG,J. RADEMANN, Angew. Chem. 2001, 113, 4532-4535;Angew. Chem. Int. Ed. 2001, 40,4395-4397. 9

150

I

IBX - New Reactions with an Old Reagent 12 A. P. THOITUMKARA,T. K. VINOD, 13

14

15

16

17

18

19

Tetrahedron Lett. 2002, 43, 569-572. a) K. C. NICOLAOU, Y:L. ZHONG,P. S. BARAN, Angew. Chem. 2000, 112, 636-639; Angew. Chem. Int. Ed. 2000, 39, 622-625; b) K. C. NICOLAOU,K. SUGITA,P. S . BARAN,Y.-L. ZHONG,Angew. Chem. 2001, 113, 213-216; Angew. Chem. Int. Ed. 2001, 40, 207-210; c) K. C. NICOLAOU, Y.-L. ZHONG,P. S. BARAN.K. SUGITA,Angew. Chem. 2001, 113, 2203-2207; Angew. Chem. Int. Ed. 2001, 40. 2145-2149. K. C. NICOLAOU, Y.-L. ZHONG,P. S. BARAN, / . A m . Chem. SOC.2000, 122, 7596-7597. K. C. NICOLAOU, T. MONTAGNON, P. S. BARAN,Angew. Chem. 2002, 114, issue 6; Angew. Chem. Int. Ed. 2002, 41, issue 6. K. C. NICOLAOU,T. MONTAGNON, D. L. F. GRAY,S. T. HARRISON, Angew. Chem. 2002, 114, 1035-1038; Angew. Chem. Int. Ed. 2002, 41, 993-996. G. CABARROCAS, M. VENTURA, M. J. M A H ~ AI. , M. VILLALGORDO, MAESTRO, Tetrahedron:Asymmetry 2001, 12, 18511863. a) K. C. NICOLAOU, Y.-L. ZHONG,P. S . BARAN,Angew. Chem. 2000, 112, 639-642; Angew. Chem. Int. Ed. 2000, 39, 625-628; b) K. C. NICOLAOU, P. S . BARAN,R. KRANICH,Y.-L. ZHONG,K. SUGITA,N. Z o u , Angew. Chem. 2001, 113, 208-212; Angew. Chem. Int. Ed. 2001, 40, 202-206. K. C. NICOLAOU,P. S. BARAN,Y.-L. ZHONG,1. A. VEGA,Angew. Chem. 2000,

20

21

22

23

24

25 26

27

28

112, 2625-2629; Angew. Chem. lnt. Ed. 2000, 39, 2525-2529. a) J. L. ESKER,M. NEWCOMB,Tetrahedron Lett. 1993, 34, 6877-6880; b) B. GIESE,B. KOPPING,T. GOBEL,J. DICKHAUT,G . THOMA,K. 7. KULICKE, F. TRACH, Org. React. 1996, 48, 301-856. K. C. NICOLAOU, P. S. BARAN,Y.-L. Z H O N G , ~Am. . Chem. SOC. 2001, 123, 3183-3185. D. MAGDZIAK, A. A. RODRIGUEZ, R. W. VAN DE WATER,T. R. R. PEITUS, Org. Lett. 2002, 4, 285-288. C. A. BUNTON,H. 7. FOROUDIAN, N. D. GILLIIT,/. Phys. Org. Chem. 1999, 12, 758764. R. A. Moss, H . MORALES-ROJAS, H. ZHANG,B. PARK,Langmuir 1999, 15, 2738-2744. D. S. BOSE,P. SRINIVAS,Synktt 1998, 977-978. V. V. ZHDANKIN, I. T. SMART,P. ZHAO, P. KIPROF,Tetrahedron Lett. 2000, 41, 5299-5302. a) A. R. KATRITZKY, B. L. DUELL,H. D. DURST,B. L. KNIER,/. Org. Chem. 1988, 53, 3972-3978; b) V. V. ZHDANKIN,R. M. ARBIT,B. J. LYNCH,P. KIPROF,/. Org. Chem. 1998, 63, 6590-6596.

For the reduction and quantitative removal of iodine species after IBX oxidations by a thiosulfate resin, see: 1. I. PARLOW,B. L. CASE,M. S. SOUTH,Tetrahedron 1999, 55, 6785-6796.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I151

Parallel Kinetic Resolutions Jason Eames

The continuing development of new resolution procedures within Organic Synthesis is still an important area [ 11. Traditionally, kinetic resolution involves separating a racemic mixture of two enantiomeric substrates (A and A’) using a single chiral reagent to give two enantiomerically enriched derivatives ( P or P’) (Scheme 1) [2]. For resolution to occur the reaction rates must be unequal ( k A # kA8) and for efficiency the reaction must be stopped at some stage before completion [2]. Theoretically, when only one enantiomer reacts (e.g., A) with a chiral reagent B, it can lead to a maximum of 50% product P (derived from A) and 50% recovered A’, both of which are enantiomerically pure. For such selectivity to occur, the selectivity factor s ( k A / k A I ) needs to be greater than 200 [2]. This required selectivity is generally above that of most chemical kinetic resolutions, and even for some enzyme-based processes [ 31. Due to this selectivity difference, further problems can arise due to the buildup of the less reactive enantiomer having a much greater concentration than the more reactive enantiomer A due to its preferential removal. As a result of this, as the resolution approaches completion, both enantiomers react equally due to a balance between this inherent rate and available concentration [ 21. One way of preventing the concentration effect of this less reactive enantiomer A’ being dominant near the end of the resolution is to remove it in parallel using a complementary Kinetic Resolution

Parallel Kinetic Resolution chiral

-

reagent B kA#kA#

enantiomeric products are formed Scheme 1.

kA=kA!

different products are formed

152

I

Parallel Kinetic Resolutions

reagent C to form Q during the course of the resolution (Scheme 1).Ideally, the rate needs to be similar to that of the other enantiomer. This has lead to a new strategy termed Parallel Kinetic Resolution (PKR) [4].The theory of this concept has been around for sometime [ S ] , and it has been shown that the selectivity factor s can be significantly lower for a parallel resolution than that of a tradition kinetic resolution to achieve the same result; for example, an s factor of 49 corresponds to that of a kinetic resolution with an s factor of 200, where the products are isolated in 49% (out of a maximum 50%) in 96% ee. One of the first reports [GI using this PKR strategy involved the use of a stereorandom substitution reaction to remove the unwanted less reactive enantiomer (Scheme 2). Faber [ 61 has demonstrated that enantioselective hydrolysis of the racemic epoxide ( rac)-1 can occur using the Rhodococcus sp immobilized enzyme (SP 409) giving the diol (S)-2 in a modest 40%yield with a modest 72% enantiomeric excess (Scheme 2). They have further shown that conducting the reaction in the presence of an additional non-natural nucleophilic azide (N;) increased the enantiomeric excess of this diol (S)-2 to >90% ee. It appears that this additional nucleophile (Ny)removes the less reactive (Qenantiomer 1 by a non-catalyzed S N ~ reaction to give the azide alcohol (R)-3 in around 60% ee. The lower ee for this alcohol is not unusual due to the reaction being uncatalyzed and clearly the azide reacts equally with both enantiomers of epoxide 1 , but preferentially with ( R ) - l due to its higher concentration. A superb example illustrating this PKR strategy has been developed by Vedejs [4] using a chiral DMAP acyl transfer reaction involving two quasi-enantiomeric pyridines (R)-4and ( S ) 5 (Scheme 3). Activation of these pyridines (R)-4 and (S)-5 with a hindered chloroformate 6 and (+)-fenchyl chloroformate 7 gave the acyl transfer agents 8 and 9, both of which have previously been shown to have opposite and complementary stereocontrol. The alkyl substituent of these chloroformates is very important, since it is transferred to the resolved alcohol, and is obviously different to enable product separation. The fact that the fenchyl group in 9 is chiral it is assumed to be irrelevant to the selectivity. Addition of equimolar amounts (1.1 mol equivalent) of the separately formed pyridinium salts 8 and 9, combined with an excess of MgBr2 and EtsN to a solution of racemic 1-(1-naphthy1)ethanol(rac)-10 (1 mol equivalent) gave the mixed carbonates 11 in 46% yield (>88% ee) and 12 in 49% yield (95% de). Separation was made much simpler by treatment of the mixture with Zn in acetic acid (which chemoselectively removed the trichlorobutyl protecting group) to give the more separable resolved alcohol (S)-10 and the fenchyl carbonate 12. The stereoselectivity was excellent, both mixed carbonates were isolated in near perfect yield and enantiomeric excess. These quasi-enantiomeric chiral DMAP equivalents (R)-4 and (S)-5 have additionally been shown to be fully recyclable. Vedejs has extended this idea even further by using two unrelated complimentary reagents [7, 81; the chiral phosphine 14 and the purified crosslinked lipase (ChiroCLEC)16 to serve as the acyl transfer catalyst (Scheme 4). This catalytic adaptation [7] was achieved by ensuring both reagents 14 and 16 ignore their complimentary activating reagent 17 and 13 respectively. This was achieved using an insoluble polymeric mixed carbonate 13 (to activate the phosphine 14) and an organic soluble vinyl pivalate 17 (to activate the insoluble lipase ChiroCLEC 16). This use of a triphasic reaction is an elegant way of ensuring that the activated P-acylphosphonium carboxylate 15 does not come into contact with the other cornplementary reagent, lipase ChiroCLEC 16. Addition of racemic 1-(naphthy1)ethanol (rac)-lO to a solution of carbonate 13, phosphine 14, ChiroCLEC 16 and vinyl pivalate 17 gave the ( R ) -

Scheme 2.

less reactive enantiomer removed

(R)-3;60% ee

*

*

Tris-buffer N3-

SP 409

Tris-buffer

SP 409

(9-2;>90% ee

( S ) - 2 ;72% ee; 40%

154

I

Parallel Kinetic Resolutions

NMe2

NMez

I

I

1 Hco:, chloroformate (+)-fenchyl

NMe2

NMez

I

I

0

I

8

Np

A.

t-Bu

0 dBn

9

Et3N (3 eq.) MgBr2 (2.25 eq.)

Zn, AcOH Me

Np = 1-naphthyl

H

x

HO

+ NP

(S)-lO

Ax H0 0

12

H

0

Me NP

Scheme 3.

enantiomer in the form of an ester 19 (97% ee) and the (S)-enantiomer as a polymeric ester (S)-lO - simple filtration and cleavage with Bu4NOH in THF gave the required (S)-l(naphthy1)ethanol 10 in 92% ee. Both of these products, (S)-10 and (R)-19 were isolated within 2% of their theoretical enantiomeric excess [8]. Goti, Brandi, and co-workers have investigated this PKR strategy using two quasienantiomeric dihydropyrans 21 and 22 as complimentary reagents (Scheme 5) [ 91. They have shown that under a traditional kinetic resolution procedure the racemic syndihydroxypyrroline N-oxide 23 can be partially resolved using a 1,3-dipolar cycloaddition

Parallel Kinetic Resolutions

13

I

- MstlO’

15

mod( ChiroCLEC

18

16

(R)-10

(S)-10

16,17 0

II

I

13,14

OH

0

THF

+&

(R)-19; 97% ee

(S)-20

(S)-lO; 92% ee

Scheme 4.

to give the recovered 23 enantiomer in either configuration with a modest enantiomeric excess (37-43%) depending on which dihydropyran used. In the parallel kinetic resolution experiment - racemic nitrone 23 was treated with a slight excess of the two dihydropyrans 21 and 22, both of which displayed complementary selectivity and thus afforded two distinct and separable adducts 24 and 26. Since the two competing reactions have similar rates, maintenance of the optimum S0:50 substrate ratio was achieved, and therefore the maximum inherent selectivity was preserved throughout. These exo-adducts 24 and 26 were formed exclusively derived from the ‘matched’ interactions in an expected 5050 ratio by a 1,3-dipolar cycloaddition on the more electon rich bottom-face of the dihydropyran. No minor diastereoisomeric adducts 25 and 27 were observed, indicating that a near perfect match in their relative rates were achieved. These adducts were further converted into quasienantiomeric imino-C-disaccharides [ 91. These reports into the use of a PKR strategy have relied on an additional complementary reagent C to remove the less reactiue enantiomer (Scheme 6). However, this need not be the

I

155

Scheme 5.

O x 0

(3S,4R)-23

(3R,4S)-23

00

O x 0

H e H +

?a

26; 29%

AcO

24; 34%

22(1.5equiv.)

21 (1.5 equiv.)and

AcO

..

24: 23%

I bottom face preferred I

..

27; 7%

25; 10%

AcO

e

H

26; 24%

O X 0 (3R,4S)-23 32%ee; 43%

H@H

00

O x 0 (3S,4R)-23 37% ee; 34%

H

?@

Parallel Kinetic Resolutions

I

157

case if a single chiral reagent B allows two distinct pathways; one for one enantiomer and one for the other enantiomer to give two distinct products P and Q [lo]. As long as their reaction rates are equal; all conditions for a PKR strategy are satisfied. This has lead to a new strategy termed Divergent Kinetic Resolution [ 11, 121 ( DvKR) (Scheme 6). Parallel Kinetic Resolution

Divergent Kinetic Resolution

chiral

chiral

pF* p

iQ chiral reagent B kA=kA’

different products are formed

different products are formed

Scheme 6.

One of the first examples to illustrate the usefulness of this strategy surfaced in the intramolecular cyclopropanation of racemic secondary allylic diazoacetates (Scheme 7) [13]. Treatment of (rac)-28 with the catalyst Rh2(4S-MEOX)429 gave the tricyclic ketone (lS,2R,GS)-30in 40% yield with an enantiomeric excess of 94%. Surprisingly, the byproduct which accounted for the fate of the other enantiomer (R)-28 gave the 2-cyclohexenone 31 which was formed via an intramolecular hydride abstraction with subsequent ketene loss. Furthermore, it has been shown that the chiral catalyst selectively removes just one enantiomer in the resolution by converting it into the ketone and consequently the concentration effect is removed. Both enantiomers of the catalyst are available, and thus either enantiomer of the tricyclic ketone 30 can be synthesized efficiently. It is also worthy of note that under a mutual kinetic resolution - by using (rac)-28 gives exclusively (lSR,2RS,GSR)-30in near perfect yield without formation of the byproduct cyclohexanone 31 which is due to the complementary recognition. Deng has recently reported [ 141 the use of a modified cinchona alkaloid (DHQD)zAQN 32 as a nucleophilic catalyst to resolve a series of succinic anhydrides (Scheme 8). This catalyst (DHQD)2AQN32 was used in a sub-stoichiometric quantity (10 mol%) and was shown to be particularly selective in controlling the reaction pathway for each enantiomer of substrate; for example the (S)-enantiomerof 2-methyl succinic anhydride 33 preferred to react at its more hindered carbonyl group [to give the monosubstituted succinic ester (S)-34],whereas the (Qenantiomer reacted preferentially at the less hindered carbonyl group to give complementary separable product, (R)-35. As long as each enantiomer of the racemate (rac)-33 react at an equal rate, but with opposite regiocontrol all conditions of the parent PKR strategy are satisfied. The overall selectivity was found to be influenced by the structural nature of the alcohol (ROH). Increasing the size of the primary alcohol from MeOH to both EtOH and PrOH moderately increased the enantiomeric excess up to 82% for 34 (Scheme 8, entries 1, 2, and 3). However, by using a slightly more sterically demanding secondary alcohol like

158

I

Parallel Kinetic Resolutions

0

+

v

0

6f +

m

(S)-34

0

Scheme 8.

HO

RO?Me

O (S)-33

0

0

I

+

+ (R)-35

0

M e t : :

ROH, Ether

Me0

/

"

\/

-25

25

25

(DHQD)2AQN 32

-

/ \

/

91

4456

o /

85

-

-

49:5 1

81

4555

82

OMe

80

12

-

12

67

xgog

CF3CH20H

i-PrOH

(DHQD)2AQN 32 (10 mol%) 6

4

CF3CH20H

0 5

(R)-33

Me$

25

4951

n-PrOH

61

(R)-35;% ee

3

14

(S)-34; % ee

EtOH

39:61

25 25

2

(S)-34:(R)-35

Temp./'C

MeOH

ROH

1

Entry

160

1

Parallel Kinetic Resolutions

i-PrOH completely prevented the reaction from occurring (Scheme 8, entry 4). By increasing the steric demand of the alcohol at the p-position (by using trifluoroethanol) allows the reaction to occur with good stereocontrol (Scheme 8, entry 5) and with near perfect regiocontrol. This stereocontrol can be further improved to 91% ee by conducting the reaction at a slightly lower temperature (Scheme 8, entry 6). Further improvements in the stereocontrol were achieved by changing the substitution pattern of the succinic anhydride; 2-phenyl succinic anhydride (rac)-36gave the best control giving the monosubstituted succinic ester (R)-37 and (S)-38in 95% ee and 85% ee respectively (Scheme 9). Simple chemoselective reduction gave the corresponding y-lactones ( R)-39 and (S)-40in similar enantiomeric purity. 0

0

(10 mol%)

CF3CHlOH 0

(rac)-36

Ether, -24OC

*

FBCHPCO

0

( 0 3 8 ; 85% ee

(R)-37;95% ee

1

LiHNEt3 then H30+

(R)-39 44%; 95% ee

(S)-40 32%; 82% ee

Scheme 9.

Pineschi and Feringa have also used this DvKR strategy to resolve a series of vinyl epoxides using their phosphoramidite (R,R,R)-41as the chiral pro-catalyst (Scheme 10) [11, 151. Treatment of racemic vinyl epoxide 42 with an excess of diethyl zinc (1.5 equiu.) in the presence of the catalyst [prepared in-situ from [Cu(OTf)2](1.5 mol%) and phosphoramidite (R,R,R)-41( 3 mol%)] gave the homoallylic alcohol 43a in 99% ee [by S N catalysed ~ epoxide ring opening of (3R,4S)-42]and the complementary allylic alcohol 44a in 80% ee (formed by S N ~addition ’ to the vinyl epoxide (3S,4R)-42)[ 111. Clearly, this catalyst (R,R,R)-41efficiently controls the reaction pathway for both enantiomers of the vinyl epoxide (rac)-42,thus giving the two positional products in near perfect ratio (SN2&2’ 45:55). The structural nature of the dialkyl zinc reagent was found to be important factor in improving the enantiomeric excess of the allylic alcohol 44. The use of a less sterically demanding dimethyl zinc appears to be slightly more stereoselective towards sN2‘ addition of the epoxide 42 than using diethyl zinc; e.g., 44b was formed in 96% ee, whereas, 44a was formed in 80% ee.

Parallel Kinetic Resolutions

+ N

I

161

162

I

Parallel Kinetic Resolutions

Cook has similarly reported a palladium-mediated regio-divergent kinetic resolution of a racemic 5-vinyloxazolidinone45 (Scheme 11) [ 121. This study was prompted by the discovery that the chiral ligand associated with the catalyst was responsible for the regiochemical outcome of a phthalimide addition to (S)-45. Potassium phthalimide displacement of the carbamate group (within the oxazolidinone ring) mediated by the palladium( O ) / ( R)-BINAP catalyst gave the allylic phthalimide (S,S)-46with a trace of the other regioisomeric phthalimide (S)-47[ratio 20:1]. However, using the (S)-enantiomerof BINAP, this regiocontrol was significantly lowered to 3:l (Scheme 11). This result suggested that (R)-enantiomer of the catalyst favoured formation of (S,S)-46 (under both substrate and reagent control), whereas the (S)-enantiomer favoured the alternative pathway to give the allylic phthalimide (S)-47. Interestingly, the control exerted by the substrate appears to be more dominant than that associated with the chirality of the ligand.

[ C ~ H S P ~ CLigand ~]~, Ph

*

phthalimide K-phthalimide (20 mol%) THF, rt

Bi (S)-45

Ph

+

Bi

ph

B i

(S, S)-46

(S)-47

(R)-BINAP 46:47 S N ~ : S N 20:1 ~' (S)-BINAP 46147& 2 : s ~ 2 '3: 1 Scheme 11.

By using this approach they have selectively resolved 5-vinyloxazolidinone ( 4 - 4 5 with a (R)-BINAP-palladium(0)based catalyst (Scheme 12). At best, the enantioselectivity was moderate; up to 62% ee for (R)-47. The choice of solvent was also very important; THF favoured the (S,S)-allylicphthalimide (S,S)-46 (kl),whereas acetonitrile favoured the complementary phthalimide (R)-47 (2.4:1)(Scheme 12: entry 1 versus 3). Ideally, the selective removal of both enantiomers need to occur at an equal rate to satisfy this PKR approach. This relative rate was achieved by changing the solvent to dichloromethane (Scheme 12: entry 2); but sadly the overall enantiocontrol was much lower. Whereas, by changing the chiral ligand to (S,S)-DIOP the relative rate of removal of both enantiomers were near perfect (1:1.2) and equally the enantiomeric control in both allylic phthalimides (S,S)-46 and (R)-47were very similar; 50% ee and 46% ee respectively (Scheme 12: entries 4 and 5). From these studies, they have clearly shown that by removing both enantiomers of substrate (A and A') at an equal rate during the course of a resolution significantly improves the overall efficiency with regard to a traditional kinetic resolution procedure (Scheme 1). However, a disadvantage for this strategy lies in the fact that these procedures can only a give maximum yield of 50% of a minimum of two possible products. Alternatively, the overall yield can be improved to 100% by conducting a dynamic kinetic resolution [16] (DKR), but only a single product can be formed. This strategy also relies on removal of the less reactive enantiomer - in this case by recycling through racemisation - rather than by direct derivatization with an additional complementary chiral reagent as in a parallel kinetic resolution.

References

BNA0

0

I

163

0

Ph

(S)-45

+

PhKNH

(S, S)-46

[C3H5PdC1]2, Ligand phthalimide K-phthalimide (20mol%) THF, rt

Ph

(S)-47

+

w

0 PhKNH

0 NPhth

Ph

k

Bn

Bn

(R)-45

(R, R)-46

EntV

Ligand

Solvent

(S, S)-46:(R)-47

1

(R)-BINAP

THF

5:1

2

(R)-BINAP

CHzC12

1:l

3

(R)-BINAP

NH U Bn

P

(R)-47

Products

(S,S)-46; 73%; 14% ee (S,S)-46; 35%; 33% ee

(R)-47 11%; 62% ee (R)-47; 37%; 29% ee

CH3CN

12.4

(S,S)-46; 24%; 36% ee

(R)-47;47%; 17% ee

4 (S,S)-DIOP

THF

1:1.8

(R)-47;47%; 37% ee

5 (S,S)-DIOP

toluene

1:l.z

(S,S)-46; 23%; 44% ee (S,S)-46; 35%; 50% ee

(R)-47; 41%; 46% ee

Scheme 12.

From these studies it has been shown that for a successful and efficient parallel kinetic resolution the following guidelines need to be adhered to; a) derivatisation with two complementary chiral reagents have to occur without mutual interference [ 171; b) both reactions need to occur with similar but preferably equal rate and have complementary stereocontrol and c) afford distinct and easily separable products. Whereas, for a related divergent kinetic resolution ( DvKR) the following guidelines need to be taken into consideration; a) both regio-divergent reactions must occur with a single chiral reagent and give two distinct and different products and b) both these regio-divergent pathways must occur at an equal rate.

References M. KEITH,J. F. LARROW,E. N. JACOBSEN, Adu. Synth. Catal. 2001, 343, 5. 2 H . B. KAGAN, J . C. FIAUD,Topics Stereochem. 1988, 18, 249. 3 C. J . S I H , S.-H. Wu, Topics Stereochem. 1989,19,63. 4 E. VEDEJS, X. CHEN,J. Am. Chem. SOC. 1997, 119,2584. 1 J.

h

U G I , P. J O C H U M , Tetrahedron 1997, 33, 1353. K. FABER, Tetrahedron Lett. 6 M. MISCHITZ, 1994, 35, 81. 7 E. VEDEJS, E. ROZNERS, J. Am. Chem. SOC. 2001, 123, 2428. 8 E. VEDEJS, 0.DAUGULIS, J . A. MACKAY,E. ROZNERS,Synlett 2001, 1499. 5 J . BRANDT,C. J O C H U M , I.

t

h

164

I

Parallel Kinetic Resolutions

F. CARDONA, S. VALENZA, A. GOTI, A. BRANDI,Eur. J. Org. Chem. 1999, 1319. 10 H. KAGAN,Croat. Chem. Acta 1996, 69, 669. 11 F. BERTOZZI, P. CROTTI,F. MACCHIA,M. PINESCHI,B. L. FERINGA,Angew. Chem. Int. Ed. 2001, 40, 930. 12 G. R. COOK,S. SANKARANARAYANAN, Org. Lett. 2001, 3, 3531. 13 M. P.DOYLE, A. B. DYATKIN, A. V. KALININ,D. A. RUPPAR,S. F. MARTIN, S. L I R A S , Am. ~ . Chem. SOL. M. R. SPALLER, 1995, 117, 11021. 9

Y. C H E NA N D L. DENG,J. Am. Chem. SOC. 2001, 123, 11302. 15 F. BERTOZZI, P. CROTTI,F. D. MORO,B. L. FERINGA,F. MACCHIA,M. PINESCHI, Chem. Commun. 2001, 2606. 16 R. S. WARD,Tetrahedron: Asymmetry 1995, 6, 1475. 17 A n example where lower selectivity was reported using a combination of reagents than just a single reagent; see T. M. E. L. HANSEN,J. KANE,T. REIN, PEDERSEN, P. HELQUIST,P.-0. NORRBY, D. TANNER, J. Am. Chem. SOC. 2001, 123, 9738. 14

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I165

The Asymmetric Baylis-Hillman-Reaction Peter Langer

Optimization o f the Chemical Yield o f the Baylis-Hillman-Reaction

The stereoselective formation of carbon-carbon bonds is an important problem in organic chemistry. The Baylis-Hillman-reaction allows the direct preparation of a-methylene-Phydroxycarbonyl compounds by base-catalyzed reaction of a,P-unsaturated carbonyl compounds with aldehydes [ 1-31. The first step of this reaction involves nucleophilic attack of the catalyst onto the Michael-acceptor 1 under formation of the zwitterionic intermediate 2. Subsequently, this intermediate reacts in the rate-determing step of the Baylis-Hillmanreaction with the aldehyde 3 under formation of the alcoholate 4 (Scheme 1).The product 5

1

2A

..

2B

-

R3N + A 0

DABCO

3-QDL

6

7

Scheme 1.

Mechanism of t h e Baylis-Hillman reaction.

OMe

166

I

The Asymmetric Baylis-Hillman-Reaction

is finally formed by a shift of a proton from the cc-carbon to the oxygen atom of the alcoholate and extrusion of the catalyst [4]. The densely functionalized Baylis-Hillman-products can be stereoselectively transformed for example into azirines [S], epoxides [6], trioles [7] and antialdol-products [ 81. In addition, cc-methylene-p-hydroxycarbonylcompounds represent versatile starting materials for the synthesis of a variety of natural and non-natural target molecules [9, 101. Unfortunately, the applicability of the Baylis-Hillman-reaction is very often limited by low rates and conversions and low, highly substrate-depending yields. It is particularly important for the development of an efficient asymmetric version of the Baylis-Hillman-reaction that these problems are adequately addressed. The use of high pressure or of the microwave technique resulted in significant increase of the rate of the reaction, but only for a few substrates [Ill. Increase of the reaction temperature above 20 "C resulted in polymerization of the sensitive acrylates. Recent work by Leahy and coworkers suggested that, counterintuitively, better yields and higher rates were observed at lower temperatures [12]. These results can be explained by the different rates of the formation of the diastereomeric baseacrylate-adducts ( 2 A and 2B). Product formation and yields in the Baylis-Hillman reaction also depend on a balance between the reactivities of the carbonyl and olefin partners as was shown, for example, for reactions of fluorine-containing carbonyl compounds [ 131. The rate and the conversion of the Baylis-Hillman-reaction was significantly improved when nucleophilic non-hindered bases, such as diaza[2.2.2]bicyclooctane (DABCO, G), rather than simple tertiary amines were used. Further improvements were observed when 3quinuclidinole (3-QDL,7)was employed, due to stabilization of the zwitterionic intermediate 2 by formation of intramolecular hydrogen bonds [ 14a-c]. Similar effects were observed by the addition of methanol [14d] or acetic acid [14e] to the reaction mixture (formation of intermolecular hydrogen bonds) or by the presence of a hydroxy group in the acrylate [ 14f 1. The rate of the reaction was decreased by the presence of substituents in the cc-position of tertiary amines. This was explained by the decrease of the rate of the addition of the catalyst onto the acrylate [ 151. Recent work by Agganval and coworkers has shown that very good rates and chemical yields could be obtained using the non-nucleophilic base DBU [16]. However, the use of enolizable ketones led to formation of aldol-products. The success of the use of DBU was explained by the assumption that the reaction of the zwitterionic intermediate with the acrylate rather than the attack of the catalyst onto the acrylate represents the rate-determing step of the reaction: although DBU represents a sterically hindered base, the zwitterionic intermediate is stabilized by conjugation of the positive charge. The concentration of the intermediate in the equilibrium is increased and, hence, the overall rate of the reaction is enhanced. A stabilization of the zwitterionic intermediate and a significant enhancement of the rate of the reaction was also induced by the use of metal salts, such as La(OTf)3and LiC104 [ 171. Shi and coworkers have reported that the rate and product distribution of Baylis-Hillman reactions of aldehydes with a,p-unsaturated ketones can be drastically affected by the reaction temperature and by the presence of Lewis bases [ 181. When the reaction was carried out at -78 "C using catalytic amounts of quaternary ammonium salts as Lewis bases, in the presence of titanium( IV) chloride, chlorinated syn-aldol adducts were obtained as the major products. Quaternary ammonium bromides and iodides showed higher catalytic activity than

Asymmetric Baylis-Hillman-Reactions of Chiral Substrates

I

167

the corresponding chlorides. When the reaction was carried out at room temperature, the elimination products were predominantly formed. A substantial acceleration of the Baylis-Hillman reaction has been observed when the reaction was conducted in water 119, 201. Several different amine catalysts were tested by Agganval and coworkers, and as with reactions conducted in the absence of solvent, 3hydroxyquinuclidine was found to be the optimum catalyst in terms of rate [19]. The reaction has been extended to other aldehyde electrophiles including pivaldehyde. Further studies on the use of polar solvents revealed that formamide also provided significant acceleration. Asymmetric Baylis-Hillman-Reaaions of Chiral Substrates Diastereoselective Baylis-Hillman-Reactions

of Chiral MichaeCAcceptors

During the course of the Baylis-Hillman-reaction two stereocenters are formed, one of which remains in the Baylis-Hillman-product.An obvious concept for the development of an asymmetric version of the reaction represents the use of an enantiomerically pure acrylic acid derivative. The use of enantiomerically pure menthyl acrylates resulted, but only in certain cases, to respectable diastereomeric excesses [ 211. A significant improvement was reported in 1997 by Leahy and coworkers who used the Oppolzer-sultame as a chiral auxiliary in DABCO-catalyzed Baylis-Hillman-reactions (Scheme 2) [ 221. In this reaction, the

IL-

MeoL 10

\

MeOH, CSA 85 %

M

e O HO

12 Scheme 2.

k

Rh', H2 85 %

HO

13

Diastereoselective Baylis-Hillrnan-reaction using Oppolzer sultarn (Leahy et a/.).

168

I

The Asymmetric Baylis-Hillman-Reaction

1,3-dioxan-4-one 11 was obtained, which was transformed by methanolysis into the c(methylene-p-hydroxyester 12 which was subsequently diastereoselectively hydrogenated to give the anti-aldol product 13. The esters 12 were isolated in good yields. However, 15 equivalents of the aldehyde had to be used. The stereoselectivity can be explained by the following: Michael-addition of the catalyst onto the acrylate 8 results in formation of a Zenolate which mainly resides in the anti-conformation 9-B, since in this case the dipolrepulsion between the sulfone- and the carbonyl group is minimized. Due to the steric interaction with the axial oxygen atom of the sulfone, the attack of the aldehyde proceeds diastereoselectively from the re-site of the acrylate to give the adduct 10, which subsequently reacts with a second aldehyde molecule to give a hemiacetale. Extrusion of the catalyst and cyclization with extrusion of the chiral auxiliary finally afforded the 1,3-dioxan-4-one11. Asymmetric Baylis-Hillman reactions using sugar acrylates have been reported to proceed with moderate diastereoselectivity (5-40% ee) [ 231. The reaction of camphor-based chiral acryloylhydrazides with aldehydes in the presence of DABCO afforded D-hydroxy-ccmethylene carbonyl derivatives in 68-92% yield with high diastereoselectivity (up to 98% de) [24]. Both diastereomers could be selectively obtained simply by changing the solvent.

PhSeLi 60 “C

py7&& \%

SePh

14

15 R-CHO - 60 “C

k

17

\

- 20

Scheme 3.

“C

\

Chirality transfer in a lithium phenylselenide induced domino-Michael-aldol-retro-Michaelreaction (Jauch et 01.).

R = Ph. iPr. tBu. CH=CHPh

Asymmetric Baylis-Hillman-Reactions of Achiral Michael-Acceptors a n d Aldehydes

R

R-(-)-I9

20 R = CN, C02Me

R,R-(+)-21

aa%, 295%

de

Diastereoselective Baylis-Hillman reaction o f planar chiral arylaldimine tricarbonylchrornium complexes (Kundig et a / , ) .

Scheme 4.

An interesting protocol for the diastereoselective Baylis-Hillman reaction under mild conditions has been reported by Jauch (Scheme 3) [25a]: The lithium phenylselenide induced domino Michael-aldol-retro-Michael reaction of aldehydes with (enantiomerically pure) Feringa's butenolide 24 afforded, after quenching with NH4C1/H20 at -GO "C, y-lactones 27 with very good diastereoselectivity. Treatment of 26, prior to aqueous work-up, with either PhCH2Br/n-Bu4NI at -GO "C or simply warming the reaction mixture to -20 "C gave the Baylis-Hillman adducts 28 in excellent yield and with high stereoselectivity. Formation of 28 can be explained by diastereoselective Michael addition of PhSeLi to butenolide 24 to give intermediate 25 and subsequent diastereoselective aldol-reaction (intermediate 26). The selectivity of the aldol-reaction can be rationalized through the Zimmermann-Trader model of the transition state. The methodology was applied to the total synthesis of the natural products Mniopetal F and kuehneromycin A [ 25b-c]. Diastereoselective Baylis-Hillman-Reactions of Chiral Carbonyl Derivatives

Aggarwal and coworkers have studied the electrophilic behavior of enantiomerically pure N-ptoluenesulfinimines and N-tea-butanesulfinimines in the asymmetric Baylis-Hillman reaction with methyl acrylate with and without Lewis acids [2G]. In the presence of In(0Tf)j good yields and high diastereoselectivities have been achieved providing an effective route to jl-amino-cc-methyleneesters. The Morita-Baylis-Hillman reaction of chiral glyoxylic acid derivatives with cyclic a$unsaturated ketones proceeded under the catalytic influence of dimethyl sulfide in the presence of titanium tetrachloride [27]. The adducts were obtained with high diastereomeric excess (>95% de) and typical yields around 80%. Kundig and coworkers have reported the Baylis-Hillman-reaction of methyl acrylate and acrylonitrile with planar chiral arylaldimine tricarbonylchromium complexes, such as 19 (Scheme 4)[ 2 8 ] . These reactions proceeded by attack of the acrylate from the sterically less encumbered site of the metal complex and afforded the products 21 with very good diastereoselectivity. Asymmetric Baylis-Hillman-Reactions of Achiral Michael-Acceptors and Aldehydes

Much work related to the development of a catalytic, enantioselective version of the BaylisHillman-Reaction by the use of chiral bases has been published. Only low enantiomeric excesses were obtained when brucin, N-methylprolinol, N-methyl-ephedrine and nicotine

I

169

170

I

The Asymmetric Baylis-Hillman-Reaction

were employed. The use of Cinchona alkaloids and of enantiopure 3-QDL 7 resulted in significant increase of the rate of the reaction, but only in low enantiomeric excesses which decreased when the reactions were carried out under pressure [29a-d]. Enantiomeric excesses of 9 4 4 % ee were obtained in the reaction of pyrimidine-5-carbaldehydeswith acrylates using (S)-BINAP as the catalyst [ 301. Baylis-Hillman reactions were promoted by mild cooperative catalysts of PBu3 with phenols, such as (*)-1,l'-bi-2-naphthol (BINOL), in THF to give cc-methylene [I-hydroxy alkanones in good yield and with good ee [31]. Besides the stereoselectivity, the reactions proceeded much faster in the presence of l,l'-bi-2naphthol than in its absence. Enantioselectivities of 21-7056 ee were observed in the reaction of ethyl- and methylvinylketone with aromatic aldehydes 22 using the chiral hydroxy-pyrrolizidine-catalyst24 which was prepared in four steps starting from BOC-L-prolinol (Scheme 5) [32]. The enantioselectivity was explained by the predominant formation of intermediate 2G-A, which is less sterically hindered than the isomeric intermediate 26-B. The employment of a reaction temperature of -40 "C, the use of NaBF4 as a co-catalyst,and the presence of a hydroxy group in the base (which allows the formation of intramolecular hydrogen bonds) resulted in good conversions and rates.

22

25

23

R

26-A

26-B

Scheme 5. Enantioselective Baylis-Hillrnan reaction using a chiral hydroxy-pyrrolizidine-catalyst (Barrett et a/.).

Very good enantioselectivities were recently reported by Hatakeyama and coworkers [ 331. The reaction of a variety of aldehydes 28 with the highly reactive 1,1,1,3,3,3-hexafluoroisopropylacrylate 27 using modified Cinchona-alkaloids as the catalyst resulted, at a temperature of -55 "C, in formation of the Baylis-Hillman-products 30 in 31-58% yields with 91-99% ee (Scheme 6). The use of the tricyclic derivative 29, which was prepared from quinidine in one step [34], proved crucial in order to obtain high enantioselectivities. The success of catalyst 29 can be explained by the [compared with quinidine) increased nucleophilicity, by the

Syntheses of Non-Racernic Bay/is-Hi//rnan-Productsby Other Methods

29 -55 "C

27 CF3

28

OH 0

CF3

R V O h C F 3

R-30

0-0

+Rye S-31

-

29

32

Scheme 6. Enantioselective Baylis-Hillman reaction using modified Cinchona-alkaloids (Hatakeyama et a/.).

presence of a free hydroxy group at the quinoline moiety, and by the anti-open-conformation [ 351 of the alkaloid which allow an optimal stabilization of the zwitterionic intermediate 32 by formation of intramolecular hydrogen bonds. Using the Oppolzer-auxiliary (vide supra) only low enantioselectivities could be obtained for aldehydes branched at the a-position. In contrast, the Baylis-Hillman-products derived from isobutyric aldehyde and cyclohexane carbaldehyde could be prepared in 31 and 36% yields with 99% ee when the catalyst 29 was used. A disadvantage of the method of Hatakeyama results from the decrease of the yields due to formation of the dioxanones 31, which were formed with opposite absolute configurations and with lower enantioselectivities compared to the products 30. However, the formation of these undesired side products was helpful for the elucidation of the mechanism of the reaction. The methodology was successfully used for an enantiocontrolled synthesis of the potent immunosuppressant (-)-mycestericin E [ 361. The conjugate addition of (R)-N-methyl-N-a-methylbenzylamide 33 to tert-butyl cinnamate 34, followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination afforded the p-substituted homochiral Baylis-Hillman product 39 in good yield (Scheme 7) [ 371. This chemistry requires the use of stoichiometric rather than catalytic amounts of the chiral base. Warren and coworkers have reported an interesting synthesis of nonracemic allenes by reaction of vinylphosphine oxides with aldehydes in the presence of chiral lithium [( R)-1phenylethyl](benzy1)amide to give hydroxyvinylphosphine oxides in 33-87% yields (051% ee) [38]. These products underwent a Horner-Wittig elimination reaction to produce nonracemic allenes. A mechanism similar to the Baylis-Hillman reaction was suggested. Syntheses of Non-Racemic Baylis-Hillman-Products by Other Methods

A number of alternative syntheses of non-racemic Baylis-Hillman-products by other

methods have been reported. Barrett and coworkers developed a two-step synthesis of Emethylene-D-hydroxyketones43 with 34-94% ee (Scheme 8) [ 391. From a preparative view-

I

171

172

I

The Asymmetric Baylis-Hillman-Reaction

Me

PhK N , M e Li

THF

A

(5)-33

A N - M e Ph PhL C O 2 t B u

-78 "C 94%, 88% de

&C02tBu

Ph

35

34

Me CWBu

H,&. '

1

1) 3 LDA, THF -78 "C 2) B(OMe13

3) R-CHO

2 mCPBA

Ph

CHC13,20 "C

H

H

38, R = Ph, 74%, >99% ee Scheme 7.

36, R = Me, 76%, 93:7 dr 37, R = Ph, 62%, 9218 dr

Stepwise Baylis-Hillman reaction using (R)-N-rnethyl-N-a-methylbenzylarnide (Davies et 01.).

39

40

OiPr 0

C02H

X=S,Se

4 2 ~

I

42 B CHzC12 H202

OH 0

41 Scheme 8.

43

Stepwise synthesis of nonracernic Baylis-Hillrnan adducts (Barrett et a/.)

point, this sequence was equivalent to an asymmetric Baylis-Hillman-reaction. The overall yields were in the range of 18% (X = S, R' = Me, R2 = Et) to 52% (X = Se, R' = Me, R2 = Me). In the first step, the enantioselective condensation of the cc,fi-unsaturatedketone 39 with the aldehyde 40 and trimethylsilylphenyl sulfide or - selenide afforded the diaster-

Syntheses of Non-Racemic Baylis-Hillman-Products by Other Methods

eomeric 8-hydroxyketones 42A and 42B with 63-97% ee. This reaction was catalyzed by the chiral acyloxyborane 41. The Baylis-Hillman-products 43 were subsequently prepared by oxidative elimination using mCPBA or H202. The enantioselectivities of this step were in the range of 50 to 96% ee. The copper-catalyzed S N ~addition ’ of organozinc reagents ZnR2 to allylic substrates ( Z ) ArHC=C(CH2X)(COzEt)(X = Br, C1, OSOzMe) yielded Baylis-Hillman products ArH( R)C-C(=CH2)(CO2Et)[40]. The use of chiral ligands gave up to 64% ee. Sat0 and coworkers have reported an asymmetric synthesis of Baylis-Hillman-type allylic alcohols 48,49via a chiral acetylenic ester titanium alkoxide complex (Scheme 9) [41]. These reactions rely on the use of the novel acetylenic ester titanium alkoxide complex 44 with a camphor-derived chiral auxiliary. Optically active, stereodefined hydroxy acrylates 46,47 were obtained in high yields and with excellent regio- and diastereoselectivities. The chiral auxiliary was subsequently cleaved off by alcoholysis.

0

44

45

C02H I

MesSi\//\/R

-

1

R-CHO

KOH. EtOH

OH

0

48, R = Et, 92% ee 49, R = Ph, 98% ee

SiMe3

46, R = Et, 94% de 47,R = Ph, 98% de

Scheme 9. Asymmetric synthesis of Baylis-Hillman-type adducts via a chiral acetylenic ester titanium alkoxide complex (Sato et a/.).

Unusual P-branched Baylis-Hillman adducts have been prepared by Li and coworkers by a novel Et2A1C1 promoted domino Michael-aldol reaction of propynoates 50 with organocuprates and chiral p-toluenesulfinimines 52 (Scheme 10) [42]. These condensations proceeded with very good diastereoselectivity to give allylic amines 53. The selectivity can be explained through the chairlike transition state 54.The anion intermediate approaches the sulfinimine from the sterically less hindered side of the lone pair of electrons. The nucleo-

I

173

174

I

The Asymmetric Baylis-Hillman-Reaction

Et2AICI

R' = H, Me, Ph R2 = Me, nBu, Ph

To1

H

52

R3 = Ph, 2-Fut~4 54 - 81%

complete diastereo-

and EIZ-selectivity

53

54 Domino Michael-aldol reaction of propynoates with organocuprates and chiral p-toluenesulfinimines (Li et a / . ) .

Scheme 10.

philic attack is controlled by the size of the substituents (RL, Rs, S = small, L = Large) of the vinylic organocopper intermediate which coexists with the respective allenoate species in equilibrium. In contrast to the work of Agganval (vide supra), propynoates rather than acrylates were used as starting materials. In addition, stoichiometric rather than catalytic amounts of a vinylic carbanion were formed. The asymmetric catalytic aldol reaction of silyl allenolates ICH=C=CR20SiMe3with aldehydes R'CHO has been achieved by Li et al. by using N-C3F,CO oxazaborolidine as the catalyst [43]. The fluoroacyl group of the catalyst was found to be crucial for control of enantioselectivity.The reaction provides the first enantioselective approach to j'-halo BaylisHillman-type adducts. Trost and coworkers have shown that Baylis-Hillman adducts can be efficiently deracemized by Pd2dba3,CHCl3catalyzed reaction of the corresponding carbonates 55 with phenols 56 in the presence of chiral Cz-symmetric P,N-ligands (Scheme 11) [44].The strategy follows a dynamic kinetic asymmetric transformation process via n-ally1 palladium chemis-

Acknowledgment

OC02Me

Pd2(dba)3.CHCl3 (1 mol-Yo) ligand (3 mol-%)

55

CH2Cl2, 20 "C

+ Ar-OH

57

0.05- 0.1 M

56

ligand

*

=d

R' = Alkyl R2 = C02Et, CN Ar =Aryl

ys

NH

'

PPh2

HN

Ph2P

72 - 77% 85 - 99% ee

/

58 Scheme 11.

Palladium-catalyzed deracemization of Baylis-Hillman adducts (Trost et a/.).

try. Using the chiral ligand 58, the reactions proceeded with excellent enantioselectivity. Depending on the substrate, ligand and reaction conditions, moderate to high regioselectivities were observed. Conclusions

The development of efficient, asymmetric versions of the Baylis-Hillman-reaction for the synthesis of enantiomerically pure cc-methylene-jl-hydroxycarbonyland related compounds is still a rewarding issue. Interesting recent approaches for the solution of this problem include the use of chiral Michael acceptors or aldehyde/aldimine components. The use of stoichiometric or catalytic amounts of chiral base is also of great current importance. Besides the development of an asymmetric version of the Baylis-Hillman-reaction, alternative reaction sequences giving nonracemic Baylis-Hillman-adducts have attracted considerable attention. Likewise, the recently reported Palladium-catalyzed deracemization of Baylis-Hillmanadducts appears to be promising. Besides stereoselectivity, the low rate and chemical yields often observed in Baylis-Hillman reactions remain important issues to be carefully addressed in all future studies. Acknowledgment

This work was supported by the Fonds der Chemischen Industrie (Liebig-scholarship and funds for P. L.) and by the Deutsche Forschungsgemeinschaft (Heisenberg-scholarship for P.L.). P. L. thanks Prof. Dr. A. de Meijere for his support.

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175

176

I

The Asymmetric Baylis-Hillman-Reaction References 1 Reviews: a)

P. LANGER,Angew. Chem. 2000, 112, 3177-3180; Angew. Chem. Int. Ed. 2000, 39, 3049-3052; b) E. CIGANEK, Org. React. 1997, 51, 201-350; C) D. BASAVAIAH, P. D. RAo, R. S. HYMA, Tetrahedron 1996, 52, 8001-8062; d) S. E. DREWES, G. H. P. Roos, Tetrahedron 1988, 44, 4653-4670; e) K. MORITA,2. S u z u ~ r , H. HIROSE,Bull. Chem. SOC.]pn. 1968, 41, 2815. 2 A. B. BAYLIS, M. E. D. HILLMAN, German Patent 2155113, 1972 [Chem.Abstr. 1972, 77, 34174q1. 3 a) H. M. R. HOFFMANN, J. RABE,Angew. Chem. 1983, 95, 795-796; Angew. Chem., Int. Ed. Engl. 1983, 22, 795-796; b) J. RABE,H. M. R. HOFFMANN, Angew. Chem. 1983, 95, 796-797; Angew. Chem., Int. Ed. Engl. 1983, 22, 796-797; c) H. M. R. J. RABE,Angew. Chem. 1985, HOFFMANN, 97, 96-112; Angew. Chem., Int. Ed. Engl. 1985, 24, 94-109. 4 Mechanistic studies: a) J. S. HILL,N. S. ISAACS,]. Phys. Org. Chem., 1990, 3, 285293; b) M. L. BODE, P. T. KAYE,Tetrahedron Lett. 1991, 32, 5611-5614; c) Y. FORT,M. C. BERTHE,P. CAUBERE, Tetrahedron 1992, 48,6371-6384; d) E. M. L. ROSENDAAL, B. M. W. Voss, H. W. SCHEEREN, Tetrahedron 1993, 31, 6931-6936. 5 a) R. S. ATKINSON, J. FAWCETI,D. R. RUSSEL,P. J. WILLIAMS, ]. Chem. SOC., Chem. Commun. 1994, 2031-2032. 6 M. BAILEY,I. E. MARKO,W. D. OLLIS, Tetrahedron Lett. 1991, 32, 2687-2690. 7 I. E. MARKO,P. R. GILES,2. J A N O U S E K , N. J. HINDLEY, J:P. DECLERCQ, B. TINANT,J. FENEAU-DUPONT, J. S. SVENDSEN, Red. Trav. Chim. Pays-Bas 1995, 114, 239-246. 8 J. M. BROWN, Angew. Chem. 1987, 99, 169182; Angew. Chem., Int. Ed. Engl. 1987, 26, 190-203. 9 a) A. H. HOVEYDA, D. A. EVANS,G . C. Fu, Chem. Rev. 1993, 93, 1307-1370; b) R. ANNUNZIATA, M. BENAGLIA, M. CINQUINI, F. COZZI,L. RAIMONDI,]. Org. Chem. 1995, 60,4697-4706; c) 0. B. FAMILONI, P. T. KAYE, P. J. KIAAS, Chem. Commun. 1998, 2563-2564. 10 W. R. ROUSH,B. B. BROWN,].Org. Chem. 1993, 58, 2151-2161.

1 1 a) J.AuGE, N. LUBIN,A. LUBINEAU, Tetra-

hedron Lett. 1994, 58, 7947-7948; b) M. K. KUNDU,S. B. MUKHERJEE, N. BALU, R. S. V. BHAT,Synlett 1994, PADMAKUMAR, 444. 12 S. RAPEL,J.W. LEAHY,]. Org. Chem. 1997, 62, 1521-1522. 13 P. RAMACHANDRAN, P.,R. VEERARAGHAVAN, M. REDDY,R. VENKAT,M. T. RUDD, H. C. BROWN,R. B. WETHERILL, Chem. Commun. 2001, 757-758. 14 a) S. E. DREWES, S. D. FREESE, N. D. G. H. P. Roos, Synth. Commun. EMSLIE, 1988, 18, 1565-1668; b) M. BAILEY,I. E. MARK^, W. D. OLLIS,P. R. RASMUSSEN, Tetrahedron Lett. 1990, 4509-4512; c) M. L. BODE,P. T. KAYE, Tetrahedron Lett. 1991, 5611-5614; d) F. AMEER,S. E. DREWES, S. FREESE, P. T. KAYE,Synth. Commun. 1988, 18,495-498; e ) H . M. R. HOFFMANN? ]. Org. Chem. 1988, 53, 3701-3712; f ) D. BASAVAIAH,P. K. S. SARMA,Synth. Commun. 1990, 20, 1611-1614. 15 R. J. W. SCHUURMAN, A. VANDERLINDEN, R. P. F. GRIMBERGEN, R. J. M. NOLTE, H. W. SCHEEREN, Tetrahedron 1996, 52, 8307-8314. 16 V. K. AGGARWAL, A. MEREU,Chem. Commun. 1999, 2311-2312. 17 V. K. AGGARWAL, A. MEREU,G. J. TARVER, R. J. MCCAGUE, ]. Org. Chem. 1998, 63, 7183-7189. 18 M. SHI, Y . 3 . FENG,]. Org. Chem. 2001, 66, 406-411. 19 V. K. AGGARWAL, D. K. DEAN,A. MEREU, R. WILLIAMS, ]. Org. Chem. 2002, 67, 510-514. 20 C. Yu, B. LIU, L. Hu,]. Org. Chem. 2001, 66, 5413-5418. 21 N. S. ISAACS, A. GILBERT, T. W. HERITAGE, Tetrahedron:Asymmetry 1991, 2, 969-972. 22 L. J. BRZEZINSKI,S. RAFEL, J. W. LEAHY,]. Am. Chem. SOC.1997, 119, 4317-4318. 23 K. P. RADHA V. KANNAN, A. ILANGOVAN, G. V. M. SHARMA, Tetrahedron:Asymmetry 2001,829-837. 24 K . 4 . YANG, K. CHEN,Org. Lett. 2000, 729731. 25 a) J. JAUCH,]. Org. Chem. 2001, 66, 609611 and references cited therein; b) J. JAUCH,Eur. I. Org. Chem. 2001,473-476;

References I 1 7 7

26

27 28 29

30

31 32

33

34

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c) J. JAUCH,Angew. Chem. 2000, 112, 2874-2875; Angew. Chem. Int. Ed. 2000, 39, 2764-2765. V. K. AGGARWAL, A. M. M. CASTRO, A. MEREU,H. ADAMS,Tetrahedron Lett. 2002, 1577-1581. T. BAUER,J. TARASIUK, Tetrahedron: Asymmetry 2001, 1741-1745. E. P. KUNDIG, L. H. Xu, B. SCHNELL, Synlett 1994, 413-415. a) Ref. lb; b) Ref. 17; c) I. E. MARKO,P. R. GILES,N. J. HINDLEY, Tetrahedron 1997, 53, 1015-1024; d) D. BASAVAIAH,N. KUMARAGURUBARAN,D. S. SHARADA, R. M. REDDY, Tetrahedron 2001, 57, 8167-8172. a) T. HAYASE, T. SHIBATA, K. SOAI,Y. WAKATSUKI, Chem. Commun. 1998, 12711272; b) M. SHI, J.-K. JIANG, S.-H. Cur, Y . 4 . FENG,]. Chem. Soc., Perkin Trans. 1 2001, 390-393. Y. M. A. YAMADA,S. IKEGAMI,Tetrahedron Lett. 2000, 2165-2169. A. G. M. BARRETT, A. S . COOK,A. KAMIMURA,Chem. Commun. 1998, 2533-2534. Y. IWABUCHI, M. NAKATANI, N. YOKOYAMA, S. HATAKEYAMA, ]. Am. Chem. Soc. 1999, 121, 10219-10220. a) C. VON RIESEN,H. M. R. HOFFMANN, Chem. Eur. 1.1996, 2, 680-684; b) W. P. LANCER, BFAJE,1. FRACKENPOHL, H. M. R. HOFFMANN, Tetrahedron 1998, 54, 3495-3512. For the conformational analysis of Cinchona-alkaloids, see: a) G. D. H. DIJKSTRA, R. M. KELLOGG,H. J. WYNBERG, J . S. SVENDSEN, 1. MARKO,K. B.

36

37

38

39

40

41

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SHARPLESS,]. Am. Chem. SOC.1989, 111, 8069-8076; b) G. D. H. DITKSTRA, R. M. KELLOGG,H. J. WYNBERG, J. Org. Chem. 1990, 55, 6121-6131. Y. IWABUCHI, M. FURUKAWA, T. ESUMI, S. HATAKEYAMA, Chem. Commun. 2001, 2030-2031. S. G. DAVIES, C. A. P. SMETHURST, A. D. SMITH,G. D. SMYTH,Tetrahedron: Asymmetry 2000, 1 I , 2437-2441. D. J. Fox, J. A. MEDLOCK, R. VOSSER, S. WARREN,].Chem. Soc., Perkin Trans. 1 2001, 18, 2240-2249. A. G. M. BARRETT, A. KAMIMURA,]. Chem. SOC.,Chem. Commun. 1995, 17551756. C. BORNER, P. J. GOLDSMITH, S. WOODWARD, ].GIMENO,S. GIADIALI, D. RAMAZZOTTI, Chem. Commun. 2000, 2433-2434. D. SUZUKI, H. URABE, F. SATO,Angew. Chem. 2000, 112, 3428-3430; Angew. Chem. Int. Ed. 2000, 39, 3290-3292. a) G . LI, H.-X. WEI, B. R. WHITTLESEY, N. N. BATRICE,]. Org. Chem. 1999, 64, 1081-1064; see also: b) G. LI, H.-X. WEI, J. D. HOOK,Tetrahedron Lett. 1999, 46114614; c) H.-X. WEI, J. D. HOOK,K. A. FITZGERALD,G. LI, Tetrahedron: Asymmetry 1999, 661-665. G. LI, H.-X. WEI, B. S. PHELPS,D. W. PURKISS,S. H. KIM, H. SUN,Org. Lett. 2001,823-826. B. M. TROST,H.-C. Tsur, F. D. TOSTE,J . Am. Chem. SOC.2000, 122, 3534-3535. See also: S. V. LEY,F. RODRIGUEZ, Chemtracts 2000, 13, 596-601.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Simple Amino Acids and Short-chain Peptides as Efficient Metal-free Catalysts in Asymmetric Synthesis Harald Croger, Jorg Wilken, and Albrecht Berkessel Introduction

The development of suitable enzyme mimics as (0rgano)catalysts in asymmetric syntheses is highly attractive, not at least due to the fact that enzymes are regarded to be the most efficient catalysts. Since these efficient natural catalysts are based on a sequence of amino acids organic chemists became interested to investigate if peptide fragments thereof or simple amino acid monomers can act like an enzyme itself [ 11. It is noteworthy that such a reaction, namely the intramolecular aldol reaction with proline as a catalyst [2],was reported already in 1971. The question if a simple amino acid or a short-chain peptide thereof can act like an enzyme for a broad range of reactions was impressively answered recently by numerous important contributions showing that those small building blocks represent highly active and enantioselective organocatalysts [ 31. These asymmetric syntheses with organocatalysts possess a high synthetic value since they represent a remarkable alternative to many established asymmetric transformations. In the following a brief overview about advantages of amino acid and peptide catalysts, and selected recent synthetic highlights of amino acid-, and peptide-catalyzed reactions, including a comparison of mechanistic aspects of those reactions with enzymatic reacions, is given.

Advantages o f Amino Acid and Peptide Catalysts

In particular, such type of processes might allow a cost effective manufacture of chiral building blocks on an industrial scale in the future. Furthermore, the application of enantiomerically pure, “small” amino acid or oligopeptide molecules represents a promising alternative catalytic concept in addition to other frequently used syntheses based on metalcontaining catalysts [l].These organic catalysts not only function like an enzyme, but also with respect towards technical application - show the following interesting properties: (a) easy availability,(b) both enantiomers are often available with comparable price, (c) low price of amino acids since often directly accessible from the “chiral pool” or produced in large amount by fermentation, (d) low molecular weight, (e) easy separation from the product and ( f ) easy recovery after work-up.

Asymmetric Synthesis Using Amino Acid Catalysts

Asymmetric Synthesis Using Amino Acid Catalysts lntermolecular Amino Acid-catalyzed Asymmetric Aldol Reaction

The capability of L-proline - as a simple amino acid from the “chiral pool” - to act like an enzyme has been shown by List, Lerner und Barbas 111 [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [ 51. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4]. It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or 11, a “direct” asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [ 51. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [ 7 ] .

1 + I

H3C

CH,

(20 vol-Yo)

(R)-2a 94% yield 69% ee

H L-proline (30 mol-Yo)

DMSO /acetone (4:l)

1

* H3C

(R)-2 up to 97% yield up to 96% ee

(R)-2b 54% yield 77% ee

(R)-2C 97% yield 96% ee

Scheme 1. The direct intermolecular asymmetric aldol reaction using L-proline

Promising prospects for synthetic applications in the future were opened up by List et al.’s experimental studies into the substrate range (Scheme 1).The proline-catalyzed reaction proceeds well when using aromatic aldehydes as a starting material with enantioselectivities of 60 to 77% ee and yields of up to 94%. The direct L-proline-catalyzed aldol reaction proceeds very efficiently when using isobutyraldehyde as a substrate. For this reaction the

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Simple Amino Acids and Short-chain Peptides as Eficient Metal-free Catalysts in Asymmetric Synthesis

product 2c has been obtained in a very good yield of 97% and with an excellent enantioselectivity of 96% ee. An enantioselective proline-catalyzed self-aldolization of acetaldehyde was found very recently by Barbas and co-workers (Scheme 2, reaction 1) [8]. As a product, the valuable building block 5-hydroxy-(2E)-hexenal3 was obtained with up to 90% ee, albeit yield did not exceed 13% independently from the reaction conditions. 0

L-proline (ca. 2.5 rnol-Yo)

THF / acetaldehyde (4:l); 5h; 0 . c

(20 vol-%)

*

H3CU

H3.4

OH

(20 vol-%)

Scheme 2.

+

3

(R=alkyl,aryl)

DMSO / hydroxyacetone * (4:l)

OH

0

(20 - 30 rnol-oh) H3C

HKR

(reaction 1)

10% yield 90% ee

L-proline

0

H

-

(reaction 2)

OH

4 up to 95% yield dr (sydanti) up to >20:1 up to >99% ee

Further L-proline-catalyzed intermolecular asymmetric aldol reactions.

The concept of the proline-catalyzed aldol reaction has been recently extended by List et al. towards the synthesis of aldol products with two stereogenic centers [9). The desired antidiols 4 have been obtained in a regio-, diastereo- and enantioselective step starting from achiral compounds. Impressive diastero- and enantioselectivities were observed, with a diastereomeric ratio up to dr > 20:l and ee-values of up to >99% ee (Scheme 2, reaction 2). In addition, the reaction leads to a high regioselectivity of >20:1. From an industrial point of view, the following characteristics of these aldol reactions are noteworthy in particular: The direct aldol reaction possess a high synthetic value since the use of modified starting materials is not necessary, and the ketones can be used directly instead of enol derivatives. Furthermore, the price of L-proline - which is available on technical scale in both enantiomeric forms - is only about 40 $/kg (referring to L-proline).This represents an economically highly attractive access to a chiral catalyst - in particular compared with other types of chiral catalysts. In addition, the possibility of easily separating the proline catalyst from the product and recovering it by aqueous work-up (due to its water solubility) is also of economical interest. At present, the increase of the enantioselectivity and the improvement of the substrate range indicate a challenge of the future. Such improvements could enable the realization of a technical applicability of the direct asymmetric aldol reaction using r-proline. Another disadvantage is the large excess of the ketone component. In addition, a further decrease of the required catalytic amount of 20-30 mol% would be desirable.

Asymmetric Synthesis Using Amino Acid Catalysts

The Mechanism: Similarities of Amino Acid-catalyzed and Enzymatic Reactions

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The dose relation of the reaction mechanisms of the aldolase of type I [Sb] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines IIa and IIb, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ira and IIb, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or r-proline) furnishes the aldol product. a) Catalytic cycle with the aldolase of type I

b) Catalytic cycle with L-proline

(Lys (aldolase)

la

8.

H3C

. *R OH OH

CH3

L-proline H3C

2

(R = OPO:o)

However, a difference between both catalytic cycles can be seen in the reaction sequence for the formation of the enamines which are key intermediates of these aldol reactions. In case of the aldolase of type I a primary amino function of the enzyme is used for the direct formation of a neutral imine (Ia), while the enamine synthesis proceeds through a positive iminium system (Ib) when starting from L-proline (Scheme 3). In this connection, inves-

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Simple Amino Acids and Short-chain Peptides as Eflcient Metal-free Catalysts in Asymmetric Synthesis

tigations by List et al. on the dependence of the catalytic potential from the type of amino acid are of particular interest. In these studies it has been shown that for the catalytic activity the pyrrolidine cycle (in L-proline) is required as well as the carboxylic acid group [4]. In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [ 1, 3). This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. lntramolecular Amino Acid-catalyzed Asymmetric Aldol Reaction

For the Hajos-Eder-Sauer-Wiechert reaction [2a, b], which was found in the 7Oties, Barbas 111 et al. recently reported an optimized protocol [lo]. This reaction furnishes the chiral Wieland-Miescher ketone. It has now been shown, that this synthesis (which comprises three reactions) can be carried out as a one-pot synthesis (49% yield; 76% ee; Scheme 4) [lo]. Prolin functions as an efficient catalyst for all three reaction steps (Michael-addition, cyclization, dehydratization). A very interesting theoretical study of the mechanism of this reaction has been recently published by the Houk group [ 111.

XCH2

0

CH3

+

L-proline (35 mol-%)

DMS0;35 C

0

5 49% yield 76% ee Scheme 4.

The direct intramolecular asymmetric aldol reaction using L-proline.

Amino Acid-catalyzed Asymmetric Mannich-reaction

A further application of L-proline as a catalyst in asymmetric synthesis, which was found by List, is the three-component-Mannich reaction for the preparation of p-amino ketones [ 121. In the presence of L-proline as a catalyst the Mannich product 6 has been obtained in 50% yield and with 94% ee (Scheme 5, reaction 1). This method can be applied to a series of different aldehydes, whereby enantioselectivities of up to 96% ee are obtained. I t is noteworthy that - similiarly to the proline-catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process. For example, the uic-aminoalcohol 7 is formed with a diastereomeric ratio of 17:l and an enantioselectivity of 65% ee (Scheme 5; reaction 2). Amino Acid-catalyzed Asymmetric Michael Reaction Using C-donors

Recent contributions by several groups revealed that L-proline is also a suitable catalyst for the asymmetric Michael reaction using C-donors [l, 13-15]. In the first reports, in general

Asymmetric Synthesis Using Short-chain Peptide Catalysts

a

H3C

CH3

9

+

0 Htj,PMP

L-proline (35 mol-%); p-anisidine (1.1 eq.,)

(20 vol-%)

NO2

H3C'

DMSO I acetone (4:l)

1:-

n N o 2 ( r e a c t i o n 1)

6 50% yield

94% ee (PMP = pmethoxyphenyl) L-proline (35 mol-%); panisidine (1.1 eq.)

H 3 C 3 OH

-t

.

H CH3

0 HNSPMP (reaction 2)

H3C*cH3

DMSO / hydroxyacetone

OH CH3

(4:l)

7

(20 vol-%)

57% yield dr (sydanfi) 17:l 65% ee Scheme 5.

Asymmetric Mannich reactions using L-proline as a catalyst.

excellent yields and high diastereomeric ratio but low enantioselectivities were obtained [ 131. Using modified reaction conditions, however, Enders et al. found an improved enantio- and diastereoselective proline-catalyzed Michael addition of ketones to nitrostyrenes [ 151. The optically active y-nitro ketone products of type 8 were obtained with increased enantioselectivities of up to 76% ee. The yields remained in a medium to excellent range of up to 99%, and diastereomeric ratio of up to 98.5:l.S were observed. So far, however, the long reaction time of 2-8 d represents a limitation which has to be further improved. A representative example is shown in Scheme 6.

(1 0 equiv.)

Scheme 6.

8 74%yield dr (sydanti) 16:l 76% ee

Asymmetric L-proline-catalyzed Michael reactions with C-donors.

Asymmetric Synthesis Using Short-chain Peptide Catalysts feptide-catalyzed Asymmetric Michael Reaction with N-donors

An asymmetric version of a Michael addition with nitrogen nucleophiles can be also realized with simple short-chain peptides as catalysts. This has been demonstrated by Miller et al. for the addition of an azide to a,p-unsaturated carbonyl compounds [16]. In the presence of the tripeptide 9 as a catalyst (2.5 mol-%) the products 10 have been formed in excellent yields and with up to 85% ee (Scheme 7). In addition, this reaction represents an attractive access to p-amino acids.

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Simple Amino Acids and Short-chain Peptides as E$cient Metal-free Catalysts in Asymmetric Synthesis

0

0

Bn

9 (2.5 mol-Yo) A

N

L

R

TMSN3; HOAC toluene; 25 C

10 up to 97% yield up to 85% ee

Scheme 7.

Asymmetric tripeptide-catalyzed Michael reaction with an N-donor.

Short-chain Peptide-catalyzed Asymmetric Epoxidation

In addition, solid-phase bound short-chain peptides have been recently found by the Berkessel group to act as highly efficient catalysts in asymmetric epoxidation reactions [ 171. In the early 1980s, J u k and Colonna reported that chalcone 11 can be epoxidized asymmetrically by akaline hydrogen peroxide in the presence of poly-amino acids as catalysts [ 18, 191. The work by Berkessel et al. revealed that in fact as little as five L-Leu residues are sufficient for the epoxidation of the enone 11 with 96-98% ee (Scheme 8).

11 Scheme 8.

c a t a l y s t : (L-Leu), on TentaGel S NH2 Asymmetric enone epoxidation with solid-phase bound peptide catalysts.

Their results strongly suggest that one turn of a helical peptide is the minimal structural element required for catalysis. Based on structure-activity studies of the catalyst, and based on molecular modeling, it was concluded that the N-terminus of the peptide functions as the active site of these "mini-enzymes". Three N-H bonds (not involved in intrahelical Hbonding) protrude from the N-terminus of a-helices. Binding and activation of the enone is effected by H-bonding of the carbonyl oxygen atom to the terminal amino acid (n) and the one at position (n-2). The oxidant, i.e. a nucleophilic hydroperoxide anion, is delivered selectively to one enantiotopic face of the enone by the remaining NH-bond of the penultimate amino acid (n-1) (Figure 1). In other words, the sense of asymmetric induction is determined by the helicity of the peptide. A catalytic method for the preparation of enantiomerically pure cc,P-epoxy ketones as building blocks for organic synthesis is highly desirable. Unfortunately, the Julia-Colonna

References and Remarks

Fig. 1. Proposal for the mechanism o f asymmetric induction i n peptide-catalyzed enone epoxidations. Note that the enone carbonyl oxygen atom forms two H-bonds t o the N-terminal amino acid (n) and to the one at position (n-2); a hydroperoxide anion is delivered faceselectively by NH (n-1).

method is still limited to chalcones and closely related substrates [ 2 0 ] . It is hoped that the above mechanistic model will aid in the design of peptide catalysts for the asymmetric epoxidation of enones other than chalcones, e.g. cyclohexenones or quinones. Summary

In conclusion, the recent contributions by several groups in the field of asymmetric syntheses with amino acids and short-chain peptides as efficient chiral catalysts appear to be very interesting for chemists from academia as well as from industry. In addition, those new syntheses are promising alternatives to existing asymmetric technologies. Without any doubts it is surprising to observe that a simple amino acid molecule - as shown in case of proline - can in principle act like an enzymatic system, thus representing an efficient enzyme mimic. References and Remarks 1

For recent reviews in the field of organocatalytic reactions, see: a) H. GROGER,J. WILKEN,Angew. Chem. 2001, 113, 545; Angew. Chem. Int. Ed. 2001,40,529; b) B.

LIST,Synlett 2001, 1675; c) P. I. DALKO, L. MOISAN,Angew. Chem. 2001, 113, 3840; Angew. Chem. Int. Ed. 2001,40, 3726.

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3

4 5

a) U. EDER, G. SAUER, R. WIECHERT, Angew. Chem. 1971, 83, 492; Angew. Chem. Int. Ed. Engl. 1971, 10, 496; b) 2. G . HAJOS,D. R. PARRISH, J . Org. Chem. 1974, 39, 1615; c) C. AGAMI,N. PLATZER, H. SEVESTRE, Bull. SOC.Chim. Fr. 1987, 2, 358. For selected previous contributions about the application of further simple organic molecules as chiral catalysts in asymmetric synthesis, see: a) Hydrocyanation using cyclic dipeptides: K. TANAKA, A. MORI,S. INOUE, /. Org. Chem. 1990, 55, 181; b) Hydrocyanation using a chiral imine: M. S. SIGMAN, E. N. JACOBSEN, /, Am. Chem. SOC.1998, 120, 4901; c) Hydrocyanation using chiral bicyclic guanidine derivatives: E. J. COREY,M . J. GROGAN, Org. Lett. 1999, 1, 157; d) Baylis-Hillman reaction: Y. IWABUCHI, M. NAKATANI,N. YOKOYAMA,S. HATAKEYAMA, J . Am. Chem. SOC.1999, 121, 10219; e) Michael-Addition using alkali metal salts of proline: M. YAMAGUCHI,T. SHIRAISHI, M. HIRAMA, /. Org. Chem. 1996, 61, 3520, and cited references therein; f ) Diels-Alder reacC. J. BORTHS, tion: K. A. AHRENDT, J . Am. Chem. SOC. D. W. C. MACMILLAN, 2000, 122, 4243; g) /3-lactam formation: A. E. TAGGI, A. M. HAFEZ,H. WACK,B. YOUNG, W. J. DRURY, Ill, T. LECTKA,J . Am. Chem. SOC.2000, 122, 7831. B. LIST, R. A. LERNER,C. F. BARBAS 111, /. Am. Chem. SOC.2000, 122, 2395. For a review about the asymmetric catalytic aldol reaction, see: a) H. GROGER,E. M. VOGL,M. SHIBASAKI, Chem. Eur. J. 1998, 4, 1137; b) T. D. MACHAJEWSKI, C.-H. WONG,Angew. Chem. 2000, 112, 1406; Angew. Chem. Int. Ed. 2000, 39, 1352.

This also means that a further reaction step - deprotonation or silylation - in order to prepare the required enolates and enol ethers, respectively, can be avoided. 7 a) Y. M. A. YAMADA, N. YOSHIKAWA, H. SASAI, M. SHIBASAKI, Angew. Chem. 1997, 109, 1942; Angew. Chern. Int. Ed. Engl. 1997, 36, 1871; b) N. YOSHIKAWA, Y. M. A. YAMADA,J. DAS,H. SASAI,M. SHIBASAKI, J . Am. Chem. SOC.1999, 121; 4168. 8 A. CORDOVA, W. NOTZ,C. F. BARBASIl1,J. Org. Chem. 2002, 67, 301. 9 W. NOTZ,B. LIST, J . Am. Chem. SOC.2000, 122, 7386. 10 T. BUI, C. F. BARBAS, Ill, Tetrahedron Lett. 2000, 41, 6951. 11 S. BAHMANYAR, K. N. HOUK,J. Am. Chem. SOC.2001, 123, 12911. 12 B. LIST,/. Am. Chem. SOC.2000, 122, 9336. 13 B. LIST, P. POTARLIEV, H. 1. MARTIN, Org. Lett. 2001, 3, 2423. 14 J. BETANCORT, K. SAK-ITHIVEL, R. THAYUMANAVAN, C. F. BARBAS,111, Tetrahedron Lett. 2001, 3, 4441. 15 D. ENDERS,A. SEXI,Synlett 2002, 26. 16 T. E. HORSTMANN, D. J. GUERIN, S. J. Angew. Chem. 2000, 112, 3781; MILLER, Angew. Chem. Int. Ed. 2000, 39, 3635. 17 A. BERKESSEL, N. GASCH,K. GLAUBITZ, C. KOCH, Org. Lett. 2001, 3, 3839. 18 S. JULIA, J. MASANA, J. VEGA,Angew. Chem. 1980, 92, 968; Angew. Chem. Int. Ed. Engl. 1980, 19, 929. 19 S. JULIA, J. GUIXER, J. MASANA, J. ROCAS, S. COLONNA, R. ANNUZIATA, H. MOLINARI, J. Chem. SOC., Perkin Trans. 11982, 1317. 20 M. J. PORTER, J. SKIDMORE, Chem. Commun. 2000, 1215. 6

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

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Recent Developments in Catalytic Asymmetric Strecker-Type Reactions Larry Yet

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate cc-amino nitriles to provide cc-amino acids (Scheme l),was first reported in 1850 [ 11. This method has been applied on an industrial scale toward the synthesis of racemic cc-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of cc-amino acids [ 21. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of cc-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. RCHO

+

Scheme 1.

NH,

+

HCN

-

Classical Strecker synthesis of r-amino acids.

Lipton and co-workers investigated the viability of the asymmetric Strecker amino acid synthesis in which they utilized cyclic guanidine dipeptide 2 in the reaction of N-benzhydrylimines 1 with hydrogen cyanide to give N-benzhydryl-cc-aminonitriles3 (Scheme 2) [3]. N-Benzhydrylimines 1, derived from aromatic aldehydes, gave products 3 in generally high enantiomeric excess. However, electron-deficient 3-nitro, 3-pyridyl, and aliphatic aldehyde derivatives afforded racemic products. H

2 (2 mol%)

0 MeOH, 75 "C 1 Scheme 2.

71-97%, 10-99% ee

H

3

Asymmetric Strecker synthesis with cyclic dipeptide 2 (Lipton and co-workers)

188

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Recent Developments in Catalytic Asymmetric Strecker-Type Reactions

Sigman and Jacobsen reported the first example of a metal-catalyzed enantioselective Strecker-type reaction using a chiral Al"'-salen complex (salen = N,N'-bis(salicy1idene)ethylenediamine dianion) [4]. A variety of N-allylimines 4 were evaluated in the reaction catalyzed by complex 5 to give products 6,which were isolated as trifluoroacetamides in good yields and moderate-to-excellent enantioselectivities (Scheme 3). Substituted arylimines 4 were the best substrates, while alkyl-substituted imines afforded products with considerably lower ee values. Jacobsen and co-workers also reported that non-metal Schiff base catalysts 8 and 9 proved to be effective in the Strecker reaction of imines 7 with hydrogen cyanide to afford trifluoroacetamides 10 after reaction with trifluoroacetic anhydride, since the free amines were not stable to chromatography (Scheme 4) [S].

0 N-

RAH 4

1. 5 (5 mol%), PhMe, -70 "C, 15 h +

HCN

!=,CANd

RACN

2,TFAA 91-99%, 37-95% ee

6

5 Asymmetric Strecker synthesis with chiral Al"'-salen catalyst 5 (Sigman and Jacobsen). TFAA = trifluoroacetic anhydride.

Scheme 3.

0

N,R2

+ R1JL

HCN

1 . 9 (2 mol%), PhMe, -70 "C, 20 h 9

2. TFAA

7

65-99%, 77-97% ee

R2 = Bn, ally1

CF3AN*R2 R'&N 10

8 R = polystyrene, X = S

9 R=Ph,X=O OC(0) tBu Asymmetric Strecker synthesis with salicylimine catalyst 9 (Vachal and Jacobsen). Bn = benzyl.

Scheme 4.

Catalyst 9 was very effective for the hydrocyanation of both aromatic and aliphatic imines 7 in high enantioselectivities and yields, and either N-benzyl- or N-allylimines could be used. The key elements responsible for the high enantioselectivity were the presence of bulky tea-

Recent Developments in Catalytic Asymmetric Strecker- Type Reactions

butyl substituents at both the amino acid position and at the 3-position of the salicylimine moiety. Resin-bound catalyst 8 allowed purification of the Strecker products by simple filtration and solvent removal, and the catalyst could be reused indefinitely without loss of either activity or enantioselectivity. Recently, Vachal and Jacobsen have applied catalyst 9 to ketoimines in the presence of hydrogen cyanide in the catalytic synthesis of quaternary a-carbon atoms [6]. Snapper, Hoveyda and co-workers employed a similar salicylimine Schiff base ligand 12 in the asymmetric titanium-catalyzed Strecker reaction of aromatic N-benzhydrylimines 11 to give addition products 13 (Scheme 5) [ 7 ] . It was found that catalyst turnover was facilitated significantly in the presence of 2-propanol as an additive. The aminonitriles 13 are stable and directly purified by chromatography (acylation is not needed) and can be readily converted into the corresponding amino acids with 6 N HCI by concomitant cyanide hydrolysis and amine deprotection. Schiff base-type ligands 12 were also usefully employed in the titanium-catalyzed regio- and enantioselective addition of cyanide to unsaturated imines to give P,X-unsaturated a-amino nitriles in good yield and enantiomeric excesses [ 8 ] . Both aromatic and aliphatic substrates presented no problems in these reactions. Cyanide hydrolysis and amine deprotection could be carried out to afford optically enriched cc-amino amides and acids. Hoveyda, Snapper and co-workers have also investigated in detail the mechanism of this enantioselective titanium-catalyzed Strecker reaction with the appropriate kinetic, structural, and stereochemical data [9]. A mechanistic model consistent with the kinetic and stereochemical data was presented in which the titanium center is coordinated to the Schiff base unit of the ligand and the AA2 moiety of the peptidic segment of the chiral ligand associates and delivers the hydrogen cyanide molecule to the activated bound substrate in a bifunctional fashion. tBU H

0

Ph RANAPh 11

12 (10 mol%)

Ti(OiPr)4 (10 mol%), TMSCN (2 equiv) iPrOH (1.5 equiv), PhMe, 4 "C, 20 h

H 13

80-97%, 85-99% ee Strecker synthesis with chiral Schiff base ligand 12 (Snapper, Hoveyda, and co-workers). TMS = trirnethylsilyl.

Scheme 5.

Shibasaki and co-workers disclosed a general asymmetric Strecker-type reaction that was controlled by bifunctional Lewis acid-Lewis base catalyst 14 [ 101. N-Fluorenylimines 15 underwent catalytic asymmetric Strecker-type reactions with binaphthol catalyst 14 to give a-aminonitriles 16 in good to excellent enantioselectivities and yields (Scheme 6). aAminonitrile 16 (R = Ph) could then be converted to cc-aminoamide 17 in several steps. Aromatic, aliphatic, heterocyclic and ccJ-unsaturated imines 15 were used as general substrates in these reactions. The origin of the highly enantioselective cataylsis by 14 is believed to be attributed to the simultaneous activation of imines and trimethylsilyl cyanide by the

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190

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Recent Developments in Catalytic Asymmetric Strecker-Jype Reactions

Ph, ,Ph

;p

Cl-Al<E

14

0

9'

Ph' \Ph

1. HCI (g), HCOpH

1. 14 (9 mol%), TMSCN (2 equiv), PhOH (20

3. 1N HCI

2.2N HCI 66-97%, 70-96% ee

15

16

17

4. Amberlyst A-211MeOH

91%, 98% ee (R = Ph) Asymmetric Strecker synthesis with bifunctional Lewis acidLewis base catalyst 14 (Shibasaki and co-workers). DDQ = 2,3-dichloro5,6-dicyano-l,4-benzoquinone.

Scheme 6.

Lewis acid and the oxygen atom of the phosphane oxide, respectively. With this catalyst system, N-allyl- and N-benzhydrylimines generally gave lower enantioselectivities. The addition of phenol was found to have a beneficial effect on the reaction rates. The JandaJELTMsupported bifunctional catalyst of 14 has also been shown by Shibasaki and co-workers to promote the Strecker-typereaction of aromatic and cc,p-unsaturatedimines in excellent yields with 83437% ee in the presence of tert-butanol (110%) [ l l ] .The reactivity of the JandaJELTM catalyst was comparable to the homogeneous analogue 14, and the catalyst could be recycled at least four times. Corey and Grogan recently developed a novel catalytic enantioselective Strecker reaction which utilized the readily available chiral Cz-symmetric guanidine 19 as a bifunctional catalyst [12]. The addition of hydrogen cyanide to achiral aromatic and aliphatic Nbenzhydrylimines 18 gave N-benzhydryl-cc-aminonitriles 20 (Scheme 7), which were readily converted to the corresponding amino acids with G N HC1. The use of N-benzyl- or Nfluorenylimines afforded products of poor enantiomeric purity.

Ph

R

~

A

N ph

+

HCN

H 19 (10 mol%) * PhMe. -40 "C. 20 h

18 Scheme 7.

CN

80-99%, 76-88% ee

Ph

RANAPh H 20

Asymmetric Strecker synthesis with chiral guanidine catalyst 19 (Corey and Crogan).

Kobayashi and co-workers employed the chiral zirconium binuclear catalyst 22 in the asymmetric Strecker-type synthesis of cc-aminonitriles 23 from aldimines 21 with tributyltin cyanide (Scheme 8) [ 131. Aldimines 21 were in turn derived from aliphatic, aromatic, and

Recent Developments in Catalytic Asymmetric Strecker-Type Reactions I 1 9 1

heterocyclic aldehydes. High levels of enantioselectivities were observed in these reactions. These u-aminonitriles could be converted to cc-amino acid derivatives by methylation of the phenolic hydroxyl group, followed by acid or base hydrolysis and oxidative cleavage with cerium ammonium nitrate. Furthermore, the catalytic asymmetric Strecker amino acid synthesis starting from achiral aldehydes, amines, and hydrogen cyanide using catalyst 22 has been achieved (Scheme 9). It is noted that 150 years after the first discovery of the Strecker reaction, a truly efficient three-component asymmetric version has been accomplished. While the use of tributyltin cyanide is suitable for laboratory-scale experiments, industrial applications are expected for a more benign three component catalytic asymmetric Strecker process using hydrogen cyanide.

22 (3 rnol%), Bu,SnCN, PhMelPhH (1:l)

-65"C + 0 "C, 12 h t

HN

55-98%,74-92% ee RXCN 21

23

L = N-rnethylirnidazole 22 Asymmetric Strecker synthesis with chiral zirconium binuclear catalyst 22 (Kobayashi and co-workers).

Scheme 8.

RCHO

+

Hop +

HZN

HCN

22 (1-5rnol%) CHZCIZ, -45"C

*

76-1OO%, 84-94% ee

Me

Hop HN

ACNMe

Three-component Strecker synthesis with chiral zirconium binuclear catalyst 22 (Kobayashi and co-workers).

Scheme 9.

Two other types of catalysts have been investigated for the enantioselective Strecker-type reactions. Chiral N-oxide catalyst 24 has been utilized in the trimethylsilyl cyanide promoted addition to aldimines to afford the corresponding aminonitriles with enantioselectivities up to 73% ee [14]. Electron-deficient aldimines were the best substrates, but unfortunately an equimolar amount of catalyst 24 was used in these reactions. The asymmetric Strecker addition of trimethylsilyl cyanide to a ketimine with titanium-based BINOL catalyst 25 gave fast conversions to quarternary aminonitriles with enantiomeric excesses to 59% 1151.

192

I

Recent Developments in Catalytic Asymmetric Strecker-Type Reactions

0

0

\ / MeMe 24

25

Several reports have employed a more traditional approach where the use of enantiopure chiral amino auxiliaries, that, after the successful Strecker reaction, can be chemically modified to yield the free amino acids. For example, Chakraborty and co-workers have reported the highly diastereoselective addition of trimethylsilyl cyanide to a variety of aphenylglycinol-derived benzaldimines [ 161. (S)-a-Methylbenzylamine has been used as a chiral auxiliary for the asymmetric Strecker reaction [ 171. (R)-Phenylglycinol has been utilized as a chiral auxiliary from the asymmetric Strecker reaction products of aldehydes in the synthesis of apdisubstituted amino acids [ 181. (R)- and (S)-2-Amino-2-phenylethanol were used as chiral auxiliaries in the synthesis of optically pure a-arylglycines [19]. Ohfune and co-workers have developed several methodologies involving an asymmetric version of the Strecker synthesis called asymmetric transferring Strecker synthesis (ATS) which has been successfully applied to the synthesis of optically active p-hydroxy-asubstituted wamino acids [20]. This technique was further applied toward the synthesis of the Corey intermediate of lactacystin [21]. This Highlight has shown that catalytic asymmetric Strecker-type reactions are possible but are still under active investigation for improvements and generalizations. Important areas for future study will include wider application of starting aldimine substrates, finer catalyst tuning, and of the simple conversion of a-aminonitriles to a-amino acid derivatives. More importantly, large-scale industrial applications of these methods to the production of optically active a-amino acids will be the ultimate goal of these investigations. References A. STRECKER, Ann. Chem. Pharm. 1850, 75, 27. a) R. M. WILLIAMS, Synthesis of Optically Active @-AminoAcids; Pergamon: Oxford, 1989; b) R. M. WILLIAMS, J. A. HENDRIX, Chem. Rev. 1992, 92, 889; c) R. 0. DUTHALER, Tetrahedron 1994, SO, 1539; d) M. AREND,Angew. Chem. Int. Ed. 1999, 38, 2873; Angew. Chem. 1999, I I I, 3047. a) M . S. IYER, K. M. GIGSTAD, N.D. M. LIPTON, ]. Am. Chem. SOC. NAMDEV, 1996, 118,4910; b) M. S. IYER,K. M. GIGSTAD,N. D. NAMDEV, M . LIPTON, Amino Acids 1996, I I, 259. M. S. SIGMAN, E. N. JACOBSEN, ]. Am. Chem. SOC.1998, 120, 5315.

M. S. SIGMAN, P.VACHAL,E. N. Chem. Int. Ed. 2000, 39, 1279; b) M. S. SIGMAN,E. N. JACOBSEN, J . Am. Chem. SOC.1998, 120, 4901. 6 P. VACHAL, E. N. J A C O B S E N , Org. Lett. 2000, 2, 867. 7 C. A. KRUEGER, K. W. KUNTZ, C. D. J . D. DZIERBA, W. G. WIRSCHUN, GLEASON, M. L. SNAPPER, A. H. HOVEYDA, I . Am. Chem. SOC.1999, 121, 4284. 8 J. R. PORTER, W. G. WIRSCHUN, K. W. KUNTZ,M. L. SNAPPER, A. H. HOVEYDA,]. Am. Chem. SOC.2000, 122, 2657. 9 N.S. JOSEPHSOHN, K. W. KUNTZ, M. L. SNAPPER, A. H . HOVEYDA,].Am. Chem. SOC.2001, 123, 11594. 5 a)

JACOBSEN, Angew.

References 10

11

12

13

14

15

a) M. TAKAMURA, Y. HAMASHIMA, H. USUDA,M. KANAI,M. SHIBASAKI, Angew. Chem. Int. Ed. 2000, 39, 1650 b) M. TAKAMURA,Y. HAMASHIMA, H.USUDA,M. KANAI,M. SHIBASAKI, Chem. Pharm. Bull. 2000. 48, 1586. H . NOGAMI,S. MATSUNAGA, M. KANAI, Tetrahedron Lett. 2001, 42, M. SHIBASAKI, 279. E. J. COREY,M. J. GROGAN,Org. Lett. 1999, I , 157. a) H. ISHITANI,S. KOMIYAMA, S. KOBAYASHI, Angew. Chem. lnt. Ed. 1998. 37, 3186; b) H. ISHITANI, S. KOMIYAMA, Y. HASEGAWA, S. KOBAYASHI, J . Am. Chem. SOC.2000, 122, 762; c) S. KOBAYASHI, H. ISHITANI,Chirality 2000, 12, 540. B. LIU, X. FENG,F. CHEN,G. ZHANG,X. CUI. Y. JIANG, Synlett 2001, 1551. J . J . BYRNE,M. CHAVAROT, P.-Y. CHAVANT, Y.V A L L ~ Tetrahedron E, Lett. 2000, 41, 873.

a) T. K. CHAKRABORIY, K. A. HUSSAIN, G. V. REDDY,Tetrahedron 1995, 51, 9179; b) T . K. CHAKRABORIY, G. V. REDDY,K. A. HUSSAIN,Tetrahedron Lett. 1991, 32, 7597. 17 R. WARMUTH, T . E. MUNSCH,R. A. STALKER, B. LI, A. B E A T ” , Tetrahedron 2001, 57, 6383. 18 a) D. MA, K. DING, Organic Lett. 2000, 2. 2515; b) K. DING,D. MA, Tetrahedron 2001, 57, 6361. 19 R. H.DAVE,B. D. HOSANGADI, Tetrahedron 1999, 55. 11295. 20 a) K. NAMBA,M. KAWASAKI, I. TAKADA,S. IWAMA,M. IZUMIDA,T. SHINADA, Y. OHFUNE,Tetrahedron Lett. 2001, 42, 3733; b) S.-H. MOON,Y. OHFUNE,J . Am. Chem. , SOC.1994, 116, 7405; c) Y. O H F U N EM. HORIKAWA, J . Syn. Org. Chem. Jpn. 1997, 55, 982. 21 S. IWAMA, W.-G. GAO,T. SHINADA, Y. OHFUNE,Synlett 2000, 1631. 16

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Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Highly Enantioselective or Not? - Chiral Monodentate Monophosphorus Ligands in the Asymmetric Hydrogenation lgor V. Kornarov and Armin Borner

The development was over before it had really begun - this was certainly true for the use of monodentate chiral monophosphorus ligands in rhodium( I) catalysts for enantioselective hydrogenation reactions. Initially everything seemed very promising. In 1965 Wilkinson and co-workers discovered that [ RhCl(PPh3)3] catalyzes the hydrogenation of olefins [ 11. Only a few months later Vaska and Rhodes reproted the use of trans-coordinated bis(monophosphane) iridium complexes in the reduction of alkenes [ 21.Monophosphane ligands were also prominent in other newly discovered metal catalysts, whereas cis-chelating diphosphanes, such as bis(diphenylphosphany1)-ethanegreatly reduced the rate of hydrogenation. Mechanistic studies showed that the dissociation of a phosphane from Wilkinson's complex is essential for the initiation of the catalytic cycle. For this reason bidentate diphosphane ligands were regarded as unsuitable since the chelate effect enhances their binding to the metal center [ 31. In 1968, the suggestion from Horner and co-workers to employ chiral monophosphanes for the enantioselective hydrogenation of prochiral olefins was both timely and logical [4].Two Monsanto chemists, Knowles and Sabacky, realized this idea only a few months later through the use of a rhodium complex with the P-chiral ligands PAMP (oanisylmethylphenyl-phosphane la) and CAMP (0-anisylcyclohexylmethyl-phosphane Ib) for the hydrogenation of atropic acid [S]. They generated hydratropic acid in a 15% optical yield. With this report itaconic acid (ItH2) began its career as a prochiral test substrate, it was reduced with a 3% optical yield. la: R' = o-MeO-C,H,,

R2 = Ph (PAMP)

b: R' = Ph, R2 = CpCeH11 (CAMP) c: R' = Ph, R2 = mCsH7

MeQ>R2 R

Still in the same year Horner et al., now showed that a prochiral styrene could be hydrogenated in up to 8% optical yield by using an in situ formed Rh' complex of rnetbylphenyln-propyl-phosphane (Ic) [ 61. Clearly the disappointingly low enantioselectivities were a deciding factor that greatly hindered the rapid adoption of the new hydrogenation method. In addition came the blinkered focus on P-chiral phosphane ligands, the synthesis of

Highly Enantioselective or Not?

which, at that time, was relatively complicated and did not always proceeded without racemization. AMe: R’ = Ph, R2 = NHAc, R3 = Me AH: R’ = Ph, R2 = NHAC, R3 = H aMe: R’ = H, R2 = NHAc, R3 = Me

aH: R’ = H, R2 = NHAc, R3 = H ItMe2:R1= H, R2 = CH2COOMe, R3 = Me

R

ItH2: R’ = H, R2 = CHpCOOH, R3 = H

The situation changed drastically in 1971 when Dang and Kagan reported the synthesis and use of (R,R)-DIOP, the first chiral diphosphane ligand (71. The corresponding Rh’ complex was used for the hydrogenation of (2)-N-acetylaminocinnamic acid (AH) and promptly gave an optical yield of 72% and almost quantitative conversion - all this with the rhodium complex of a diphosphane! Four requirements were central to the design of DIOP 1)maximum conformational rigidity of the ligand, 2) strong coordination to the metal center 3) use of a ligand with chemically equivalent phosphorus atoms (C2-symmetry) and 4) facile and short access [8].

PPh2

H (R,R)-DIOP

(S)-BINAP

(S,S)-DuPHOS

It remains for chemical historians to analyze the reasons in all their complexity for the change in the direction of research, from mono- to diphosphane ligands, that now followed. The simple preparation of enantiomerically pure (R,R)-DIOP from naturally occuring (+)tartaric acid, the typically short hydrogenation times with seven-membered ring chelates, and the, for that time, impressive enantioselectivities even for the reduction of other substrates no doubt played an important role and stimulated the search for similarly effective (diphosphane) ligands. In the following years huge numbers of this type of ligand were prepared and tested in particular in the normal-pressure hydrogenation of the substrates itaconic acid ( ItH2), N-acetylaminoacrylic acid (aH), and (2)-N-acetylaminocinnamic acid (AH), or their methylesters (ItMez, aMe, AMe)-substrates which are still the standards against which hydrogenation catalysts are measured [ 91. Milestones in the development of the diphosphane family include the establishment of BINAP [lo] and DuPHOS 1111. The potential offered by the chiral diphosphane complexes of ruthenium [ 121 and iridium [ 131 in hydrogenation was also recognized. In parallel inves-

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Highly Enantioselectiue or Not?

tigations into the mechanism of the enantioselective hydrogenation [ 141 and the influence of the ligand parameters on it were carried out [15]. Diphosphinites [lG] and more recently diphosphonites [ 171 and diphosphites [ 181 as well hybrid ligands [ 191 have also been shown to be similarly effective to diphosphanes. That in 1972 Knowles and co-workers achieved an optical yield of 90% in the hydrogenation of unsaturated N-acetylphenylalanine precursors with an Rh catalyst containing the monophosphane CAMP, was completely lost in the euphoria over the bidentate ligands [20]. In the subsequent 30 years as far as enantioselective hydrogenation is concerned monophosphorus ligands have been living in the shadows. Of course, every now and then chiral monophosphane ligands would be prepared, but usually only as intermediates on the road towards more efficient and hopefully unpatented diphosphoms ligands. Almost ironically it is Kagan, who with DIOP initiated the rapid development of the chelating diphosphane ligands and who has had such a lasting influence on this area, who recently in a retrospective over monophosphanes, with regard to enantioselective hydrogenation, came to the following conclusion: “We can expect that they [monophosphanes] will play a role of increasing importance in many aspects of organometallic catalysis. We hope that this review will encourage practitioners of asymmetric catalysis to consider the potential of chiral monodentate phosphines and to investigate this area which has been quite neglected till now” [21]. This impulse from such a respected source found an unexpectedly rapid response. In the last two years several groups have reported the use of monophosphorus ligands in highly enantioselective hydrogenation reactions, whereby different oxidation state of the trivalent phosphorus atom have received attention. Leading the way Guillen and Fiaud reported as early as 1999 a rhodium complex of 1,2,5-triphenylphospholane(2a), a monodentate species of the DuPHOS-type, that reduces AMe with 82% ee (Table 1) [22, 231. Incidentally this ligand is closely related to 2,s-dimethylphospholane 2b the compound that stands at the beginning of the development of the bidentate DuPHOS by Burk et al., but on ground of its

Tab. 1. Highly enantioselelective Rh-catalyzed hydrogenation with

monophosphorus ligands. Ligand

Substrate

ee [%]

Author(s), Ref:

2a

AMe aMe aMe ItMe2 ItMe2 AMe AH aMe aH ItH2 ItH2 ItH2 ItH2

82-92 (S)

Fiaud [22, 231 Orpen and Pringle [26] Reetz [ 271 Reetz [ 271 Reetz [28] de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 de Vries and Feringa [ 301 Beller [ 311 Helmchen [ 321 Helmchen [ 321

(S)-3a (R)-3b (R)-3b (S)-3c (S)-3d (Sj-3d (S)-3d (S)-3d (S)-3d (574 5a

ent-5b

92 (4 94 ( S ) 90 ( R ) >99 ( S ) 98.4 ( R ) 97.1 (R) >99 ( R ) 98.7 (R) 96.6 (S) 90.0 (R) 92.6 (R) 96.0 (S)

Highly Enantioselective or Not?

poor enantioselectivity in hydrogenation reactions (maximum 60% ee) [24] has since only been used as a synthetic building block on the way to bidentate ligands [ 251.

mo'

R q P - P h

3a: R = ferf-Bu 3b: R = Et 3c: R = (R)-0-CH(Me)-Ph 3d: R = NMe2

R 2a: R = Ph b:R=Me

4

5a: R = iPr b: R = C y

In 2000 Orpen, Pringle, and co-workers attained the hydrogenation of aMe in 92% ee with the asymmetric monophosphonite 3a and thus a higher enantioselectivity than is possible with comparable Cz-symmetricdiphosphonite analogues [ 261. With this publication the widely accepted dominance of the bidentate diphosphorus ligands was questioned for the first time. Reetz and Sell showed in response that through the exchange to the tert-butyl group for an ethyl group (+3b) the enantioselectivity can be increased further [ 271. With the same catalyst ItMez was also hydrogenated with a respectable 90% ee. However, in spite of this a related diphosphonite ligand when tested delivered >99% ee. The old rule that chelating diphosphorus ligands are superior still appeared to hold. A clear tie in regard to performance, with enantioselectivities that could not be topped, was achieved with the use of monodentate binaphtholphosphites and phosphoramidites. Reetz and Mehler prepared the monophosphite 3c [28]. The corresponding catalyst induces >99% ee in the hydrogenation of ItMez. Particularly noteworthy is the high substrate:rhodium ratio of up to 5000:1, that still guarantees complete conversion in 20 h under normal pressure. Surprisingly the configuration of the chiral carbon atom of the benzyl ether does not play any kind of role. The enantioselectivity of this type of ligands is dominated by the chiral binaphthyl unit, in complete contrast to other P substituents, for example, sterically demanding aryloxy groups, that have a very significant influence on the enantioselectivity and conversion. Phosphoramidites, a ligand class that has only recently been introduced into asymmetric hydrogenation, in the form of hybrid chelate ligands [291, induce excellent enantioselectivity as monodentate ligands. Thus de Vries, Feringa, and co-workers could reduce standard substrates in >96% ee with a rhodium complex based upon the binaphtholphosphoramidite 3d, once the solvent and reaction temperature had been optimized [ 301.

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Highly Enantioselective or Not?

A

B

Fig. 1. Monodentate (A) and chelating (B) binaphthyl ligands on a metal center and their effect on the stereoselective occupation of the squares.

The high stereodiscriminating ability of the binaphthyl backbone was also shown by Beller et al. with the relevant phosphane (S)-4 in hand [31]. Thus, up to 90% ee were achived in the hydrogenation of AMe in toluene as solvent. A breakthrough in the design of a new class of ligands was achieved by Helmchen and co-workes in 2002 [32]. They found that oxaphosphinanes like Sa,b can provide up to 96% ee in the Rh-catalyzed hydrogenation of ItH2. Moreover, this paper describes the first example that even secondary phosphanes can be successfully employed as ligands in enantioselective catalysis. I t is noticeable that most monodentate ligands that induce a high enantioselectivity are phosphorus derivatives of binaphthol. Based on the crystal structure of a Pt” complex with monophosphonite ligands Orpen and Pringle have proposed a plausible explanation that could be helpful in the development of other selective monophosphorus ligands [26]. Through the cis coordination both the sterically demanding monophosphonite ligands take up an exceptionally stable configuration around the metal center, through which rotation about the P - 0 bond is reduced. In this conformation the two biaryl fragments point out of the plane of the projection in what is described as edge-on arrangement. In a virtual coordination system two diagonally opposing squares are occupied (Figure 1 A). The squares at the top left and bottom right are not effectively occupied, because of the planar arrangement of the two phenyl groups in the plane of the projection (face-on). From investigations with chelating bis(diary1)phosphorus ligand complexes it is known that such an alternating edge/ face arrangement [ 331 can support the diastereo-differentiating coordination of a prochiral substrate through the minimization of repulsive interactions [ 341. In contrast, by the cis coordination of the diphosphonite ligands the rotamer stabilized is that in which the biaryl units are in the face-on orientation; none of the squares is favored (Figure 1 B). Thus the chances of diastereomeric recognition of the prochiral substrate are greatly reduced. On the basic of the model by Pringle and Orpen [ 2 G ] and supported by first semiempirical calculations from de Vries and Feringa [30] it is clear that for the mechanism of chiral transfer in asymmetric hydrogenation, mono- and diphosphorus ligands do not necessarily fundamentally differ [ 35-37]. The requirement originally laid down by Kagan, that the catalyst must be conformationally rigid, is clearly also achievable with two appropriate monodentate monophosphorus ligands. As a consequence of these results the strategic decision as to whether one should favor mono- or diphosphorus ligands comes down to the principle question asked of every asymmetric catalyst: is it highly enantioselective or not?

References

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Clearly the potential that chiral monophosphorus ligands have in hydrogenation reactions is far from exhausted, a hypothesis that is supported by the well known and excellent results from other asymmetric catalytic reactions [21]. Naturally the demands for the design of monophosphorus ligands that effect high enantioselectivity are higher, something that stimulate the search for new principles for the selective stabilization of diastereomeric catalysis intermediates, for example, by secondary interactions between the ligand and the metal or substrate [38]. The synthesis of monophosphorus ligands is often simpler than that of diphosphorus compounds, which is justification enough to look closer at these types of ligands that in the past were often undervalued. References 1

J. F. YOUNG, J. A. OSBORNE, F. A. J A R D I N E , G. WILKINSON, ]. Chem. Soc.; Chem. Commun. 1965, 131-132.

2 L. VASKA, R. E. RHODES, ]. Am. Chem. SOC.

1965, 87,4970-4971. 3 A highly informative review over the

initial problems associated with the use of diphosphane ligands in homogeneous catalyst: P. W. N. M. VAN LEEUWEN,P. C. J. KRAMER,J. N. H. REEK,P. DIERKES, Chem Rev. 2000, 100, 2741. 4 L. HORNER, H. BUTHE, H. SIEGEL, Tetrahedron Lett. 1968, 4023-4026. 5 W. S. KNOWLES, M. J. SABACKY,]. Chem. Soc.; Chem. Commun. 1968, 1445-1446. 6 L. HORNER, H. SIEGEL, H. BUTHE, Angmv. Chem. 1968, 80, 1034-1035; Angew. Chem. Int. Ed. Engl. 1968, 7, 942-943. 7 T. P. DANG,H. B. KAGAN, ]. Chem. Soc.; Chem. Commun. 1971, 481. 8 H. B. KAGAN. T. P. DANG,]. Am. Chem. SOC.1972, 94, 6429-6433. 9 H. BRUNNER, W. ZETTLMEIER, Handbook of Enantioselectiue Catalysis with Transition Metal Compounds, Vol. 1, VCH, Weinheim, 1993; U. NAGEL, J. ALBRECHT, Top. Catal. 1998, 5, 3-23. 10 A. MIYASHITA, A. YASUDA.H. TAKAYA, K. TORIUMI, T. ITO,T. SOUCHI,R. NOYORI,/. Am. Chem. SOC.1980, 102, 7932-7934. 11 M. J. BuRK,J.Am. Chem. SOC.1991, 113, 8518-8519. 12 R. G. BALL, B. R. JAMES, J. TROTTER, D. K. DANG,]. Chem. SOC.;Chem. Commun. 1979, 460-461; J,-P. G E N ~inT Aduanced Asym-metric Synthesis (Ed.: G. R. STEPHENSON), Chapman & Hall, London, 1996, pp. 146-180.

N. C. CHAN,J. A. OSBORNE!].Am. Chem. SOC.1990, 112, 9400-9401; F. SPINDLER, B. PUGIN,H.-U. BLASER, Angew. Chem. 1990, 102, 561-562; Angew. Chem. Int. Ed. Engl. 1990, 29, 558559. 14 A. S. C. CHAN,J. J. PLUTH,J. HALPERN, ]. Am. Chem. SOC.1980, 102, 5952-5954; J. M. BROWN,P. A. CHALONER,]. Chem. SOC.; Chem. Commun. 1980, 344-346; J. M. BROWNin Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN, A. PFALTZ, H. YAMAMOTO), Springer, Berlin, 1999, pp. 121-182. 15 K. INOGUCHI, S. SAKURABA, K. ACHIWA, Synlett 1992, 169-178; T. V. RAJANBABU, T. A. AYERS,A. L. CASALNUOVO,]. Am. Chem. SOC.1994, 116,4101-4102. 16 R. SELKE, ]. Organomet. Chem. 1989, 370, 249-256. 17 M. T. REETZ, A. GOSBERG, R. GODDARD, S.-H. KYUNG, Chem. Commun. 1998, 2077-2078. 18 M. T. REETZ,T. NEUGEBAUER, Angew. Chm. 1999, 111, 134-136; Angew. Chem. Int. Ed. 1999, 38, 179-181. 19 A collection of ligands can be found in: H. BRUNNER, W. ZETTLMEIER, Handbook of Enantioselectiue Catalysis with Transition Metal Compounds, Vol. 11, VCH, Weinheim, 1993; J. HOLZ,M. QUIRMBACH, A. BO RN E R,Synthesis 1997, 983-1006; M. A. OHFF,J. HOLZ,M. QUIRMBACH, BORNER, Synthesis 1998, 1391-1415. 20 W. KNOWLES,M. J. SABACKY, B. D. VINEYARD,]. Chem. Soc.; Chem. Commun. 1972, 10-11. 21 F. LAGASSE, H. B. KAGAN, Chem. Pharm. Bull. 2000, 48, 315-324.

13 Y.

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24 25

26

27 28

29

30

31

32

33

F. GUILLEN, J.-C. FIAUD,Tetrahedron Lett. 1999, 40, 2939-2942. By optimizing the reaction conditions values of up 92% ee are possible: F. GUILLEN, Dissertation, Universitb ParisSud, 1999. M. J. BURK,J. E. FEASTER, R. L. HARLOW, Tetrahedron: Asymmetry 1991, 2, 569-592. M. J. BURK,A. PIZZANO,J. A. MARTIN, L. M. LIABLE-SANDS, A. L. RHEINGOLD, Organometallics 2000, 19, 250-260. C. CLAVER,E. FERNANDEZ, A. GILLON,K. HESLOP,D. J. HYEIT, A. MARTORELL, A. G. O R P E NP. , G. PRINGLE,Chem. Commun. 2000,961-962. M. T. REETZ,T. SELL,Tetrahedron Lett. 2000, 41, 6333-6336. M. T. REETZ,G. MEHLER,Angew. Chem. 2000, I1 2, 4047-4049; Angew. Chem. Int. Ed. 2000, 39, 3889-3890. G. FRANCIO,F. FARAONE, W. LEITNER, Angew. Chem. 2000, 112, 1486-1488; Angew. Chem. Int. Ed. 2000, 39, 14281430. M. VAN D E N BERG,A. I. MINNAARD, E. P. SCHUDDE, J. VAN ESCH,A. H . M. D E VRIES,J. G. D E VRIES;B. L. FERINGA, ]. Am. Chem. SOL.2000, 122, 11539-11540. K. JUNGE,G. OEHME,A. MONSEES, T. RIERMEIER, U. DINGERDISSEN, M. BELLER, unpublished results. M. OSTERMEIER. 1. PRIER, G . HELMCHEN, Angew. Chem. 2002, 114, 625-628; Angew. Chem. Int. Ed. 2002, 41, 612-614. B. D. VINEYARD, W. S. KNOWLES, M. J. SABACKY, G. L. BACHMANN, D. J.

34

35

36

37

38

WEINKAUFF, J . Am. Chem. SOC. 1977, 99, 5946-5952. H. BRUNNER, A. WINTER, I. BREU,]. Organomet. Chem. 1998, 553,285-306; C. R. LANDIS,S. FELDGUS, Angew. Chem. 2000, 112, 2985-2988; Angew. Chem. Int. Ed. 2000, 39, 2863-2866, and refs. therein. That n-stacking effects, such as those recently reported for a Pdbis(monophosphane) complex, contribute to the conformer stabilization cannot be ruled out ( H . BRUNNER, I. DEML,W. DIRNBERGER, B. NUBER,W. REIRER,Eur.]. Inorg. Chem. 1998, 43-54). Unfortunately, the square model does not hold for a [ PtC12(Sa)] complex, where significant distortion of the oxaphosphinane ringes were observed. Ref. [ 321. In contrast to the hydrogenation measurements reported in ref. [26, 27, 301, Reetz et al. in ref. [28] used predominantely an Rh:ligand ratio of 1:1, although with a 1:2 ratio no significantly different enantioselectivity was observed. Unpublished NMR spectroscopy experiments indicate that 1:2 precatalyst complexes are formed in the in situ reaction of [ Rh(cod)~]BF4(cod = 1,5-cyclooctadiene) with the monophosphites. In addition the hydrogenation reactions show a strong (positive) nonlinear effect, an indication that two monophosphite groups are also involved in the transition state. (M. T. REETZ,personal communication). Review see: A. BORNER,Eur. ]. Inorg. Chem. 2001, 327-337.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I201

Improving Enantioselective Fluorination Reactions: Chiral N-Fluoro Ammonium Salts and Transition Metal Catalysts

Within the still growing area of enantiomerically pure compounds, chiral fluorinated molecules are gathering momentum due to the unique properties of the carbon-fluorine bond, and the importance of the fluorine moiety in molecules of pharmaceutical and biological interest is undisputed [ 11. Among all the asymmetric processes towards organofluoro compounds, the direct synthesis of fluorinated stereogenic centres, avoiding a resolution procedure [ 21, remains of special challenge. Basically, two different routes are conceivable for their asymmetric construction: 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic atrimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. Ever since, routes towards fluorinated stereogenic centres have relied on electrophilic fluorine sources for substitution reactions [4].This caused the development of a variety of suitable achiral N-F fluorinating reagents [ 51 and their exploitation in diastereoselective fluorinations which are characterised by efficient substrate control and reasonably high diastereoselectivities [6a]. Important contributions were made by Davis [ 61, Enders [ 71 and others [4,81. In an elegant approach, Enders has employed enantiopure a-silylketones that upon regioselective deprotonation and fluorination with N-fluorobenzosulfonimide 1 yield the corresponding mono-fluorinated compounds in good to high diastereomeric excesses. For example, acyclic ketone 2 can be converted into a-fluorinated 3 which was purified to 96% de. The geometry of the intermediary enolate could be controlled by the use of either LDA or LHMDS as base, and the removal of the TBDMS-group was achieved without racemization to yield 4 (96% ee). Most importantly, this protocol allows for the controlled synthesis of secondary stereogenic centers [ 7b]. At about the same time of the work on diastereoselective fluorination, chiral non-racemic N-fluoro compounds for direct enantioselective fluorination of C-H acidic substrates were developed. Initial work on reagent control by Differding and Lang, who introduced chiral N-fluoro

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aS-f7Q q,o o,,o 1

3

2

4

Scheme 1. Substrate mediated dia- and enantioselective fluorination with an achiral quaternary N-F ammonium salt.

sultam 5a [9], was followed by modified structures 5b,c [lo] as well as development of All these chiral reagents require a related compounds such as 6 [ 111 and 7 [ 121 [Fig. (l)]. sulfonamido group for activation of the N-F bond. In situ generated metallated enolates serve as substrates and the enantiomeric excesses generally reach satisfying values of up to 80%. However, preparation of these reagents is hampered by tiresome multi-step synthesis and use of hazardous fluorine sources such as FClO3 or F2 itself. Recently, two groups have now described the preparation and application of enantiopure N-fluoro ammonium salts from cinchona alkaloids [Fig. (2)]. In an elegant contribu-

5a:R=H b: R = CI c: R = OCH3 Fig. 1.

7 (R' = H, OAC; R" = CH3, pTol)

6

Achiral neutral N-fluoro reagents for electrophilic fluorination

BF4-

CH2CI OCH3 &OCH3 8

9

10

Fig. 2. Reagents for the stoichiometric enantioselective fluorination.

11

Improving Enantioselective Fluorination Reactions

tion, Takeuchi and Shibata used an in situ protocol to generate the active fluorinating species from neutral 9 and 10, respectively, and Selectfluor 8 [13, 141.Independently, Cahard described the synthesis of preformed cinchona alkaloid ammonium salts such as 11 [15]. While preliminary I9F nmr studies had revealed that the F+ transfer from Selectfluor onto the cinchona alkaloid is seemingly fast and irreversibe [ 13a], both groups have recently characterised some of these compounds in the solid state, thereby clearly establishing the existance of a N-F bond [13b, 16, 171. Using the conventional in situ generation of metallated enolates, 11 could be employed for enantioselective fluorination of a-methyl tetralone 12, however, two equivalents of base were necessary to deprotonate the acidic hydroxyl functionality of 11 in order to prevent competitive enolate protonation [Scheme 2, eq. (I)]. Unlike the case for unreactive neutral 5-7, preformed silylenolether 14 was now cleanly fluorinated by both the synthesised reagent 11 and the combination of 8 and 9 showing that the cationic nature of the new reagents results in higher fluorination power [eq. (2)]. However, since in the present systems both rate and enantioselectivity appear to be highly dependent on the reaction temperature, a precise comparison of the results is difficult. Under otherwise unchanged conditions, Takeuchi observed an increase in ee for five-membered substrates such as 16 [eq. (3)] and further successful examples include P-keto esters (up to 80% ee) and acyclic P-cyano esters such as 18 [eq. (4)].For the latter case, high enantioselectivity required preformation of the ammonium reagent from 10 and 8. Recent additional work by Shibata [13b] has shown that related compounds such as oxindoles 20 can also be employed as substrates. Fluorinated oxindole 22 could be obtained with up to 82% ee when the preformed N-F ammonium salt of the Sharpless ligand (DHQD)*PYR(21) was used. Based on their fluorination protocol, Cahard and co-workers have elaborated a convenient synthesis of a-fluoro-a-phenylglycinderivatives [ 181. For example, upon reaction with reagent 24 racemic nitrile 23 was converted into the fluorinated derivative 25 with 94% enantiomeric excess. The corresponding ester derivatives of 23 gave rise to somewhat lower ees. This difference was contributed to the fact that a-lithiated nitriles can be in equilibrium with axialchiral lithio ketene imines of low racemization barriers thus leading to a potential dynamic kinetic resolution. Obviously, the switch from neutral N-F compounds to N-F ammonium salts had not only a strong beneficial effect on reactivity but the commercial availability of both Selectfluor and cinchona alkaloids also ensures easy accessability of the chiral reagents. Still, from an economical point of view a catalytic version of the process would certainly be desirable and, based on recent catalytic variants by Lectka for bromination and chlorination [ 191, should be within reach. A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. Here, the catalyst was ammonium compound 27, and 1 served as F-source. Under optimized conditions, methyl indanone carboxylate 26 was fluorinated with up to 68% ee. Within the context of asymmetric synthesis, it must be intriguing that no use of chiral

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13 80% cy, 56% ee

12

A: 11, NaOH, THF, -6OOC

14

B: 918, CH3CN, -2OOC

15 A: 93% cy, 61% ee

B: 93% cy, 54% ee

918, CHsCN,

-2OOC 16

17 99% cy, 89% ee F ,CN

d C O & H s

CH2C12, 1018, CHsCN, -6OOC

18

d C /O z C H 3

(4)

19 80% cy, 87% ee

21, CHaCN,

(5)

CH2C12, -6OOC H

H

20

22

H3C0

OCH3

21 Scheme 2. Representative enantioselective fluorinations with chiral quaternary N.F ammonium salts. The absolute configuration of product 22 is unknown.

Improving Enantioselective Fluorination Reactions

w

J C

BF4-H&?~~~3

0 2 LiHMDS, THF, 24, -78%

OCH3

-

$CNo

23

/

25

24

56% cy, 94% ee Scheme 3. Synthesis o f fluorinated amino acids via enantioselective fluorination. The absolute configuration of the product i s unknown.

27

27 (10 mol%)/ 1, COpCH3

&F

toluene, rt 26

CO2CH3 28

92% cy, 69% ee Scheme 4. Enantioselective fluorination via asymmetric phase-transfer reaction. The absolute configuration of the product is unknown.

non-racemic metal complexes for fluorination reactions had been reported. Given the extreme success of asymmetric metal-mediated and -catalysed processes [ 221, such an approach must appear highly attractive. Bmns and Haufe have described the first examples of a transition metal complex mediated asymmetric ring opening (ARO) of both rneso- and racemic epoxides via formal hydrofluorination [23]. Initial attempts with chiral Eu"' complexes led to very low asymmetric induction. Opening of cyclohexene oxide 30 with potassium hydrogendifluoride in the presence of 18-crown4 and a stoichiometric amount of Jacobsens chiral chromium salen complex 29 [ 24a] finally yielded two products 31 and 32 in a 89:11 ratio and 92% combined yield, the desired product 31 being formed with 55% ee. Limiting 29 to a catalytic amount of 10 mol% led to an increase in the ratio of 31, however, with the enantiomeric excess dropping to 11%(Scheme 5).

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29

29, KHFp,

30

*

18-crown-6, DMF A: 100 mol% 29 B: 10mo1°h29

31

32

55% ee 11% ee

First nucleophilic enantioselective epoxide opening with enantiopure transition metal Lewis acid 29. Scheme 5.

In the stoichiometric reaction the low extend to which chloride promoted ring opening occurs is noteworthy. In a stoichiometric ARO of cyclohexene oxide 30 with 29 and TMSN3, Jacobsen reported complete C1 incorporation [ 24a] indicating that under the reaction conditions no anion exchange takes place at the metal complex prior to ring opening. Since in the present case C1- displays a much higher nucleophilicity than FF, an identical product distribution should have been expected. The fact, however, that this is not the case, leads to the conclusion that the Cr complex acts as a conventional Lewis acid that activates the epoxide for ARO by fluoride. The amount of C1 incorporation is likely to be the consequence of competing ring opening by free chloride generated under the reaction conditions. One can almost assume that the present catalytic system cannot be operating by the cooperative mechanism [24a, b] that has been so successful in the related AROs described by Jacobsen [ 24~1.Furthermore, the dramatic drop in enantioselectivity in the catalytic reaction suggests that the fluoride source does not allow for rapid release of the catalyst after the ARO has occurred thus resulting in uncatalysed unselective ring opening. Final conclusions will have to await further detailed mechanistic investigation [ 251. A first real breakthrough in transition metal catalysed fluorination has recently been achieved by Hintermann and Togni [26]. In their work, monosubstituted 8-keto esters such as 34 were chosen as starting materials and focus was made on Lewis acid activation. It was anticipated that the necessary enolisation of the P-keto esters would be accelerated by catalytic amounts of metal complexes. From kinetic screening, complexes based on Ti emerged as the most suitable catalysts and TADDOL-modified [27] Ti complexes 33a and 331, as the best ones in terms of asymmetric induction. Isolation of these Ti complexes, which during course of this work [2G] was achieved for the first time, was necessary to guarantee reproducibility and enantioselectivity. In the presence of 5 mol% of catalyst and a slight

Improving Enadoselective Fluorination Reactions

excess of the fluorinating agent 8 conversion to the fluorinated products such as 35 occurred smoothly in acetonitrile at room temperature (Scheme 6). Not surprisingly, the sterically more elaborated complex 33b gave rise to higher enantioselectivities (62-90% ee for given examples vs. 28-59% ee with 33a) but it is interesting to see that it also represents the more reactive catalyst: for example, in the presence of 33b the reaction time for conversion of 34 is 20 min while it is 2 h with 33a!

33 a) R = Ph, L2 = ( C H Z O C H ~ ) ~ b) R = 1-Nph, L2 = 2 NCCH3

8 (1 16 mol%)

OCHPh2

34

33 CHSCN, b (5 mol%) RT, * 20 min

CzH5VOCHPh2

(6)

35 81 'Yo ee

Scheme 6. First enantioselective electrophilic fluorination reaction catalysed by enantiopure Ti-TADDOLates 33a,b. The absolute configuration o f the product is unknown.

Current understanding of the reaction suggests that an unprecedented mechanism is operating. Unlike in classical Lewis acid catalysed reactions [ 281, the metal complex does not activate the carbonyl moiety but is understood to enhance the degree of enolisation and thus create the necessary nucleophilic enol structure for reaction with the fluorinating agent [ 291. Regarding enantioselectivities, this new catalytic fluorination can readily compete with the results from stoichiometric reactions with chiral N-F compounds, and the fact that both the TADDOL ligands and the fluorine source Selectfluor are commercially available makes it the most convenient one presently at hand. Since the reaction is so far limited to B-keto esters, it will be interesting to see whether this catalyst system can be transferred successfully to other substrate classes. Clearly the enantioselective synthesis of fluorinated stereogenic centres other than quaternary remains a huge challenge. Future work could also aim to combine the two novel fluorination procedures. Especially where reaction rate is concerned, the combined use of (achiral) transition metal catalyst and substoichiometric amounts of cinchona alkaloids might give rise to successful complementary catalytic systems. An interesting complimentary approach has been devised by Togni and Mezzetti who reported on Ru-F complexes for a catalytic fluorination by exchanging existing halide groups for fluoride [30]. Use of a chiral nonracemic Ru" catalyst led to initially moderate asym-

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metric induction, however, at higher conversions the enantiomeric excess of the fluorinated product dropped significantly. This implies that a desired kinetic resolution might only be involved during the early stages of the reaction. To summarise, the development of novel enantioselective fluorination methods with the aid of either chiral N-fluoro ammonium salts or transition metal catalysts has established truely practical routes towards chiral fluorinated compounds. Despite the current mechanistic uncertaincies it appears that a door has been opened for exciting and promising further development of asymmetric (catalytic) fluorination reactions in the near future [ 31, 321. References

a) Enantiocontrolled Synthesis of FluoroOrganic Compounds (Ed.: V. A. SOLOSHONOK), Wiley, New York, 1999; b) Asymmetric Fluoroorganic Chemistry, Applications, and Future Directions, P. V. RAMACHANDRAN, ACS Symp. Ser. 746, Washington, 2000. 2 Myers has reported on interesting fluorinated HIV protease inhibitor analogues. However, their stereoselective synthesis as relying on the respective enantiopure fluorinated building blocks derived from resolution: A. G. MYERS,J. K. BARBAY, B. ZHONG,/. Am. Chem. SOC. 2001, 123, 7207-7219. 3 G . L. H A N N ,P. SAMPSON, /. Chem. SOC., Chem. Commun. 1989, 1650-1651. 4 S. D. TAYLOR, C. C. KOTORIS,G. H U M , Tetrahedron 1999, 55, 12431-12477. 5 G. S. LAL, G . P. PEZ. R. G. SYVRET, Chem. Rev. 199G, 96, 1737-1755. 6 a) F. A. DAVIS,P. V. N. KAsu, in Org. Prep. Proced. Int. 1999, 31, 125-143; see also: b) F. A. DAVIS,P. V. N. KAsu, Tetrahedron Lett. 1998, 39, 6135-6138; c) F. A. DAVIS, W. HAN, Tetrahedron Lett. 1992, 33, 11531156; d) F. A. DAVIS,R. E. REDDY,Tetrahedron Asymmetry 1994, 5,955-960. 7 a) D. ENDERS,M. POTTHOFF,G. RAABE,J. RUNSINK,Angew. Chem. 1997, 109, 24542456; Angew. Chem. Int. Ed. Engl. 1997, 36, 2362-2364; b) D. ENDERS,S. FAURE,M. POITHOFF,J . RUNSINK,Synthesis 2001, 2307-2319. 8 J. J. MCATEE,R. F. SCHINAZI, D. C. LIOTTA,/. Org. Chem. 1998, 63, 2161-2167. 9 E. DIFFERDING, R. W. LANG,Tetrahedron Lett. 1988, 29, 6087-6090. 10 a) F. A. DAVIS,P. ZHOU,C. K. MURPHY, Tetrahedron Lett. 1993, 34, 3971-3974; 1

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18

19

b) F. A. DAVIS,P. ZHOU,C. K. MURPHY, G. SUNDARABABU, H . QI, W. H A N ,R. M. PRZESLAWSKI, B.-C. CHEN,P. J. CAROLL, ]. Org. Chem. 1998, 63,2273-2280,9604. Y. TAKEUCHI, T. SUZUKI,A. SATOH,T. SHIRAGAMI, N. SHIBATA,].Org. Chem. 1999, 64, 5708-5711. a) Y. TAKEUCHI, A. SATOH,T. SUZUKI, A. KAMEDA, M. DOHRIN,T. SATOH,T. KOIZUMI? K. L. KIRK,Chem. Pharrn. Bull. 1997, 45, 1085-1088; b) See also: 2. LIU, N. SHIBATA,Y. T A K E U C H I ,Org. ~ . Chem. 2000, 65, 7583-7587 and cited literature. a) N. SHIBATA,E. SUZUKI,Y. TAKEUCHI,]. Am. Chem. SOC.2000, 122; 10728-10729. b) N. SHIBATA,E. SUZUKI,T. ASAHI, M. SHIRO,/. Am. Chem. SOC. 2001, 123, 70017009. a) Selectfluor is l-chloromethyl-4-fluoro-1,4diazoniabicyclo[ 2.2.2loctane bis{tetrafluoroborate} and is also known under the abbreviation F-TEDA; b) R. E. BANKS,/. Fluorine Chem. 1998, 87, 1-17. D. CAHARD,C. AUDOUARD, J.-C. PLAQUEVENT, N. ROQUES,Org. Lett. 2000, 2, 3699-3701. For a first isolation of the chiral ammonium salt of quinuclidine: M. ABDUL-GHANI, R. E. BANKS,M. K. BESHEESH, I. SHARIF,R. G . SYVRET, /. Fluorine Chem. 1995, 73, 255-257. D. CAHARD,C. AUDOUARD, J.-C. PLAQUEVENT, L. TOUPET,N. ROQUES, Tetrahedron Lett. 2001, 42, 1867-1869. B. MOHAR,J. BAUDOUX,J.-C. PIAQUEVENT, D. CAHARD,Angew. Chem. 2001, 113, 4339-4341; Angew. Chem. Int. Ed. Engl. 1997, 40, 4214-4216. Lectka has recently described an impressive asymmetric wchlorination

References I 2 0 9

20

21 22

23 24

25

reaction (up to 99% ee) in which the stereoselective step relies on only a catalytic amount of cinchona alkaloid: H. WACK,A. E. TAGGI,A. M. HAFEZ,W. J. DRURY 111, T. LECTKA,1.Am. Chem. Soc. 2001, 123, 1531-1532. D. CAHARD, C. AUDOUARD, J. BAUDOUX,B. MOHAR,J.-C. PIAQUEVENT, contribution A0081 at the ECSOC-4. See: http:// www.mdpi.org/ecsoc-4. htm D. Y. KIM, E. J. PARK,Organic Lett. 2002, 4, 545-547. a) R. NOYORI, Asymmetric Catalysis in Organic Synthesis, Wiley, New York, 1994; b) Transition Metalsfor Organic Synthesis (Eds.: M. BELLER,C. BOLM),Wiley-VCH. Weinheim, 1998; c) Catalytic Asymmetric Synthesis (Ed.: I. OJIMA), 2nd Edition, Wiley-VCH, New York, 2000; d) Comprehensive Asymmetric Catalysis (Eds.: E. N. JACOBSEN; A. PFALTZ; H. YAMAMOTO), Springer, Berlin, 1999. S. BRUNS,G. HAUFE, J . Fluorine Chem. 2000, 104, 247-254. a) E. N. JACOBSEN, Acc. Chem. Res. 2000, 33, 421-431; b) R. G. KONSLER,J. KARL, E. N. ]ACOBSEN,J. Am. Chem. SOC. 1998, 129, 10780-10781; c) Apparently, ARO with other halide sources does not proceed with high enantioselectivity neither (ref 24a). a) Formation of competing nucleophiles might be prevented by use offluorinated chiral Lewis acid catalysts; b) B. L.

PAGENKOPF, E. N. CARREIRA, Chem. Eur.1. 1999, 5, 3437-3442. 26 L. HINTERMANN, A. TOGNI,Angew. Chem. 2000, 112, 4530-4533. Angew. Chem. Int. Ed. 2000, 39,4359-4362. 27 TADDOL is 2,2-dimethyl-cc,cc.cc',cc'-tetraaryl28

29

30

31

32

1,3-dioxolane-4,5-dimethanol. a) S. SHAMBAYATI, S. L. SCHREIBER, J. A. RAGAU,R. F. STANDAERT in Strategies and Tactics in Organic Synthesis (Ed.: T. LINDBERG),Academic Press, San Diego, 1991, Vol. 3, 417-461; b) Lewis Acids in Organic Synthesis (Ed.: H. YAMAMOTO), Wiley-VCH, Weinheim, 2000. The related reactions regarding chlorination and bromination have also been A. TOGNI, described: L. HINTERMANN, Helu. China. Acta 2000, 83, 2425-2435. a) P. BARTHAZY, A. TOGNI,A. MEZZETTI, Organometallics 2001, 20, 3472-3477; b) P. BARTHAZY,R. M. STOOP,M. WOHRLE,A. TOGNI,A. MEZZETTI, Organometallics 2000, 19, 2844-2852. For a complementary approach of enantioselective enofisation by aid of chiral amide base and subsequent fluorination witch achiral8: A. ARMSTRONG, B. R. HAYTER,Chem. Commun. 1998, 621-622. For a complementary approach of asymmetric photodeconjugation to yield secondary stereogenic centers containing fluorine: F. BARGIGGIA,S. Dos SANTOS, 0. PIVA,Synthesis 2002, 427-437.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Catalytic Asymmetric Olefin Metathesis Amir H. Hoveyda and Richard R. Schrock Introduction

Rarely has a class of transformations so strongly influenced the field of organic synthesis as catalytic olefin metathesis has in the past decade [I]. Whether it is in the context of development of new methods or as part of total synthesis of a complex molecule, these catalytic reactions have been utilized to prepare a wide range of compounds, including small, medium and large rings [2]. Only a few years ago, an alkene metathesis step was viewed as a daring application of a relatively unknown technology in a multi-step synthesis. Today, metathesis-based approaches are employed with such regularity that their use is considered routine. With regard to the synthesis of optically pure materials, however, catalytic olefin metathesis has largely served a supporting role. In cases where ringclosing metathesis (RCM) is called for, an already optically pure diene is treated with an achiral metal catalyst to deliver a non-racemic cyclic unsaturated product [ 2a-c, 2e-f, 2h]. Alternatively, a racemic product obtained by metathesis may be catalytically resolved [2b]. Optically enriched cyclic alkenes are similarly employed in instances where ring-opening metathesis (ROM) is needed [Id, 2gl. Although such strategies have led to a number of notable and impressive accomplishments in asymmetric synthesis, some of the unique attributes of catalytic olefin metathesis can only be realized if chiral optically pure catalysts for olefin metathesis are available. This claim is tied directly to the fact that one of the most useful characteristics of metathetic processes is their ability to promote efficient skeletal rearrangements: simple achiral or racemic substrates may be transformed into complex non-racemic organic molecules by a single stroke. In numerous instances, products that are rendered readily available by a chiral metathesis catalyst would only be accessible, and often less selectively, by a longer route if alternative synthetic methods were to be used. The Catalyst Construct

From the outset, we judged that the makeup of Mo-based complexes, represented by 1 [3], offers the most attractive opportunity for the design, synthesis and development of effective chiral metathesis catalysts. This predilection was based on several factors: 1) Mo-based com-

Asymmetric Synthesis with Chiral Ma Catalysts

plexes such as 1 possess a modular structure involving imido and alkoxide moieties that do not disassociate from the metal center in the course of the catalytic cycle [4].Any structural alteration of these ligands may thus lead to a notable effect on the reaction outcome and employed to control both selectivity and reactivity. 2) Alkoxide moieties offer an excellent opportunity for incorporation of chirality within the catalyst structure through installment of non-racemic chiral bis(hydroxy) ligands. 3) Mo-based complexes provide appreciable levels of activity and may be utilized to prepare highly substituted olefins.

ligand

1

I N

i-Pr

Me s#t,ph

; “ . ; I . : ‘ F3C Me k M e Me

alkoxide ligands

1

With the above considerations in mind, in the past five years, we have prepared and examined numerous chiral Mo-based catalysts for both asymmetric RCM (ARCM) and ROM (AROM) transformations [51. In this article, we highlight several efficient and enantioselective reactions that are catalyzed by these chiral complexes [GI. The structural modularity inherent to the Mo-based systems allows screening of catalyst pools, so that optimal reactivity and selectivity levels are identified expeditiously. Initial advances towards the development of chiral Ru-based metathesis catalysts are also discussed. Mo-catalyzed Kinetic Resolution with Hexafluoro-Mo Catalysts [7]

The preparation and catalytic activity of chiral complex 2, based on the original Moalkylidene 1, has been disclosed by Grubbs and Fujimura [8].These workers report on the kinetic resolution of various dienes [9J. As the case regarding the resolution of 3 indicates however, levels of enantiodifferentiation were typically low ( krel < 3).

i-Pr

tPr

M6-s

Me

I

211

212

I

Catalytic Asymmetric Olefin Metathesis

Chiral Biphen-Mo Catalysts

To examine the possibility of a more selective catalytic olefin metathesis, we first prepared chiral Mo-based complexes, 4a and 4b [lo]. This approach was not without precedence: related chiral Mo complexes were initially synthesized in 1993 and used to promote polymer synthesis [6]. We judged that these biphen-based systems would initiate olefin metathesis with high asymmetric induction due to their rigidity and the steric differentiation imposed on the chiral complex's binding pocket. Mo complexes 4a and 41, are orange solids and indefinitely stable when kept under an inert atmosphere.

I 4a R = i P r 4b R = M e

X-ray structure of 4a

Catalytic Kinetic Resolution through Mo-Catalyzed ARCM

The catalytic kinetic resolution of various dienes through ARCM can be carried out efficiently at 22 "C in the presence of 5 mol% 4a [lo]. As the data in Scheme 1 illustrate, 1,6dienes 5-7 are resolved with excellent enantiocontrol (krel > 20) [ll].Chiral catalyst 4a promotes the resolution of allylic ethers 8-10 as well [ 121. The higher levels of enantioselectivity attained through the use of 4a (vs 2) is likely due to a strong preference for ARCM reactions to proceed via Mo-alkylidenes such as I (Scheme 1). The intermediacy (higher reactivity) of the anti Mo-alkylidene(alkylidene C-C anti to Mo=N) is based on extensive mechanistic studies [ 131. The stereochemistry of olefin-transition metal association is consistent with the position of the Mo-centered LUMO of the chiral complex [14],[13b]. The 1,l-disubstituted olefin interacts with Mo away from the protruding t-Bu group of the diolate and i-Pr groups of the imido ligands (see X-ray structure of 4a). Catalyst Modularity and Optimization of Mo-Catalyzed ARCM Eflciency and Selectivity

In spite of the high asymmetric induction observed in the Mo-catalyzed ARCM of 1,6-dienes, when 4a and 41, are used in reactions involving 1,7-dienes,inferior asymmetric induction is obtained. For example, as illustrated in Scheme 2, dienes 12 and 13 are not resolved with useful selectivity ( k , ? ~< 5) when 4a is employed as the catalyst. To address this shortcoming, we took advantage of the modular character of the Mo complexes and prepared a range of chiral complexes as potentially effective catalysts. Accordingly, as depicted in Scheme 2, we

Asymmetric Synthesis with Chiral Mo Catalysts I 2 1 3

Me?

OTES

Me?

OTES

Me?

OBn

Me

m-6

(R)-5

(R)-7

krel = 23

krel > 25

krel = 22

= OR or alkyl = CH2 or 0

I

krel = 10 Scheme 1.

enantiomer

krel = 23

krel = 17

Mo-catalyzed kinetic resolution of 1,6-dienes through ARCM.

l l a R=i-Pr l l b R=Me

(S)-12

\\

with 4a

krel = <5

with l l a

krel= 24

with 1 1 b

krel = <5

Me+

Mo-catalyzed kinetic resolution o f 1,7-dienes and the importance of subtle structural modification of the chiral catalysts.

Scheme 2.

discovered that binol-based complex l l a promotes the RCM of dienes 12 and 13 with outstanding levels of selectivity (kIel = 24 and >25, respectively) [15]. Binol-based complex l l b , bearing the (dimethy1)phenylimido ligand (vs (di(iso)-propy1)phenylimidoof l l a ) , is not an efficient catalyst for the kinetic resolution of the dienes 12 and 13.

214

I

Catalytic Asymmetric Olefin Metathesis

The data in Scheme 3 illustrate that various 1,7-dienes can be resolved with excellent levels of selectivity and efficiency. These findings provide further evidence regarding the importance of the availability of a diverse set of chiral catalysts: Although binol-based complexes (e.g., lla) typically promote ARCM of 1,7-dienes with higher selectivity than the biphenbased catalysts (e.g., 4a), such a generalization is not always true. As expected, lla catalyzes the kinetic resolution of 1,7-dienes 14 and 15 with krel > 25. Unlike biphen complex 4a, however, the closely related 41, also provides appreciable enantioselection, albeit less effectively than lla. With substrates 16 and 17, where two terminal alkenes are involved, the situation is completely reversed: now, it is the biphen-based complex 4a that is the only efficient catalyst. Although each catalyst is not optimal in every instance, efficient kinetic resolution of a wide range of chiral oxygenated 1,G- and 1,7-dienes can be achieved by different chiral Mo complexes.

with 4a

krel= <5

krel= <5

krel = 21

krel= >25

with 4b

krel= 10

krel= 14

krel= <5

krel= 15

with 11 a

krel= >25

krel = >25

krel= <5

krel= <5

Scheme 3. Small structural changes within the substrate structure can alter the identity of the optimum chiral metathesis catalyst.

Catalytic Asymmetric Synthesis through Mo-Catalyzed ARCM

The arena in which catalytic asymmetric olefin metathesis can have the largest impact on organic synthesis is the desymmetrization of readily accessible achiral molecules. Two examples are illustrated in Scheme 4.Treatment of achiral triene 18 with 5 mol% 4a leads to -0

. MefiMe 2 mol Yo4a

Me

Me

18

Me2

Me2 e S i . 0

20

99% ee, 93%

no solvent, 22 "C, 5 min

Si, 2 mol Yo l l a no solvent, 60 " C , 4 h

q.,,,,fle

>98%ee, 98%

Me (R)-21

Scheme 4. Mo-catalyzed ARCM of achiral trienes can be effected efficiently, enantioselectively and in the absence of solvent.

Asymmetric Synthesis with Chiral Mo Catalysts I 2 1 5

the formation of (R)-19in 99% ee and 93% yield [12]. The reaction is complete within five minutes at 22 “C and, importantly, does not require a solvent. Another example is illustrated in Scheme 4 as well; here, binol complex 1la is used to promote the formation of optically pure (R)-21 from doxy triene 20 in nearly quantitative yield. Once again, no solvents are needed [ 151. Readily accessible substrates are rapidly transformed to optically enriched molecules that are otherwise significantly more difficult to access without generating solvent waste. In connection with reactions where a solvent is required, it must be noted that all transformations promoted by chiral Mo catalysts may be carried out in toluene (in addition to benzene) or alkanes (e.g., n-pentane) with equal efficiency (see below for specific examples). Moreover, although 5 mol% catalyst is typically used in our studies, 1-2 mol% loading often delivers equally efficient and selective transformations. As the above studies predicate, reaction of 18 is significantly less efficient with 1la (<5% conv in 18 h) and that of 20 proceeds only to 50% conversion in 24 hours in the presence of 4a (65% ee). Remarkably, in the latter transformation, even in a 0.1 M solution, the major product is the product formed through homometathesis of the terminal alkenes. The absence of homodimer generation when l l a is used, particularly in the absence of any solvent, bears testimony to the high degree of catalyst-substrate specificity in these catalytic C-C bond forming reactions. The catalytic desymmetrization shown in Scheme 5 involves a meso-tetraene substrate: optically pure unsaturated siloxane 23 is obtained in >99% ee and 76% yield [IG]. The unreacted siloxy ether moiety is removed to deliver optically pure 24. Mo-alkylidenes derived from both enantiotopic terminal alkenes in 22 are likely formed. Since metal-alkylidene formation is reversible, the major product arises from the rapid RCM of the “matched’ segment of the tetraene. If any of the “mismatched’ RCM takes place, a subsequent and more facile matched RCM leads to the formation of the meso-bicyclized product. Such a byproduct is absent from the unpurified mixture containing 23, indicating the exceptionally high degree of stereodifferentiation induced by the chiral Mo complex. As before, catalyst 4a is not effective in promoting ARCM of 22.

5 mol% l l a b

C6H6, 60 “c

22

lhr

I

Me 24

I

Me

299% ee, 76%

70%

Mo-catalyzed desyrnrnetrization o f rneso tetraenes proceeds t o afford optically pure heterocycles. Scheme 5.

216

I

Catalytic Asymmetric Olefin Metathesis

Incorporation of electron-withdrawing groups within either the imido or diolate segments of Mo complexes might result in higher levels of catalytic activity, since the Lewis acidity of the transition metal center is enhanced. As the representative examples in Scheme 6 depict, such structural modifications can have a profound effect on the levels of enantioselectivity as well. In the desymmetrization of acetal 26, dichlorophenylimido complex 25 provides substantially higher levels of asymmetric induction than biphen- or binol-based catalysts that carry 2,6-dialkylphenylimido moieties (e.g., 4a). Acetals of the type represented by 27 in Scheme 7 retain their stereochemical integrity through various routine operations such as silica gel chromatography and can be readily functionalized to deliver a range of chiral nonracemic functionalized heterocycles [ 161.

T M l d >

C6H6,22"C 5 mot yo 25+

&P

CIQ

H 26

(S)-27

12 hr

with 4a

29% ee, >98% conv

with 4b

51YO ee, >98% conv

with 11a

13% ee, >98% conv

with 25

83% ee, >98% conv, 41%

C

I

I

Scheme 6. Chiral complex 25, bearing a 2,6-dichloro imido ligand is the catalyst o f choice for asymmetric synthesis o f acetals.

10 mol % 4a

Mee HP,Pd(C) M 87%

28 Scheme 7.

29 59% ee, 90%

e

S

H % 'Me 30 endo-brevicomin

Application of Mo-catalyzed ARCM to the synthesis o f brevicomin.

The emerging Mo-catalyzed ARCM technology summarized above has been utilized in a brief and enantioselective total synthesis of endo-brevicomin(30) by Burke. The key step, as illustrated in Scheme 7, is the desymmetrization of achiral triene 28 [17]. Mo-catalyzed ARCM may be used in the enantioselective synthesis of medium ring carboand heterocycles 1181. As shown in Scheme 8, medium ring tertiary siloxanes (e.g., 34), prepared with high levels of enantioselectivity. These processes can be effected efficiently in preparative scale and at low catalyst loading (e.g., 33134); such attributes render this catalytic enantioselective method attractive from a practical point of view. It should be noted that in this set of reactions, both 4a and the dichloroimido complex 25 provide high enantioselectivity; however, the more active 25 is preferable when lower catalyst loadings are required.

Asymmetric Synthesis with Chiral Mo Catalysts

Me2

A

31 Me

89% ee, 86% Br\

Br

13 rng 25 (1 rnol Yo) P

CsH6,22 "c

Me

34 94% ee, 98%

(0.659)

C&3,22 5 rnol Yo"4a c

- -%eM

35 Me

Me

90% ee, 50% Scheme 8. Mo-catalyzed tandem ARCM can be used t o synthesize seven-membered carbo- and heterocyclic structures efficiently and in optically enriched form.

The representative transformation in Scheme 9 illustrates that the optically enriched siloxanes obtained by Mo-catalyzed ARCM can be further functionalized to afford tertiary alcohols (e.g., 40) with excellent enantio- and diastereomeric purity. It should be noted that conversion of 37 to 38 in Scheme 9 is carried out without solvent, at 1 mol% catalyst loading and on one gram scale (only 30 mg of catalyst 4a needed) [MI.

-

30mg4a (1 rnol Yo)

1. m-CPBA

P

37

Me

(1 .o 9)

22 "C, 6 h, no solvent M~

2. n-Bu4NF

38 87% ee, 95%

Me

39 86% for two steps; 93% ee; >20:1 de

Mo-catalyzed tandem ARCM can be used to synthesize synthetically versatile intermedaites such as 1,3-tertiary diols in high enantio- and diastereopurity. Scheme 9.

Most recent studies indicate that ARCM can be used to synthesize small and medium ring N-containing unsaturated heterocycles in high yield and with excellent enantioselectivity through catalytic kinetic resolution and asymmetric synthesis [ 191. Levels of optical purity can vary depending on the nature of the arylamine (compare 44 to 46 in Scheme 10). As

I

217

218

I

Catalytic Asymmetric Olefin Metathesis

the synthesis of 48 indicates (cf. Scheme lo), particularly noteworthy is the facility and selectivity with which medium ring unsaturated amines are obtained by the Mo-catalyzed protocol. Cata/ytic Kinetic Resolution Me

krel=17 with 5 mol YO4a Me

Me I

I

Me0

41 krel=13 with 5 mol YO4a

42 krel>50 with 5 mol Yo 4a

Catalyric Asymmetric Synthesis 5 mol Yo 4a

Med

43 - PhG

M

e

d 44

R

Ph

98% ee, 78% Me

Me

d w

JLO

Me

Me

45 Ar

R

Ar

46 82% ee, 90%

&J

5mol%4b,

Me

Ph

47 Scheme 10.

C & j , 22 "C, Me 20 min

Ph

48 >98% ee, 93%

Enantioselective synthesis of amines through Mo-catalyzed ARCM.

Unlike carbocyclic and oxygen-containing heterocyclic systems, catalytic enantioselective synthesis of eight-membered ring amines not only proceeds efficiently and with excellent enantioselectivity, it can be carried out in the absence of solvent. Representative data regarding catalytic enantioselective synthesis of various N-containing heterocycles without the use of solvent is depicted in Scheme 11. This remarkably efficient and enantioselective

Asymmetric Synthesis with Chiral Mo Catalysts

95% ee, 95% (3 mol % 4a, 22 "C, 3.5h)

97% ee, >98% (4 mol % 25, 22 "C, 7 h)

Scheme 11. Catalytic enantioselective synthesis of amines in the absence of solvent through Mo-catalyzed ARCM

method again highlights the ability of asymmetric metathesis to deliver synthetically versatile materials that are otherwise difficult to prepare. Catalytic Asymmetric Synthesis through Tandem Mo-Catalyzed AROM/RCM

The appreciable levels of asymmetric induction observed in the catalytic ARCM reactions discussed above suggest a high degree of enantio-differentiation in the association of olefinic substrates to chiral Mo complexes. Such stereochemical induction may be exploited in asymmetric ring-opening metathesis (AROM). Catalytic ROM transformations [ 201 although less explored than the related RCM processes - offer unique and powerful methods for the preparation of complex molecules in a single step (2d, 2g]. The chiral Mo-alkylidenes that are products of AROM can be trapped either intramolecularly (RCM) or intermolecularly (cross metathesis, CM) to afford an assortment of optically enriched adducts. Transformations shown in Schemes 12-14 constitute the first examples of catalytic AROM reactions ever reported. Meso-triene 50 is converted to chiral heterocyclic triene 51 in 92% ee and 68% yield with 5 mol% 4a (Scheme 12) [21].Presumably, stereoselective approach of the more reactive cyclobutenyl alkene in the manner shown in Scheme 12 (11) leads to the enantioselective formation of Mo-alkylidene 111, which in turn reacts with an adjacent terminal olefin to deliver 51. Another example in Scheme 12 involves the net rearrangement of rneso-bicycle 52 to bicyclic structure 54 in 92% ee and 54% yield. The reaction is promoted by 5 mol% 4a and requires the presence of diallyl ether 53 [22]. Mechanistic studies suggest that initial reaction of 53 with 4a leads to the formation of the substantially more reactive chiral Mo=CHl complex (vs neophylidene 4a) which can react with the sterically hindered norbornyl alkene to initiate the catalytic cycle. In contrast to 52 (Scheme 12) diastereomer 55 (Scheme 13), because of its more exposed and highly reactive strained olefin, undergoes rapid polymerization in the presence of 4a. The less reactive Ru complex 56 [23] can however be used under an atmosphere of ethylene to effect a tandem ROMjCM to generate 57. The resulting triene can be subsequently

I

219

220

I

Catalytic Asymmetric Olefin Metathesis

Me

92% ee, 68%

R

J--

I

5 rnol % 4a

pMe

P /

pentane 52

\\// 53

c0)

54 92%ee,54%

10 mol % Mo-catalyzed tandem AROM/RCM allows access t o complex heterocyclic structures efficiently and i n optically enriched form.

Scheme 12.

induced to undergo Mo-catalyzed ARCM (5 mol% 4a) to afford optically pure 58, the AROM/ RCM product that would be directly obtained from 55. The Mo-catalyzed transformations shown in Scheme 14 may also viewed as AROMiRCM processes [24]. However, it is possible that initiation occurs at the terminal olefin, followed by an ARCM involving the cyclic alkene. Regardless of the attendant mechanistic possibilities, the enantioselective rearrangements shown in Scheme 14, catalyzed by binaphtholatebased catalyst l l a , deliver unsaturated pyrans bearing a tertiary ether site with excellent efficiency and enantioselectivity. It should be noted that this class of heterocycles would not be readily accessible by an enantioselective synthesis of the precursor diene, followed by RCM promoted by an achiral catalyst. The requisite optically enriched pure tertiary ether or alcohol cannot be easily accessed. It also merits mention that in this class of asymmetric reactions, biphenolate-based complexes provide significantly lower levels of enantioselectivity (e.g., 4a affords GO in 15% ee). The enantioselective synthesis of the pyran portion of the antiHIV agent tipranavir (Scheme 14) serves to demonstrate the significant potential of the method in asymmetric synthesis of biomedically important agents. The non-racemic pyrans shown in Scheme 14 can also be accessed by Mo-catalyzed ARCM

Asymmetric Synthesis with Chiral Mo Catalysts I 2 2 1

L

O

A

5 mol Yo 4a

*

pentane, 22 "C

POLYMERIZATION

55

ethylene

-

56

1

5 mol Yo 4a, pentane, 22 "C

57 >99%ee; 84%

58 Crubbs's Ru complex 56 (ROM) is used in conjunction with chiral catalyst 4a (ARCM) to obtain 58 in the optically pure form.

Scheme 13.

59

60 96% ee, 87%

61

62 96% ee, 73%

Mo-catalyzed enantioselective rearrangement o f mesocyclopentenes to chiral unsaturated pyrans. Scheme 14.

222

I

Catalytic Asymmetric Olefin Metathesis

of the corresponding trienes. The example shown in E q (1)is illustrative. Interestingly, elevated temperatures are required for high levels of enantioselectivity;under conditions shown in Scheme 14,trienes such as 65 afford the desired pyrans in significantly lower ee (e.g., 66 is obtained in 30% ee at 50 "C). Detailed mechanistic studies must be carried out before the origin of such variations in selectivity are understood.

I

5 mol Yol l a

*

toluene, 80 "C

Me

(1)

66 >98% ee, 90% Catalytic Asymmetric Synthesis through Tandem Mo-Catalyzed AROMICM

The chiral Mo-alkylidene complex derived from AROM of a cyclic olefin may also participate in an intermolecular cross metathesis reaction. As depicted in Scheme 15, treatment of meso-67a with a solution of 5 mol% 4a and 2 equivalents of styrene leads to the forma-

A0 . phg " OTBS

5 mol yo cat

67a

98% ee

with 4b

79% ee

with 11a

86% ee

"H

68

C6H6, 22 "c

with 4a

optimized (2 equiv styrene): >98% ee, >98% trans, 57% (Me0)3Si

67b

(MeO)3SiA C6H6, 22 "c

69 2.5 mol Yo

I >98% ee, >98% trans, 51% Scheme 15. Mo-catalyzed tandem AROM/CM proceeds with high enantioselectivity and olefin stereocontrol.

Asymmetric Synthesis with Chiral Mo Catalysts I 2 2 3

tion of optically pure 68 in 57% isolated yield and >98% trans olefin selectivity [25].The Mo-catalyzed AROM/CM reaction can be carried out in the presence of vinylsiloxanes: the derived optically pure 69 (Scheme 15) can subsequently be subjected to Pd-catalyzed crosscoupling reactions, allowing access to a wider range of optically pure cyclopentanes. The Mo-catalyzed AROM/CM may be performed on highly functionalized norbornyl substrates (e.g., 71 and 72 in Scheme 16) and those that bear tertiary ether sites (e.g., 73-75, Scheme 16). Although initial studies indicate that the relative orientation of the heteroatom substituent versus the reacting olefin can have a significant influence on reaction efficiency, the products shown in Scheme 16 represent versatile synthetic intermediates accessed in the optically pure form by Mo-catalyzed AROM/CM.

%

F h+ ’ i

71

:

Acd

72

6Ac

>90% ee, 94%

73

06% ee, 67%

74

>98% ee, 05%

76

>90% ee, 84%

>90% ee, 04%

(>98% trans in all cases) Scheme 16. Mo-catalyzed tandem AROM/CM delivers highly functionalized cyclopentanes in the optically pure form.

Towards User-Friendly and Practical C h i d Mo-Based Catalystsfor Olefin Metathesis

Although the main focus of our programs have so far been on issues of reactivity and enantioselectivity, we have recently begun to address the important issue of practicality in Mo-catalyzed asymmetric metathesis. Two key advances have been reported in this connection: (1)A general chiral Mo catalyst that can be prepared i n situ from commercially available compounds. (2) A recyclable polymer-supported chiral Mo catalyst. Chiral M o Catalyst Prepared in Situ from Commercially Available Materials

Up to this point, there have been two general classes of chiral Mo catalysts discussed: biphenolate-based complexes such as 4 and binaphtholate systems represented by 11 (Scheme 2). From a practical point of view, binaphthol-based systems have a significant advantage, as the synthesis of the optically pure diolate begins from the inexpensive and commercially available ( R ) -or (S)-binaphthol. Access to the optically pure biphenol ligand in 4 and its derivatives requires resolution of the racemic material by fractional crystallization of the derived phosphorus(V) mentholates [2].Accordingly, we prepared chiral Mo complex 77 [ 261, bearing a “biphenol-type” ligand, but synthesized from the readily available optically pure binaphthol. Complex 77 shares structural features with both the biphen-(4) and binol-

224

I

Catalytic Asymmetric Olefin Metathesis

based (11)systems and represents an intriguing possibility regarding the range of starting materials for which it may be a suitable catalyst. Two examples are depicted in Scheme 17. Catalyst 77 delivers compounds of high optical purity where either biphen- or binol-based complexes are ineffective. It is not in all instances that 77 operates as well as 4a and l l a . As an example, in the presence of 5 mol% 77, triene 18 (Scheme 4)is converted to furan 19 in 77% ee and 73% yield (vs 99% ee and 93% yield with 4a). It should be noted that catalyst 71 serves as an additional example, where modification of the chiral alkoxide ligand can lead to substantial variation in selectivity.

krel> 25 with 4 a krel<5 w i t h l l a ( 5 mol o/o loading)

Me2

vH.)rMe fSi-o

-70% ee with 4a

>99% ee with l l a

Me 21 96% ee, 56% Scheme 17. Chiral complex 77 represents a hybrid between biphenand binol-based catalysts and provides a unique selectivity profile that is often not seen with the latter two classes individually.

It is not only that catalyst 77 is more easily prepared than 4. As illustrated in Scheme 18, a solution of 77, obtained by the reaction of commercially available reagents bis(potassium salt) 78 (Strem) and Mo triflate 79 (Strem), can be directly used to promote enantioselective metathesis. Similar levels of reactivity and selectivity are obtained with in situ 77 as with isolated and purified 4a or 77 (cf. Scheme 18). Moreover, asymmetric olefin metatheses proceed with equal efficiency and selectivity with the same stock solutions of (R)-78and 79 after two weeks. The use of a glovebox, Schlenck equipment or vacuum lines is not necessary (even with the two-week old solutions). The First Polymer-Supported and Recyclable Chiral Catalyst for Olefin Metathesis

We have synthesized and studied the activity of 82, the first supported chiral catalyst for olefin metathesis (Scheme 19) [27]. Catalyst 82 efficiently promotes a range of ARCM and AROM processes; a representative example is shown in Scheme 19. Rates of reaction are lower than observed with the corresponding monomeric complex 4a, but similar levels of enantioselectivity are observed. Although 82 must be kept under dry and oxygen-free conditions, it can be recycled. Catalyst activity, however, is notably diminished by the third cycle. As the data and the figure in Scheme 19 show, the product solution obtained by filtra-

'

Practical and Recyclable Chiral Metathesis Catalysts

Me OTf

0,.I HNAr Me

THF,

-50+.22 "c ~ H ~ o ~ a , , , pinhood h ' O K Me OTf M~ \ .+oO K l h 79 / direct from (@-78 Strem bottle Strem

77 in THF

'

0

5 mol yo in situ

MeliYMe 78 & ; : : 22

88% ee, 80% with 5 mol Yo isolated 4a: 93% ee, 86% 5 mol Yo in situ

80

67c

>98% ee,>98% trans, 86% with 5 mol Yoisolated 4a: >98% ee, >98% trans, 87% Scheme 18.

In situ preparation and utility of chiral metathesis catalyst 77.

tion contains significantly lower levels of metal impurity than detected with the monomeric catalysts, where >90% of the Mo used is found in the unpurified product (by ICP-MS analysis). The supported chiral Mo catalyst is, as should perhaps be expected, less active than the parent system (4a).The lower levels of activity exhibited by 82 may be due to inefficient diffusion of substrate molecules into the polymer. The supported catalyst is expected to be less susceptible to bimolecular decomposition of highly reactive methylidene intermediates [28]. Synthesis of more rigid polymer supports or those that represent lower Mo loading should further minimize bimolecular decomposition and lead to a more robust class of catalysts. Towards Chiral Ru-Based Olefin Metathesis Catalysts

Grubbs and co-workers have recently reported a new class of Ru catalysts (83, Eq 2) [29] that bear a chiral monodentate N-heterocyclic carbene ligand [30]. The reactions illustrated in E q 2 include the highest ee reported (13-90% ee); asymmetric induction is clearly dependent on the degree of olefin substitution (6Schemes 18 and 4 for comparison with the Mo-catalyzed reactions of the same substrates). As is the case with nearly catalytic enantioselective reactions [4], the identity of the optimal catalyst depends on the substrate; a number of chiral

I

225

226

I

Catalytic Asymmetric Olefin Metathesis

OCH20Et

OCH20Et tBu

81 Ph

2 equiv styre; C6H6,22 "c

67c

80

Cycle 1: >98% conv, 30 min; 97% ee product contains 3% of total Mo initially used Cycle 2: 98% conv, 30 min; 98% ee product contains 10% of total Mo initially used Cycle 3: 55% conv, 16 h; 89% ee product contains 16% of total Mo initially used Scheme 19. The first recyclable and supported chiral catalyst for olefin metathesis, 82 delivers reaction products that contain significantly less metal impurity. The two dram vials show unpurified 80 from a reaction catalyzed by 4a (left) and 82 (right).

Ru catalysts were prepared and screened before 83 was identified as the most suitable. In addition, reactions were shown to be more selective in the presence of NaI. This important initial investigation is likely the harbinger of upcoming highly effective and practical chiral Ru-based metathesis catalysts.

0 -

MeAMe R

R

THF, 38 "C,1 equiv Nal R = H 78-+79 R =Me 18+19

39% ee, 22% conv 90% ee, 82% conv

References I 2 2 7

Conclusions and Outlook

The exciting results of the above investigations clearly indicate that the modular Mo-based construct initially reported for catalyst 1 can be exploited to generate a range of highly efficient and selective chiral catalysts for olefin metathesis. Both ARCM and AROM reactions can be promoted by these chiral catalysts to obtain optically enriched or pure products that are typically unavailable by other methods or can only be accessed by significantly longer routes. Substantial variations in reactivity and selectivity arising from subtle changes in catalyst structures, support the notion that synthetic generality is more likely if a range of catalysts are available [4]. The chiral Mo-based catalysts discussed herein are more senstive to moisture and air than the related Ru-based catalysts [l].However, these complexes, remain the most effective and general asymmetric metathesis catalysts and are significantly more robust than the original hexafluoro-Mo complex 1. It should be noted that chiral Mo-based catalysts 4,11,25, 34 and 77 can be easily handled on a large scale. In the majority of cases, reactions proceed readily to completion in the presence of only 1 mol% catalyst and, in certain cases, optically pure materials can be accessed within minutes or hours in the absence of solvents; little or no waste products need to be dealt with upon obtaining optically pure materials. Chiral catalyst 4a is commercially available from Strem, Inc. (both antipodes and racemic). The advent of the protocols for in situ preparation of chiral Mo catalyst 77, the supported and recyclable complex 82 and the debut of a chiral Ru catalyst (83) augur well for future development of practical chiral metathesis catalysts. The above attributes collectively render the chiral catalysts discussed above extremely attractive for future applications in efficient, catalytic, enantioselective and environmentally conscious protocols in organic synthesis. Acknowledgements

Financial support was provided from the National Institutes of Health (GM-59426 to A. H. H. and R. R. S.) and the National Science Foundation (CHE-9905806to A. H. H. and CHE9700736 to R. R. S.). We are grateful to all our workers whose names appear in the references for invaluable intellectual and experimental contributions. References select reviews on catalytic olefin S. metathesis, see: a) R. H. GRUBBS, CHANG,Tetrahedron 1998, 54, 4413-4450; b) A. FURSTNER, Angew. Chem. Int. Ed. 2000, 39, 3012-3043. For example, see: a) A. F. HOURI,2. Xu, D. A. COGAN, A. H. HOVEYDA,]. Am. Chem. SOC. 1995, 117, 2943-2944; b) 2 . Xu, C. W. J O H A N N E S , A. F. HOURI,D. S. LA, D. A. COGAN, G. E. HOFILENA, A. H. HOVEYDA, J . Am. Chem. SOC.1997, 119, 10302-10316; c) D. MENG,D-S. Su, A. BALOG, P. BERTINATO,E. J. SORENSEN, S. J.

1 For

2

DANISHEFSKY, Y-H. ZHENG,T-C. CHOW,L. HE, S. B. HORWITZ, J . Am. Chem. SOC. 1997, 119, 2733-2734; d) K. C. NICOIAOU, N. WINSSINGER, J. PASTOR, S. NINKOVIC, F. SARABIA, Y. HE, D. VOURLOUMIS, 2. YANG, T. LI, P. GIANNAKAKOU, E. HAMEL, Nature 1997, 387, 268-272; e) C. W. JOHANNES, M. S. VISSER,G. S. WEATHERHEAD, A. H. HOVEYDA, J . Am. Chem. SOC.1998, 120, 8340-8347; f ) M. DELGADO, J. D. MARTIN, J . Org. Chem. 1999, 64,4798-4816; g ) A. FURSTNER, 0. R. THIEL,]. Org. Chem. 2000, 65, 1738-1742;

fatalytic Asymmetric Olefin Metathesis

h) J. LIMANTO, M. L. SNAPPER,].Am. Chem. SOC.2000, 122,8071-8072; i) A. B. SMITH,S. A. KOZMIN,C. M. ADAMS,D. V. PAONE, ]. Am. Chem. SOC.2000, 122,49844985. 3 a) R. R. SCHROCK, J. S. MURDZEK, G. C. M. DIMARE,M. BAZAN,J. ROBBINS, O’REGAN,]. Am. Chem. SOC.1990, 112, 3875-3886; b) G. C. BAZAN,J. H . OSKAM, H.-N. CHO, L. Y. PARK,R. R. SCHROCK,]. Am. Chem. SOC. 1991, 113, 6899-6907. 4 a) K. W. KUNTZ,M. L. SNAPPER, A. H. HOVEYDA, CUT. Opin. Chem. Biol. 1999, 3, 313-319; b) K. D. SHIMIZU,M. L. SNAPPER, A. H. HOVEYDA In Comprehensive Asymmetric Catalysis I-IIk E. N. JACOBSEN, Eds.; Springer: A. PFALTZ,H. YAMAMOTO, Berlin, 1999; Vol. 3, 1389-1399; For a report regarding synthesis of various Mo complexes, see: c) J. H. OSKAM,H. H. Fox, K. B. YAP, D. H. MCCONVILLE, R. O’DELL, R. R. SCHROCK,]. B. J. LICHTENSTEIN, Organomet. Chem. 1993,459, 185-198. 5 For a previous brief overview of this Mocatalyzed asymmetric olefin metathesis, R. R. SCHROCK, see: A. H . HOVEYDA, Chem. Eur. ]. 2001, 7, 945-950. 6 For early reports regarding the preparation of chiral Mo-based catalysts used for ROMP, see: a) D. H. MCCONVILLE, J. R. WOLF,R. R. SCHROCK, J. Am. Chem. SOC. 1993, 115,4413-4414; b) K. M. TOTLAND, T. J. BOYD,G. G. LAVOIE,W. M. DAVIS, R. R. SCHROCK, Macromolecules 1996,29, 6114-6125. 7 Throughout this article, the identity of the recovered enantiomer shown is that which is obtained by the catalyst antipode illustrated. Moreover, transformations with binol-based complexes (e.g., 11) were carried out with the opposite antipode of the catalyst versus that illustrated. Because (S)-biphen and (R)-binolcomplexes were employed in our studies, this adjustment has been made to facilitate comparison between biphen- and binol-based catalysts. 8 a) 0. FUJIMURA, R. H. GRUBBS,]. Am. Chem. SOC.1996, 118: 2499-2500; b) 0. FUJIMURA, R. H. GRUBBS, ]. Org. Chem. 1998,63,824-832. 9 For a review on metal-catalyzed kinetic M. T. resolution, see: A. H. HOVEYDA, DIDIUK,CUT. Org. Chem. 1998,2,537574.

B. ALEXANDER, D. S. LA, D. R. CEFALO, A. H. HOVEYDA, R. R. SCHROCK, J . Am. Chem. SOC. 1998,120,4041-4042. 11 The value for k,l is calculated by the equation reported by Kagan: H. B. KAGAN, J. C. FIAUD,Top. Stereochem. 1988,53, 708-710. 12 D. S. LA, J. B. ALEXANDER, D. R. CEFALO, D. D. GRAF,A. H . HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC. 1998, 120, 9720-9721. 13 a) J. H. OSKAM,R. R. SCHROCK,].Am. Chem. SOC. 1993, 115, 11831-11845; b) H. R. R. SCHROCK, H . Fox, M. H. SCHOFIELD, Organometallics 1994, 13, 2804-2816. 14 a) R. R. SCHROCK, Polyhedron 1995, 14, 3177-3195; b) Y.-D. W u , 2.-H. PENG,J. Am. Chem. SOC.1997, 119,8043-8049. 15 S. S. ZHU, D. R. CEFALO, D. S. LA, J. Y. JAMIESON, W. M. DAVIS,A. H. HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC.1999, 121,8251-8259. 16 G. S. WEATHERHEAD, J. H. HOUSER,G . J. FORD,J. Y. JAMIESON, R. R. SCHROCK, A. H. HOVEYDA, Tetrahedron Lett. 2000, 41, 9553-9559. 17 S. D. BURKE,N. MULLER, C. M. BEUDRY, Org. Lett. 1999, 1, 1827-1829. 18 A. F. KIELY,J. A. JERNELIUS, R. R. SCHROCK, A. H. HOVEYDA,].Am. Chem. SOC.2002, 124, 2868-2869. 19 S. J. DOLMAN, E. S. SATTELY, A. H . HOVEYDA, R. R. SCHROCK,].Am. Chem. SOC.2002, 124, 6991-6997. 20 For representative studies regarding nonasymmetric ROM reactions, see: a) M. L. RANDALL, J. A. TALLARICO, M. L. SNAPPER, ]. Am. Chem. SOC.1995,117, 9610-9611; b) W. J. ZUERCHER, M. HASHIMOTO, R. H. GRUBBS,].Am. Chem. SOC. 1996, 118, 6634-6640; c) J. P. A. HARRITY,M. S. VISSER,J. D. GLEASON, A. H . HOVEYDA,J. Am. Chem. SOC.1997, 119, 1488-1489; d) M. F. SCHNEIDER, N. LUCAS,J. VELDER, S. BLECHERT, Angew. Chem. Int. Ed. 1997, 36, 257-259; e) F. D. CUNY,J. CAO,J. R. HAUSKE,Tetrahedron Lett. 1997,38, 5237-5240. 21 G. S. WEATHERHEAD, J. G. FORD,E. J. ALEXANIAN, R. R. SCHROCK, A. H. HOVEYDA, ]. Am. Chem. SOC.2000, 122,8071-8072. 22 J. P.A. HARRITY,D. S. LA,D. R. CEFALO, ]. Am. M. S. VISSER,A. H . HOVEYDA, Chem. SOC.1998, 120, 2343-2351.

10 J.

References I 2 2 9

M. B. FRANCE,J. W. ZILLER, 23 P. SCHWAB, R. H . GRUBBS, R. H. Angew. Chem. Int. Ed. 1995, 34, 2039-2041. 24 D. R. CEFALO, A. F. KIELY, M. WUCHRER, J. Y. JAMIESON, R. R. SCHROCK, A. H. HOVEYDA, J . Am. Chem. SOC.2001, 123, 3139-3140. 25 D. S. LA, G. J. FORD,E. S. SAITELY, P. J. BONITATBUS, R. R. SCHROCK, A. H. HOVEYDA,]. Am. Chem. SOC.1999, 121, 11603-11604. 26 S. L. AEILTS,D. R. CEFALO, P. J. BONITATEBUS, JR., J. H. HOUSER, A. H.

27

28

29

30

HOVEYDA, R. R. SCHROCK, Angew. Chem. Int. Ed. 2001, 40, 1452-1456. K. C. HULTSZCH, J. A. JERNELIUS, A. H. HOVEYDA, R. R. SCHROCK, Angav. Chem. Int. Ed. 2002, 41, 589-593. J. ROBBINS, G. C. BAZAN,J. S. MURDZEK, M. B. O’REGAN, R. R. SCHROCK, Orgunometullics 1991, 10, 2902-2907. T. J. SEIDERS, D. W. WARD,R. H. GRUBBS, Org. Lett. 2001, 3, 3225-3228. W. A. HERRMANN, L. J. GOOSSEN, C. KOCHER,G. R. J. ARTUS,Angew. Chem. Int. Ed. 1996, 35, 2806-2807.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Activating Protecting Groups for the Solid Phase Synthesis and Modification o f Peptides, Oligonucleotides and Oligosaccharides Oliver Seitz Introduction

Merrifields pioneering invention of solid phase peptide synthesis revolutionised the field of biological and medicinal chemistry [ 11. Quickly, the solid phase synthesis of peptides and oligonucleotides reached a high level of maturity. Ultimately, automation of the repetitive process gave non-chemists the opportunity to readily synthesise these complex biopolymers and allowed the first detailed investigations of the structure-affinity-relationships of peptides and oligonucleotides. The efficiency of the automated process led many to the assumption that all problems had been solved and that new developments would be unnecessary. However, the increasing pressure in pharmacological research to find more lead structures in even shorter periods of time has rejuvenated solid phase methods, demonstrated best by the developments in combinatorial chemistry. Not only has this effected the preparation of peptides and oligonucleotides, but also has encouraged research for the solid phase synthesis of the highly complex class of oligosaccharides. In the following, new strategies for the solid phase synthesis of these three classes of biopolymers will be presented. This article will focus on the use of activating protecting groups, which are capable of increasing the diversity in a given system. It is not intended to give a comprehensive overview of this field but to highlight some concepts [ 2, 31. Peptides

Peptides and proteins are characterised by a large structural and functional variability. A key feature of peptide synthesis is, thus, the need for numerous protecting groups. In the following the concept of activating protecting groups will be exemplified by discussing Cterminal and N-terminal as well as amide blocking groups. C-Terminal Modfication

During solid phase synthesis peptides are bound to the solid support by means of the Cterminal carboxyl group. The properties of the anchor group positioned between the growing oligomer and the solid support are crucial for the success of a solid phase synthesis. Usually, specialised linkers are used which provide either peptide carboxylic acids or peptide carboxylic amides upon cleavage [4]. A cleavage mechanism that proceeds by a nucleophilic attack

Peptides I 2 3 1

at the peptide carboxyl group offers access to a variety of C-terminal peptide modifications such as peptide esters, peptide thioesters, secondary and tertiary peptide amides and many more. One of the early examples of a linker that enables such a diversity-increasing peptide release is the Kaiser-oxime linker 1 (Scheme 1) [5]. A host of nucleophiles including alcohols, amines, thiols and even hydroxybenzotriazole has been shown to displace the oxime linkage. Aminolysis of the activated peptide ester has been performed in an intramolecular fashion to afford cyclic peptides [GI. Thioester resins have also been used for inter- and intramolecular aminolysis [4].However, these “permanently activated’ linkers are only compatible with the use of the Boc-strategy. The application of the popular Fmoc-strategy would lead to premature peptide losses due to the lability of the ester bond towards nucleophiles such as the piperidine used during Fmoc-removal. Both the Boc-strategy and the Fmoc-strategy can be applied with Kenners sulfonamide linker 2 [7]. The secondary sulfonamide 2 is stable against acids and bases but rendered labile against nucleophilic attack upon transformation to the tertiary sulfonamide 3. This safety-catch principle has been used for the preparation of peptide acids, peptide amides, peptide hydrazides and peptide thioesters. Recently, a more reactive linker has been developed by Ellman [8].Cyanomethylation instead of methylation (see Scheme 2 , 445),and the use of the alkane sulfonamide increase the cleavability with poor nucleophiles. One impressive application has been demonstrated by Bertozzi and co-workers (Scheme 2) [9]. The acid- and base-sensitive glycopeptide thioester G was synthesised by using Ellmans modification of Kenners sulfonamide linker and was subsequently employed in a fragment coupling with glycopeptide segment 8. The latter contained a N-terminal cysteine residue that according to the so-called Native Chemical Ligation [ 101 enabled the segment coupling to proceed in the absence of protecting groups. Acylated aryl hydrazides (10) can be cleaved upon oxidition to acyl diazenes 11 (Scheme 3).

= polystyrene

The Kaiser-oxim resin 1 is permanently activated and can be cleaved by nucleophiles. Kenners sulfonamide resin 2 is stable against acids and bases but rendered labile against nucleophilic attack after conversion t o the tertiary amide 3.

Scheme 1.

GalNAca

= polystyrene

8

6

Scheme 2.

T;rio

J.

-CHIEn

BnSH, THF

CICHzCN, DIPEA, NMP

GalNAca

AcsGalNAca

1OOmM NaH2P04, 4% PhSH, 55% b) 5% eq. HzNNH2, D l T . 53%

a) 6M GnHCI,

TFAPhOH/H20/PhSMe/EDT (82.5:5:5:5:2.5), 4h, 21% overall yield

Ac3GalNAca

I -+

Rl

(DIPEA, N-ethyl-N,N-diisopropylamine; DTT, dithiothreitol; EDT, ethanedithiol; GnHCI, guanidinium hydrochloride; NMP, N-methylpyrrolidone).

Boc-HN

Ellmans sulfonamide linker allowed the synthesis o f the acid- and base-labile glycopeptide thioester 6 , which was used for the Native Chemical Ligation with glycopeptide fragment 8

9

0

Ac-HN

Ac3GalNAca =

5, R =CHzCN

4,R=H

Ac3GalNAca

E.

z

Y

3

H

H

+

a) 50% TFNCH2C12 b) NBS, pyridine, CH2CI2,7 min

NuH

""0O

11

0

19% overall yield

Ala-Pro-Leu-Phe-Ala

The hydrazlde linker 10 can be activated by mild oxldatlon (NBS, N-bromosucctnlmide).

12

Boc-HN - Ala-Pro-Leu-Phe-Ala

Scheme 3.

10

H

Cu(OAc)p, NuH or NBS, pyridine, CH&, NuH

13

N w

-

234

I

Activating Protecting Groupsfor the Solid Phase Synthesis

This linker concept was originally introduced by Wieland and co-workers [ 111 but has been fashioned to suit practical applications by the groups of Semenov, Lowe and Waldmann [ 12141. The aminolysis has been achieved by treatment of the hydrazide 10 with copper (11) acetate in solutions of the amine in methanol. NBS in pyridine has been employed as an alternative oxidising agent that triggered a cyclative release of cyclopeptide 13 [ 151. The postsynthetic activation of a peptide ester was performed in the laboratories of Wells and Wong [lG,171. For the synthesis of a partial sequence of the C-terminal region of ribonuclease B, conjugate 14, consisting of N-Fmoc-protected alanine and the acid- and basestable PAM-Linker,was coupled to the Rink-Amide resin 15 (Scheme 4) [17]. The elongation of 1G followed standard Fmoc-protocols. Standard TFA-cleavageconditions removed all acidlabile side-chain protecting groups and also detached the N-Fmoc-protected peptide-PAM ester 17 from the solid support. Since a benzhydrylamine-type-linker was used, the peptidePAM conjugate 17 was liberated as a PAM-amide. Side-chain unprotected peptide esters of this type can serve as acyl donors in enzyme-catalyzed peptide couplings. Accordingly, OMe

Fmoc-Ala-0 a

C

O

O

H

15

+

HZN Fmoc-Ala-PAM-OH

14

I

’

OCH2CO-N

a) HBTU, HOBt, NMM, DMF; b) Ac20, Pyr

16

Fmoc-Ala-PAM-Rink

Fmoc-solid-phase peptide synthesis, 89% TFNEt3SIHIHZO (95:25’2.5),

= polystyrene

Fmoc-Lys-Thr-Thr-Gln-Ala-Asn-Lys-His-lle-lle-Val-Ala-0 C O W

18 H-Gly-Gly-Ser-NH, I

AQGIcNAcP

Y

subtilisin (8397K256Y),

84%.

Fmoc-Lys-Thr-Thr-Gln-Ala-Asn-Lys-His-lle-lle-Val-Ala-G ly-Gly-Ser-NH,

19

I

AcaGlcNAcP Solid-phase synthesis of the peptidePAM ester 17 which served as an acyldonor in the subtilisin-catalysed segment condensation with glycopeptide fragment 18 (Ac~GIcNAc, 2-acetamido-3,4,6-tri-O-acetyl-2-deoxyglucose; Scheme 4.

HBTU, 2-(1 -H)-benzotriazole-1-yl)-1,1,3,3tetrarnethyluroniumhexafluorophosphate; HOBt, 1-hydroxy-1H-benzotriazole; NMM, Nmethylmorpholine).

Peptides I 2 3 5

the segment condensation of 17 with the N-terminally unprotected glycotripeptide 16 was achieved by catalysis of the protease subtilisin affording the glycopentadecapeptide 18 in 84% yield. Thus, the presented solid phase synthetic strategy is a viable alternative for the preparation of acid- and base-stable peptide esters. Since these esters are converted to active esters in the presence of subtilisin, they can be used in enzymic segment condensations, therefore serving as an useful alternative to the corresponding chemical process. N-Terminal Modification

Miller and co-workers utilised the acidifying effect of the ortho-nitrobenzenesulfonyl group (oNBS) to activate amide groups for a selective N-alkylation [18]. The incorporation of Nalkylated amino acids has often been used to probe the bioactive conformation of a peptide. In order to perform N-alkylations on the solid phase, N-oNBS protected amino acids were coupled to the unprotected amino group of a peptide 20 (Scheme 5). Subsequently, the NoNBS-peptidederivatives 21 were selectively alkylated at their acidic sulfonamide group. For example, reaction of the supported tetrapeptide 21a with methyl 4-nitrobenzenesulfonate and the base MTBD quantitatively yielded 22a. The Pdo-catalysed N-allylation of 21b succeeded with allylmethyl carbonate in a yield of 98%. For the cleavage of the oNBS-group the tertiary sulfonamides 22 were treated with mercaptoethanol/DBU. Under these conditions, the unalkylated secondary sulfonamides remained intact. The oNBS-group could also be used as a general temporary protecting group in the solid phase synthesis of unalkylated peptides [ 191. In the cleavage step, 21 was treated with 0.5 M potassium thiophenolate for 10 minutes, this liberated the amino group of 23 as well as a yellow chromophore. Thereby, the course of the cleavage reaction can be conveniently monitored photometrically. For comparison purposes, the synthesis of the thrombinereceptor-agonist 24 was carried out by both the oNBS- and the Fmoc-strategy. After HPLCpurification of the crude materials, which were obtained in 85% (oNBS) and 91% (Fmoc) purity, the pure peptide 24 was furnished in 50% (oNBS) and 62% (Fmoc) overall yield. Amide-backbone Substitution

Despite the great success of solid phase peptide synthesis there are a few sequences which are known as difficult. It is thought that the difficulties of achieving quantitative coupling and deprotection yields arise from intermolecular association of the resin-bound peptide chains [ 201. Sheppard and co-workers identified the amide-backbone as being responsible for maintaining an intermolecular hydrogen bonding network and introduced amide-backbone substitution with the 2-hydroxy-4-methoxybenzyl(Hmb) group as a means to prevent secondary structure formation [21]. However, the usefulness of the Hmb auxiliary is limited by the low reactivity of the secondary amino group of N-Hmb-modified peptides such as 25 (Scheme 6). The acylation of N-Hmb-amino acids proceeds through the 0-acyl intermediate 26 which undergoes a relatively slow 0 - N acyl transfer to form the peptide bond in 27. Miranda, Alewood and co-workers improved acyl transfer rates by attaching the electronwithdrawing nitro group in ortho-position [22]. For example, the difficult coupling of a valine to the valine peptide 25a proceeded with a N-acylation yield of only 23% 30a when the Hmb-auxiliary was employed. In contrast, the use of the Hnb-auxiliary greatly enhanced acyl

236

I

Activating Protecting Croupsfor the Solid Phase

d

2

6

Carbohydrates I 2 3 7

transfer efficiency affording coupling product 301, in 93% yield. The removal of the Hnbgroup was achieved by photolysis which liberated the unprotected peptide 31. Nucleic Acids

Protecting groups, which allow the introduction of additional functional groups after a solid phase assembly, are of particular interest for the construction of medicinally relevant DNAand RNA-conjugates. Contrary to proteins, only a few functional groups of nucleic acids can be used for the conjugation of reporter groups or crosslinkers without compromising their biological function. In 1990, Verdine reported a method, in which uridine derivatives were incorporated into oligonucleotides and subsequently modified [ 231. This concept has recently been extended to the synthesis of functionalised oligoribonucleotides [ 241. The inosine base 32 and the uridine base 34 carry para-chlorophenyl groups at the 06-or 04-position(Scheme 7). Simple substitution with primary amines (RNH2) resulted in the formation of the corresponding adenosine- and cytidine-derivatives. Thus, the R-group will be positioned in the major groove of a nucleic acid duplex. After substitution the fluoride and cleavage of the nitrophenylethyl(NPE)-protecting group the fluoroinosine 33 forms a guanosine system, positioning the R-group in the minor groove. For the synthesis of the RNA-oligomers 36a-c the phosphoamidites 35a-c were incorporated using a slightly modified RNA-synthesis-protocol(Scheme 8). The functionalisation of the oligomers 3Ga-c proceeded using the amines listed in Table 1. Subsequent treatment with either TBAF or NEt3.HF removed the NPE- and TBDMS-protecting groups. The relative yields were evaluated after purifying the products 37a-c by denaturing polyacrylamide gelelectrophoresis (PAGE) and enzymic hydrolysis. Finally, the composition of the nucleic acid was determined by HPLC. All conversions proceeded virtually quantitatively with exception of the reactions with benzylamine and of 36a with ammonia. Carbohydrates

The solid phase synthesis of complex oligosaccharides presents demanding challenges [ 25281. Each monomer embodies a multitude of functional groups of similar reactivity. A large number of protecting groups is available for the various needs of oligosaccharide synthesis. A few of them can be activated and converted to leaving groups such that subsequent functional group interconversions are facilitated. Anomeric Protection

The coupling of two building blocks involves a glycosylation reaction, which creates a new stereogenic centre (in contrast to peptides or nucleic acids). On solid phase the glycosidic linkage can be formed by two approaches. It is either the glycosyl donor that is attached to the solid support or the glycosyl acceptor. The former strategy requires an anomeric protecting group that can be selectively removed prior to activation of the anomeric centre. It is obvious that a protecting group amenable to a selective activation offers significant advantages as far as conciseness is concerned. Thioglycosides [ 291, n-pentenyl glycosides [ 301 and

238

I

Activating Protecting Croups for the Solid Phase Synthesis

(D

rb

a

N

K

8

E

U

N

0

29a (Hmb) 29b (Hnb)

Ala-Gly-Phe

+

1 Ala-Gly-Phe

CH2

30a (Hmb), 23% 30b (Hnb), 93%

""y

1) DMF,piperidme 2) mild TFA cleavage

Scheme 6. The Hnb-protecting group serves as an activated 0 - N transfer auxiliary for the efficient synthesis of difficult peptides.

R2

acyl

1

R*

Hmb: TFA Hnb: hv

HoeR1 HoeR

' CH2

HN

= trityl

240

I

Activating Protecting Groupsfor the Solid Phase Synthesis

A

I

34

RNH2, MeOH

Major Groove

N-H-

0

- -0

Minor Groove Scheme 7. Convertible nucleosides that allow for major-groove and minor-groove modifications.

glycosyl fluorides fulfil the demands and serve both anomeric protection and anomeric activation. Ito and co-workers were one of the first to attach a thioglycoside donor to a polymeric support [31]. In an approach that is known as orthogonal glycosylation they employed the polymer-bound thioglycoside 39 as glycosyl donor and the glycosyl fluoride 40 as glycosyl acceptor (Scheme 9). The formed dimannoside 41 was converted into a glycosyl donor by treatment with hafnocene, which promoted the glycosylation of the mannoside 42 to afford the trisaccharide resin 43.The following cleavage from the soluble support yielded the trimannoside 44 in 40% overall yield. There are some drawbacks of the donor-bound approach. Fraser-Reid and co-workers showed that the glycosylation with an immobilised n-pentenyl glycoside produced the desired glycoside but also the corresponding hemiacetal which resulted from hydrolysis of the resin-bound donor [ 321. Takahashi and co-workers compared several polymer-bound glycosyl donors and found that thioglycosides and glycosyl sulfoxides provided quantitative yields of disaccharide products [33]. The highest flexibility would be provided if the supported oligosaccharide were useful as both glycosyl donor and glycosyl acceptor. Such a bidirectional strategy has been reported by Zhu and Boons who demonstrated the elaboration of a growing oligosaccharide in both directions [ 341. For example, the polymer-bound thioglycoside 45 displayed one unprotected hydroxyl group, which was used as the glucosyl acceptor site in the glucosylation with the trichloroacetimidate donor 46 (Scheme 10). The formed 1,4-linked diglucoside 47 proved to be a good glycosyl donor when coupled with the acceptor 48 to give trisaccharide 49 in GO% overall yield.

Carbohydrates I 2 4 1

9;,\ -

RNA-solid-phase synthesis according to the phosphoamidite strategy

OTBDMS

-

DMT-0

TL

.,I OTBDMS

N(iPr)2

0 P ;

RNA OCH&H2CN

35 a: B=32, b: B = 33, c: B = 34

-0

-

0 RNA

36 a: 5'-GAC UU(32) GUA CC-3' b: 5'-AGU CC(33) GCU AG-3' C: 5'-GCU AA(34) CCU AU-3'

a) 2M RNH2 in MeOH b) a s : 1 M TBAF in THF; b: NEt3.3HF

J

KN.H

37 a: 5-GAC UUA'

GUA CC-3'

b: 5'-AGU CCGRGCU AG-3 C: 5'-GCU AACR CCU AU-3'

RNA Scheme 8.

- 0OH;$

0

- RNA

Postsynthetic modification of RNA by using the convertible nucleosides shown in Scheme 7.

Linkers

The feasibility of converting a protecting group into a leaving group is of high utility for the design of diversity-increasing linkers. Thioglycosides have been employed as solid-phase linkers and shown to withstand a wide range of reaction conditions [35]. Schmidt and Tab. 1. Relative yields of substitutions of 36a-c with RNH2 to give 37a-c (see Scheme 8).

R

aa

bb

Cb

H CH3 HzNCHzCHz HzN(CHz)4 HOCHzCHl PhCHz

0.24 1.0 1.0 1.04 1.1 0.67

1.0

0.85 0.9 0.88 1.0 0.65

1.0 1.0 0.96 1.0 1.04 0.79

"based on the reaction with methylamine; "based on the reaction with ammonia.

242

I

Activating Protecting Croups for the Solid Phase Synthesis

O(CH2)5CO

a

O(CHz)&O

Q B:;qQ

a

Bn:q B:iw Bntw Bn:q 1 40

BnO

F

BnO

MeOS02CF3, MeSSMe, 4A MS, CH2C12,89%

SMe

39

BnO

41

BnO

F

CpnHfCl2, AgOS02CF3, 4A MS, CH2C12,99%

BnO

O(CHz)&O

n = monomethyl-polyethyleneglycol

a

OSE

Bn:-i

%:H HO

40%

42

BnO

H-9 HO

overall

H O T

44

o

Bn:q BnO

43

%:nB BnO OSE

Scheme 9.

OSE Thioglycoside 39 and the fluoro disaccharide 41 as polymer-bound glycosyl donors.

co-workers used thioalkylated supports (see 50) and a NBS-mediated activation of the thioglycosidic linkage to prepare a pentamannoside or the branched pentasaccharide 51 as methyl glycosides (Scheme 11) [ 36, 371. The cleavage step can be fashioned into a diversityincreasing reaction which is of high interest in combinatorial synthesis [38]. Kunz and co-workers took advantage of a bromine-induced cleavage of the thioglycosides 52 and used the formed bromo sugar intermediate for the glycosylation of various alcohols (Scheme 12) [39]. Nicolaou and co-workers presented a seleno-based linker which allows for a stereocontrolled construction of 2-deoxy glycosides and orthoesters 1401. The carbohydrate was attached to the solid support by means of a glycosylation reaction using the trichloroacetimidate 54 as donor and the resin-bound selenol 55 as acceptor (Scheme 13). The C-2 ester of 56 was removed by basic methanolysis. Treatment of the 2-hydroxy compound with DAST induced a 1,2-selenophenyl migration affording the 2-seleno-1-fluoro sugar 57. The resin-

244

I

Activating Protecting Croupsfor the Solid Phase Synthesis

-

.-4

0

/

B:-4 BnO

NBS, DTBP, CH2CI2,MeOH

BnO

OBn

_____t

BnO&

= polystyrene

I BE=

0

Lco+:Troc

50

“O OAc

The thioglycoside linkage in 50 was activated to yield methyl glycoside 51 (DTBP, 2,6-di-tert-butyI-pyridine).

Scheme 11.

-

Br2, DTBP, cyclohexene

NH-~6

CH2C12, R’OH, Et4NBr

$’

H 0

R3-HN

52

&&,,vOR1 OR2

53

0

R’OH = MeOH, EtOH, iPrOH

= polystyrene

The activation of a thioglycoside linkage such as 52 enables the usage of galactose as a five-dimension diversity scaffold.

Scheme 12.

bound donor 57 was employed in a SnClz-promoted glycosylation of the glucoside 58 yielding the disaccharide resin 59. For release of the 2-deoxy glycoside 60, resin 59 was exposed to nBu3 SnH/AIBN, which afforded the radical cleavage of the Se-C bond. Alternatively, oxidation of 59 to a selenoxide intermediate and subsequent syn-elimination led to the formation of the orthoester 61. Schmidt and Seeberger developed linkers that can be cleaved by olefin metathesis. For example, ring-closing metathesis cleaved the diene linkage of 62 and released the ally1 glycosides 63 (Scheme 14) [41].Seeberger and co-workers used a cross-metathesis reaction to release oligosaccharides in form of n-pentenyl glycosides such as 65 [42]. These conjugates can be submitted to a variety of modification reactions or employed as donors in “postsynthetic” glycosylations [43].

n

54

BnO AGO

O

s

59

55

Bu3SnSe

b) A

1

Me0

CH2C12, -78°C

a) mCPBA,

Me0 OMe

Hoe* OMe

O Y N H cc13

~

58

Me0

B

BF3.Et20 ___)

Scheme 13. The seleno linkage in 56 and a 1 ,Z-seleno-migration (56-57) provided access to 2-deoxy-saccharldes such as 60 and orthoesters such as 61 (mCPBA, rneta-chloro perbenzoic acld; DAST, diethylamonium sulfur trifluoride).

BnO% BnO

nBu3SnH, AIBN, benzene

B

+ OMe B

BnO

56

= polystyrene

57

a) NaOMe, THF, MeOH b) DAST, CH2C12

OMe

c

AcO

246

I

Activating Protecting Croupsfor the Solid Phase Synthesis

63

BnO BnO

BnO

= polystyrene

0

PivO

HzC

= CHz

Clr.

I

65 PivO Ring-closing olefin metathesis o f 62 detached the ally1 glycoside 63.A cross-metathesis with 64 and ethylene liberated targetoligosaccharides such as 65 in form o f their n-pentenyl glycosides. Scheme 14.

Protecting Croupsfor Internal Aglycon De/;very

The stereoselective formation of a glycosidic bond is the key feature of oligosaccharide synthesis. Despite the many powerful glycosylation methods that have been developed, there are still a few glycosidic linkages that are difficult to synthesise. For example, the /I-mannosidic bond presents a synthetic challenge because the anomeric effect favours the formation of

Conclusion I 2 4 7

a-mannosides. Usually, P-glycoside formation can be accomplished by arming the glycosyl donor with a participating neighbouring acyl group at the 0-2 position. This approach is inappropriate when attempted with mannosides since participation of an axial 0-2-acyl substituent also leads to a-mannoside formation. With this difficult task in mind new types of protecting groups were developed which are able to stereospecifically direct the introduction of a reagent [44). The approach of attaching the aglycon to a bifunctional protecting group has been termed intramolecular aglycon delivery and has been frequently applied to the solution-phase synthesis of P-mannosides and a-glucosides. Ito and Ogawa demonstrated the utility of a polymer-bound protecting group for p-mannoside synthesis. According to a strategy published in 1991 by Barresi and Hindsgaul, the axial 2-OH-group can be utilised to present the aglycon in the glycosylation reaction to the b-face [45]. Similarly, Ito and Ogawa introduced a para-alkoxybenzyl group at this position [46]. For the attachment to a polymeric support, the alkoxybenzyl group of methyl thiomannoside 66 carried a carboxyl group (Scheme 15) [47]. Oxidation of the polymer bound mannoside 67 with DDQ in the presence of an alcohol yielded the acetal 68. Upon activation of the thioglycoside with methyl triflate, 68 reacted in an intramolecular transacetalisation to give b-mannoside 69. I t is necessary to emphasise that only the desired glycosylation products were liberated from the polymeric resin into the liquid phase. By-products such as the hydrolysis product 70 or the elimination product 71 remained on the solid phase. The polymeric resin hence serves as a molecular gatekeeper, which in the final synthetic step liberates only the desired products. Conclusion

The presented examples illustrate that protecting groups can be actively used in synthesis and achieve more than temporary blocking of a functional group. Permanently activated protecting groups such as the oxime- and thioester linkers, the oNBS- and the chlorophenylgroups allow for subsequent transformations that raise the diversity of a given system. In order to increase the orthogonality protecting groups were developed which can be converted to leaving groups. A prototype is the methylation-induced activation of sulfonamide linkers. Other groups such as the hydrazides, the thioglycosides, the n-pentenyl glycosides, the glycosy1 fluorides and the PAM-esters are activated in presence of certain reagents or (bio)catalysts. The products formed after such activation would normally have to be synthesised in a less efficient fashion. The example of the Hmb-peptide backbone protection and the polymer supported synthesis of P-mannosides demonstrated how protecting groups can facilitate peptide couplings and stereoselective glycosylation reactions, respectively, once a suitable orientation is obtained. The development and use of such multi-purpose protecting groups is certainly attractive for future research. One of the most difficult tasks of chemical biology is to match the different time scales of chemical and biological research. A combination of solid-phase techniques with “smart” protecting groups offers the prospect of significantly shortening the often time consuming synthesis of modified biopolymer probes, which are essential for the advancement of molecular life-sciences.

248

I

Activating Protecting Croups for the Solid Phase Synthesis

O(CH2)&+

R

I

phT+

66, R = Et

a) NaOH, tBuOH b) PEG-monomethylether, DEAD, PPh3, CH&, THF, 80%.

67, R = PEG

TBS)

SMe

J

liquid phase

4

R'-0 =

O a BnO

o

DDQ, MS4& CHzClp, 3h

polymeric phase

MeOTf, MeSSMe, DTBP, CICH&H2CI, MS4A, 21-120h

B

n

50%

9

1

O(CH2)5C-

I

OBn

R'-0 =

BnO -0

F NPhth

37%

; I I I

P

h TBS)

Scheme 15. The polymer-bound alkoxybenzyl protecting group in 67 serves as a directing group and enabled the intramolecular aglycon delivery t o afford a stereoselective formation of p-mannosides 69. By products such as 70 and 71 remained on the polymeric support

T

a o-R'

71

References

I249

References R. B. MERRIFIELD,]. Am. Chem. SOC.1963, 85, 2149. 2 K. JAROWICKI, P. KOCIENSKI,]. Chem. SOC. Perkin Trans. 1 2001, 2109-2135. 3 M. SCHELHAAS, H. WALDMANN, Angav. Chem. Znt. Ed. 1996, 35, 2056-2083. 4 For an excellent review about linker and cleavage strategies in solid-phase synthesis: F. GUILLIER, D. ORAIN,M. BRADLEY, Chem. Rev. 2000, 100, 2091-2157. 5 W. F. DEGRADO, E. T. KAISER,]. Org. Chem. 1980, 45, 1295-1300. 6 G. OSAPAY, A. PROFIT,J. W. TAYLOR, Tetrahedron Lett. 1990, 31, 6121-6124. 7 G. W. KENNER, MCDERMOT. J R , R. C. SHEPPARD,]. Chem. Soc., Chem. Commun. 1971, 636. 8 B. J. BACKES, A. A. VIRGILIO, J. A. ELLMAN,]. Am. Chem. SOC.1996, 118, 3055-3056. 9 Y. SHIN,K. A. WINANS, B. J. BACKES, S. B. H. KENT,J. A. ELLMAN,C. R. BERTOZZI,]. Am. Chem. SOC.1999, 121, 11684-11689. 10 P. E. DAWSON, T. W. MUIR,I. CLARKLEWIS,S. B. H. KENT,Science 1994, 266, 776-779. 11 T. WIELAND, J. LEWALTER, C. BIRR, Ann. Chem. 1970, 740, 31. 12 A. N. SEMENOV, K. Y. GORDEEV, Int. J . Pept. Protein Res. 1995, 45, 303-304. 13 C. R. MILLINGTON, R. QUARRELL, G. LOWE, Tetrahedron Lett. 1998, 39, 7201-7204. 14 F. STIEBER, U. GRETHER, H. WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 10731077. 15 C. ROSENBAUM, H. WALDMANN, Tetrahedron Lett. 2001, 42, 5677-5680. 16 D. Y. JACKSON, J. BURNIER,C. QUAN,M. STANLEY, J. TOM,J. A. WELLS, Science 1994, 266, 243-247. 17 K. WITTE,0. SEITZ,C. H. WONG,]. Am. Chem. SOC.1998, 120, 1979-1989. 18 S. C . MILLER, T. S. SCANLAN,].Am. Chem. SOC.1997, 119, 2301-2302. 19 S . C . MILLER, T. S. SCANLAN,]. Am. Chem. SOC.1998, 120, 2690-2691. 20 A. G. LUDWICK, L. W. J E L I N S K I , D. LIVE, A. KINTANAR, J. J . DUMAIS,].Am. Chem. SOC.1986, 108, 6493-6496. 21 C. HYDE,T. J O H N S O N , D. OWEN,M. Int.]. Pept. QUIBELL, R. C. SHEPPARD, Protein Res. 1994: 43, 431-440. 1

P.MIRANDA, W. D. F. MEUTERMANS, /. Org. M. L. SMYTHE,P. F. ALEWOOD, Chem. 2000, 65, 5460-5468. 23 A. M. MACMILLAN, G. L. VERDINE,]. Org. Chem. 1990, 55,5931-5933. 24 C. R. ALLERSON, S. L. CHEN,G. L. VERDINE,].Am. Chem. SOC.1997, 119, 7423-7433. 25 P.SEARS, C. H. WONG,Science 2001, 291, 2344-2350. 26 P. H. SEEBERGER, W. C. HAASE,Chem. Rev. 2000, 100,4349-4393. 27 0. SEITZ,Chembiochem 2000, I, 215-246. 28 Solid Support Oligosaccharide Synthesis and Combinatorial Carbohydrate Libraries, SEEBERGER, P. H. ed., John Wiley & Sons, New York, 2001. 29 For a review: P. J. GAREGG, Adu. Carbohydr. Chem. Biochem. 1997, 52, 179-205. 30 B. FRASER-REID, U. E. UDODONG, 2. F. I. R. MERRITT,C. S. Wu, H. OTTOSSON, RAo, C. ROBERTS, R. MADSEN, Synlett 1992, 927-942. 31 Y. ITO, 0. KANIE, T. OGAWA, Angew. Chem. Int. Ed. 1996, 35, 2510-2512. 32 R. RODEBAUGH,S. JOSHI,B. FRASERREID, H. M. GEYSEN,].Org. Chem. 1997, 62, 5660-5661. 33 T. DOI, M. SUGIKI, H. YAMADA, T. TAKAHASHI, J. A. PORCO,Tetrahedron Lett. 1999, 40, 2141-2144. 34 T. ZHU, G. J. BOONS,Angew. Chem. Int. Ed. 1998, 37, 1898-1900. 35 S . H. L. CHIU,L. ANDERSON, Carbohydr. Res. 1976, 50, 227-238. 36 I. RADEMANN, R. R. SCHMIDT,].Org. Chem. 1997, 62, 3650-3653. 37 J. RADEMANN, A. GEYER, R. R. SCHMIDT, Angew. Chem. Int. Ed. 1998, 37, 1241-1245. 38 T. WUNBERG, C. KALLUS, T. OPATZ,S. HENKE, W. SCHMIDT, H. KUNZ, Angew. Chem. Int. Ed. 1998, 37, 2503-2505. 39 C. KALLUS, T. OPATZ,T. WUNBERG, W. S. H E N K EH. , KUNZ, Tetrahedron SCHMIDT, Lett. 1999, 40, 7783-7786. 40 K. C. NICOLAOU, H. J. MITCHELL, K. C. FYLAKTAKIDOU, H. SUZUKI,R. M. RODRIGUEZ, Angew. Chem. Int. Ed. 2000, 39,1089-1093. 41 L. KNERR, R. R. SCHMIDT, Synlett 1999, 1802-1804. 22 L.

250

I

Activating Protecting Groupsfor the Solid Phase Synthesis

R. B. ANDRADE, 0. 1. PIANTE,L. G. MELEAN, P. H. SEEBERGER, Org. Lett. 1999, 1, 1811-1814. 43 T. BUSKAS,E. SODERBERG, P. KONRADSSON, B. FRASER-REID,].Org. Chem. 2000, 65,958-963. 44 For a review about intramolecular 0glycoside bond formation: K. H. J U N G ,M.

MULLER, R. R. SCHMIDT,Chem. Rev. 2000,

42

100,4423-4442. 45 46

47

F. BARRESI,0. HINDSGAUL,].Am. Chem. SOC.1991,113, 9376-9377. Y. Iro, T. OGAWA,Angew. Chem. Int. Ed. 1994,33,1765-1767. Y. ITO, T. OGAWA,].Am. Chem. SOC.1997, 119,5562-5566.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I251

Traceless Linkers for Solid-Phase Organic Synthesis Florencio Zaragoza Donodd Introduction

To expand the scope of products available by solid-phase synthesis, a series of strategies have been developed in recent years which enable the generation of C-H and C-C bonds upon cleavage from a support, and in this way enable the preparation of unfunctionalized hydrocarbons. These linkers are sometimes also called ‘traceless’ linkers, because in some types of product the attachment point to the support can no longer be located. Such traceless linkers can give access to compound libraries devoid of a common functional group that was required for covalent attachment of the intermediates to the support. The preparation of highly diverse compound arrays by solid-phase synthesis should, therefore, be possible with such linkers [ 1-31. The strategies described to date for the generation of C-H and C-C bonds during cleavage include decarboxylative cleavage, acidolysis of silanes, reductive cleavage of acetals, thioethers, selenides, sulfones, sulfonates, triazenes, sulfonylhydrazones, or organometallic compounds (Figure I ) , the nucleophilic cleavage of resin-bound alkylating agents by carbon nucleophiles, and the oxidative cleavage of hydrazides [ 31. Cleavage followed by decarboxylation has been used for the preparation of ketones [4-6], nitriles [5, 71, amides (81, quinazolines [9], amines [lo], and 3-methylindoles [ll].Because decarboxylation generally requires an additional functional group to promote decarboxylation, which reveals the original point of attachment, this cleavage strategy usually does not enable the preparation of unfunctionalized hydrocarbons, and does therefore not belong to the class of truely traceless linkers. Cleavage of Silanes, Organogermanium, and Organoboron Compounds

Polystyrene-bound silanes are usually prepared by reaction of organolithium compounds with resin-bound silyl chlorides [12,131. The C-Si bonds of aryl-, heteroaryl-, vinyl-, and allylsilanes are stable towards alcoholates or weak reducing agents, but can be cleaved under mild conditions by treatment with acids or fluoride to yield a hydrocarbon and a silyl ester or silyl fluoride. Several linkers of this type have been tested and have proven useful for the preparation of unfunctionalized arenes and alkenes upon cleavage from insoluble supports.

252

I

Traceless Linken for Solid-Phase Organic Synthesis

Z Nu(e.g. H-, Z,HC-)

Pd

R w O v P o l

i"

*

I

R -Nu

PdL,

RnxPol

homolytic or heterolytic, reductive cleavage

*

R"H

Fig. 1. Generation of C-C and C-H bonds upon cleavage from supports. Pol: polymeric support; Z: electron-withdrawing group; X: metal. NzNR, PR2+, 0, SO,, Se, etc.

The optimal conditions for cleavage of resin-bound arylsilanes depend on the substitution pattern of the arene (Table 1). Some donor-substituted arenes can already be cleaved from silyl linkers by treatment with trifluoroacetic acid (TFA) [ 141. Particularly acid-sensitive are resin-bound 3-(dialkylarylsilyl)propionamides(Entry 1, Table 1).Arylsilanes bearing electronwithdrawing groups on the arene are more difficult to desilylate with weak acids (compare, e.g., Entries 2 and 3, Table 1).When TFA fails to promote protodesilylation, hydrogen fluoride, cesium fluoride, or TBAF might bring about the cleavage (Table 1).Alternatively, resinbound arylsilanes can also be cleaved by treatment with 1,2-dihydroxybenzene (5 eq, MeCN, 50 "C, 20 h) or with glycolic acid, whereby bis(dio1ato)silicatesare formed [15]. Support-bound allylsilanes can be cleaved either by treatment with acids or by treatment with carbon electrophiles. The third reaction in Figure 2 is an example of a cleavage, in which the electrophile is an cc-alkoxy carbocation generated from an acetal and TiC14. Arylboronic acids esterified with support-bound 1,2-diols undergo Suzuki reaction with aryl iodides, whereby biaryls are released into solution (first reaction, Figure 3; see also [ 2 7 ] ) . This technique has also been used to prepare p-turn mimetics by simultaneous macrocyclization and cleavage from the support [ 281. The C-B bond of resin-bound boronates can also be converted to a C-H bond by treatment with aqueous silver ammonium nitrate (second reaction, Figure 3). Reductive Cleavage of Carbon-Oxygen Bonds

The direct homolytic, reductive cleavage of C-0 bonds has not been used to release products from polymeric supports. C-0 Bonds are too strong to undergo homolytic cleavage under acceptably mild reaction conditions, but acetals and allyl esters can smoothly be cleaved heterolytically. When resin-bound acetals are treated with Lewis acids in the presence of a reducing agent or a carbon nucleophile, reductive cleavage from the support can occur. Ethers and sulfonamides have been prepared using this cleavage strategy (Figure 4). Esters of allylic alcohols with resin-bound carboxylic acids can be converted into palladium allyl complexes by treatment with palladium(0). These allyl complexes react with carbon

Entry

Tab. 1.

CN

Loaded resin

100%

TBAF, DMF, 65 "C, 1 h Ar: 4-(MeO)CaH4

TBAF (1mol/L), THF, 12 h

Ph

58%

a

93%

see also 22

21

see also 19

18 H

TFAIDCM 1:1, 20 "C, 24 h

13

16

Re$

17

80%

pho'o

Ar

Product, yield

CSF, DMF/H20 4x1, 110 "C (no cleavage b y neat TFA, 25 "C) Ar: 4-formylphenyl

TFA/DCM 1:1, 25 "C, 3 h

TFA/DCM 1:1, 20 "C, 2 h Ar: 1-naphthyl

Cleavage conditions

Generation of arenes upon cleavage of support-bound aryl silanes and arylgerrnaniurn compounds. PS: cross-linked polystyrene; (PS): PS with spacer.

N W In

9

5

8

7

Entry

Tab. 1.

O

H


Ar

Loaded resin

(continued)

Ar: 4-(MeO)C6H4

TFA, GO "C, 24 h

Me2S/H20 85:lO:S) Ar: 4-(MeO)CbH4

HF, 12 h (nocleavage by TFAI

Cleavage conditions

-f$O

Product, yield

58%

68% 23 see also 24

23

Re$

sa

3.

4.

$

ul -c

3

P s

2a

%

2

fi

t

m,

-i

Reductive Cleavage of Carbon- Nitrogen Bonds

Fig. 2.

I

255

Cleavage of polystyrene-bound allysilanes by TFA or carbocations [25,261.

nucleophiles and with hydride sources to yield the products of allylic nucleophilic substitution (Entries 1 and 2, Table 2). Alkyl sulfonates have been reduced to alkanes with NaBH4 or cleaved from supports by treatment with Grignard reagents (Entries 3 and 4, Table 2). Aryl sulfonates (Entry 5 , Table 2) and aryl perfluoroalkylsulfonates [ 311 can be reduced to alkanes by treatment with catalytic amounts of palladium(I1) and formic acid as hydride source. Polymer-supported aryl perfluoroalkylsulfonates have been used to prepare biaryls from aryl boronic acids [ 321. Reductive Cleavage o f Carbon-Nitrogen Bonds

Support-bound triazenes, which can be prepared from resin-bound secondary, aliphatic amines and aromatic diazonium salts [37], undergo cleavage upon treatment with acids, whereby the aromatic diazonium salts are regenerated. In cross-linked polystyrene these diazonium salts decompose to yield nitrogen and, preferentially, aryl radicals. If the acidolysis of polystyrene-bound triazenes is conducted in the presence of hydrogen-atom donors

4-iodoanisole (5 eq), aq &PO, (2 mol/L, 3 eq) PdCI,BINAP (0.05 eq), DMF, 60 "C, 24 h

*

85%

Ag(NH,),NO,

Meon Ph

> 95% pure

(0.25 mol/L, 10 eq)

H,O/THF 1:1,67 "C, 8 h

57% SP, 0 Fig. 3.

Polystyrene-bound boronates as traceless linkers [28, 291

> 90% pure

256

I

Traceless Linkersfor Solid-Phase Organic Synthesis

TFA (5 eq), Et3SiH (10 eq), DCM 20 "C, 24 h

+ 41%

e S i M e 3

\

(2.5 eq), SnCI, (1.1 eq)

DCM, 20 " C , 24 h 47%

*

YNo \

\

Fig. 4.

Reductive cleavage of polystyrene-bound acetals and herniaminals [30].

(e.g. THF), unsubstituted arenes can be obtained (Entries 1 and 2, Table 3). In the presence of alkenes or alkynes and Pd(0Ac)Z the initially formed diazonium salts can undergo Heck reaction to yield vinylated or alkynylated arenes (Entry 3, Table 3). Similarly, unsubstituted arenes can be obtained by oxidative cleavage of support-bound N-aryl-N'-acylhydrazines (Entry 4, Table 3). Oxidation leads to the formation of N-aryl-N'-acyldiazenes,which in the presence of nucleophiles undergo deacylation to yield acid derivatives and aryldiazenes. The latter are unstable and decompose into arenes and nitrogen. Air in the presence of catalytic amounts of Cu(OAc)z,or NBS [38, 391 can be used as oxidants for hydrazides. Support-bound sulfonylhydrazones have been reduced to alkanes by sodium borohydride (Entry 5, Table 3). This reaction, which has not yet been fully optimized for solid-phase synthesis, should enable the support-aided conversion of ketones into alkanes under mild reaction conditions. Reductive Cleavage o f Carbon-Phosphorus and Carbon-Sulfur Bonds

Phosphonium salts can be dealkylated by treatment with alkoxides to yield alkanes. Although the hydrolytic cleavage of phosphonium salts in solution has been investigated extensively, the solid-phase variant of this reaction has not yet found broad application. One example, in which traceless linking was based on the alkoxide-induced dealkylation of a resin-bound phosphonium salt, is given in Table 4 (Entry 1). Hydrocarbons can be generated by nucleophilic cleavage of resin-bound ally1 sulfones with carbon nucleophiles (e.g. Entry 3, Table 4),whereby the resin-bound sulfinate acts as the leaving group. Thioethers, sulfoxides, and sulfones can also undergo C-S bond cleavage upon photolysis or upon treatment with reducing agents such as tin hydrides, sodium amalgam, or Raney nickel (Entries 4-6, Table 4). These reducing agents are, unfortunately, non-volatile, and further purification of the crude products will be necessary in most instances, making this cleavage strategy unsuitable for parallel synthesis. Resin-bound benzylic thioethers can be converted to sulfonium salts by S-alkylation with triethyloxonium tetrafluoroborate. These sulfonium salts react with palladium(0) complexes to yield benzylpalladium complexes, which undergo Suzuki coupling with arylboronic acids (Entry 7,Table 4).

5

4

2

1

Entry

,o& ,+ (s 0 PS

r/tkOSiMe'

HC02H (7.5 eq), NEt3 (8 eq), Pd(OAc)2 (0.2 eq), dppp, 110 "C, 12 h

(15 eq), Mg (15 eq), CuBr.SMez (1 eq), THF, 20 "C, 3 h, then CSA, MeOH, H20

B

NaBH4 (0.1 mol/L), DMSO, GO "C, 12 h

( M e 0 2 Q C H N a (3 eq), 7% Pd(PPhs).t, THF. SO "C, 8 h

THF, triethyl ammonium formate (5 eq), 7% Pd(PPh3)4,70 "C

PS

+
Cleavage conditions

Loaded resin

Tab. 2. Formation of C-H and C-C bonds upon reductive cleavage o f ally esters and sulfonates.

OR

(43-90%)

78%

35

34

33

33

Ref:

36-74%

k/J

47%

H i

36 see also 31

po

BnO"

OBn

69%

Product, yield (purity)

U

N

-

in

p

5

4

3

2

1

Entry

Tab. 3.

Ph

\

H

("NAPS

CO,tBu

CPh

CPh

cx2N-pS

\

OH

Loaded resin

NaBH4 (1.1 mol/L, 8 eq), THF, 67 "C, 8 h

Cu(0Ac)z (0.5 eq), pyridine (10 eq), air, MeOH, 20 "C, 2 h

Pd(0Ac)Z (5%), TFA, MeOH, 40 "C, 2-12 h

HCl/THF or H)P02/C12HCCOzH or HSiC13, DCM, 32 "C, 15 min

THF/conc HCI l O : l , 50 "C, ultrasound, 5 min

Cleavage conditions

Formation of C-H and C-C bonds upon reductive cleavage o f C-N bonds.

27%

93% (> 900/)

//

p

53% (85%)

81%

-co2tBu

Ph

OH

53%

0

7oKp;-o

Product, yield (purity)

44

39

40. 41 see also 42

Re$

d2.

0

B

s

2

8m

0) U

N

Reductive Cleavage of Carbon-Phosphorus and Carbon-Sufur Bonds

* 00

-P

sE

YI

U 13 0

wl

s

I

V U m

LA

n I

V c W

2 -m U W

._ Y 3

3

x

n VI

U

x

0 5)

f-p

V V U S m

I V c 0 ._ 4-

\

oc

m

E LL

4 n

F

qR

0

S

N

m

t

I

259

260

I

Traceless Linkersfor Solid-Phase Organic Synthesis

-

Reductive Cleavage of Carbon-Selenium Bonds

R,Sn*

+

R/\*

I SnR, S Pe o,l

e S n R 3 -R,Sn*

R,SnH - R,Sn'

oxidant

H Rc/elP , ol

- R,SnHal

R- *

R/\/H

O

R,Sn*

-

/

R -

SeV' POI

-

H,

R-

+

R-

+

5)SPeo,l

S *eP ,ol

Fig. 5. Selenides as linkers for alkanes a n d alkenes.

Reductive Cleavage of Carbon-Selenium Bonds

Selenides are more readily cleaved by tin radicals than thioethers. Products bound to crosslinked polystyrene by a C-Se bond can be released from the support either by treatment with an oxidant to yield alkenes [ 1, 55-58], or by treatment with tin radicals to yield alkanes or alkenes (Figure 5). Various methods have been developed which enable the preparation of selenides bound to cross-linked polystyrene [ 31. As starting material either nucleophilic or electrophilic resinbound selenium derivatives are used. Alkali metal selenides, selenoborate complexes, or tin selenides are strong nucleophiles which react swiftly with organic halides or other alkylating agents to yield alkyl selenides [59]. Electrophilic selenium derivatives, such as the bromides BrSe-Pol, phthalimides PhtNSe-Pol [60], or sulfonates RSOzSe-Pol [61], undergo addition to alkenes under mild reaction conditions. The reaction of alkenes containing a nucleophilic functional group with polystyrene-bound selenenyl bromide can lead to the cyclization of the alkene by C-C, C-0, or C-N bond formation with simultaneous attachment to the support (see, e.g., first and third reaction, Figure 6; see also [57, 621). Enantiomerically pure, supportbound selenenyl bromides react with functionalized alkenes to yield resin-bound, enantiomerically enriched lactones, ethers, and acetals (e.g., first reaction, Figure 6 [63]). Examples of the tin radical mediated cleavage of selenides are sketched in Figure 6; more examples have been reported (59, 62, 641. The carbon-centered radicals initially formed by homolytic C-Se bond cleavage can be directly reduced to the alkane by treatment with a tin hydride, allylated by treatment with ally1 tin derivatives (Figure 5), or may add to multiple bonds before reduction. The fourth reaction in Figure 6 is an example of the formation of a polycyclic indoline through radical cyclization. Radical-mediated cleavage proceeds under mild, essentially neutral reaction conditions and is well suited for the release of sensitive organic compounds from insoluble supports. Because non-volatile, tin-derived byproducts are formed during these cleavage reactions, purification of the resulting products will, however, generally be required.

I

261

262

I

Traceless Linkersfor Solid-Phase Organic Synthesis

Bu,SnH (5 eq)

OMe

BrSe

58%

71% de

Bu,SnHPhMe, (3 eq), 110 AlBN "C, (0.005 6h eq)

B

n

O

aps

V Se

OBn

B n o T c p h

BnO'

OBn

SnC14 (3 eq), DCM 0 "C, 1 h BrSe

NH, 1 eq

H

3 eq 1. COCI,, DCM, 0 "C, 1 h 2. rnorpholine (10 eq), N,Et, DCM, 25 "C, 12 h 3. Bu,SnH (4 eq), AlBN (1.3 eq), PhMe, 90 "C, 2 h 17%

,,.Ph

0 Fig. 6.

0

Reductive cleavage of C-Se bonds (60, 63, 651.

Conclusion

Traceless linkers enable the solid-phase synthesis of products which were formerly only accessible by tedious, multistep solution-phase chemistry. Some of these linkers tolerate a broad range of reaction conditions, giving the chemist plenty of freedom in the design of new solid-phase synthetic sequences. Interestingly, polystyrene-bound selenium reagents can also mediate useful chemical transformations of substrates during their attachment to the support, and thereby function both as reagents and as linkers. Unfortunately, most traceless linkers described to date require non-volatile cleavage reagents. Future developments should focus on cleavage protocols that yield crude products devoid of non-volatile byproducts. Such cleavage strategies would enable the preparation of pure crude products, as required for the parallel synthesis of large arrays of compounds. New traceless linkers cleavable with volatile reagents would be a useful supplement to existing cleavage methodologies, and would have the potential of finding widespread application.

References I 2 6 3

References F. ZARAGOZA, Angew. Chem. Int. Ed. 2000, 39,2077-2079. 2 S . B ~ s E S. , DAHMEN, Chem. Eur./. 2000, 6, 1899-1905. 3 F. ZARAGOZA, Organic Synthesis on Solid Phase; Wiley-VCH: Weinheim, New York, 2000. 4 P. GARIBAY, J. NIELSEN, T. HBEG-JENSEN, Tetrahedron Lett. 1998, 39, 2207-2210. 5 M. M. SIM,C. L. LEE, A. GANESAN, Tetrahedron Lett. 1998, 39, 2195-2198. 6 M. M. SIM,C. L. LEE. A. GANESAN, Tetrahedron Lett. 1998, 39, 6399-6402. 7 F. ZARAGOZA, Tetrahedron Lett. 1997, 38, 7291-7294. 8 B. C. HAMPER, K. 2. GAN,T. J. OWEN, Tetrahedron Lett. 1999, 40, 4973-4976. 9 J. M. COBB,M. T. FIORINI,C. R. GODDARD, M. E. THEOCLITOU, C. ABELL, Tetrahedron Lett. 1999, 40, 1045-1048. 10 G. J. KUSTER,H. W. SCHEEREN, Tetrahedron Lett. 2000, 41, 515-519. 11 J. R. HORTON, L. M. STAMP,A. ROUTLEDGE,Tetrahedron Lett. 2000, 41, 9181-9184. 12 F. X. WOOLARD, J. PAETSCH, J. A. ELLMAN. /. Org. Chem. 1997, 62, 6102-6103. 13 Y. Hu, J. A. PORCO,J. W. LABADIE,0. W. GOODING, B. M. TROST,/.Org. Chem. 1998, 63,4518-4521. 14 S. CURTET, M. LANGLOIS, Tetrahedron Lett. 1999, 40, 8563-8566. 15 R. TACKE, B. ULMER,B. WAGNER, M. ARLT,Organometallics2000, 19, 5297-5309. 16 N. D. HONE,S. G. DAVIES, N. J. DEVEREUX, S. L. TAYLOR, A. D. BAXTER, Tetrahedron Lett. 1998, 39, 897-900. 17 B. CHENERA, J. A. FINKELSTEIN,D. F. VEBER, /. Am. Chem. SOC.1995, 117, 11999-12000. 18 Y. LEE, R. B. SILVERMAN,/. Am. Chem. SOC.1999, 121,8407-8408. 19 Y. LEE, R. B. SILVERMAN, Org. Lett. 2000, 2, 303-306. 20 C. A. BRIEHN,T. KIRSCHBAUM, P. BAUERLE,/. Org. Chem. 2000, 65, 352359. 21 T. L. BOEHM, H. D. H. SHOWALTER,]. Org. Chem. 1996, 61, 6498-6499. 22 L. S. HARIKRISHNAN, H. D. H. SHOWALTER, Tetrahedron 2000, 56, 515519. 1

M. J. PLUNKETT, J. A. ELLMAN,/. Org. Chem. 1997, 62, 2885-2893. 24 A. C. SPIVEY, C. M. DIAPER,H. ADAMS, A. J. RUDGE,/. Org. Chem. 2000, 65, 5253-5263. 25 M. SCHUSTER, S. BLECHERT, Tetrahedron Lett. 1998, 39, 2295-2298. 26 M. SCHUSTER, N. LUCAS,S. BLECHERT, Chem. Commun. 1997, 823-824. 27 M. GRAVEL, C. D. BERUBE,D. G. HALL,/. Comb. Chem. 2000, 2, 228-231. 28 W. LI, K. BURGESS,Tetrahedron Lett. 1999, 40, 6527-6530. 29 C. POURBAIX, F. CARREAUX, B. CARBONI, H. DELEUZE, Chem. Commun. 2000, 12751276. 30 D. CRAIG,M. J. ROBSON, S. J. SHAW, Synlett 1998, 1381-1383. 31 Y. PAN,C. P. HOLMES, Org. Lett. 2001, 3, 2769-2771. 32 Y. PAN,B. RUHLAND,C. P. HOLMES, Angew. Chem. Int. Ed. 2001, 40,44884491. 33 S. C. SCHURER, S. BLECHERT,Synlett 1998, 166-168. 34 T. TAKAHASHI, H. INOUE, Y. YAMAMURA, T. DOI,Angew. Chem. lnt. Ed. 2001, 40, 3230-3233. 35 I. HIJIKURO, T. DOI,T. TAKAHASHI, J . Am. Chem. SOC.2001, 123, 37163722. 36 S. J I N , D. P. HOLUB,D. J. WUSTROW, Tetrahedron Lett. 1998, 39, 3651-3654. 37 J . C. NELSON,J. K. YOUNG?J. S. MOORE,/. Org. Chem. 1996, 61, 8160-8168. 38 C. R. MILLINGTON, R. QUARRELL, G . LOWE, Tetrahedron Lett. 1998, 39, 7201-7204. 39 F. STIEBER, U. GRETHER, H. WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 10731077. 40 S. BR~SE, D. ENDERS,J. K O BBE RL I N GF. , AVEMARIA, Angew. Chem. Int. Ed. 1998, 37, 3413-3415. 41 M. LORMANN, S. DAHMEN, S. B R ~ S E , Tetrahedron Lett. 2000, 41, 3813-3816. 42 S. SCHUNK, D. ENDERS, Org. Lett. 2000, 2, 907-910. 43 S. B ~ S EM., SCHROEN, Angew. Chem. Int. Ed. 1999, 38, 1071-1073. 44 H. KAMOGAWA, A. KANZAWA, M. KADOYA, T. NAITO,M. NANASAWA, Bull. Chem. SOC. Jpn. 1983, 56, 762-765. 23

264

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Traceless Linkersfor Solid-Phase Organic Synthesis

I. HUGHES,Tetrahedron Lett. 1996, 37, 7595-7598. 46 L. F. HENNEQUIN, S. PIVA-LEBLANC, Tetrahedron Lett. 1999, 40, 3881-3884. 47 C. HALM,J. EVARTS, M. J. KURTH, Tetrahedron Lett. 1997, 38, 77097712. 48 W.-C. CHENG, C. HALM,J. B. EVARTS,M. M. OLMSTEAD, M. J. KURTH,J. Org. Chem. 1999, 64, 8557-8562. 49 K. W. J U N G , X. Y. ZHAO,K. D. J A N D A , Tetrahedron Lett. 1996, 37, 6491-6494. 50 K. W. J U N G , X. Y. ZHAO,K. D. J A N D A , Tetrahedron 1997, 53, 6645-6652. 51 I. SUCHOLEIKI, Tetrahedron Lett. 1994, 35, 7307-7310. 52 F. W. FORMAN, I. SUCHOLEIKIJ. Org. Chem. 1995, 60, 523-528. 53 X. Y. ZHAO,K. W. J U N G , K. D. JANDA, Tetrahedron Lett. 1997, 38, 977-980. 54 C. VANIER, F. L O R C ~ A. , WAGNER, C. MIOSKOWSKI, Angew. Chem. Int. Ed. 2000, 39, 1679-1683. 55 K. C. NICOLAOU,J. A. PFEFFERKORN, G.-Q. CAO,Angew. Chem. Int. Ed. 2000, 39, 734739.

45

K. C. NICOLAOU, G.-Q. CAO,J. A. Angew. Chem. Int. Ed. 2000, PFEFFERKORN, 39,739-743. 57 K.-I. FUJITA, K. WATANABE, A. OISHI,Y. IKEDA, Y. TAGUCHI, Synlett 1999, 1760-1762. 58 R. MICHELS, M. KATO, W. HEITZ, Makromol. Chem. 1976, 177, 2311-2320. 59 T. RUHLAND, K. ANDERSEN, H. PEDERSEN, J. Org. Chem. 1998, 63, 9204-9211. 60 K. C. NICOLAOU,J. PASTOR, S. BARLUENGA, N. WINSSINGER,J. Chem. SOC.,Chem. Commun. 1998, 1947-1948. 61 H . QIAN,X. HUANG, Synlett 2001, 1913-1916. 62 K. C. NICOLAOU, J. A. PFEFFERKORN, G.-Q. CAO,S. KIM, J . KESSABI, Org. Lett. 1999, 1, 807-810. 63 L. UEHLIN, T. WIRTH,Org. Lett. 2001, 3, 2931-2933. 64 2. LI, B. A. KULKARNI,A. GANESAN, Biotechnol. Bioeng. (Comb. Chem.) 2000, 71, 104-106. 65 K. C. NICOIAOU, A. J. ROECKER, J. A. PFEFFERKORN, G:Q. CAO,J . Am. Chem. SOC. 2000, 122, 2966-2967.

56

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique Andreas Kirschning and Riidiger Wittenberg Introduction

R. B. Merrifield [ 11 and the solid phase synthesis based on his concepts revolutionized polypeptide and polynucleotide synthesis and more than ten years ago it set the stage for combinatorial chemistry. Todays driving force for this still rapidly growing technique is associated with the need to quickly generate libraries of compounds [ 2 ] . As an alternative, the utilization of functionalized polymers as reagents and catalysts has recently appeared on this scene after an incubation time of more than 25 years (31. Here, it is not the substrate which remains attached to the solid support during a multistep synthesis but instead, the polymerbound reagent or catalyst promotes a chemical transformation of a substrate which is present in solution. One advantage of this polymer-assisted solution phase synthesis is the possibility to monitor the reaction using known analytical techniques [4]. Besides the use of stoichiometric reagents another technique for polymer-assisted solution-phase purification has often been employed recently. Polymer-bound scavengers are resins which are added after a chemical reaction to remove excess reactants and byproducts [ 51. However, the true potential of polymers in organic synthesis will fully be exploited if the whole orchestra of techniques are combined. And in fact, a hybrid technique that combines the concept of solid-phase synthesis with the idea of polymer-supported scavenging reagents has seen increased interest in polymer-assisted synthesis. Often, this method, which is only one example among other polymer-assisted combinations, has been termed the “resincapture-release” methodology and we shall use this terminology throughout this report. The functionalized polymers which have been developed for this technique allow the trapping of a small molecule as an activated polymer intermediate. After washing to remove soluble byproducts, this intermediate is subjected to a second transformation by adding a new reaction partner in solution. This reactant not only chemically alters the polymer-bound intermediate but at the same time provokes release of the product from the resin back into solution (Scheme 1). Sometimes the second transformation is only used to modify the immobilized

B-A Scheme 1.

C

-+

A-C

The “resin-capture-release” methodology

+

D

266

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

intermediate and it is a third transformation which leads to release of the product from the resin. However, it needs to be pointed out that due to the fact that this methodology is located in between two distinct polymer-assisted techniques a clear cut is not always possible and therefore, some of the sequences given in this article could well be defined as examples for solid phase synthesis. Nevertheless, it is the intention of this report to familiarize the reader with methodologies that merge various polymer-assisted techniques. The “resincapture-release’’methodology even if the terminology will not prevail in the longrun is one important group of polymer-assisted techniques in organic synthesis, which clearly illustrates this development. The transformations given here though some of them showing reminiscence to solid phase synthesis are easily incorporated into a multistep polymerassisted synthesis in solution where polymer-supported reagents or catalysts are employed prior or after the “resin-capture-release” transformation. Functional Polymers for “Capture-Release” Techniques

Acyl and Sulfonyl Transfer Protocols

Probably the most widely employed applications of the “resin-capture-release” methodology are acylation and sulfonylation reactions using polymer-supported amines such as polyDMAP (polymer-bound dimethylamino pyridine) 1, poly(4-vinylpyridine) [G] and (poly-TBD) 2 (polymer-attached 1.5.7-triaza-bicyclo[4.4.0]dec-5-ene). Reagent 1 is well suited for trapping acyl chlorides as well as sulfonyl chlorides [7]which then react with amines to the corresponding amides and sulfonamides, respectively (Scheme 2) [8]. Furthermore, it should be noted that silylation of alcohols can be achieved in an analogous manner using Amberlyst A21 (poly-CHzNEtz)in the presence of silyl chloride. Again the reagent is trapped on the resin prior to reaction with the alcohol and release into solution [9].

RCOCl (2 equiv), CH2C12

RSO2Cl (2 equiv), ICH2C12 ~

Scheme 2.

0

R’NH2 (0.7 equiv), CHpC12 77 - 83%

+ R’\NKR

+1

H

R’NH2 (0.7 equiv), 0 CH2C12 R’\N,S \\‘R 1 0 66 - 88% H

+ 1

Capture-release resins in acylation reactions

Polystyrene-bound pyridineboronic acid 5 is another example of an acylation catalyst which is easily recovered and reusable. Based on work by Yamamoto and coworkers [lo] Wang et al. [ 111 developed an acylation protocol for amines, in which the carboxylic acid is

Functional Po/yrnenfor “Capture-Release” Techniques

6

5

7

8

activated as a mixed anhydride on the polymer 5 prior to release into solution as amide in up to 98% yield. Alternatively polymer-bound sodium selenide 6 served as the starting point for an acylating protocol (Scheme 3) [ 121. Transformation into selenol ester 9 afforded an active polymerbound intermediate which was cleaved in the presence of an alkinylcopper species to generate a$-alkinyl ketones 10 while the copper selenide can be reacylated using acyl chlorides. Weakly nucleophilic heterocyclic amines have efficiently been acylated utilizing solidsupported reagent 7 [ 131. Here, the electron-deficient phenol group allows for intermediate anchoring of an acyl chloride onto the resin which then is released upon treatment with various 2-aminopyridines and 2-aminothiazoles. Traces of unreacted starting material were then conveniently removed by addition of the acidic ion exchange resin Amberlite IRA-120. Likewise, polymer-anchored 1-hydroxybenzotriazole (HOBT) 3 was originally developed as a highly reactive N-acylating agent for the formation of peptide bonds in solution [ 141. Recently, it was shown that this functionalized polymer also performs coupling of acids and amines, including the transfer of protecting groups (Fmoc, Cbz, Boc) [ 151 and the synthesis of N-hydroxysuccinimideesters [ 161 in a “resin-capture-release” mode. In a similar fashion, an acylsulfonamide library was constructed by immobilizing and activating carboxylic acids on functionalized diimide resin 4 [ 171 which reacted further to acylsulfonamides with sulfonamides [ 181. Recently, polymer-bound diimide served as a coupling reagent in the synthesis and preparation of the bisquinone alkloid (-) saframycin A [19].

6 X= Na 9 X= COR Scheme 3.

2 RCOCl

SeCu

Acylation via selenol ester.

The use of basic poly-TBD 2, allows for the rapid synthesis of aryl triflates (Scheme 4) [20]. Phenols were immobilized on resin 2 to afford intermediate polymer 11. This resin was

I

267

268

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

Ar-OH

10 examples, 65 - ~ 9 9 %

11 Scheme 4.

Preparation of aryl triflates promoted by PTBD 2.

treated with 4-nitrophenyl triflate, which plays the role of a triflate transfer reagent thereby releasing the desired aryltriflate into solution. In an earlier example of the “resin-capture-release” methodology trifluoracetylation of amines was achieved using polymer-bound benzyl thiol 8. Trifluoroacetic anhydride was employed in the capturing process while addition of amines to the intermediate polymerbound thiolester released the desired trifluoroacetamide from the resin [ 211. Finally, polymer-supported oxime 12 has served as a reagent for trapping primary amines after treatment with phosgene [22] to furnish intermediate oxime carbamates 13 (Scheme 5) [ 231. Thermolysis in the presence of amines results in release of ureas into solution.

1. COC12, CHzCI2 2. R’NH2, CH2Cl2

12 R2R3NH, toluene, A

0 10 77examples, - 99% yield,

R’HNKNR2R3

76 - 98% purity Scheme 5.

Polymer-assisted preparation of substituted urethanes using polymer-anchored oxime 12.

Functional Polymers for “Capture-Release” Techniques

Alkylation Protocols

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6 ) [ 241. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 281 while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. SO2CI

14

1

ROH (10 equiv.), CH2C12, PY

r

I

@s-OR

oo

1. R’R2NH (2 equiv.), DlEA (6 equiv.), CH3CN 2. W Y Y , T H F

1

66 - >99%

7 R’”,R2

1. R’COzH, CH2CI2

N-methylimidazole

Scheme 6. Polymer-supported sulfonyl chloride 14 as a capture-release resin

Recently, three research groups independently disclosed that benzotriazoles 18 attached through various linkers to a polymeric support react with aldehydes and amines to form polymer-anchored Mannich-type adducts 19 (Scheme 7) [ 291. These intermediates are cleaved under reducing conditions and in the presence of organomagnesium or organozinc reagents to provide libraries of secondary and tertiary amines in moderate yield (1145%) and with acceptable purity (13->99%) [29]. Cleavage Protocols with Srnultaneous Ring Closure

In various cases, the release step is accompanied by a cyclization leading to heterocycles. It should be noted that under these conditions parts of the linker can become part of the product which is released into solution. Thus, gel-type polystyrene-sulfonyl-hydrazideresin 20, which originally was developed for carbonyl scavenging applications [30] can also serve as a linker for carbonyl compounds in solid phase synthesis and gives access to support-bound sulfonyl hydrazones 21 (Scheme 8)

I

269

270

I

Merging Solid-Phase and Solution-Phase Synthesis: The "Resin-Capture-Release" Hybrid Technique

R'R2NH

+

N "N N 18 H t = various linkers

R3CH0

r

1 N "N N

R4MgHal or R4ZnHal or NaBH4 (R4= H) R3 t R4 Scheme 7.

R' N 'R2

Preparation o f tertiary amines assisted by polymer-bound benzotriazoles.

1. nBuMgCI, THF, 0 "C

Br

20 NHNH2 AcOHTTHF, 50 "C

3(

r

1

Q -

Scheme 8.

21

Br

Polymer-assisted preparation o f 1,2,3-thiadiazoles

J

Br

[ 511. Treatment with thionyl chloride initiated the Hurd-Mori reaction and cleavage from the resin afforded 1,2,3-thiadiazoles. In order to generalize this strategy non-commercially available ketones were first generated by reacting a set of Weinreb-amides with Grignard reagents followed by immobilized sulfonic acid-mediated decomposition of the tetrahedral intermediate. Additional diversifications of resin-bound sulfonylhydrazones 21 such as Stille coupling or Shapiro olefin synthesis are possible. Polymer-supported oxime 12 (see also Scheme 5) may also serve as a nucleophile in SNAr reactions (Scheme 9) [32]. This procedure afforded aryl oxime adducts 22 which were released as 3-aminobenzoisoxazoles by means of an acid-promoted cyclization.

Funct;onal Polymersfor “Capture-Release” Techniques

12 CN

R

Scheme 9.

8 examples, 55 - 86% yield, 79 - >99% purity

Polymer-assisted synthesis of 3-arninobenzoisoxazoles

In analogy to a related strategy by Jung et al. for the solid phase preparation of pyridines [ 33a,b], Katritzky and co-workers devised a very elegant polymer-assisted “cyclizationcleavage” approach which starts from functionalized polymer 23. It allows the synthesis of variously substituted phenols (Scheme 10) [ 33~1. Base-catalyzed reaction between polymer-bound acetonyl building block 24 and an cc,/i’-unsaturated ketone resulted in a tandem addition/annulation reaction to afford immobilized intermediate 25. This sequence was followed by elimination and rearrangement to the corresponding phenol. Selenium-Based Polymer-Assisted Synthesis

Another example of the “resin-capture-release” technique which should see widespread applications in the future is the selenium-mediated functionalization of organic compounds. Polymer-supported selenium-derived reagents [ 341 are very versatile because a rich chemistry around the carbon-selenium bond has been established in solution and the difficulties arising from the odor and the toxicity of low-molecular weight selenium compounds can be avoided. Thus, reagent 26 (X = C1) was first prepared by Michels, Kato and Heitz [35] and was employed in reactions with carbonyl compounds. This treatment yielded polymer-bound wseleno intermediates, which were set free back into solution as enones from hydrogen peroxide induced elimination. Recently, new selenium-based functionalized polymers 26 (X = Br)-28 were developed, which have been utilized in syntheses according to Scheme 11 (refer also to Scheme 3) [36].

I

271

272

I

1;:1-1--

Merging Solid-Phase and Solution-Phase Synthesis: The "Resin-Capture-Release" Hybrid Technique

\

0Q

N

/

\

EtOH, NaOEt

p

3.

L

t

24 11 examples; 52 - 85% yield, 72 - 299% LC-purity

Scheme 10.

Polymer-assisted preparation of complex phenols,

nBu3SnH AIBN (cat.) Me-R

92% 1. H20, CSA

2. nBu3SnH AlBN (cat.) 82%

26 X= Br

OH

MeAR

and regioisomer

-Np 0

27 X=

0

Scheme 11.

Applications of organoselenium reagents covalently bound t o polymers.

OH

0

Functional Polymersfor “Capture-Release” Techniques

The reactivity of functionalized polymer 26 was elegantly exploited for the cyclization of alkenyl-substituted 8-dicarbonyls by Nicolaou and co-workers which gave access to the core structure of garsubellin A [ 371. Recently, Wirth and Uehlin further extended the selenium-based solid-phase assisted chemistry by introducing a new polymer-bound chiral selenium electrophile 29. Regioand stereoselective 1,2-methoxyselenylation of propenylbenzene gave intermediate adduct 30 which was cleaved by oxidative elimination via the selenoxide to yield the corresponding allylmethyl ether (Scheme 12) [38].

1. MeOH,

O d L v l O M ?Me M e -J(

2.

H202

29 56% (48% ee)

*

r

Scheme 12.

Electrophilic addition o f polyrner-bound chiral organoselenium reagents to alkenes.

Miscellanous Applications

An extended application of the resin-capture-release technique is depicted in Scheme 13. With the help of reagent 31, a functionalized pyridine was captured as an acyl pyridinium cation 32 on a solid support which was followed by Grignard addition and hydrolysis under acidic conditions to afford polymer-supported N-acylated dehydropyridinones 33 [ 391. Advantageously, any unreacted acylium complex collapses to the parent resin upon workup. These heterocycles, which ideally can serve as scaffolds, are then released under basic conditions. A very interesting variant of the polymer-supported Mitsunobu reaction was recently disclosed by Gelb and Aronov (Scheme 14) [40]. Polymer-bound phthalimide 34 was designed which is able to trap alcohols such as nucleosides under Mitsunobu conditions. After purification by washing the loaded resin the corresponding amine was subsequently released into solution in high yield by hydrazinolysis. Polystyrene loaded with cyanoethoxy N,N-diisopropylamine phosphine 35 has turned out to be a versatile and mild phosphitylating agent (Scheme 15) [41].The intermediate phosphite triester 36 was oxidized and the cyanoethoxy group was removed using DBU followed

I

273

274

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

t

2. R’MgX, THF 3. 3N aq. HCI, THF

-

33

7 examples 31 - 67% yield, 92 - 98% purity

Preparation of dehydropyridinones utilizing the “capture-release” technique.

Scheme 13.

34

HN& J J 1.- (

0

n v

FN HO%NaN HO

N W

NHBn

PPh3, DEAD, THF 2. NzH4, EtOH, CHpClz

OH

Scheme 14.

N W

> 96%

HO

OH

A polymer-based Mitsunobu-reaction. 1. t-BUOOH 2. DBU, THF 3. NaOMe

AcO AcO 0-

37

CN

0 0

r-0

0

1Ktetrazole,

2 ROH=

35 X= N(iPr)z

36 X= OR

AcO

OH Scheme 15.

Phosphitylation of alcohols.

by basic cleavage of the p-hydroxybenzyl linker to yield monophosphates including the labile glycosyl phosphate 37 in remarkable 78% yield and high purity. Very recently, Ito and coworkers disclosed a a resin-aided capture-release strategy in conjunction with oligosaccharide synthesis on a polymer support (Scheme 16) [42]. Interest-

Functional Polymers for “Capture-Release” Techniques I 2 7 5

ingly, the strategy is based on two polymers of which the first one, the soluble PEG monomethyl ether (MPEG), serves as a support in a conventional sense. The second polymer is based on insoluble polystyrene and is employed for purification reasons. The immobilized disaccharide 40 which is obtained from thioglycoside 39 and glycosyl acceptor 38 is captured through the chloroacetyl protecting group with functionalized polymer 41 to yield insoluble disaccharide 42. The disaccharide is purified in this way and released as disaccharide 43 from the polystyrene resin back into solution where it can serve as a new glycosyl acceptor or can be cleaved from MPEG in an oxidative manner to yield disaccharide 44. This is an excellent example for mixing various polymer-assisted techniques in synthesis. An interesting polymer-assisted variant of the Suzuki-reaction was recently disclosed by Vaultier and coworkers (Scheme 17) 1431. Aryl boronic acids can be immobilized on an ion exchange resin. Under Suzuki-Miyaura coupling conditions bisaryl species are released into solution and isolated with minimum purification. The authors also demonstrated that this strategy can be employed for the synthesis of macroheterocycles.

0 Ho&OMP BnO

0

NPhth

0

Me2S-SMe OTf

38

,94%

40

3 equiv. NHFmoc

41 ____L

0

42 NHMe I

15 equiv.

6 .I

l.Zn/Cu then AQO, Et3N 2. DDQ

*copo NPhth

h

82%

86%

BnO

Release

OBn

44 = PEG monomethyl ether

= Wang resin Scheme 16. Solid-phase capture-release strategy applied t o oligosaccharlde synthesis.

276

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

45

cat. Pd(Ph&

I

46

Scheme 17. Polymer-assisted Suzuki reaction.

Other synthetic applications of this technique are the immobilization of vinylboronates by means of a Suzuki-coupling. Release from the resin by a second transformation afforded substituted styrenes including tamoxifen and analogues derived therefrom, a drug to be used clinically for treatment of estrogen dependent breast cancers [44]. In a related purely for purification designed version [45, 461 of the “resin-capture-release”technique p-amino alcohols were captured by PEG-supported dialkylborane [47]. Purification of the target molecules was achieved after precipitation, washing and release under mildly acidic conditions. In Scheme 18 Wang resin 47 is depicted, which is functionalized with N-hydroxy thiazole 2(3)-thione 1481. This supported reagent can be used as a radical source thus allowing a solid phase version of the Hunsdiecker reaction. Acylation using O-benzotriazol-yltetramethyluronium hexafluorophosphate (HBTU) yielded intermediate 48, which was subjected to a BrCC13 solution under irradiating conditions. This photochemical induced fragmentation released the corresponding bromide into solution.

Outlook

Here, we gave a brief description of a hybrid technique in the realm of polymer-assisted synthetic methodologies which merges scavenger protocols with solid-phase synthesis 1491. This singular strategy is part of a broader development in this field. Indeed, the true potential of polymers in organic synthesis will fully be exploited if the whole orchestra of techniques is combined 1501. Hybrid-techniques will play an increasingly important role that combine both solid phase organic synthesis followed by derivatization of functional groups with polymer-supported reagents after release and cleavage of the substrate from the polymer or vice versa. These developments will also enhance the utility of soluble polymers in automated parallel synthesis. Thus, soluble polymers may be loaded with substrates which are processed by polymer-anchored reagents or catalysts. In summary, the “resin-capture-release” hybrid methodology will become one important instrument in this orchestra of techniques.

References I 2 7 7

Ho*cL C02tBu

NHBoc N A s HO

HBTU, DIPEA, rt, 6h

48

47 BrCCI3, benzene, 200 W lamp, 2h

NHBoc

75%

kCoztBu + NHBoc

(4 examples; 62 - 75%) Scheme 18. Photochemically induced Hunsdiecker reaction.

References R. B. MERRIFIELD, J. Am. Chem. Soc. 1963, 85, 2149-2154. 2 a) F. 2. DORWALD, Organic Synthesis on Solid Phase, Wiley VCH, Weinheirn 2000; b) N. K. TERRETT, Combinatorial Chemistry, Oxford University Press 1998; c) D. OBRECHT, J. M. VILLALGORDO, Solidsupported combinatorial and parallel synthesis of small-molecular-weight compound libraries, Pergamon, Elsevier Science Ltd, Oxford, 1998; d) S. R. WILSON, A. W. Combinatorial Chemistry, CZARNIK, Synthesis, Application, Wiley, New York 1997; e) J. S. FRUCHTEL,G. J U N G , Angew. Chem. 1996, 108, 19-46; Int. Ed. Engl. 1996, 35, 17-42. 3 Recent reviews on polymer-supported reagents: a) A. KIRSCHNING, H. MONENSCHEIN, R. WITTENBERG, Angew. Chem. Int. Ed. Engl. 2001, 40, 650-679; b) S. V. LEY, I. R. BAXENDALE,R. N. BREAM, P. S. JACKSON, A. G. LEACH, D. A. LONGBOTTOM.M. NESI,J . S. SCOTT, R. I. STORER, S. J . TAYLOR, J. Chem. Soc.. Perkin. Trans. I , 2000, 3815-4195; A. KIRSCHNING,H. MONENSCHEIN. R. WITTENBERG, Chem. Eur. /. 2000, 6,44451

4

4450; d) D. H. DREWRY, D. M. COE,S. POON,Med. Res. Rev. 1999, 19, 97-148; S. M. ALLIN,P. K. e) S. J. SHUTTLEWORTH, SHARMA, Synthesis 1997, 1217-1239; f ) C. U. PIITMAN,JR., Polym. News 1998, 23, 416-418; g) S. W. KALDOR, M. G. SIEGEL, C u r . Opin.Chem. Bid. 1997, I, 101-106; h) P. h sz r o , Preparative Chemistry using Supported Reagents, Academic Press, San Diego, 1987. For reviews on polymer-supported catalysts D. J. refer to ref. [3] and a) B. JANDELEIT, SCHAEFER, T. S. POWERS, H. W. TURNER, W. H. WEINBERG, Angew. Chem. 1999, 11I , 2648-2689; Angew. Chem. Int. Ed. Engl. 1999, 38, 2476-2514; b) E. LINDNER, T. SCHNELLER, F. AUER,H. A. MAYER, Angew. Chem. 1999, 11 1, 2288-2309; Angew. Chem. Int. Ed. Engl. 1999, 38, 2154-2174; c) J. H. CAMERON in Solid state organometallic chemistry: Methods and applications, (Eds.: M . GIELEN, R. WILLEM, B. WRACKMEYER), Wiley, Chichester 1999, p. 473-519; d) J. H. CLARK, D. J. MACQUARRIE, Chem. SOC.Rev. 1996, 3033 1 0 e) D. C. BAILEY, S. H. LANGER,Chem. Ren 1981, 81, 109-148.

278

I

Merging Solid-Phase and Solution-Phase Synthesis: The “Resin-Capture-Release” Hybrid Technique

For reviews on scavenger techniques refer to: a) D. L. FLYNN, R. V. DEVRAJ, J. J. PARLOW, in Solid Phase Organic Synthesis (Eds.: K. BURGESS), Wiley, New York, 2000, p. 149-194; b) J. J , PARLOW, R. V. DEVRAI, M. S. SOUTH,Cum. Opin. Chem. Bid. 1999, 3, 320-336; c) J . C. HODGES, Synlett 1999, 152-158; d) D. L. FLYNN,R. V. J. J. PARLOW, Cum Opin. Drug DEVRAJ, Disc. Deu. 1998, I, 41-50; e) L. M. GAYO, Biotechnob Bioeng. 1998, 61, 95; f ) R. J. BOOTH, J. C. HODGES, ACC.Chem. Res. 1999, 32, 18-26; g) D. L. FLYNN, R. V. Med. DEVRAJ, N. NAING. J. J. PARLOW, Chem. Res. 1998, 8, 219-243. 6 J:G. R O D R ~ G U R. E ZMART~N-VILIAMIL, , S. RAMOS,New. I . Chem. 1998,865-868. 7 a) J. G. KEAY, E. F. V. SCRIVEN, Chem. Ind. 1994, 53, 339-350; b) C. GIRARD,I. TRANCHANT, P.-A. NOIRE,J. HERSCOVICI, Synlett 2000, 1577-1580. 8 L. L. TAMANAHA, J. A. P o ~ c oJR., , Synthesis @ Punjcation 1999, 2, 1-4 (Catalogue of Argonaut Technologies). 9 N. HOFFMANN, Diplomarbeit Universitat Hannover 2001. 10 K. ISHIHARA, S. OHARA,H. YAMAMOTO,]. Org. Chem. 1996, 61, 4196-4197. 1 1 R. LATTA, G. SPRINGSTEEN, B. WANG, Synthesis 2001, 1611-1613. 12 QIAN,L.-X. SHAO,X. HUANG, Synlett 2001,

STEPHENS STRAMIELLO, Tetrahedron Lett.

5

1571-1572. 13 K. KIM, K. LE, Synlett 1999, 1957-1959. 14 a) R. KALIR,A. WARSHAWSKY, M. FRIDKIN, Eu.]. Biochem. 1975, 59, A. PATCHORNIK, 55-61; b) M. STERN, R. KALIR,A.

PATCHORNIK, A. WARSHAWSKY, M. J. Solid-Phase Biochem. 1977, 2, FRIDKIN, 131-139; c) I. E. POP, B. P. DEPREZ,A. L. TARTAR,].Org. Chem. 1997, 62, 2594J. J E O N G , W. 2603; d) K. DENDRINOS, HUANG, A. G. KALIVRETENOS, Chem. Commun. 1998, 499-500. 15 K. G. DENDRINOS, A. G. KALIVRETENOS.]. Chem. Soc., Perkin Trans I , 1998, 14631464. A similar functionalized polymer, based on N-hydroxysuccinimide was disclosed by M. ADAMCZYK, J. R. P. G. MATTINGLY, Tetrahedron FISHPAUGH, Lett. 1999, 40, 463-466. 16 K. G. DENDRINOS, A. G. KALIVRETENOS, Tetrahedron Lett. 1998, 39, 1321-1324. 17 Other applications of reagent 4 include the preparation of amides: M. C. DESAI,L. M.

1993, 34, 7685-7688 and thiol esters: M.

Tetrahedron ADAMCZYK, J. R. FISHPAUGH, Lett. 1996, 37, 4305-4308. 18 C. F. STURINO, M. LABELLE,Tetrahedron Lett. 1998, 39, 5891-5894. 19 A. G . MYERS, A. T. PLOWRIGHT,]. Am. Chem. SOC.2001, 123, 5114-5115. 20 S. BOISNARD,J. CHASTANET, J. Zu, Tetrahedron Lett. 1999, 40, 7469-7472. 21 P. I. SVIRSKAYA, C. C. LEZNOFF,M. STEINMAN]. Org. Chem. 1987, 52, 1362-1364. 22

M. A. SCIALONE, S. W. SHUEY,P. SOPER, Y. HAMURO, D. M. BURNS,].Org. Chem.

1998, 63, 4802-4807. 23 S . KOBAYASHI,T. FURUTA, K. SUGITA,0.

OKITSU,H. OYAMADA, Tetrahedron Lett. 1999,40, 1341-1344. 24 a) J. K.

RUETER, S. 0. NORTEY, E. W. BAXTER,G. C. LEO, A. 8 . REITZ,Tetrahedron Lett. 1998, 39, 975-978. Polymerbound arylsulfonate esters can undergo various reactions at remote functionalities prior to cleavage from the resin with diethyl amine: E. W. BAXTER, J. K. RUETER, S. 0. NORTEY,A. B. REITZ, Tetrahedron Lett. 1998, 39, 979-982.

F. H u , J . A. PORCO,Synth. Pur. Lett. 1999, 1, 1-5. 26 a) A. PATCHORNIK, Nouu.]. Chim. 1982, 6, 639-643. b) N. ZANDER, R. FRANK,Tetrahedron Lett. 2001, 42, 7783-7785. 27 a) S. W. KALDOR, J. E. FRITZ,J. TANG,E. R. MCKINNEY, Bioorg. Med. Chem. Lett. 1996, 6, 3041-3044; b) M. W. CRESWELL, G. L. BOLTON, J. C. HODGES, M. MEPPEN, Tetrahedron 1998, 54, 3983-3998. 28 B. RAJU,J. M. KASSIR, T. P. KOGAN, Bioorg. Med. Chem. Lett. 1998, 8, 3043-3048. 29 a) K. SCHIEMANN, H. D. H. SHOWALTER,]. Org. Chem. 1999, 64, 4972-4975; b) A. R. KATRITZKY,S . A. BELYAKOV,D. 0. TYMOSHENKO,]. Comb. Chem. 1999, 1. 173-176; c) A. PAIO,A. ZARAMELLA, R. FERRITO,N. CONTI,C. MARCHIORO, P. SENECI,].Comb. Chem. 1999, I, 31725

325. 30 a) 0. GALIOGLU, A. AKAR,Eur. Polym. I. 1989, 25, 313-316. b) D. W. EMERSON, S. C. J O S H I , E. M. R. R. EMERSON,

J. M. TUREK,].Org. Chem. SORENSEN, 1979, 44,4634-4640; c) H. KAMOGAWA,

T. NAITO, M. A. KANZAWA, M. KADOYA,

References

31 32 33

34

35 36

37

38 39

NANASAWA, Bull. Chem. SOC.Jpn. 1983, 56, 762-765. Y. H u , S. BAUDART,J. A. PORCO,JR.,]. Org. Chem. 1999, 64, 1049-1051. S. D. LEPORE.M. R. WILEY,J . Org. Chem. 1999, 64,4547-4550. a) P. GROSCHE, A. HOLTZEL,T. B. WALK, A. W. TRAUTWEIN, G. J U N G , Synthesis 1999, 1961-1970; b) D. G. SCHMID,P. GROSCHE,G. J U N G , Rapid Commun. Mass Spectrom. 2001, 15, 341-347; c) A. R. KATRITZKY, S. A. BELYAKOV, Y. FANG, J. S. KIELY, Tetrahedron Lett. 1998, 39, 8051-8054. For various examples of immobilized selenium reagents see a) Y. OKAMOTO, K. L. CHELLEPPA, R. HORNSANG,].Org. Chem. 1973, 38, 3172-3175; b) E. J. GOETHALS, Eu. Polym. ]. 1974, 10, 847849; c) K. KONDO,J . Polym. Sci., Polym. Lett. Ed. 1974, 12, 679-683; d) M. KATO, R. MICHELS, W. HEITZ,]. Polym. Sci., Polym. Lett. Ed. 1976, 14, 413-415; e) K.-I. FUJITA, K. WATANABE, A. OISHI,Y. IKEDA,Y. TAGUCHI, Synlett 1999,1760-1762. R. MICHELS, M. KATo, W. HEITZ, Makromol. Chem. 1976, 177,2311-2320. K. C. NICOLAOU, J. PASTOR,S. BARLUENGA, N. WISSINGER, Chem. Commun. 1998, 1947-1948. K. C. NICOLAOU, J. A. PFEFFERKORN, G.-Q. CAO,S. KIM, J. KESSABI,Org. Lett. 1999, I , 807-810. L. UEHLIN,T. WIRTH,Org. Lett. 2001,3, 2931-2933. a) C. CHEN,I. A. MCDONALD, B. MUNOZ, Tetrahedron Lett. 1998, 39, 217-220; b) B. MUNOZ,C. CHEN,I. A. MCDONALD, Biotechn. Bioengin. (Comb. Chem.) 2000, 71, 78-84. For the preparation of a resin-

bound chloroformate; see J. R. HAUSKE, P. DORFF,Tetrahedron Lett. 1995, 36, 1589-1592. 40 A. M. ARONOV, M. H. GELB,Tetrahedron Lett. 1998, 39, 4947-4950. 41 K. PARANG,E. J.-L. FOURNIER, 0. HINDSGAUL, Org. Lett. 2001,3, 307-309. 42 H. ANDO,S. MANABE, Y. NAKAHARA, Y. ITO, Angew. Chem. Int. Ed. 2001, 40, 4725-4728; Angew. Chem. 2001, 113, 4861-4864. 43 V. LOBREGAT, G. ALCAREZ, H. BIENAYME, Chew Commun. 2001, M. VAULTIER, 817-818. 44 a) S. D. BROWN,R. W. ARMSTRONG,].Org. Chem. 1997, 62, 7076-7077; b) D. BROWN, R. W. ARMSTRONG,].Am. Chem. SOC. 1996, 118,6331-6332. 45 An early example of this concept, using polystyrylboronic acid for separating and purifying 1,2-cis diols from cisltransmixtures, was presented by E. SEYMOUR, J. M. J. FRECHET,Tetrahedron Lett. 1976, 3669-3672. 46 S. SUNAMI, T. SAGARA, M . OHKUBO,H. MORISHIMA, Tetrahedron Lett. 1999, 40, 1721-1724. 47 M. H. KIM, D. JANDA,]. Org. Chem. 1998, 63, 889-894. 48 L. DE LUCIA, G . GIACOMELLI, G . PORCU, M. TADDEI,Org. Lett. 2001, 3, 855-857. 49 Recently, the first alkylating functionalized polymer was described by J. RADEMANN,J. SMERDKA, G. J U N G , P. GROSCHE,D. SCHMID,Angew. Chem. 2001, 113, 390393; Angew. Chem. Int Ed. 2001, 40, 381-385. 50 X. OUYANG, R. W. ARMSTRONG, M. M. MURPHY,J. Org. Chem. 1998, 63, 1027-1032.

I279

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Polymeric Scavenger Reagents in Organic Synthesis Jason Eames and Michael Watkinson

Solid-phase organic synthesis (SPOS) has become a popular method for the preparation of low molecular weight organic molecules [l, 21. A great deal of this attention has been focused on the lead optimisation of biologically active molecules within the pharmaceutical industry [ 31. One clear advantage of this biphasic methodology over traditional synthetic methods is in the area of purification - simple filtration of the reaction mixture generally leads directly to the required product in high purity [4]. However, this methodology is not without its limitations; excess of at least one reagent is generally required to drive the reaction to completion 151, and in some cases up to two additional synthetic steps may be required to mount and remove the substrate from its solid support. Moreover, the required target invariably has to be re-synthesised on a larger scale using classical solution methodology to provide sufficient quantities for screening [GI. Due to the problems associated with solid phase organic synthesis such as scalability and characterisation, considerable effort has being devoted to the development of new methodologies to assist in the purification of solution phase reactions. In addition to the existing use of solid-supported reagents [7-101, this area has recently been expanded towards the use of solid-supported reagents as purification aids within solution phase synthesis. These solid-supported reagents have been used to remove an excess of reactants to give the product in high yield and in a single operation (Scheme 1).This technique offers many of the advantages of solid supported organic synthesis such as ease of work-up, and product purification with the additional advantages associated with traditional Reactants A (xs)

+

A-B

Scheme 1.

B

-

Product A-B

I

+

A

e

x

polymeric-supported scavenger

I

A-B

+

XA

Polymeric Scavenger Reagents in Organic Synthesis

solution phase synthesis (scalability and ease of characterisation). These polymeric reagents have been referred to as polymer scavengers$
Chemical reactivity

Scavenger Resins

acidic

basic

NMe2

electrophilic

NCO

nucleophihc

NH2

W

N

CHO

Scheme 2.

Kaldor and co-workers [ 111 have reported an application of both nucleophilic and electrophilic polymer supported reagents within the synthesis of substituted ureas like 4a (Scheme 3 ) . Benzylamine 1was added to an excess of pmethoxyphenylisocyanate 2 in chloroform-dl for 1 hour, after which an excess aminomethylpolystyrene 3 (0.8 equiv/gram) was added to scavenge the unreacted and remaining isocyanate 2. Filtration of the reaction mixture (to remove the polymeric urea 4b), followed by 'H NMR analysis revealed only the required urea 4a was present, with no trace of the original isocyanate 2. This procedure was shown to be quite general, and a moderate library containing approximately a thousand different ureas and thioureas has been synthesised using this methodology (for a representative account see Table 1, entry 1).This methodology was further extended towards the preparation of amides, sulfonamides and carbamates. In these reactions the polymeric aminomethylated styrene 3 behaved as a double scavenger by removing unreactive electrophilic and acidic species. This technique has been applied to a variety of synthetic procedures (see Table 1: entry 1). t

This strategy has previously been referred to as solid-supported scavengers (SSS), polymersupported quench (PSQ) and complementary molecular reactivity and molecular recognition ( CM R/ R) .

.r

A nucleophilic polymer is a scavenger of

electrophiles and vice versa.

I

281

282

I

Polymeric Scavenger Reagents in Organic Synthesis

Q

+

b-

Polymeric Scavenger Reagents in Organic Synthesis

I

Representative Product

Yield

Purity

67%

94%

94%

93%

73%

90%

62%

>95%

283

Table 1. Selective scavenging of excess reagents

Entry

Limiting Reagent

Excess Reagent

1

R'R~NH

R'NCO R3COClt R30COC1t R'SOzCIt

3

Scavenger

/IR3 R'NH2

R2

R'R~NH

o(,:ocl 12

t piperidinomethyl

H

O

C

N

D

polystyrene or other solid-supported bases were added as an acid scavenger.

Two complementary procedures have been developed for alkylation of secondary amines [ 111 - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1: entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [ 121. As an alternative, secondary amines (e.g., 8) have also been prepared by reductive amination of primary amine 6 and aldehyde 7, using a polymer supported borohydride reducing agent (Scheme 4) [ 111. The excess primary amine 6 was removed using a polymer supported polystyrene carboxaldehyde 11. The high yield of secondary amine 8 presumably indicates that addition of the primary amine to the polymeric aldehyde 11 was considerably faster than the corresponding reduction involving both polymeric reagents. This secondary amine 8 was further converted into a urea 10 by the addition of an excess of isocyanate 9. The remaining unreacted isocyanate 9 was captured by the addition of the polymeric scavenger, amine 3. This type of methodology has proved very popular and has given rise to the synthesis of a variety of amines (for a representative account see Table 1: entry 3). An analogous procedure has been adopted for the formation of tertiary amines, which utilised a polymer supported acid chloride 12 to scavenge the excess secondary amine, (Table

284

I

Polymeric Scavenger Reagents in Organic Synthesis

R'NHz(1.5 eq.) 6

+ R2CHO(1 eq.)

(i-iv) w

H R,, N-

R2

8

7

@CHO

()-cH,NH,

11

+ R3NC0 (1.25 eq.) 9

I

(v-vii)

3 10

MeOH, r.t., 1 h; (ii) Amberlite@IRA-400 borohydride resin, r.t; (iii) polystyrene carboxaldehyde 11, CH2C12, overnight; (vi) filter; (v) ethanol-free CHCI,, 1 h; (vii) 3, 1 h, filter.

Reagents and conditions: (i)

Scheme 4.

1, entry 4).By coupling such procedures together, a series of substituted ureas were synthesised in excellent yield (89-100%) and chemical purity (81-97%). More recently, Bradley has demonstrated the chemoselective capture of primary amines over secondary amines using a polymeric methacrylate (AAEM) 13 as a purification method for an in-situ reductive amination procedure (Scheme 5) [13]. Reduction of the imines 17a-c (formed by addition of benzaldehyde 15 to an excess of the primary amines 16a-c) gave the required secondary amines Ma-c. The remaining unwanted primary amines 1Ga-c was chemoselectively removed by the addition of the scavenger resin, acetoacetoxy ethyl methacrylate (AAEM) 13 to give the enamines 19a-c. Simple filtration of the reaction mixture gave the required secondary amine in good yield and excellent purity. Previously, within this area benzaldehyde-based resins (like 14)have been used, but were problematic, as they were particularly air sensitive. Booth and Hodges [14]have investigated the use of three separate polymer supported reagents 20, 21 and 22, all of which were derived from commercially available polymers (Scheme 6 ) . These have either been used individually or in multiple Combinations to aid quenching and further purification during the solution phase synthesis of ureas, thioureas, sulfonamides, amides and pyrazoles. The utility of the covalent isocyanate scavenger 22 was individually demonstrated in both reactions steps, whilst the polymeric triamine 20 and morpholine 21 were employed as polymeric supported bases. These scavengers were shown to be efficient and provided reliable methods for removing unwanted reaction impurities. This strategy was also tested within single and multi-step reactions. For example, the substituted pyrazole 25 was synthesised by modifying the traditional method by simply incorporating their covalent scavenger resin (Scheme 6 ) . Although the yield for the first step of this synthesis, involving the condensation of 1,3-diketone 23 with an excess of phenylhydrazine-4-carboxylicacid (in the presence of the two scavengers 21 and 22) was

19a-c

o

y HN-R’

y

15

+

+

18a-c

Ph

14

(iii) f-------

0

I 18a-c

Ph

Benzyl

18c

3

(ii)

17a-c

2-Fu~l

18b

2

16a-c

R1-NH2

16a-c

100%

100%

100%

Purity

Scheme 5.

Reagents and conditions: (i) MeOH, 2h; (ii) MeOH, 24h, Amberlite IRA 400 borohydride resin (2 equiv.); (iii) MeOWCH,CI, (1 :1. viv), 36h, 13 (2 equiv.).

O

Ph

A,

13

O 0 Y 0 Y

Phenyl

R1

18a

18

1

Entry

87%

88%

81%

Yield

N ul 00

1.

0

3

286

I

Polymeric Scavenger Reagents in Organic Synthesis

N/\I

H 20

NH2

W

N

C

O

22

21

i) i-BuOCOC1,21, CH2Cl2 ii)

H2N"o'p-ir

Scheme 6.

moderate (75%), the reaction appeared to be very clean and this yield was accepted in favour of high purity (97% measured by HPLC). The second step of the synthesis involved amide bond formation by activation of the carboxylic OH group in 24 (with a mixed anhydride), followed by displacement with i-propyloxyaminopropane to give the amide 25 - both basic 20 and 21 and the electrophilic 22 scavengers were used to ensure efficiency [ 141. The reaction proceeded in good yield (75%) with excellent chemical purity (97%) (Scheme 6). The synthetic utility of ion exchange resins in combinatorial chemistry has been demonstrated by the use of a basic polymeric base PTBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 26 in a series of 0-and N-alkylation experiments (Scheme 7) [ 151. For example, deprotonation of the phenol 27 with this polymeric base PTBD 26 gave the ionic polymeric species 28 which contained the more nucleophilic phenolate. Addition of the 2-bromo aryl ketone 29 gave the aryl ether 30 in reasonable yield and in high purity (Scheme 7). The basic polymeric scavenger PTBD 26 removed all the unwanted HBr produced within the reaction mixture (in the form of 31) and advantageously eliminated the need for an aqueous extractive work-up procedure. In a related report [ 161 it has been further demonstrated that aryl triflates could be readily synthesised using 4-nitrophenyl triflate 33 as the transfer reagent (Scheme 8). Deprotonation of the phenol 32 with PTBD 26 in acetonitrile at an elevated temperature (80 "C), followed by the addition of 4-nitrophenyl triflate 33 gave the required aryl triflate 35 after simple filtration. Any unreacted phenolate still present was removed as the ionic polymer 34 through filtration (Scheme 8). It has also been shown that initial deprotonation of the phenol was not necessary for optimal reactivity and that epimerisation of base sensitive compounds is not a problem

Polymeric Scavenger Reagents in Organic Synthesis

a3 3:

+

\

+

..a

\

n

I

287

288

I

Polymeric Scavenger Reagents in Organic Synthesis

al

E,

+

0

z

+

..m I

u N

6 m.

Polymeric Scavenger Reagents in Organic Synthesis

I

289

[ 161. This procedure appears to be particularly mild; racemisation of the tryptophane derivative 32 does not occur (Scheme 8). The chemoselectivity of this reaction is remarkable when considering the nucleophilic behaviour of the neighbouring amide group. Cresswell and coworkers 1171 have used a combination of both covalent and ionic scavengers to achieve an efficient library synthesis of piperidinones 39 using a Lewis-acid catalysed hetero-Diels-Alder reaction (Scheme 9). The scavenger resin 20 was used to remove any unreacted imine 36 as well as any hydrolysed product resulting from Danishefsky's diene 37, following an acid work-up (1M HCl) which was required to remove the ytterbium catalyst. This procedure was particularly efficient and up to forty piperidinones such as 39 were prepared using a representative group of building blocks (made up of four aldehydes and ten amines) in good yields and excellent purity. Chemoselective reduction of the carboncarbon double bond in 38 using L-Selectride gave the required piperidinone 39.

20

'NH,

CH(OCH3)3 PhCHZNH2

+ ArCHO 36

L-Selectride 4

THF, -78'C

0

39

I

31

(i-iv)

a:2ph

0

38; 73%; 99% purity

Reagents and conditions; (i) Yb(OTf)3 (0.1 eq.), CH3CN; (ii) 20, CH2Clz; (iii) filter; (iv) EtOAdlN HCI Scheme 9.

As this area of polymer supported reagents continues to expand the complexity of the polymeric supported resins has increased [ 181. Although electrophilic supported reagents like the isocyanate 5 and acid chloride 12 have been shown to be efficient reagents for the covalent capture for primary and secondary amines (Table I), they are not without their difficulties. The isocyanate resin is particularly expensive and the loading is rather low (approximately 1 mmol NCO/gram).

290

1

Polymeric Scavenger Reagents in Organic Synthesis

In an attempt to solve this problem, Coppola has designed a novel electrophilic scavenger based on an isatoic anhydride motif (Scheme 10) [IS]. This reactive mixed anhydride was shown to be particularly effective towards primary and secondary amines. The loading for this polymer was also shown to be high (3.2 mmol/gram). A series of amides (e.g. 41) and ureas (e.g. 43) were synthesised by the addition of benzylamine to the isatoic anhydride 40 and thioisocyanate 42 respectively. The excess and unreacted benzyl amine was removed by the addition of the polymeric scavenger anhydride 44 - simple filtration of the resultant scavenged polymer 45 gave the amide 41 and urea 43 in high yield and purity (Scheme 10).

41 Purity = 99%

40

0'

NCS

91%

(i) PhCH2NH2

*

(ii) 44 42

43 Purity = 99%

PhCH2NHz b

44

45

Scheme 10.

Despite the use of boronic acids as intermediates in Suzuki cross-coupling reactions, and in the biological application to sugar recognition, there are limited scavengers available for this functional group. In an attempt to solve this problem, Hall has designed and developed [ 191 a novel polymer scavenger resin DEAM-PS (N,N'-diethanolaminomethyl polystyrene) 47 for the parallel synthesis of aryl boronic acids in solution phase (Scheme 11).This resin was used to purify the crude dienylboronic acid 49 which was known to be difficult. The use of resin 47, to capture boronic acid 49, eliminates excess reagents and cyclohexanol byproducts and greatly facilitates its purification through simple rinsing of the resin bound form 48.

Polymeric Scavenger Reagents in Organic Synthesis

Y

I

46

(iii)

48

49

\

95% based on 46 Reagents and conditions: (i) addition of (C6Hl1)2BH(1 .O equiv.), then Me3NO; (ii) DEAM-PS resin 47; (iii) H20, THF. Scheme 11.

Of particular interest to combinatorial chemistry is the use of immobilised functionalised boronic acid templates which are capable of further transformations [20]. For instance, an aryl carboxylic acid 50 can be converted into the corresponding amide 51 (Scheme 12), whilst still being attached to the resin. Benzyl amine and butylamine were coupled efficiently to afford (after cleavage) the corresponding amides 52 in high yield (Scheme 12).

51

50

52

Reagents and conditions: (i) RNH2 (2.5 equiv), N-hydroxbenzotriazole(2.5 equiv) N,N'-diisopropylcarbodiimide(2.5 equiv); (ii) DEAM-PS resin 47; (iii) H20, THF. Scheme 12.

Taddei has developed a soluble PEG supported scavenger 53 to capture a variety of nucleophilic functional groups (Scheme 13) [21]. This scavenger was based on an electrophilic dichlorotriazine core and relied on selective precipitation (by the addition of ether to acetonitrile) to remove it from the reaction mixture. This scavenger 53 is particularly versatile, and has been used to remove primary, secondary and tertiary alcohols, diols and thiols

I

291

292

I

Polymeric Scavenger Reagents in Organic Synthesis

+ a V

3:

2

2

+

+

m r

Polymeric Scavenger Reagents in Organic Synthesis

I

293

within a multitude of different reactions ranging from the formation of esters such as 55, silyl ethers 56, ketals 57 and thioacetals 58 by the selective removal of the scavenged polymer 54. The versatility of this methodology was further illustrated in the conversion of citronellol 59 into the corresponding chloride GO using triphenylphosphine in tetrachloromethane. The reaction mixture was efficiently purified by the addition of the scavenger triazine 53, which not only removed the unreacted citronellol 59, but also the unreacted triphenylphosphine (in the form of 61) and triphenylphosphine oxide byproduct (in the form of 62). After selective precipitation the chloride GO was isolated in 65% yield (Scheme 13). By far, the majority of these reports into the applications of polymeric scavengers have been within the pharmaceutical field. However, recently this methodology has been used to assist in the development of new catalysts. In particular, the ability of high throughput catalyst screening for improving efficiency has generated a lot of interest. The use of a polymeric amine 20 and pyridine G3 as scavengers in the synthesis of substituted sulfonamides 66 and 75, which were known to catalyse EtZZn addition to a variety of carbonyl derivatives (Scheme 14 and 15) [22, 231. The required sulfonamide ligands 66 were efficiently synthesised by addition of a 1,l-diamine 64 to an excess of substituted chloride 65 to ensure complete conversion [ 221. The use of a polymeric nucleophilic covalent catalyst, dimethylamino pyridine 63, not only accelerates the rate of addition but also scavenges the HCl by-product (Scheme 14). The excess sulfonyl chloride was removed using the polymeric bound tris(2-

i) 63, CH2C12 ii) 20,CHzC12

YXN 65

R.R'. X and Y can be varied

N H -N-NH2 20

66

NHBOC

NH 024&

63

Ph

67

R~CHO 68

+

Et&n

+

Ti(O-i-Pr)4

67

9H R2& (R)-69

R2 = Cy, Ph, Ph(CH2)2and p-ClCbH4 Scheme 14.

294

I

Polymeric Scavenger Reagents in Organic Synthesis

N

d 3:

z

-9 N

/

d

Iv)

3?

zi=

N

d

+

+ I

+

U v)

References I 2 9 5

aminoethy1)amine 20. Thirty of the possible thirty-six component library were screened against the enantioselective Ti(O-i-Pr)4-mediatedaddition of Et2Zn to a series of four aldehydes 68. This screening revealed a number of interesting points; the best ligand was shown to be 67 - using the (lS, 2S)-diaminocyclohexane scaffold and the sulfonyl chloride derived from L-phenylalanine giving in all cases studied the (R)-alcohol 69 in high selectivity (8696% ee). The effect of varying the R' substituent has revealed the selectivity to increase in the following order CHzPh > CH3 > i-Bu > i-Pr > -(CH2)3-,which may assist in the design of future catalysts. Related sulfonamide ligands 75 have been used in the Cu(OTf)2 catalysed enantioselective 1,4-addition of Et,Zn to a series of enones 76; n = 1 and 2 to give the ketone 77 (Scheme 15) [231. Similar scavenger methodology was used to synthesise the sulfonamide component 72. This was further functionalised by incorporation of a substituted salicylaldehyde 74 to generate a library of chiral Schiff base ligands, which contain three different metal binding sites (imine, phenol and secondary sulfonamide). The acid scavenger 63 was used to purify this library to remove the generated HC1 from the Boc deprotonation step. Screening this 100 or so library, revealed that the ligand 78 (R' = i-Pr; R2 = (S)-CH(Me)Cy;R' = 3,5-CI2)gave the best selectivity for 2-cyclohexenone (82% ee) and 2-cycloheptenone (81% ee). These results have shown the importance of combinatorial techniques for probing the efficiency of a particular reaction to allow further optimisation. The use of polymer supported reagents and scavengers has greatly improved the efficiency of classical solution phase chemistry [ 241. This development has allowed combinatorial solution phase chemistry to be further extended. The advantages being; 1. Use of excess reagents or reactants to drive the solution phase reaction to completion; 2. Removal of the need for substrate linkage to the polymer support; 3 . Removal of the need for a liquid phase extraction and chromatography.

References E. M. GORDON,M. A. GALLOP,D. V. PATEL,Acc. Chem. Res. 1996, 29, 144-154. 2 S. V. LEY,I. R. BAXENDALE, R. N. BREAM, P. S. JACKSON, A. G. LEACH,D. A. LONGBOROM,M. NESI,J. S. SCOOT,R. I. STORERA N D S. J. TAYLOR, J . Chem. SOC., Perkin Trans 12000, 3815-4195. 3 N. K. TERRET,M. GARDNER, D. W. GORDON,R. J. KOBYLECK A N D J. STEELE, Tetrahedron 1995, 51; 8135-8173. 4 F. BALKENHOHL, C. VON D E M BUSSCHEHUNNEFELD, A. LANSKYA N D C. ZECHEL, Angew. Chem., Int. Ed. 1996, 35, 22881

2337. 5 6

S. H. DEWIIT A N D A. W. CZARNIK,Acc. Chem. Res. 1996, 96, 114-122. J. A. ELLMAN, ACC.Chem. Res. 1996, 29, 132-143.

s. v. LEYA N D R. SMITS, J . Chem. SOC.,Perkin Trans. I 1999, 24212423. 8 J. S. FRUCHTEL A N D G. JUNC,Angew. Chem., Int. Ed. 1996, 35, 17-42. 9 R. B. MERRIFIELD, J . Am. Chem. SOC.1963, 85, 2149-2154. 10 (a) B. HINZEN A N D S. V. LEY,J . Chem. SOC.,Perkin Trans. 1 1998, 1-2; (b) F. HAUNERT,M. H . BOLLI,B. H I N Z E NA N D S. V. LEY,J. Chem. SOC., Perkin Trans. 11998, 2235-2237; and references therein. 11 S. W. KALDOR,M. G. SIEGEL,J. E. FRITZ, B. A. DRESSMAN A N D P. J. HAHN, Tetrahedron Lett. 1996, 37, 7193-7196. 12 B. A. DRESSMAN, U. SINGHA N D S. W. KALDOR, Tetrahedron Lett. 1998, 39, 3631-3634. 7 J. HABERMANN,

296

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Polymeric Scavenger Reagents in Organic Synthesis 13 2. Yu, S.

ALESSO, D. PEARS,P. A. WORTHINGTON, R. W. A. LUKE A N D M. BRADLEY,Tetrahedron Lett. 2000, 41, 8963-8967. 14 R. J. BOOTHA N D J. c. HODGES, /. Am. Chem. Soc. 1997, 119,4882-4886. 15 W. Xu, R. MOHANA N D M. MORRISSEY, Tetrahedron Lett. 1997, 38, 7337-7340. 16 S . BOISNARD,1. CHASTANET A N D J. Z H U , Tetrahedron Lett. 1999, 40, 7469-7472. 17 M. W. CRESSWELL, G. L. BOLTON,J. C. A N D M. MEPPEN, Tetrahedron HODGES 1998, 54,3983-3998. 18 G. M. COPPOIA,Tetrahedron Lett. 1998, 39, 8233-8236. 19 D. G. HALL,J. TAILOR A N D M. GRAVEL, Angew. Chem., Int. Ed. 1999, 38, 30643067. 20 S. RANA.P. WHITEA N D M. BRADLEY, Tetrahedron Lett. 1999, 40. 8137-8140. 21 A. FALCHI A N D M. TADDEI, Org. Lett. 2000, 2, 3429-3431. 22 C. GENNARI, S. CECCARELLI, U. PIARULLI, C. A. G. N. M O N T A L B EA ~N DI R. F. W. JACKSON, J. Org. Chem. 1998, 63, 5312-5313. 23 I. CHATAICNER, C. GENNARI, U. PIARULLI A N D S. CECCARELLI, Angew. Chem., Int. Ed. 2000, 39,916-918. 24 Other representative examples in which polymeric scavenger reagents are used, include; L. A. THOMPSON A N D J. A. ELLMAN,Chem. Rev. 1996, 96, 555-600; D. H. DREWRY, D. M. COEA N D S. POON, Med. Res. Rev. 1999, 19, 97-148; B. J. COHEN,M. A. KRAUSA N D A. PATCHORNIK, /.Am. Chem. SOC.1981, 103, 7620-7629; J.

I.

PARLOW, Tetrahedron Lett. 1995, 36, 1395-1396; T. A. KEATINGA N D R. w. ARMSTRONG, I. Am. Chem. SOC.1996, 118, 2574-2583; D. L. FLYNN,J. 2. CRICH, R. V. DEvRAT, S. L. HOCKERMAN, J. J. PARLOW, M. S. SOUTHA N D S. WOODWARD, J. Am. Chem. SOC. 1997, 119,4874-4881; S. W. KALDOR,J. E. FRITZ,J. TANGA N D E. R. MCKINNEY,Bio. Med. Chem. Lett. 1996, 6, 3041-3044; S. E. AULT-JUSTUS, J . C. HODGESA N D M. W. WILSON,Biotechnol. Bioeng. (Comb. Chem.) 1998, 61, AND 17-22; J. J. PARLOW,D. A. MESCHKE S. S. WOODARD, /. Org. Chem. 1997, 62, 5908-5919; L. M. GAYOA N D M. J. SUTO, Tetrahedron Lett. 1997, 38, 513-516; M. G. SIEGEL,P. J. HAHN,B. A. DRESSMAN, J. E. FRITZ,J. R. GRUNWELL A N D S. W. KALDOR, Tetrahedron Lett. 1997, 38, 3357-3360; K. IIJIMA, W. FUKUDA A N D M. TOMOI,Pure Appl. Chem. 1992, A29, 249-261; U. SCHUCHARDT, R. M. VARGAS A N D G. GELBARD, /. Mol. Cat. A: Chem. 1996, 109, 37-44; B. A. KULKARNI A N D A. GANESAN, Angav. Chem., Int. Ed. 1997, 36; 2454A N D M. LABELLE, 2455; C. F. STURINO Tetrahedron Lett. 1998, 39, 5891-5894; C. K. BIACKBURN, B. GUAN,P. FLEMING, SHIOSAKI A N D S. TSAI,Tetrahedron Lett. 1998, 39, 3635-3638; J. J. WEIDNER, J. J. PARLOW A N D D. L. FLYNN, Tetrahedron Lett. 1999, 40, 239-242; J. S. WARMUS, T. R. RYDER,J. C. HODGES,R. M. K E N N E D YA N D K. D. BRADY,Bio. Med. Chem. Lett. 1998, 8, 2309-2314; Review: J. EAMES A N D M . WATKINSON, Eur. 1.Org. Chem. 2001, 1213-1224.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Total Syntheses o f Vancomycin Lars H. Jhoresen and Kevin Burgess

Five consecutive papers in Angew. Chem. recently described syntheses of the vancomycin aglycon. D. A. Evans and co-workers developed one route at Harvard [ 1, 21, while the other comes from K. C. Nicolaou’s group at Scripps [3-51. They represent an amalgamation of synthetic methodologies in schemes that took some of the most skillful bench chemists in academia years to execute. CI

OR

R=H vancomycin aglycon

R=

I

\

F 0

O 0

H

vancomycin

Stereoselective syntheses of several unnatural amino acids were required to initiate this work. Evans’ group used asymmetric reactions of chiral enolates to generate these starting materials, as illustrated in the diagram shown below. In this particular example, an isothiocyanate functionality traps the alcohol of an aldol product giving a thiooxazolidinone that provides 0- and N-protection in subsequent steps.

298

I

Total Syntheses of Vancomycin

+ CI

'4

iCS aldol-

cox,

0

CI

The Scripps group initiated their project to prepare vancomycin after many routes to the requisite amino acids had been published. They could have made their building blocks by repeating and/or modifying published procedures, but instead chose to develop new approaches or rely on those of colleagues at Scripps. An example featuring Sharpless' methodology is illustrated below [ 61.

Sharpless'

~

C02Et

_& _

aminohydroxylation

Et0&

I..,

"'NHCbz

A major obstacle to synthesis of the vancomycin aglycon has been construction of the fused macrocyclic ring systems with generation of the correct atropisomers. The Harvard and Scripps groups overcame this in different ways (Schemes 1 and 2, respectively). Evans' group began by forming the macrocycle encapsulating the AB biaryl functionality; for this they used an oxidative coupling developed almost ten years ago [ 7 ] . A SNAr reaction was then used to form the biaryl ether linkage between rings C and D (ie the C - 0 - D ring) [S]. That cyclization reaction also set one of the amide bonds in the AB ring into its required cisorientation. Scheme 2 indicates that, unlike the Evans' approach, the Nicolaou group constructed the C - 0 - D ring before the AB system. They used their copper-mediated coupling methodology, involving a triazine ligating-group, to form the ether linkage in the first macrocyclization. Unfortunately, this step gave no significant selectivity with respect to the atropisomer formed, hence separation of epimeric products was necessary. The precursor to the AB ring contained an amino acid with a preformed (Suzuki) AB biaryl fragment. Cyclization to form the AB ring system was accomplished via a macrolactamization reaction. Another significant difference in the two syntheses relates to the C-terminus of the ABC0 - D entity, ie at the amino acid precursor fragment attached to aryl nucleus A. That chiral center is stereochemically delicate; it epimerized if the C-terminus was an ester, for instance. The Evans group found that the corresponding N-methylamide imparted resistance to epimerization at this center making it resilient to subsequent steps in the synthesis, while the Nicolaou group avoided the problem by using a corresponding 0-protected alcohol. These

Total Syntheses of Vancomycin

I

299

300

I

Total Syntheses of Vancornych

CZ-2

'z0

Total Syntheses ofvancornycin

strategies necessitated some interesting functional group manipulations towards the end of the synthesis, as described later. Our interpretation of the two synthetic strategies is that the nature of the C-terminus, and the order of construction of the AB and C-0-D rings, is relatively unimportant, but the latter factor did have significant indirect consequences. Specifically>the Harvard group was able to achieve atropisomeric stereoselectivity in their C-0-D ring construction process and this might not have possible if the AB ring was not already in place. Development of a stereoselective C-0-D macrocyclization reaction came about by evaluating a flawed approach to give the C-0-D ring, formulating a hypothesis concerning factors governing the stereoselectivity of that process, then adjusting the overall synthetic strategy to accommodate its intrinsic stereochemical bias. Thus the Harvard group originally focused their efforts on an analog of compound 1 (Scheme 1) without a chlorine atom on ring C. Their intent was to transform the C-ring nitro group into a chlorine atom. However, a 7:l atropisomeric selectivity in the undesired sense was achieved under several sets of reaction conditions. Consequently, they accepted the fact that the nitro group was somehow forced into that orientation during the cyclization, and added the chlorine substituent shown in compound 1. Their new, and ultimately successful, plan was to substitute the nitro group with a hydrogen after it had served to facilitate the SNAr process with the desired atropisomeric selectivity. In this way the C-0-D structure was formed with a 5:l bias in favor of the isomer required for the new approach. The macrocyclization process was also accelerated by the chlorine substituents (reaction time 1.5 h uersus 66 h previously) since it increased the electrophilicity of the aryl fluoride. In fact, the aryl fluoride was so reactive that the steps leading to formation of compound 1 had to be designed very carefully to avoid premature SNAr reactions. Both groups wisely elected to couple their ABC-0-D ring intermediates with preformed protected-tripepetides, thus making the synthesis more convergent. As a result, the East and West US-Coast teams entered the end-game with similar intermediates, ie compounds 2 and 3, respectively. Only the Harvard team could construct the D-0-E ring with selectivity for the desired atropisomer. Their SNAr macrocyclization approach gave a 5:1 ratio of diastereoisomers, whereas in California a disappointing 1:3 selectivity was obtained. The Nicolaou group was able to recycle the undesired isomer by exploiting observations made by Boger and co-workers [9, lo]. Thus the undesired atropisomer was heated to 140 "C in DMSO for 4 h; this gave a thermodynamic 1:l mixture of D-0-E ring isomers which was separated to give the desired one. However, this discovery must have been a small conciliation for the sour stereochemical twist of fate that afflicted them in this final macrocyclization. Having formed the ABC-0-D-0-E skeleton, both groups were left with the task of functional group manipulations and deprotection steps to form the final product. These seem routine to describe but can be exceedingly difficult in practice. Nicolaou's group formed the desired C-terminal acid via a deprotection/oxidation operation on their masked alcohol. Conversion of an N-methyl amide to the corresponding group in the Evans synthesis seems harder, but was in fact accomplished in 68% yield via nitrosation then treatment with basic peroxide. This transformation was possible since that particular amide functionality is the least hindered of the eight present in Harvards aglycon precursor.

I

301

302

I

Total Syntheses of Vancomycin

The Scripps approach to the C-0-D-0-Eframework required that they convert a triazine to a phenol on ring D. This was accomplished in several steps. The triazine was reduced to an amine, and diazotized in the presence of KI to give the corresponding aryl iodide. Unfortunately, 40% of the diazonium compound was reduced to the compound with the corresponding Ar-H bond, and the problem of converting the remaining aryl iodide into a phenol remained. In a very bold step, this iodide was reacted with excess MeMgBr and 'PrMgBr to effect transmetallation, then quenched with trimethylborate. Finally, the phenol was formed via oxidation with basic peroxide. The Nicolaou group entered this area relatively recently, hence it is truly remarkable that they were able to develop a synthesis of the vancomycin aglycon so quickly. However, their route stumbles over the sections that involve atropisomeric selectivity or removal of the triazine. Evans' group synthesis addresses or avoids these problems. It is a more polished effort that took many years and high levels of financial and human resources to develop. In 1999 a third synthesis of the vancomycin aglycon was reported, this time by Boger and co-workers, also at Scripps [11, 121. Boger's synthesis has similarities to the first two syntheses. Like the Nicolaou route, it constructs the rings in the order: C-0-D to ABC-0-D to ABC-0-D-0-E,and uses an amide bond construction to form the AB ring. However, SNAr displacements on fluoronitro aryl systems were used to construct the C-0-D and D-0-E rings, just as in the Evan's syntheses. The feature that distinguishes the Boger syntheses from the other two is a very detailed consideration of the thermodynamics of equilibration of the atropisomers [9, 10, 131. Some illustrative data are shown in Scheme 3. At equilibrium, the two atropisomers of the D-0-E fragment shown in Scheme 3a form in near equimolar amounts, but the nitro derivative is more easily equilibrated than the chloro-compound. Consequently, equilibration of the nitro compound was used to augment the supply of the natural atropisomer, then the nitro group was converted to a chloride to give enhanced stability to isomerization throughout the rest of the synthesis. Scheme 3b is intended to illustrate that the acyclic AB fragment shown is relatively easy to equilibrate, and the thermodynamic resting point favors the natural atropisomer. After the AB ring is closed to form a completely cyclized ABC-0-D fragment, however, both rings become more resistant to isomerization. However, in the complete ABC-0-D-0-Eshown in Scheme 3c, it is, conveniently, the D-0-E that is most amenable to isomerization, again allowing the unnatural atropisomer to be equilibrated and recycled. Full details of the Nicolaou syntheses have now been reported [ 6 , 141, along with successful transformation of the vancomycin aglycon into vancomycin itself [ 15-17]. Their procedure featured three protection steps, ie silylation of all six hydroxyl groups, formation of a methyl ester at the C-terminus, and N-terminal protection with a benzyloxycarbonyl group. The central phenolic-OH was then selectively unmasked (KF A1203), and sequentially coupled with two monosaccharide units. The glycosyl donors used were first a trichloroacetimidate, then a glycosyl fluoride. Finally, deprotection gave the desired product. Of course, it is not necessary to go through the whole synthesis to explore the glycosidation steps; experiments may be done using the vancomycin aglycon from a natural source. Consequently, Kahne et al. were also able to show that vancomycin aglycon can be converted into vancomycin itself. They used a different protection/deprotection scheme and their own glycosidic sulfoxide/

Total Syntheses of Vancornycin I 3 0 3

eiyi)c

a

OMe

TBSO..,,,,

Me02C""' N H

140°C

~

'

Br OMe

TBSO..,,,, Me02C'

NHBOC H

R = NO2 1.O:l .I E, = 26.6 kcal/mol R = CI 1.0:1.2 E, = 30.4 kcal/mol

b

'

Br OMe

OMe

T B S O , , , , , , F ' F o H Me02C'""'

L'

120 OC

NHBOC OMe

Q 0 /-\

MEMO

,OMe OMe

TBSO..,,,,

OMe natural NHCBZ

3:l E, = 25.1 kcal/mol

OMe

OMe '''-OMEM unnatural

Scheme 3.

304

I

Total Syntheses of Vancomycin C

A ~

L N M e B O C NC

natural

Me0 OH

no

unnatural

Me0

R = NO2 1:I E, = 24.8 kcal/mol R = CI 1:1 E, = 23.6 kcal/mol Scheme 3.

(continued)

TfiO glycosylating procedure [ 181. The Nicolaou group have used their understanding of the glycosylation process to prepare libraries of vancomycin analogs. Thus the protected aglycon was supported and glycosylated in different ways to prepare a diverse set of vancomycin analogs [ 191, including dimers linked via the sugar fragments [ 201. Dimeric analogs of vancomycin can have very special activities due to the mode of action of the compound. Since their syntheses, the Boger and Evans groups have taken a different tack, turning their attentions to the related compound, teicoplanin. This is an even more challenging target, having an additional biaryl ether ring and two more {easily epimerized} phenyl glycine units than vancomycin as well as two additional glycosylation sites. Nevertheless, both groups have reported total syntheses of the aglycon [21-241.

References

I305

CI

OR‘

/

teicoplanin aglycon

R’ = R2 = R3 = H

R’ = R2 = R3 = sugars

teicoplanin aglycon

teicoplanin

References D. A. EVANS,M. R. WOOD,B. W. TROTTER, T. I. RICHARDSON,J. C. BARROW,J. L. KATz, Angew. Chem. Int. Ed. 1998, 37, 2700. D. A. EVANS,C. I . DINSMORE, P. S. WATSON, M. R. WOOD,T. I. RICHARDSON, B. W. TROTTER, J. L. KATz, 1998, 37, 2704. K. C. NICOLAOU, S. NATARAJAN, H. LI, N. F. J A I N , R. HUGHES, M. E. SOLOMON, J. M. RAMANJULU, C. N. C. BODDY,M. TAKAYANAGI, Angew. Chem. lnt. Ed. 1998, 37, 2708. K. C. NICOLAOU, N. F. J A I N , W. NATARAJAN, R. HUGHES, M. E. SOLOMON, H. LI, J. M. RAMANJULU,M. TAKAYANAGI, A. E. KOUMBIS,T. BANDO,Angew. Chem. lnt. Ed. 1998, 37, 2714. K. C. NICOLAOU, M. TAKAYANAGI, N. F. J A I N , S . NATARAJAN,A. E. KOUMBIS,T. BANDO, J. M. RAMANJULU, Angew. Chem. lnt. Ed. 1998, 37, 2717. K. C. NICOLAOU, C. N. C. BODDY,H. Li, A. E. KOUMBIS, R. HUGHES, S. NATARAJAN, S. BRASE, N. F. JAIN,J. M. RAMANTULU, M. E. SOLOMAN, Chem. Eur.]. 1999, 5, 2602. D. A. EVANS,J. A. ELLMAN,K. M. DEVRIES, J. Am. Chem. SOC.1989, 11 I , 8912. J. ZHU, Synlett 1997, 133.

9 D. L. BOGER, 0. LOISELEUR,S. L. CASTLE,

R. T. BERESIS,J. H. Wu, Bioorg. Med. Chem. Lett. 1997, 7, 3199. 10 D. L. BOGER, S. MIYAZAKI, 0. LOISELEUR, R. T. BERESIS, S. L. CASTLE, J. H. Wu, Q. J I N , J . Am. Chem. SOC.1998, 120, 8920. 11 D. L. BOGER, M. S . , S . H. KIM, J. H. Wu, 0. LOISELEUR,S. L. CASTLE, J. Am. Chem. SOC. 1999, 121, 3226. 12 D. L. BOGER, S. MIYAZAKI, S. H. KIM, J. H. WU, S. L. CASTLE, 0. LOISELEUR,Q. JIN,J. Am. Chem. SOC.1999, 121, 10004. 13 D. L. BOGER, S. L. CASTLE, S. MIYAZAKI, J. H. Wu, R. T. BERESIS,0. LOISELEUR,I. Org. Chem. 1999, 64, 70. 14 K. C. Nicoraou, H. LI, C. N. C. BODDY, J. M. RAMANJULU,T.-Y. YUE, S. NATARAJAN, X.-J. CHU, S. BRASE, F. RUBSAM, Chem. Eur. J. 1999, 5, 2584. 15 K. C. NICOLAOU,H. J. MITCHELL, N. F. J A I N , N . WINSSINGER, R. HUGHES, T. BANDO,Angew. Chem. Int. Ed. Engl. 1998, 38, 240. 16 K. C. NICOLAOU, A. E. KOUMBIS,M. TAKAYANAGI, S. NATARAJAN, N. F. J A I N , T. BANDO, H. LI, R. HUGHES, Chem. Eur. J. 1999, 5, 2622. 17 K. C. NICOLAOU,H. J. MITCHELL, N. F. J A I N , T. BANDO, R. HUGHES, N.

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WINSSINGER, S. NATARAJAN, A. E. Chem. Eur. ]. 1999, 5, 2648. KOUMBIS, 18 C. THOMPSON, M. GE, D. KAHNE,J . Am. Chem. SOC.1999; 121, 1237. 19 K. C. NICOIAOU,S. Y. CHO, R. HUGHES, N. WINSSINGER, C. SMETHURST, H. Chem. Eur. LABISCHINSKI, R. ENDERMANN, J . 2001, 7, 3798. 20 K. C. NICOIAOU,H . R., S. Y. CHO, N. H. LABISCHINSKI, R. WINSSINGER, Chem. Eur.J. 2001, 7, 3824. ENDERMANN, 21 D. L. BOGER,J.-H. WENG,S. MIYAZAKI, J. J. MCATEE,S. L. CASTLE,S. H. KIM,Y.

MORI,0. ROGEL,H. STRITTMATTER, Q. J I N ,]. Am. Chem. SOC.2000, 122, 10047. 22 D. L. BOGER,S. H. KIM, S. MIYAZAKI, H. STRITTMATTER, J.-H. WENG,Y. MORI;0. ROGEL,S. L. CASTLE,J.J. MCATEE,J . Am. Chem. SOC.2000, 122, 7416. 23 D. L. BOGER,S. H. KIM, Y. MORI,J.-H. WENG,0. ROGEL,S. L. CASTLE,J. J. MCATEE,J . Am. Chem. SOC.2001, 123, 1862.

A. EVANS,J. L. KATZ,G. S. PETERSON, T. HINTERMANN,].Am. Chem. SOC.2001,

24 D.

123, 12411.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I307

Bryostatin and Their Analogues Ulf Diederichsen

The bryostatins are a class of twenty natural macrolides that were isolated from Bugula neritina (Linneaus) and in minor amounts from other marine organisms [ 1, 21. They all have in common a highly oxygenated twenty membered macrocyclic lactone (Figure 1). Therefore, the polyketide biosynthesis is likely to be their biosynthetic origin [ 31. The macrocycles contain three pyranose rings A-C in the preferred chair conformation, which are linked with equatorial configuration over the 2,6-positions. Most bryostatins only differ in the substituents at positions C7 and C20 where mainly hydroxyl groups or esters are found [4]. The family of bryostatins is of importance as a potential therapeuticum in cancer therapy. Bryostatin 1 (1)presently is in clinical tests, phase 11, mainly for the treatment of melanoma, non-Hodgkin's lymphoma, chronic lyphocytic leukemia, and sarcomas !5]. The molecular mode of action of bryostatins is still not known but they are agonists for protein kinase C (PKC) in uitro and in uiuo. The family of PKC enzymes are serine and threonine kinases that function as regulators within the signal transduction of cell proliferation and cell differentiation. Furthermore, the recognition of phorbol esters by PKC is competitively inhibited by bryostatins. This also seems to explain the protection of cells against an usually deadly dose of ionizing irradiation and was made responsible for the stimulation of the immune system by interleukin and interferon 2 production [6]. Even bryostatins are available by cultivation of Bugula neritina [7] but their isolation from marine organisms is laborious and hardly provides sufficient quantities. Therefore, the synthetic access to these natural products became increasingly important. Furthermore, there is interest in modified as well as more easily accessible bryostatin analogues with favourable pharmacological characteristics compared to the natural products. The synthesis of analogues might also help in evaluating the molecular mechanisms of bryostatin activity. The First Total Synthesis of a Bryostatin

Bryostatin 7 (3) was the first member of the bryostatin family that was accessible by total synthesis. Its preparation was described by Masamune et al. already briefly after its isolation Their concept was based on a Combination of the four synthons 4-7 from Bugula neritina [8]. (Figure 2): The (R,R)-2,5-dimethylborolanyl triflate mediated aldol reaction of aldehyde 4 with the enolate derived from ketone 5 leads after a sequence of deprotection steps, cycliza-

308

I

Bryostatin and Their Analogues

-

Bryostatin 1 (1): R, = O,CCH,,

R,= 0,C

/

C3H7

Bryostatin 2 (2): R, = OH,

R,= 0,C

/

C3H7

Bryostatin 7 (3): R, Fig. 1.

= O,CCH,, R, = O,CCH,

Molecular structures of bryostatin natural products which are accessible by total synthesis.

tions, and oxidations to the A/B-ring fragment 8. The C-ring fragment 7 is coupled by JuliaLythgoe olefination using PhLi as base of choice for selective deprotonation. Boron enolate 6 serves as the fourth building block for the extension of the tricyclic intermediate 9 by two carbons at position C3. Finally, the carboxylic acid is generated and macrolactonization achieved by carbodiimide activation. Synthesis of Bryostatin 2 According to Evans [9]

The total synthesis of bryostatin 2 (2) requires only three synthons: The ring systems A, B, and C are synthesized separately and can be fused in a sequence of olefination, sulfone alkylation and macrolactonization. As the methoxycarbonylmethylidene residue in the Bring turned out not to be compatible with sulfone alkylation, a subsequent functionalization of the macrolactone was necessary. Therefore, the three fragments A-C (Figure 3) were synthesized. All of them have in common the anti-l,3-diole substructure (highlighted). An aldol addition is used as the key step for the preparation of the three monocycles. The respective aldol products are obtained with good stereoselectivity using alkoxytitanate TiC12(OiPr)2 for the A-ring, catalysis with the copper complex [Cu(S,S)-Ph-py-box](SbF6)2 (10)[ 101 in case of

Synthesis of BIyostatin 2 According to Evans

'i -

Me Me

+

RO

R = TBDPS O R-M e

CHO

a O

o x o 5

PhozS\

\OR

..'

PA

7 Me Me

RO

Et,CS 6

Bryostatin 7 (3)

Fig. 2.

*

Bryostatin 7: The first total synthesis.

the B-ring, and the chiral boron enolate (-)-DIPCI(b-chlorodiisopinocampheylborane) for the aldol reaction in ring C. A suitable starting point for the connection of the ring fragments is the modified Julia olefination for the fusion of building blocks B and C. Predominantly, the desired trans-olefin is isolated ( E Z > 955). The hydroxyl group at C10 is activated as a triflate before building block A gets deprotonated with two equivalents n-BuLi and acts as a nucleophile at C10. Sulfinic acid elimination generates the hemiacetal at C9. Before macrolactonisation at C1 the ester needs to be generated from the anilide by acylation with BOQO followed by treatment with LiOCH2Ph. Furthermore, the primary alcohol at C25 needs to be selectively deprotected. In addition, the C-ring is prepared for later functionalization. Macrolactonization is obtained in good yields following the mild cyclization conditions of Yamaguchi via the anhydride, that results from activation with 2,4,6-trichlorobenzoic acid chloride [ 111.

I

309

MeOOC

*

Total Synthesis ofBryostatin 3

10

Me0

16

*

+

OTBS 0

22

'i

Bryostatin 3 (16)

18

OTES M . 3 I..=

MexMe PR T'++

PhS.

I

OHC+p

'

BOMO 19 Fig. 4.

OTBDPS

20

"+

Bryostatin 3 i s special because o f the y-lactone unit at the C-ring.

propylcarbodiimide (DIC), 4-dimethylaminopyridine (DMAP)). Oxidative cleavage of the p-methoxybenzyl ether (PMB) terminates the synthesis of bryostatin 2 (2), which can be converted into bryostatin 1 (I) through a sequence of protecting group manipulations and acylation [ 141. Total Synthesis of Bryostatin 3 [15]

Recently, also the total synthesis of bryostatin 3 (16) was completed (Figure 4) [15]. Similar to the synthesis of bryostatin 2 (2) the A/B-ring fragment 17 needs to be coupled to the C-ring 18. Especially, the synthesis of the bryostatin 3 C-ring should be mentioned since its y-lactone moiety is quite special within the family of bryostatins [lG]. An additional hydroxyl group at C22 is needed for the ring closure to the y-lactone. It is obtained by addition of vinyliodide 19 to the aldehyde 20 with a 3:l selectivity in favour of the desired anti-diol. Protecting group manipulations and cyclization yield acetal 18 as a precursor of the C-ring fragment in bryostatin 3 . Julia-Lythgoeolefination is used for the ClG-Cl7 linkage forming the desired trans double bond [17]. Deprotection and oxidation steps provide the y-lactone before macrolactonization takes place following Yamaguchi conditions. At this stage the Horner-Wadsworth-Emmons reaction with the chiral Fuji-phosphonate 12 ( Z E= 89:11) [ 121 can be used for stereoselective attachment of the missing methoxycarbonylmethylidene residue in the B-ring.

I

311

312

I

Bryostatin and Their Analogues

Bryostatin Analogues

Obviously, the access to the A, B and C ring fragments is the key to a successful synthesis of bryostatins. Therefore, next to the total syntheses several partial syntheses [ 181 and preparations of ring fragments are reported [ 191. These partial structures are also valuable components regarding the synthesis and evaluation of bryostatin analogues. A high binding affinity of bryostatin 1 is observed for protein kinase C (PKC,Ki = 1.35 nM) for which 1,2-diacyl-sn-glycerol(21, DAG) is well known as an endogenous activator. Furthermore, the activity of phorbol ester 22 as one of the strongest tumor promotors is likely to be also based on the activation of PKC [20].The structural comparison of these PKC binders suggests that the C1-carbonyl,C19-hydroxy1, and the C2G-OH groups of bryostatin 1 (1)have analogues orientation compared to the functional groups of 1,2-diacyl-sn-glycerol and those of the phorbol ester [21]. Because of the similar pharmacophors (Figure 5, circled) a common binding site seems likely. Furthermore, these PKC binders have lipophilic regions in common (highlighted). This raises the question about the function of the A and B rings in bryostatin. Following the arguments of Wender et al. the A/B-fragment is only responsible for the conformational adjustment of the macrocycle and the geometrical arrangement of the functionalities. In this case the A/B-rings could be replaced by lipophilic analogues bridging the C-ring recognition unit. Aiming for simplified bryostatin analogues might improve the therapeutic characteristics as well as the synthetic availability [22]. The

Me Me M

e

0

2

C

m 1,2-Diacyl-sn-glycerol (21)

O*CR

I

Me

Bryostatin 1 (1) Phorbol ester (22) Fig. 5. Comparison o f the most likely chromophors of bryostatin, 1,2-diacyl-sn-glyceroI and the phorbol ester. The oxygen functionalities belonging t o the pharmacophor are circled. Furthermore, non polar regions are indicated.

Bryostatin Analogues I 3 1 3

,OTBS

24

25

OH

26

l5 CHO

L 1

1

.

-

OH

0

OTBS MMee ~ , , , . . ~ y O P M B

\ COOMe 23

Fig. 6.

Me 27

Synthesis o f C-ring synthons for modified bryostatins as reported by Wender et a/. [20].

introduction of A/B-ring analogues allows a new strategy for the macrocyclization: Whereas the formation of an ester is still used to link the ends C25 and C1, the introduction of an oxygen at position 14 permits, however, efficient cyclization by macrotransacetalization. For the design of new A/B-ring analogues it is important to keep the isosterical geometry compared to the natural bryostatins. However, the knowledge that the pharmacophor is mainly located on the C-ring without direct participation of the A/B-ring system, allows the synthesis of a highly variable spectrum of derivatives. For the synthesis of bryostatin analogs a completely functionalized C-ring fragment 23 is incorporated. Cyclization takes place bridging the aldehyde at C15 and the alcohol at C27 (Figure 6 ) . The C-ring is accessible by addition of diketone 24 to aldehyde 25 followed by dehydratation, separation of the /3-isomer and Luche-reduction to yield glycal 26. Oxidation of the C-C double bond to the epoxide, ring opening with methanol, selective benzoylation of the equatorial hydroxyl group at C21 followed by oxidation at C20, and desoxygenation at C21 with Sm12 results in ketone 27. In analogy to the functionalization of bryostatin 2 (2), the methoxycarbonylmethylidene residue and the acyl side chain are attached to the building block 27. The concluding homologization by two C-atoms at C17 starts with oxidation of the deprotected alcohol to the sterically strongly hindered aldehyde, which is allylated with diethylallylborane. The hydroxyl group at C15 is acetylated, before the terminal olefin is dihydroxylated, and a glycole-cleavage follows under basic conditions (elimination to the Michael system). Finally, the hydroxyl groups at C19 and C27 are deprotected to yield the Cring fragment 23 that can be cyclized with appropriate A/B-ring analogues. The bridging A/B-segment 28 is linked as a menthone acetal to the C-ring building block 23 by ester formation following Yamaguchi conditions [ 111. A remarkable macrotrans-

"OBn

314

I

Bryostatin and Their Analogues

H

macrotransacefalization

H

I5c~o

b

+

Yarnaguchi esterification

29

23

hR

O V 0

PKC Affinity

Growth Inhibition

O\

Bryostatin 1

Ki = 1,35 nM

Bryostatin 2

Ki = 5,86 nM

Analogue 29

Ki = 3,4 nM

GI,,=

Analogue 30

Ki = 47

GI5,= 8-3300 ng.mL-'

Analogue 31

Ki = 8,3 nM

Me

nM

GI,,=

1,8-170 ng.mL-'

8-3300 ng.mL-'

30R=H 31 R = fed-butyl Fig. 7.

Bryostatin analogues and their biological activities.

acetalization is achieved in highly diluted CH2C12with amberlyst-15 and 4 A molecular sieve (Figure 7). Thermodynamically controlled only the expected cyclization product with equatorial configuration at C15 is formed. Finally, the hydroxyl groups are deprotected to yield bryostatin analogue 29. In an analogous procedure the bryostatin derivatives 30 and 31 can be obtained. The bryostatin analogues provide quite interesting PKC affinities and inhibition of tumor cell growth (Figure 7): The outstanding values for the analogues in comparison with bryostatins 1 and 2 suggest that the geometrical assumptions the structural modifications were based on. are efficient regarding PKC recognition. The C-ring building block 23, that is

References

available in gram quantities, might be combined - even by combinatorial chemistry - with further bridging units. If the hydroxyl group at C3 is missing, the PKC affinity decreases (Ki = 297 nM). This confirms the important role of the hydrogen bond between the C3oxygen atom and the C19-hydroxyl group for the active conformation, as it was already proposed from the crystal structure by Pettit et al. [ l a ] This hydrogen bond probably could be strengthened by a better proton acceptor at C3. Summary

The total synthesis of bryostatins starts with the preparation of the required ring fragments, followed by the macrocyclization as a key step, and is finished by remaining functionalizations. Even synthetic modifications of the bryostatin natural products presented here would not essentially change the underlying concept. In contrast, simpler analogues allow new and more efficient strategies. For the isosteric A/B-ring substitutes, that control the C-ring conformation, further synthetic simplifications seem possible. Future bryostatin analogues might give further insight in structure activity relationship and therefore improved pharmacological activity. References a) G. R. PETTIT,C. L. HERALD, D. L. DOUBEK,D. L. HERALD,E. ARNOLD,J. CURDY,]. Am. Chem. SOC.1982, 104, 6846-6847;b) G. R. PETTIT,Y. KAMANO, R. AOYAGI,C. L. HERALD,D. L. DOUBEK, J. M. SCHMIDT,J. J. RUDLOE,Tetrahedron 1985, 41,985-994; c) G. R. PETTIT. F. GAO,P. M. BLUMBERG, C. L. HERALD,J. C. COLL;Y. KAMANO,N. E. LEWIN,J. M. SCHMIDT,7.-C. CHAPUIS,]. Nat. Prod. 1996, 59, 286-289. 2 A review article about bryostatins: R. MUTTER,M. WILLS,Bioorg. Med. Chem. 2000,8,1841-1860. 3 R. G. KERR,J. LAWRY, K. A. GUSH, Tetrahedron Lett. 199G, 37, 8305-8308. 4 a) R. D. NORCROSS, I. PATERSON, Chem. Rev. 1995, 95, 2041-2114;b) G. R. PETTIT, J . Nat. Prod. 1996, 59,812-821. 5 a) A. S. KRAFT.S. WOODLEY, G. R. PETTIT, F. GAO,J. C. COLL,F. WAGNERF. Cancer Chemother. Pharmacol. 1996, 37, 271-278; b) R. GONZALEZ, S. EBBINGHAUS, T. K. HENTHORN, D. MILLER,A. S. KRAFT, Melanoma Rex 1999, 9, 599-606; c) M.L. M. S. VARTERASIAN, R. M. MOHAMMAD, SHURAFA, K. HULBURD, P. A. PEMBERTON, V. SPADONI,D. S. D. H. RODRIGUEZ, EILENDER, A. MURGO,N. WALL,M. DAN, A. M. AL-KATIB,Clin. Cancer Res. 2000,6,

1

6

7 8

9

10

11

12

13

825-828;d) http://www.dtp.nci.nih.gov/ docs/static~pages/compounds/339555. html. a) A. S. KRAFT,S. WOODLEY, G. R. PETTIT, F. GAO,J. C. COLL,F. WAGNER,Cancer Chemother. Pharmacol. 1996, 37, 271-278; b) 2. SZALUSI,L. Du, R. LEVINE,N. E. LEWIN,P. N. NGUYEN,M. D. WILLIAMS, G. R. PETTIT,P. M. BLUMBERG, Cancer Res. 1996, 56, 2105-2111. S. PAIN.New Scientist 1996, 151,38. M. KAGEYAMA, T. TAMURA,M. H . NANTZ, J. C. ROBERTS, P. SOMFAI,D. C. S. MASAMUNE, I. Am. WHRITENOUR, Chem. SOC.1990, 112, 7407-7408. D. A. EVANS,P.H. CARTER,E. M. CARREIRA, A. B. CHARETTE,J. A. PRUNET, Angew. Chem. Int. Ed. 1998, M. LAUTENS, 37, 2354-2359. D. A. EVANS,M. C. KOZLOWSKI, J. A. MURRY,C. S. BURGEY,K. R. CAMPOS,B. T. CONNELL, R. J. STAPLES, I. Am. Chem. SOC. 1999, 121,669-685. J. INANAGA, K. HIRATA,H. SAEKI,T. KATSUKI,M. YAMAGUCIII,Bull. Chem. Soc. ]pa. 1979, 52,1989-1993. K. TANAKA,K. OTSUBO,K. FUJI, Tetrahedron Lett. 1996, 37, 3735-3738. E. J. COREY,C. J . HEIAL,Angew. Chem. Int. Ed. 1998, 37, 1986-2012.

I

315

316

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Bryostatin and Their Analogues 14

15

16

17

18

19

G. R. PETTIT,D. SENGUPTA, D. L. HERALD, N. A. SHARKEY, P. M. BLUMBERG,Can. J. Chem. 1991, 69,856-860. K. OHMORI,Y. OGAWA, T. OBITSU,Y. ISHIKAWA, S. NISHIYAMA, S. YAMAMURA, Angew. Chem. Znt. Ed. 2000, 39, 2290-2294. T. OBITSU,K. OHMORI,Y. OGAWA,H. S. HOSOMI,S. OHBA,S. NISHIYAMA, YAMAMURA, Tetrahedron Lett. 1998, 39, 7349-7352. a) M. JULIA, J. M. PARIS,Tetrahedron Lett. 1973, 34,4071-4074; b) P. J . KOCIENSKI, ]. Chem. SOC., B. LYTHGOE, S. RUSTON, Perkin Trans. 11978, 829-834. a) M. KALESSE, M. EH, Tetrahedron Lett. 1996, 37, 1767-1770; b) J. M. WEISS, Tetrahedron: AsymH. M. R. HOFFMANN, metry 1997, 8, 3913-3920; c) S.-I. KIYOOKA, H. MAEDA,Tetrahedron: Asymmetry 1997, 8, 3371-3374; d) J. GRACIA, E. J. THOMAS, ]. Chem. SOC.,Perkin Trans. 11998, 28652872. a) K. J. HALE,M. FRIGERIO, S. MANAVIAZAR, Org. Lett. 2001, 3, 37913794; b) A. VAKALOPOULOS, T. F. J. LAMPE, H. M. R. HOFFMANN, Org. Lett. 2001, 3, 929-932; c) K. J. HALE,M. G. HUMMERSONE, G. S. BHATIA, Org. Lett. 2000, 2, 2189-2192; d) J. A. LOPEZ-PELEGR~N, P. WENWORTH, JR., F. SIEBER, W. A. METZ, K. D. JANDA, J. Org. Chem. 2000, 65, A. RAE, E. 8527-8531; e) P. ALMENDROS, THOMAS, Tetrahedron Lett. 2000, 41, 9565-

9568; f ) J. DE BRABANDER, B. A. KULKARNI, R. GARCIA-LOPEZ. M. VANDERWALLE, Tetrahedron: Asymmetry 1997, 8, 17211724; g) J. DE BRABANDER, M. VANDERWALLE, Pure Appl. Chem. 1996, 68, 715718; h) J. DE BRABANDER,K. VANHESSCHE, M. VANDERWALLE, Synthesis 1994, 855-865. 20 P. A. WENDER, Y. MARTIN-CANTALEJO, A. J. CARPENTER, A. CHIU,J. DE P. G. HARRAN, J.-M. J I M E N E Z , BRABANDER, M. F. T. KOEHLER, B. LIPPA,J. A. S. G. MULLER, S. N. MULLER, MORRISON, C. SIEDENC.-M. PARK,M. SHIOZAKI, M. TANAKA, K. BIEDEL, D. J. SKALITZKY, IRIE, Pure Appl. Chem. 1998, 70, 539-546. 21 P. A. WENDER, J. DE BRABANDER,P. G . HARRAN, J.-M. JIMENEZ, M. F. T. KOEHLER, B. LIPPA, C.-M. PARK,C. SIEDENBIEDEL, G. R. PETTIT,Proc. Natl. Acad. Sci. USA 1998, 95, 6624-6629. 22 a) P. A. WENDER, J. DE BRABANDER, P. G. HARRAN, J.-M. J I M E N E Z , M. F. T. KOEHLER, B. LIPPA,C.-M. PARK,M. SHIOZAKI,].Am. Chem. SOC.1998, 120, J. DE 4534-4535; b) P. A. WENDER, BRABANDER,P. G . HARRAN, K. W. HINKLE, B. LIPPA, G. R. PETTIT,Tetrahedron Lett. 1998, 39,8625-8628; c) P. A. WENDER, K. W. HINKLE, M. F. T. KOEHLER, B. LIPPA, Med. Res. Rev. 1999, 19, 388-407; d) P. A. WENDER, B. LIPPA, Tetrahedron Lett. 2000, 41, 1007-1011; e) P. A. WENDER, K. W. HINKLE,Tetrahedron Lett. 2000, 41, 6725-6729.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I317

Eleutherobin: Synthesis, Structure/Activity Relationship, and Pharmacophore Ulf Diederichsen

The natural product eleutherobin (1)was isolated in 1994 by Fenical et al. from a marine soft coral from an Eleutherobia species and its structure was elucidated shortly afterwards (Figure 1) [ 1).Eleutherobin is a diterpene glycoside that possesses remarkable cytotoxicity against a wide variety of cancer cells, which is likely to be based on binding to tubulin and stabilization of microtubules [2, 31. Mitosis is interrupted and the cell division cycle is terminated. The mechanism of action of eleutherobin is comparable to that of highly potent cytostatic agents such as paclitaxel (Taxol), nonataxel, epothilones, and discodermolide. The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. Total Syntheses of Eleutherobin

Two methods for the total synthesis of eleutherobin have been described, differing mainly in the formation of the tricyclic skeleton and in the introduction of the arabinosyl moiety [7]. Nicolaou et al. had previously developed a synthesis of the tricyclic core structure for the preparation of sarcodictyins, starting from the monoterpene (+)-carvone [8].This concept can be applied to the synthesis of eleutherobin (Figure 2) [ 91. Compared to the sarcodictyins, eleutherobin contains an additional 0-acetyl-D-arabinosylresidue linked as the p anomer. This is introduced early in the synthesis by glycosylation of the open-chain acetylenic aldehyde 6 . The stereospecificity of this coupling with the D-arabinosyl trichloroacetimidate 7 is not easy to control, since the ratio of the c( and j? anomers strongly depends on the reaction conditions. In dioxane/toluene the desired p-glycoside 8 is formed preferentially in an 8:l epimeric mixture. Afterwards, even at -30 "C the ten-membered ring is formed by an intramolecular acetylide-aldehyde condensation with LiHMDS, followed by immediate Dess-Martin oxidation of the arising secondary alcohol. The key step in the synthesis is the stereoselective catalytic hydrogenation of the acety-

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0 II

OH COOMe

H

.-,)

'le hn

Me Sarcodictyin A 4

Me

0

OR3

I

Me

R, = Me, R, = R, = H: Eleutherobin (1) R, = H, R, = Ac, 4 = H: Eleuthoside A (2) R, = H, R, = H, R, = Ac: Eleuthoside B (3)

Valdivone A 5 Fig. 1.

Molecular structures of eleutherobin, eleuthosides, sarcodictyins, and valdivone.

lene moiety by use of Hz with Lindlar catalyst in toluene at 25 "C. This spontaneously and selectively affords the expected lactol, which is subsequently converted into the methoxy ketal 9. In the total synthesis of Danishefsky et al. (Figure 3) the tricyclic skeleton is established before the arabinosyl unit is linked [lo]. The key steps of this synthesis are the Nozaki-Kishi cyclization to the furanophane, a sequence of rearrangements to the 4,7-oxaeunicellane framework [ 111, and the oxycarbaglycosidation of the tricyclic core structure. The ten-membered ring is established by addition of the nucleophile resulting from monometalation of 2,5-dibromofuran (11) to aldehyde 10, which is derived from the monoterpene (-)-cc-phellandrene (Figure 3). After chain-extension by one carbon atom, alcohol 12 is formed in a 1.3:l diastereomeric mixture at C8, from which the desired isomer can be isolated in 57% yield. Cyclization forms the highly strained 2,s-furanophane 13 with good stereoselectivity at C3, through reductive Nozaki-Kishi cyclization of the bromine aldehyde 12. Epoxidation of the allylic alcohol 13 initiates a rearrangement to the pyranosyl derivative 14, which after stereocontrolled 1,z-addition of methyl lithium further rearranges to the furanosyl ring system to provide the eleutheside core structure 15. The anomeric mixture that would result from classical glycosylation is avoided by the use of Stille coupling of the (arabinosy1)methyldonor 17 to the vinyl triflate 16. The respective (arabinosy1)methyldonor 17 can be obtained with tri-n-butylstannylmethanol from the thioethyl glycoside after separation of the anomeric mixture. Stille coupling does not affect the stereochemistry of the C2/C3-double bond. Nevertheless, even optimization of reaction conditions resulting in the

Cornbinatorial Sarcodictyin Libraries

OTES

I

319

OTES OTES

OTES c

CHO OH

6

OTBS

-

OTBS Fig. 2.

L

FoTB OTBS-

Total synthesis of eleutherobin by the procedure o f Nicolaou et al.

addition of LiCl did not provide yields higher than 50% for the formation of 18. This synthesis, however, does provide a suitable means for the attachment of the sugar side chain to the eleutherobin core structure. Both total syntheses of eleutherobin (1) are completed by the introduction of the methylurocanic acid moiety through acylation of the C8 hydroxyl group. Finally, the natural product is obtained by removal of protecting groups. Combinatorial Sarcodictyin Libraries

Pharmacological evidence regarding the eleutherobin side chains can be investigated preferentially by the synthesis of derivatives based on the eleutherobin/sarcodictyin core structure by combinatorial chemistry [ 1 2 ] . Modifications with varying side chains at C3, C4, and C8 are tested for tubulin polymerization and cytotoxicity (Figure 4). The C4 anomeric hydroxyl group is suitable for linkage to the Merrifield solid support, since a variety of alcohols can be introduced by trans-ketalization at the end of the synthesis simultaneously with cleavage from the resin. Twelve atoms turned out to be a good choice for the length of the linker. The sarcodictyin core structure is bound to the solid support by means of a Wittig reaction, forming a double bond in the central position of the spacer. The side chains at the C8-

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' c-

:

OPiv Me

Me

15

OH

c--

OH

OPiv

-

14

c

16 Fig. 3.

Total synthesis of eleutherobin by the procedure of Danishefsky et al.

hydroxyl group are attached as esters or carbamates. After deprotection of the primary hydroxyl group there are three possibilities for the linkage of C3 side chains to 19: direct conversion to esters or carbamates 21, oxidation to the carboxylic acid followed by ester or amide derivatisation derivatization (20), or nucleophilic substitution with an azide, subsequent reduction to the amine, and linkage of the side chains as amides (22). Therefore, activated carboxylic acids such as acetic anhydrides and acetyl chlorides, as well as isocyanates or alcohols, are applied for functionalization of the resin-bound core structure, whereas the third side chain is introduced in combinatorial fashion with various alcohols in the trans-ketalization cleavage reaction. Structure/activity relationship studies on the sarcodictyin library are performed by induction of tubulin polymerization and by cytotoxicity studies with three cancer cell lines, including Taxol-resistantlines. Derivatives that induce tubulin polymerization more strongly than the natural product sarcodictyin have been determined, and can show higher cytotoxicity even as far as Taxol-resistant tumor cells are concerned. The results of the structure/

Combiflatorial Sarcodictyin Libraries

Fig. 4. Attachment of the pharmacophoric side chains t o the sarcodictyin core structure by combinatorial synthesis.

activity relationship studies are summarized in Figure 5: the methylurocanic acid side chain is necessary for activity, and both nitrogen atoms of the imidazole ring are required. Recent studies also prove the stringent requirement for the 2’,3’-double bond [13], but ketal substitutions are tolerated well. Esters are more active than the corresponding amides in the C3 side chain. Finally, with the exception of eleutherobin, reduction of the ester to the alcohol and derivatives thereof (21) are not tolerated. From an additional study, modification or removal of the sugar moiety also has a substantial influence on the cytotoxic potency of eleutherobin and its cross-resistance in Taxolresistant cells [14].These structure/activity profiles should be usable for future design of more potent eleutherobin derivatives.

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C8 Side chain is crucial for activity 2’,3’-Double bond is required Both nitrogen atoms are important

Ketal substitutions are tolerated Esters are preferred over amides; reduction to the alcohol is not tolerated Fig. 5.

Summary of the structure/activity relationship results.

Common Pharmacophore: Prediction of New Drugs

The natural products eleutherobin (l),epothilone (23), paclitaxel (24), nonataxel (25), and discodermolide (26) (Figure 6) show a similar mode of action. Furthermore, competitive inhibition of paclitaxel binding to rnicrotubules by epothilone, eleutherobin, and discodermolide is observed, and so a common pharmacophore and the existence of a common tubulin binding site are therefore strongly suggested [ 151. The identification of comparable structural characteristics is complicated, since conformations established by NMR spectroscopy or X-ray structure analysis do not necessarily correspond to the binding conformations [161. Ojima et al. compared the preferred conformations of paclitaxel, nonataxel, epothilones A and B, eleutherobin, and discodermolide with the aid of NMR spectroscopy and molecular dynamics calculations [ 17, 181. Although these natural products are constitutionally quite different, an outstanding topological homology can be recognized. A common pharmacophore seems to exist [19], and is defined by the three regions A, B, and C (marked in Figure 6). These functional regions can be superimposed within the three-dimensional structures. By this definition of a common pharmacophore, the multicyclic baccatin core structure of Taxol seems only to be required for spatial orientation of the substituents. Furthermore, the good in vivo activities of the epothilone analogues in which the epoxide is replaced by a double bond also support the prediction that the epoxide does not belong to the pharmacophore [20]. The eleutherobin modifications obtained by total synthesis also fit with the model of a common pharmacophore: the arabinosyl residue can be substituted by its enantiomer or simply by an acetyl group without appreciable loss of activity [ 101, whereas the C8 side chain is indispensable for activity [ 91. Caribaeoside represents a recently studied eleutherobin analogue with an additional hydroxyl group at C11 [21]. The significant decrease in antimitotic activity supports the pharmacophore model regarding the proposed apolar Bregion. With this knowledge of the three-dimensional orientation of the common pharmacophore, it is possible to design new and structurally simplified analogues of therapeutic interest. As an example, the hybrid derivative SB-TE-1120 (27),based on the baccatin core structure (Figure 7), has been synthesized [17]. This analogue has a good structural homology with epothilone B and eleutherobin, which is also indicated by a remarkable activity.

Biological Activity

Fig. 6. The common pharmacophore o f the presented tubulin-binding cytostatic agents is defined by the residues A, B, and C, which are superimposed in the three-dimensional structures.

Biological Activity

The antiproliferative activity of eleutherobin is based on interaction with tubulin, as is known for epothilone and taxol. These natural products induce depolymerization of microtubules and thereby interrupt the division of cancer cells [ 2 ] . From experiments with highly purified tubulin, it was possible to show that some eleuthesides as well as epothilone A induce tubulin aggregation comparable to that of paclitaxel, and are also promoted by microtubule-associated proteins or GTP [221. Furthermore, kinetic measurements indicate

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SB-TE-1120 (27) Fig. 7.

Hybrid structure SB-TE-1120, the result of studies determining a common pharrnacophore.

the recognition of eleuthesides and epothilone at the paclitaxel binding site [23]. Eleutherobin (k, = 2.1 J ~ M )has a strength similar to epothilone A (ki = 2.6 p ~ as) an inhibitor of radiolabeled paclitaxel binding. The tubulin affinity of sarcodictyines is significantly lower. The influence on cell growth was examined quantitatively in six human cancer cell lines, including two paclitaxel-resistant lines [ 221.The results obtained for antiproliferative activity are largely in accordance with the tubulin interactions. Once again, lower activity was found for the sarcodictyines (ICso = 200-500 nM) than the similar values found for paclitaxel (I& < 10 nM), epothilone A (ICso = 10-40 nM), and eleutherobin (IC50 = 10-40 nM). Overall, quite similar antimitotic effects are observed for several constitutionally diverse natural products. There seems to be evidence for different core structures presenting a common pharmacophore. This knowledge of the spatial and functional needs of the pharmacophore should in future hopefully result in new and easy accessible derivatives with high potency, more limited side effects, and lower resistance than the natural products. References

T. LINDEL, P. R.

J E N S E N , W.

FENICAL, et al.,

M. D'AMBROSIO, A. GUERRIERO, F. PIETRA,Hefu. Chim. Acta 1987, 70, 2019A. GUERRIERO, 2027; b) M. D'AMBROSIO, F. PIETRA,Helu. Chim. Acta 1988, 71,

4 a)

1. Am. Chem. Soc. 1997, 119,8744-8745. B. H. LONG,J. M. CARBONI, A. J. WASSERMAN, et al., Cancer Res. 1998, 58,

964-976.

1111-1115.

Review articles: a) K. C. NICOIAOU, D. N. P. KING, et al., Pure Appf. HEPWORTH, Chem. 1999, 71, 989-997; b) K. C. NICOIAOU, J. PFEFFERKORN, J. Xu, eta]., Chern. Pharm. Bull. 1999, 47, 1199-1213; c) S. J. STACHEL, K. BISWAS,S. J. DANISHEFSKY, CUT. Pharm. Des. 2001, 7, 1277-1290; T. LINDEL:Organic Synthesis 2000, Highlights I V (ed. H.-G. SCHMALZ) 268-274.

BOWLEY,D. J. FAULKNER, Tetrahedron 1993, 49, 7977-7984. R. BRITTON,M. ROBERGE, H. BERISCH, et al., Tetrahedron Lett. 2001, 42,

5 Y. LIN, C. A. 6

2953-2956. 7

T. LINDEL, Angew. Chern. 1998, 110,806808.

NICOIAOU, F. L. VAN DELFT,T. OHSHIMA, et al., Angew. Chern. 1997, 109, 2630-2634; b) K. C. NICOIAOU,

8 a) K. C.

References I 3 2 5

T. OHSHIMA,S. HOSOKAWA, et al.,]. Am. Chem. Soc. 1998, 120, 867443680, 9 a) K. C. NICOLAOU, J. Y. Xu, S. KIM, et al., 1.Am. Chem. SOC.1997, 119, 11,35311,354; b) K. C. NICOIAOU,J. Y. Xu, S. KIM, et al., J . Am. Chem. Soc. 1998, 120, 8661-8673. 10 a) X.-T. CHEN,C. E. GUITERIDGE, S. K. BHATTACHARYA, et al., Angav. Chem. 1998, 110, 195-197; b) X.-T. CHEN,B. ZHOU,S. K. BHATTACHARYA, et al., Angew. Chem. 1998, 110, 835-838; c) X.-T. CHEN,S. K. BHATTACHARYA, B. ZHOU,et a].,]. Am. Chem. SOC.1999, 121, 6563-6579. 11 S. K. BHATTACHARYA, X.-T. CHEN,C. E. GUTTERIDGE, et al., Tetrahedron Lett. 1999, 40, 3313-3316. 12 K. C. NICOLAOU, N. WINSSINGER, D. VOURLOUMIS, et al.,]. Am. Chem. Soc. 1998, 120, 10,814-10,826, 13 R. BRITTON,E. DILIPD E SILVA, C. M. BIGG, et al., 1.Am. Chem. SOC.2001, 123, 8632-8633. 14 H. M. MCDAID,S. K. BHAITACHARYA,X.-T. CHEN,et al., Canc. Chem. Pharm. 1999, 44, 131-137. 15 For a microtubule structure see: P. MEURER-GROB, J. KASPARIAN, R. H. WADE, Biochemistry 2001, 40, 8000-8008.

B. CINEL,B. 0. PATRICK,M. ROBERGE, et al., Tetrahedron Lett. 2000, 41, 2811-2815. 17 I. OJIMA,S. CHAKRAVARTY, T. I N O U E , et al., Proc. Natl. Acad. Sci USA 1999, 9 6 4256-4261. 18 For further advances in the search for a common pharmacophore: L. HE, G. A. ORR,S. B. HORWITZ,Drug Discovery Today 2001, 6, 1153-1164. 19 For the determination of a common pharmacophore compare: a) J. D. WINKLER, P. H. AXELSEN, Bioorg. Med. Chem. Lett. 1996, 6, 2963-2966; b) M. WANG,X. XIA, Y. KIM, eta]., Organic Letters 1999, I , 43-46. 20 a) T. CHOW,X. ZHANG, A. BALOG,et al., Proc. Natl. Acad. Sci. USA 1998, 95, 96429647; b) T. CHOW,X. ZHANG,C. R. HARRIS,et al., Proc. Natl. h a d . Sci. USA 1998, 95, 15,798-15,802. 21 B. CINEL,M. ROBERGE,H. BEHRISCH, et al., Organic Letters 2000, 2, 257-260. 22 E. HAMMEL, D. L. SACKETT, D. VOURLOUMIS, et al., Biochemistry 1999, 38, 5490-5498. 23 For a cocrystal structure analysis of tubulin dimers with GTP, GDP, and taxol S. G. WOLF,K. H. compare: E. NOGALES, DOWNING,Nature 1998, 391, 199-203. 16

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Total Synthesis o f the Natural Products CP-263,114 and CP-225,917 Ulf Diederichsen and Katrin 6. Lorenz

Two structurally remarkable natural products were recently isolated from a Texas juniper fungus by the Pfizer research team. Today these compounds are well known as phomoidrides A and B or by their code numbers CP-263,114(1)and CP-225,917 (2), respectively [I, 21. Their overall structures and relative configurations were assigned shortly afterwards by Kaneko et al., on the basis of extensive NMR analysis, and their absolute configurations were recently determined by asymmetric synthesis (Figure 1) [3]. The interest in these compounds derives from their attractive biological properties: both show potent inhibitory activities towards squalene synthase and farnesyl transferase. Squalene synthase is widely recognized to be the enzyme responsible for the first step in the biosynthesis of cholesterol from farnesyl pyrophosphate. Inhibition of squalene synthase at the initial stage would provide a possible means of lowering cholesterol levels without interfering with the production of nonsterolic compounds based on farnesyl pyrophosphate. Against squalene synthase from rat liver, the phomoidrides exhibit ICso values of 43 pM (phomoidride A) and 160 pM (phomoidride B). Farnesyl transferase from rat brain is inhibited by CP-263,114 (1) and CP-225,917 (2) with IC50 values of G pM and 20 pM, respectively. Farnesylation of the Ras protein, which works as a molecular switch for cell growth, by farnesyl pyrophosphate as a substrate allows it to bind to the lipophilic plasma membrane. Interference with membrane binding would be a promising approach through which to affect uncontrolled cell growth caused by mutated Ras [4]. Even though CP compounds are relatively small, they represent an extremely challenging target for synthetic chemists, due to their unusual arrangement of functional groups [ 51. Based on a cage-likebicyclo[4.3.l]deca-l,G-dien-lO-one core, the CP molecules present a highly oxygenated tetra- or pentacyclic ring system with two additional alkenyl side chains (Figure 1). The bridgehead double bond (anti-Bredt), the y-hydroxy-y-lactonefunctionality, and the fused maleic anhydride moiety deserve special attention as complex structural features. Pericyclic Reactions for the Construction o f the Bicyclic Core Structure

Much of the published work dealing with the synthesis of the phomoidrides has centered on devising methods for assembling their unique bicyclic carbon skeleton. The construction of this bicyclic core with additional potential for subsequent functionalization is a central

Pericyclic Reactionsfor the Construction ofthe Bicyclic Core Structure

I" 0 /

0 d 0

hl

"'I 0

4

Y

Y

0

x

n

Y

P

F r Y 0 .

I

M .U

I

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Total Synthesis ofthe Natural Products CP-ZG3,114 and CP-225,917

task in the synthesis of the CP compounds. Most of these concepts use pericyclic reactions, offering the possibility to introduce the bridgehead double bond directly with the cyclization step [6-121. Clive et al. demonstrated in a simplified model system that the bicyclic core structure can be achieved by means of an anionic oxy-Cope rearrangement [ 7 ] , but this method unfortunately fails for more highly substituted scaffolds. A silyloxy-Cope variant has hence been established, affording the same target molecules but enabling milder conditions to be used [Sl. Leighton et al. also made use of this favorable rearrangement to synthesize the central core structure (Figure 2) [ 91. Treatment of hydroxy enol triflate 3 with Pd(PPh3)4, Et3N, and CO generates the lactone spiroketal 4,which undergoes silyloxy-Cope rearrangement to the silyl enol ether 5 in good yields. The Cope precursor 4 does not need to be isolated. The activation of the silyloxy-Coperearrangement, achieved only by the introduction of the lactone spiroketal group, is remarkable: the orientation of the Cope system and the loss of ring tension during the pericyclic reaction give rise to an acceleration such that the rate exceeds that of the anionic oxy-Cope rearrangement. A more advanced, direct route to the core structure of CP-263,114(rac-1) has recently been published by Wood et al., who used carbon-based fragmentation after a phenolic oxidation/ intramolecular Diels-Alder sequence [ 101. In addition, various cycloadditions for the synthesis of the central bicyclic skeleton have been established [ll]. Further methods to construct the bicyclic backbone by means of a Diels-Alder reaction [I21 and by an exciting multi-step domino reaction [13] are introduced in the next sections, in the context of the total syntheses of the phomoidrides by Nicolaou and Shair, respectively [ 141. Danishefsky 's Total Synthesis: Carbobicyclic Core by Aldol and Heck Reactions

A basic approach combining the introduction of the fused maleic anhydride moiety with the cyclization uses the trisubstituted furan derivative 6 as a coupling partner to the ring system 7 (Figure 3) [GI. The furan ring serves as precursor for the maleic anhydride moiety, easily accessible through subsequent oxidation [ba]. The initial aldol condensation between the aldehyde G and the cyclic enone 7 proceeds with high diastereoselectivity, positioning the hydroxyl group anti to the alkyl substituent. A silyl protecting group is attached to the hydroxyl functionality before the bicyclic 8 is generated by intramolecular syn Heck carbopalladation. The bridging keto group can be reduced with the desired diastereoselectivity with DIBAH, followed by introduction of the side chain precursors at C-4 and C-3 by Suzuki coupling and Sakurai addition, respectively [ 151. The bridgehead double bond is accomplished by SeOz-mediated allylic oxidation, with subsequent manipulations and dehydration to furnish the bicycle 9. The simultaneous introduction of the carboxy groups to install the quaternary center at C14 (Figure 4) is remarkable [IS]. The keto group of bicyclic compound 9 is first converted into an exocyclic double bond by Tebbe olefination. A dichlorocyclobutanone ring is then formed by [ 2 + 21 cycloaddition between dichloroketene and the exocyclic double bond of compound 10. This reaction proceeds regioselectively in favor of the conjugated allylic double bond to furnish spirocyclobutanone 11 after reductive cleavage of the geminal chloro groups. After base-induced diastereospecific sulfenylation to 1 2 and subsequent oxidation to the sulfoxide lactone, the terminal ally1 group can be selectively dihydroxylated. The second-

Total Synthesis by Nicolaou

Intramolecular Heck reaction

1. LDA, THF, -78"C, 2h 2. TBSOTf, 2,6-lutidine, /-CH,CI,, RT, 1. h .l oa7 3. [Pd(OAc)z(PPh3),], NEt,, THF, reflux, 4d

TBS

0

t

CHO

i

49% overall

6

/

Aldol condensation

TBSO

0

H

9

Fig. 3. Total synthesis by Danishefsky: construction o f the carbobicyclic core structure by aldol condensation and carbopalladation. TBS = tee-butyldirnethylsilyl, LDA = lithium diisopropylarnide, Bn = benzyl.

ary hydroxyl functionality induces a rearrangement to the ketal 13. Under basic conditions, this intermediate cyclizes, providing the central bicyclic core 14 of the CP molecules. The C-7 side chain is introduced by addition of a Grignard reagent to the aldehyde generated from the primary hydroxyl function by oxidation, and subsequent Dess-Martin oxidation. The total synthesis is completed by conversion of the silyl-substituted furan into the maleic anhydride. The masked anhydride is liberated by successive photooxidation and further oxidation of the intermediate lactol with PCC [Gal. Unfortunately, this synthetic route results in the isolation not of the natural compound CP-263,114 (l),but of the C-7 epimer 15, which proved to be the more stable stereoisomer. The formation of the unwanted C-7 epimer is a consequence of the Os04-catalyzed dihydroxylation of intermediate 12, which occurs from the face of the C=C double bond opposite to that desired. Epimerization at C-7 takes place under basic conditions, and on closer inspection it was possible to identify both isomers in the original sample extracted from the fungus [ 161. However, the isolation of both isomers could also be an 'artefact' of the extraction process, during which the configuration at C-7 could be partially flipped during treatment with acid and base [2]. Total Synthesis by Nicolaou

Nicolaou et al. synthesized both racemic CP-263,114 (rac-1) and racemic CP-225,917 (rac-2) by the same synthetic pathway, since the two natural products are reversibly interconver-

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Total Synthesis ofthe Natural Products CP-263, I14 and CP-225,977

Tebbe

9 -

TBS

+

1. Trichloroacetyl chloride, Zn, Et,O, DME, ultrasound 2. Zn, NH,CI, MeOH, ultrasound 3. TBAF, THF, 0°C *

(CH,)60Bn

90%

CHZ

48% overall

10

TBSO

TBSO \

\

PhSSPh, NaHIKH, THF

. 80%

T

B

s

9

1. Dess-Martin periodinane, CH,CI, 2. H,O,, MeOH 3. OsO,, NMO, acetonelwater

) 12 6

0

B

n

60%

O H = '

-

\

-

NaOMe, MeOH

44% over 3 steps

(CH,),OBn 14

2

0

0

TBS

H

iCOOCH,

Fig. 4. Danishefsky's total synthesis: formation o f cyclobutanone, sulfenylation, and successive oxidation reactions. DME = 1 Jdimethoxyethane, TBAF = tetra-n-butylammonium fluoride, NMO = N-rnethylmorpholine-N-oxide.

(7S)-CP-263,114

(15)

Total Synthesis by Nicolaou I 3 3 1

tible (Figure 1) [ 17-20]. The Pfizer group had already shown that 2 may be converted into 1 under anhydrous acidic conditions and that 1 is stable in acidic aqueous media, so CP225,917 (2) was targeted first. Because of its higher stability and to avoid the use of additional protecting groups, the pyranose substructure was chosen as template for the synthesis. This first ever published, 40-step total synthesis of the highly oxidized and functionalized tetra- or pentacyclical systems deserves closer consideration, thanks to its cascade reactions and elegant synthesis steps. The Bicyclic CP Backbone and Stereoselective Chain Extension

The prochiral triene 16 (Figure 5) is a suitable precursor for the bicyclic core structure 17, and can be obtained in ten steps starting from dimethyl malonate. The intramolecular Diels-Alder cyclization to 17 proceeds with MezAlCl catalysis in very good yield under mild conditions [ 12, 181. The side chain at C-7 is introduced with high selectivity: the aldehyde group, obtained by desilylation and Dess-Martin oxidation, reacts regioselectively with the lithiated dithiane 18, since attack at the keto group is sterically hindered. In addition, the CP skeleton shields one side of the aldehyde, so that the desired diastereomer 19 is obtained as major product in a ratio of 11:l. Cascade Reactionfor the Construction of the Maleic Acid Moiety

The carbonyl group is an easy means of entry to the fused maleic anhydride moiety [ 19, 211. For steric reasons, alkylation in the a-position to the keto group in 19 is a difficult task. The synthesis sequence starts with the transformation of ketone 19 into the vinyl triflate, followed by Pd(OAc)z-catalyzedcarboxymethylation (Figure 6). The dithiane protecting group can be replaced by a dimethyl ketal, generating 20 in good yield. Stereoselective vanadiumcatalyzed epoxidation of the allylic alcohol, obtained by reduction of the unsaturated ester, yields the /I- and the wepoxides in a 11:1 ratio. Ring-opening with Et2AICN (Nagata reagent) proceeds with exceptional stereoselectivity, which may be due to the arrangement of the epoxide in the bicyclic skeleton. In the following seven-step cascade reaction, the resulting cyanodiol is converted into the targeted maleic anhydride 21. First, the primary hydroxyl group is mesylated and substituted by the vicinal tertiary alcohol. In the presence of K2CO3, the epoxide undergoes a /I-elimination followed by a 5-exo-dig cyclization, building up an iminobutenolide. Autoxidation and subsequent imine hydrolysis complete the synthesis of the corresponding maleic anhydride in 56% overall yield. Protecting group manipulations at the C-7 side chain yield the key intermediate 21, the structure of which was confirmed by X-ray analysis. Oxidation to the y-Hydroxy Lactol

The synthesis of the y-hydroxy lactol ring starts with the cleavage of the PMB protecting group and the oxidation of the resulting hydroxy compound to the enone 22 (Figure 7) [20]. Acid-induced removal of the isopropylidene group results in the spontaneous formation of

16

Fig. 5. Total synthesis by Nicolaou: intramolecular Diels-Alder cyclization and introduction o f the C-7 side chain. TBDPS = tert-butyldiphenylsilyl, PMB = p-rnethoxybenzyl.

TBDPSO

0

PMBO

90%

c

Me,AICI, CH,CI, -lO"C, I h

0

Li

PMBO

18

17

CH3

a

fo

a

a

D

5

c"

s

m

2

G'

g

-=VI 2

2 D

w w N

I

Total Synthesis by ~ i c o l a o u 333

Stepwise formation of the maleic anhydride substructure:

73%

pelimination

.VR

*K,C03

MsCI, NEt,

Fig. 6. Nicolaou's total synthesis: construction o f the rnaleic anhydride moiety. KHMDS = potassium hexamethyldisilazide, DIBAL = diisobutyl. aluminium hydride, acac = acetylacetonate, Ms = rnethanesulfonyl.

a cyclic hemiketal. The remaining primary hydroxyl group is protected as a silyl ether, furnishing compound 23. In simplified model systems, oxidation to the y-hydroxy lactol was easily achievable at this stage as a cascade reaction on treatment with Dess-Martin periodinane [21]. However, the conversion starting from the diol turns out to be problematic in the presence of the fused maleic anhydride moiety. This may be due to the decrease in conformational freedom caused by the annellation, which influences the equilibrium of the

1

Et,AICN

334

I

Total Synthesis of the Natural Products CP-2G3,114 and CP-22597 7 0

0

21

1. DDQ 2. PDC

1. AcOH 2. TESOTf ___)

43%

75%

0

overall

$-OTES

23 Ring-chain tautornerization

0

c--

49%

I

0

""-OTES

'<-OTES

L

25

\

0 &C5Hg

'HO

\

C,H,,

0 26

=-

OTES

Fig. 7. Nicolaou's total synthesis: oxidation to the y-hydroxy lactol. PDC = pyridinium dichromate, DMP = Dess-Martin periodinane.

ring-chain tautomerization between 23 and 24 [ 20, 221. Ring-opening to 24 is essential to initiate the cyclization to the y-hydroxy lactol: the primary hydroxyl group of the open-chain tautomer 24 is oxidized to generate intermediate 25, and subsequent nucleophilic attack of water results in lactolization to give the y-hydroxy lactol 26. The equilibrium can be shifted to the open-chain compound by an increase in the reaction temperature and the choice of an appropriate solvent. Under these conditions, Dess-Martin periodinane can be used to prepare y-hydroxy lactol 26 from 23 in 49% yield and as a single stereoisomer.

Total Synthesis by Nicolaou

26

'' 2. MeS0,H TFA

0

335

n

DMP, benzene

&c5Hg

P &c5Hg

83%

.un .-

O

I

.+-

'

90%

0

'-OH

-7

LI

'

'SH15

66% overall

-C5H9

CEH,,

I._

nu

+ n , /

I

-

28 H 1. TBSOTf 2,6-lutidine 2. NaCIO,, NaHpO,

Arndt-Eistert homologation 4

'/TBSO d

C

-.. E

H

1

5

'-COOH 30

1. Indoline, EDC, DMAP 2. TFA 3. DMP, NaHCO, CH2CI,

\

1. MsCI, Et3N 2. CH,N, 3. Ag,O, DMFIH,O

TBSO COOH

35% overall

29

74% overall

1. pChloroaniI 2. LiOH; NaH,PO,

CP-225,917 50% overall 0

Fig. 8. Nicolaou's total synthesis: ketalization and homologation of the carboxylic acid side chain. TFA = trifluoroacetic acid, EDC = 1-[3-(dirnethylarnino)-propyl]-3-ethylcarbodiirnide hydrochloride, DMAP = 4-(N,N-dimethylamino)pyridine.

Ketulization and Homologution ofthe Curboxylic Acid Side Chain

Cleavage of the silyl protecting groups under acidic conditions, followed by exposure to MeS03H, results in ketalization of 26 to the pyran-lactol 27 (Figure 8) [ZO]. To complete the synthesis of the CP compounds, the primary alcohol has to be oxidized to the carboxylic acid and the carboxylic acid side chain has to be elongated by means of an Arndt-Eistert reaction.

(rac-2)

336

I

Total Synthesis of the Natural Products CP-2G3,7 74 and CP-225,917

Treatment of the diol27 with Dess-Martin periodinane in benzene predominantly yields the aldehyde lactol 28. Simultaneous oxidation of the secondary alcohol to the y-hydroxy lactone is only a side reaction. The resulting y-hydroxy lactol 28 is again silyl protected and the aldehyde group can be oxidized by NaClOz to the sterically hindered carboxylic acid 29. Despite its concave skeleton, the carboxylic acid can easily be activated as an acyl mesylate and transformed into the corresponding diazo ketone, followed by a Wolff rearrangement to generate the homologated carboxylic acid 30. Before the lactol functionality is revealed and oxidized, a indoline amide is formed to decrease the reactivity of the carboxylic acid. Lactone 31 is once more prepared by Dess-Martin periodinane oxidation. The final step in the synthesis is the release of the carboxylic acid functionality. The indoline amide protecting group can be removed by oxidation to the indole amide and subsequent hydrolysis under mild basic conditions. In this step, the pyran ring is also opened, so CP-225,917(ruc-2) is initially formed. An easy procedure for conversion of CP-263,114 (1)into CP-225,917 (2) has already been presented in Figure 1. Asymmetric Total Synthesis by Nicolaou

After the completion of their racemic total synthesis of the phomoidrides, Nicolaou et al. developed an asymmetric version of this synthesis to determine the absolute configuration of these compounds through chemical synthesis [3, 181. A strategy based on chiral reagents was originally designed for the synthesis of enantiomerically enriched building blocks. As the key reaction, the Diels-Alder cyclization can be asymmetrically induced by use of chiral catalysts. Attempts to utilize this asymmetric induction, though, yielded only poor diastereoselectivities, despite the use of numerous chiral Lewis acid catalysts [ 181. A second approach employing substrate-based control was undertaken, a bulky chiral moiety being introduced into the enone precursor to influence the facial selectivity of the Diels-Alder reaction. The bis(TBS) ketone 32 cyclizes at -80 "C in the presence of catalyst 33, to furnish a 5.7:l mixture of diastereomeric Diels-Alder products (Figure 9). The major isomer 34 is desilylated with TBAF, and oxidative cleavage of the diol with sodium periodate generates the corresponding aldehyde 35, the racemic form of which is a known intermediate in the total synthesis of racemic CP compounds. The conversion to the indoline derivative ent-31 therefore follows the strategy of the racemic route. Circular dihroism (CD) spectroscopy verified the identity of the synthetic ent-31 as the enantiomer of the naturally derived indoline (-)-31. Synthetic ent-31 was also processed to give ent-1 and ent-2. Shair's Asymmetric Total Synthesis o f (+)-CP-263,114 (ent-1) and (-)-CP-225,917 (ent-2)

The asymmetric synthesis developed by Shair et al. employs a fragment coupling/cyclization reaction to establish the correct connectivity of the bicyclic backbone (Figure 10) [13]. The enantiomerically pure cyclopentanone 36, with appropriate side chain functionalization, is alkylated with a vinyl Grignard reagent 37. The bromomagnesium alkoxide 38 immediately undergoes an anion-accelerated oxy-Cope rearrangement to 39, followed by a sponta-

Fukuyama’s Asymmetric Total Synthesis of (-)-CP-ZG3,714 (1)

.CH3

Fig. 9.

Nicolaou’s asymmetric total synthesis: stereoselective intramolecular Diels-Alder reaction.

neous transannular Dieckmann-like cyclization to afford the carbocyclic core structure in a single stereospecific reaction. After the introduction of the jl-keto ester and the enol carbonate functionalities in six steps, a multitask one-pot reaction is initiated by addition of TMSOTf and (MeO)3CHto 40, directly affording compound 41. As mechanism, a Fries-like rearrangement is postulated, followed by subsequent ionization and cyclization to form the pseudoester cage ring system. After TMSOTf-mediated deprotection, the further transformations used to furnish (+)-CP263,114 (ent-1) and (-)-cP-225,917 (ent-2) employ common homologation steps, for the most part already used in Nicolaou’s asymmetric total synthesis. Fukuyama’s Asymmetric Total Synthesis o f (-)-CP-263,114 (1)

Although the asymmetric total syntheses developed by Nicolaou and by Shair provide easy routes to enantiomerically pure CP compounds, the target molecules (+)-CP-263,114 (ent-1) and (-)-CP-225,917 (ent-2)are only the enantiomers of the natural occurring phomoidrides. After the establishment of the absolute configuration of the CP molecules by chemical synthesis, the focus of synthetic interest is the asymmetric total syntheses of (-)-CP-263,114 (1) and (+)-CP-225,917 (2). The first total synthesis furnishing (-)-CP-263,114 (1) as the correct enantiomer has recently been reported by Fukuyama et al. [231. As the stereoselectivitydetermining step, an intramolecular Diels-Alder reaction was chosen, similar to that in Nicolaou’s synthesis (Figure 11). The Diels-Alder precursor 42 is prepared in four easy

I

337

338

I

Total Synthesis ofthe Natural Products CP-263,I14 and CP-225,917

(-3//cH3 1

0 0 ’,. +

toluene -78°C A

/

-g MrB

CH,

OMOM

COOCH,

53%

37

36

‘OPMB

A

‘CH, oxyCope rearrangement

c

I

39

BrMgO LOPMB I

Dieckmann-like cyclization

l

’

n

0

0

(+)-CP-263,114 (ent-I)

Fig. 10. Shair’s asymmetric synthesis: electrocyclic ring-closure and introduction of the carboxylic acid side chain. MOM = methoxymethyl.

steps by fragment condensation between an (E,E)-diene, an acryloyl derivative, and an u,Punsaturated aldehyde. Upon treatment with zinc chloride, 42 undergoes a smooth intramolecular cyclization to give predominantly the desired bicyclic core structure 43.The stereoselectivity, confirmed by NOE studies, seems to be dictated by the stereochemistry at the C-12 position, bearing Evans’ chiral auxiliary as substituent. The construction of the maleic anhydride moiety 44 in only five steps starts with the conversion of the amide into an appropriate thioester. Upon treatment with DBU, an aldoltype cyclization occurs to provide the B-hydroxy thiolactone as a single diastereomer. After removal of the allylic protecting group, dehydration and decarboxylation are carried out simultaneously by simple heating. The thiobutenolide is oxidized to the corresponding thio-

*, I

Fukuyama's Asymmetric Total Synthesis of (-)-CP-263,774 (7)

ZnCI,.OEt,, pyridine

-

____)

H3C

H,COOC

'COOCH,

339

\

.;:::-e:s

0

H,COOC"

42

43

0 :

H,COOC

O V N v B n

-k \

H3C

(-)-CP-263,114

44

HOOC'"' H,COOC

Stepwise formation of the maleic anhydride substructure: Ally1 thioglycolate, LHMDS, 0°C

*

53% over 2 steps

R

R

93%

/I

R

0 O Y N Y B n OJ

1. Pd(OAc),, PPh,, rt 2. pyridine, AqO, 100°C

1. TBSCI, DBU

LiOH.H,O, MeOH;

>54%

R

0

40

I

87% overall

9.2. AgNO,, NIS,rt DMSO 'R h s

58% overall

0

R

Fukugama's asymmetric synthesis o f (-)-CP-263,114: intramolecular Diels-Alder reaction and formation of the rnaleic acid anhydride moiety. DBU = 1,8-diazabicyclo[5.4.O]undec-7-ene, NIS = N-iodosuccinimide.

Fig. 11.

maleic anhydride and afterwards subjected to basic hydrolysis. During the hydrolysis, the less hindered methyl ester is also saponified, and can be converted into the homologated carboxylic acid by means of the Arndt-Eistert reaction. Oxidation of the sulfide with mCPBA followed by subsequent cleavage of the acetonide induces the cyclization to afford the ylactone acetal. Finally, Jones oxidation of the secondary alcohol furnished (-)-CP-263,114 (l), identical in all respects with natural CP-263,114 (1).

0

340

I

Total Synthesis of the Natural Products CP-2G3,714 and CP-225,977

With the asymmetric synthesis of the CP compounds completed and the synthetic route to various simpler variants now established, chemists have obtained extensive knowledge about the reactivity of these small but complex natural products. This knowledge may be extremely useful for the development of therapeutically valuable analogues with increased biological activities. Whether or not this search results in the discovery of efficient drugs, the phomoidrides have already provided a platform for some outstanding, highly inventive science.

References

a) T. T. DABRAH, T. KANEKO,W. MASSEFSKI, J R . , et al., J. Am. Chem. soc. 1997, 119, 1594-1598; b) T. T. DABRAH, L. H. HUANG,et al., J. H. J. HARWOOD, Antibiot. 1997, 50, 1-7. 2 The name is derived from the producing organism (a ‘Phomaoid fungus) and the proposed relationship of these molecules to the nonadrides, see D. HEPWOKTH, Chem. Ind. 2000, 2, 59-65. 3 K. C. NICOLAOU, J.-K. J U N G , W. H . YOON, et al., Angew. Chem. Int. Ed. 2000, 39, 1829-1832. 4 For biosynthetic studies and a biomimetic synthesis approach see: a) J. L. BLOOMER, C. E. MOPPETI,J. K. SUTHERIAND,J. Chem. SOC.C. 1968, 588-591; b) M. 0. Moss, Microbial Toxins (Ed.: A. CIEGLER), Academic Press, New York, London 1971, 6, 381-407; c) P. SPENCER, F. AGNELLI, et al., J. Am. Chem. SOC. H. J. WILLIAMS. 2000, 122,420-421; d) G. A. SULIKOWSKI, F. AGNELLI, R. M. CORBETT,].Org. Chem. 2000, 65,337-342; e) G. A. SULIKOWSKI, F. AGNELLI, P. SPENCER, et al., Org. Lett. 2002, 4, 1447-1450; f ) G. A. SULIKOWSKI, et al., Org. Lett. 2002, W. LIU, F. AGNELLI, 4, 1451-1454; g) J. E. BALDWIN, R. M. ADLINGTON, F. R o u s s ~ et , al., Tetrahedron 2001, 57, 7409-7416. 5 a) S. BOKMAN,Chem. Eng. News 1999, June 7, 8-9; b) J. T. STARK,E. M. CARREIRA, Angew. Chem. Int. Ed. 2000,39, 1415-1421. 6 a) 0. KWON,D.4. Su, D. MENG,et al., Angew. Chem. Int. Ed. 1998, 37, 18771880; b) 0. KWON, D . 4 . Su, D. MENG, et al., Angew. Chem. Int. Ed. 1998, 37, 1880-1882. 7 a) P. W. M. SGARBI, D. L. J. CLIVE,Chem. Commun. 1997, 2157-2158; b) D. L. J. CLIVE,J. ZHANG,Tetrahedron 1999, 55, 12059-12068. 1

8 9

10

11

12

13

14

15 16

17

D. L. J. CLIVE,S. SUN,X. H E , et al., Tetrahedron Lett. 1999, 40, 4605-4609. a) M. M. BIO, J. L. LEIGHTON,J. Am. Chem. SOC.1999, 121, 890-891; b) M. M. BIO, J. L. LEIGHTON, Org. Lett. 2000, 2, 2905-2907. a) J. T. NJARDARSON, 1. M. MCDONALD, et al., Org. Lett. 2001, 3, D. A. SPIEGEL, 2435-2438; b) J. T. NJARDARSON, J. L. WOOD,Org. Lett. 2001, 3, 2431-2434. a) N. OHMORI,Chem. Commun. 2001, 1552-1553; b) N . OHMORI,J.Chem. SOC., Perkin Trans. 2002, 1, 755-767; c) L. ISAKOVIC, J. A. ASHENHURST, J. L. GLEASON, Org. Lett. 2001, 3, 4189-4192. K. C. NICOLAOU, M. W. HARTER,L. BOULTON, et al., Angew. Chem. Int. Ed. Engl. 1997, 3G, 1194-1196. c. CHEN,M. E. LAYTON,S. M. SHEEHAN, et a]., J. Am. Chem. SOC.2000, 122, 7424-7425. For additional synthetic approaches see: S . J. DANISHEFSKY, a) A. J. FRONTIER, C. A. KOPPEL,et al., Tetrahedron 1998, 54, 12,721-12,736; b) A. ARMSTRONG, T. J . CRITCHLEY, A. A. MORTLOCK, Synlett 1998, 552-553; c) H. M. L. DAVIES,R. CALVO,G. AHMED,Tetrahedron Lett. 1997, 38, 1737T. ITOH, T. 1740; d) N. WAIZUMI, FUKUYAMA, Tetrahedron Lett. 1998, 39, 6015-6018; e) K. C. NICOIAOU, M. H. D. et al., Angew. POSTEMA, N. D. MILLER, Chem. Int. Ed. Engl. 1997, 36, 28212823. D. MENG,S. J. DANISHEFSKY, Angew. Chem. h t . Ed. 1999, 38, 1485-1488. D. MENG,Q. TAN,S. J. DANISHEFSKY, Angew. Chem. Int. Ed. 1999, 38, 31973201. a) K. C. NICOLAOU, P. S. BARAN, Y.-L. ZHONG,et al., Angew. Chem. Int. Ed. 1999, 38, 1669-1675; b) K. C. NICOIAOU,P. S.

References I 3 4 1

18

19

BARAN,Y.-L. ZHONG,eta]., Angew. Chem. Int. Ed. 1999, 38, 1676-1678; c) D. SPENCER, F. AGNELLI, G. A. SULIKOWSKI, Org. Lett. 2001, 3, 1443-1445. K. C. NICOLAOU, J. J U N G , W. H. YOON, et al., /. Am. Chem. SOC.2002, 124, 2183-2189. K. C. NICOLAOU, P. S. BARAN,Y.-L. ZHONG,et al.,]. Am. Chem. SOC.2002, 124,2190-2201.

20

K. C. NICOIAOU,Y.-L. ZHONG,P. S. BARAN,et al., 1.Am. Chem. SOC.2002, 124, 2202-2211.

21

22 23

K. C. NICOLAOU, P. S. BARAN, R. JAUTELAT, et al., Angew. Chem. Int. Ed. 1999, 38, 549-552. K. C. NICOLAOU, Y. HE,K. C. FONG,et a]., Org. Lett. 1999, 1, 63-66.

N. WAIZUMI,T. ITOH,T. FUKUYAMA,]. Am. Chem. SOC.2000, 122, 7825-7826.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Polyene Cyclization to Adociasulfate 1 Thomas Lindel and Cordula Hopmann

Polyene cyclizations belong to the most exciting reactions in organic synthesis. Every example of such cascade reactions [I] is an encouragement to search for biomimetic synthetic pathways to natural products, not only for reasons of elegance, but also of economy. In the tradition of pioneering studies by Johnson et al. [2], Overman et al. reported the enantioselective total synthesis of adociasulfate 1 (1,Figure 1) by cationic polyene cyclization [ 31. The hexaprenoid bissulfates adociasulfate 1 (I),2 (2, main metabolite), and its congeners are marine natural products, isolated from the sponge Haliclona (aka Adocia) sp. in 1998 by Faulkner et al. [4,51. Interest in the adociasulfates results from their unique biological activity as the first specific, non-nucleotide kinesin inhibitors. A short description of this particular biological activity is given here. There are over 100 kinesin superfamily members, playing roles in cell division, and in vesicle and organelle transport [6]. Kinesin motor proteins use the free energy of ATP hydrolysis to drive intracellular movements along the microtubules [4).Kinesins are highly elongated proteins, all sharing a conserved motor domain of approximately 340 amino acids, containing ATP- and microtubule-binding sites. This motor domain is attached to a unique tail domain, which carries the cargo to be transported by binding to receptor proteins on the cargo surface [6b, 71. The transport process can be observed in elegantly designed experiments, by binding kinesins on glass slides and viewing the movement of the microtubule by microscopy. For the isolation of the active principle [S], the wet sponge Haliclona (aka Adocia) was extracted with methanol and dichloromethane, followed by concentration to an aqueous suspension and bioassay-guided partitioning between water and dichloromethane. The water fraction was separated on Fractogels TSK HW 40 to yield the active components adociasulfate 1 (1) and 2 (2). The first enantioselective polyene tetracyclization starting with a chiral epoxide was reported by Corey et al. in 1997 [Sa]. The silylated enol ether 3 (Scheme 1) was converted into the tetracycle 4 by treatment with the Lewis acid MeAIClz at -90 " C .The synthetic route is modeled on the biosynthesis of lanosterol from (3s)-squalene 2,3-epoxide and has also been applied to the biomimetic synthesis of tetracyclic polyprenoids from sediment bacteria [8bI. Adociasulfate 1 (1,Figure 1) contains nine stereogenic centers, of which eight are contig-

Polyene Cyclhation to Adociasuyafate I

I

343

Na03S0,

1: adociasulfate 1

2: adociasulfate 2

7%

Fig. 1. Marine natural products adociasulfate 1 (1) and 2 (2) from the sponge Adocia sp.

SiMe2Ph 1) 1.2 eq. MeAICI2, CH2CI2 -90% 30 min; Et3N 2) HF, MeCN, rt, 90 min 3) 10% KOH/MeOH, A, 3 h 30 Yo

HO 4

3

fi Me0

3C ;;hH ;C ;e ,p 1 ;g 2 ';.'

-@ h : HO

0 BnO

15 %

5

'necessary

/ BnO

' 6

Epoxide-initiated, enantiospecific polyene cyclizations of the substrates 3 and 5 t o the synthetic precursors (4 and 6) o f the marine natural products scalarenedial and adociasulfate 1.

Scheme 1.

uous and four are quaternary. It was not clear whether Corey's example would be transferable to the synthesis of adociasulfate 1 (1).The nucleophilic reactivity of the enoxysilane terminating the precursor 5 towards carbenium ions should be much higher than that of the hydroquinone which would have to be employed for 1 [9]. Indeed, Overman et al. found that an allyloxy substituent in the 3'-position of the 0-methylated hydroquinone ring of 5 (Scheme 1) was necessary to induce a complete, scandium triflate-induced polyene cascade to the pentacycle 6. In the absence of the allyloxy substituent, only bi-, tri-, and tetracyclic

344

I

Polyene Cyclization to Adociasulfate I

products were observed. This is a remarkable example of the beneficial effect of a higher electron density at donor termini in substrates of cationic polyene cascades. The first rare earth triflate used for such polyene cyclizations, Sc(OTf)3 was the most effective Lewis acid investigated, affording the pentacycle 6 in a yield of 15% (62% per ring). If MeAlClz was used (as for 3),a yield of below 5% was achieved. The stereochemical outcome of the cascade reaction was established by X-ray analysis of a later synthetic intermediate. It should be mentioned that the efficiencyof an overall synthetic approach is governed not only by the elegance of the key step, but also by the accessibility of starting material. In the case of Overman’s synthesis, the diterpenoid cyclization substrate 5 is available in a facile manner, starting from the aryl bromide 7 (Scheme 2). The two monoterpenoid building blocks 8 and 10 are successively attached to the substituted hydroquinone derivative 7 by standard procedures. The product 11 already contains the full carbon skeleton of the cyclization substrate and was converted into 5 in five more steps. Desulfonation of 11 was achieved by a method of Inomata et al. [lo],by treatment with LiEt3BH and Pd(dppp) (dppp: 1,3-bis(diphenylphosphino)propane)at 0 “C without double bond isomerization or desilylation. As a slight drawback, the ally1 protection group already in place at 3’-0 was removed simultaneously and had to be reintroduced in the next step. Sharpless asymmetric epoxidation (95% ee) of the allylic alcohol obtained after desilylation is the source of enantioselectivity in the total synthesis of adociasulfate 1 (1). Following the cyclization step from 5 to the pentacycle 6 (see Scheme I), the 3’-allyloxy group had done its duty and was completely removed by deallylation, triflation, and Pdcatalyzed reduction of the resulting aryl triflate (Scheme 3) [ I l l . At this stage, ten carbon atoms needed for adociasulfate 1 (1)were still missing. After Dess-Martin oxidation of the primary alcohol 12, (S)-cyclogeranyllithium(13,obtained in two steps from (S)-cyclogeraniol [ 121) was introduced by addition to the aldehyde, affording 14. It is a characteristic of natural product synthesis that specific properties of substrates prevent the use of established conversions. In this case, the steric environment surrounding C8 caused several deoxygenation reactions to fail. Overman et al. were finally successful with the Barton procedure [13], by conversion of 14 to the xanthate, which was then reduced to 15 with 100 equivalents of tributyltin hydride and 10 mol% AIBN. The change of the 0-protecting group from TBDMS to acetyl has its logic in a facilitated workup of the bis-sulfate natural product. The sulfate groups were introduced after oxidative demethylation of the methoxy groups, followed by sulfation with excess SO3/pyridine. The final step was an alkaline deacetylation. Adociasulfate 1 (1)was obtained in 28 steps and a very high total yield of 5.7%. The total synthesis also allowed the determination of the absolute configuration of the natural product. Remarkably, the adociasulfates retain their kinesin-inhibiting property even after substantial structural modification. The removal of a sulfate unit is tolerated, which makes the synthesis of less polar and hence membrane-permeating analogues promising. Even the opening of rings A, B, and E is possible, with only 50% loss of activity. The ten adociasulfates so far known have in common the central decalin system and the hydroquinone component. Adociasulfate 4 (16) is partially open-chain (Figure 2). The structure of the hydroquinone bissulfate toxicol A (17) from the marine sponge Toxiclonu toxicus [ 141 indicates the possibility of incomplete cyclization of the hexaprenoid precursors. Adociasulfate 2 (2)showed the most potent kinesin inhibition, specifically interfering with both microtubule and kinesin

OMe 7

0 -

Scheme 2.

TBDMSOT

M

\

S

-

O Br ~

10

So2Ph

74 Yo

11

Short synthesis o f the geranylgeranyl hydroquinone 5.

3) 10, 'BUOK, THF/DMF (9:1), -2O"C, 4 h; -> rt

D

~ ~ ~ F ~ ~ ? ~ , 3 h ;

1) TBAF, THF, rt, 12 h 2) MsCI, Et3N,THF, LiBr, -3O"C, 2 h

Br

-6-

B

'BuLi, Li2CuC14,THF,

T

0 -

35 %from 9

5) BnBr, NaH, THF, "Bu4NI

m. S. 4 A, CH2CI2, -2O"C, 3 h

1) Pd(dppp), LiEt3BH,THF, 5 h, 0°C 2) allylbromide, K2C03,DMF, rt, 8 h 3) pTsOH, MeOH, rt, 8 h - 5 4) (+)-DET, TBHP, Ti(OiPr)4,

9

OMe

T

ei

w

-

2

2.

3

b

E;

3

2

i 7

2 -9 %

-=."

346

6

I

Polyene Cyclization to Adociasulfate 1

1) TBDMSOTf, lutidine, CH2C12, rt, 10 min 2) Pd(PPh3)4,pyrrolidine, MeCN, CHZCI2,40"C, 2 h; CSZCO~, o"C, 6 h 80"C, 6 h 3) PhNTfz, Pd(dppp), "Bu~N, HCOzH, *

4) Hz, Pd/C, THF, rt, 12 h 55 Yo .Li

&OMe TBDMSO

H

?-

HOi

12

MeO>

1) Dess-Martin periodinane, CHpCIz, O'C, 2 h

1) "BuLi, CSz; Mel, THF, -78% 10 h 14

67 YOfrom 12

1) "Bu~NF,THF, 35 C, 32 h

&

H

&

H

l5

.

2) AIBN, "Bu3SnH, toluene, 80°C 20 min

2) 13, hexane/EtzO,-78"C, 90 min

TBDMSO&OMe?,

H

-

2) AcpO, DMAP, CHzCIz, rt, 12 h 3) (NH4)zCe(N03)6,THF, O"C, 1 h: Na~S204,HzO, rt 4) SO3 Py, pyridine, rt, 12 h 5) NaOH, MeOH, 60°C, 12 h 40 Yo

1: adociasulfate 1

Scheme 3. Completion o f the enantioselective total synthesis of adociasulfate 1 (1) by Bogenstatter, Overman, et al., with incorporation o f the (5)-cyclogeranyl unit 13.

binding. However, the natural product did not display in vivo activity, presumably due to the two charged sulfate moieties. The adociasulfates are nevertheless considered to be valuable tools for obtaining further information about kinesin motor functions. Recently, abnormal nuclear displacement caused by adociasulfate 2 (2) provided the first evidence for the occurrence of kinesin like proteins in the unicellular green alga Micrasterias denticulata and suggested their function as force generating motor in postmitotic nuclear migration [Gc]. The synthesis of cell-permeable derivatives would be of particular interest. Scheme 4 gives the endgame from Corey's cyclization product 4 (Scheme 1)to the marine natural product scalarenedial (20, [15]), which is a strong fish feeding deterrent. The Barton-McCombie process [16] was employed to deoxygenate at C3, followed by conversion of the ketone to the vinyl triflate 18 with PhNTfz (McMurry's method [17]). After hydroxydesilylation of 18, the carbonylation to 19 was catalyzed by Pd(dppp) (see above). The vicinal

\F

Polyene Cyclization to Adociasu@te I

oH

I

347

NaO3S0<

OS03Na

16:adociasulfate 5

17: toxicol A

Fig. 2. Hexaprenoid hydroquinones adociasulfate 5 (19) and toxicol A (20). The hexaprenoid skeleton is shown in bold.

4

1.2 eq. CGF~OCSCI, 3 eq. DMAP CH2C12, O'C, 10,95Yo 2. 3 eq. Bu3SnH,0.1 eq. AIBN, benzene, 80"C, 3 h, 94 Yo 3. 2.5 eq. PhNTf2, 1.2 eq. KHMDS, THF, -78"C, 20 min, 90 %

SiMe2Ph

3p 18

0

1.3eq. DIBAL-H,CH2CI2, -78 to -2O"C, 1 h, 95 Yo

* 2.20 eq. DMSO, 10 eq. (COC1)2, 15 eq. EtsN, CH2C12, -5O"C, 1 h, 90 %

19 Scheme 4.

1. 10 eq. BF3 2 HOAc, CHCI3, 5 h; KF, KHC03, THFlMeOH (l:l), H202, O"C, 12 h, 94 Yo 2. 0.1 eq. Pd(OAc)2, 0.1 eq. dppp, CO, 'Pr2NEt, DMF, 65"C, 5 h, 100%

pc H

20

Endgame o f Corey's synthesis o f scalarenedial (20).

aldehyde groups of scalarenedial (20) were generated in two standard steps. Corey et al. synthesized other cyclized terpenoids in a similar manner [ 181. Unlike adociasulfate 1 ( I ) ,which is derived from a C30 building block assembled by headto-tail connection of two CIS sesquiterpenoid units, the key biosynthetic metabolite squalene, precursor of lanosterol and hence the steroids, is based on a head-to-head connection of those building blocks. Every double bond in squalene may be epoxidized (Scheme 5). Several natural products derived not from monoepoxides, but from oligoepoxides of squalene have been isolated from red algae, in particular from Laurencia obtusa. Among them are magireol A (21) and the meso compound teurilene (22), both of which originate from a central tetraepoxide of squalene (Scheme 5). The record is held by glabrescol, from the Caribbean plant Spathelia glabrescens 1191, the precursor of which should be a squalene hexaepoxide. (23) into the squalene Xiong and Corey successfully converted (3R)-2,3-dihydroxysqualene pentaepoxide 25, which was cyclized in the second step to the squalenoid 26, consisting of five contiguous tetrahydrofuran rings, in a yield of 31% (Scheme 5) [20].The epoxidation

348

I

Polyene Cyclization t o Adociasuljafate 7

21: magireol A

22: teurilene

oxone, pH 10.5

xo'::(-&Ox 0'

24

0

0

25

1

CSA !

OH

26

Natural products derived from oligoepoxides o f the key building block squalene (as highlighted). Elegant total synthesis o f the pentakis tetrahydrofuran system 26 by Xiong and Corey.

Scheme 5.

was formally diastereoselective, but in view of the distance of the terminal double bond from the single stereogenic center of 23 it may be regarded as enantioselective. Shi's chiral dioxirane [21], which did the job, was generated in situ from 24 (treatment with oxone) which in turn is derived from fructose. Comparison of 26 with the data for glabrescol indicated that the stereochemistry of the natural product had been incorrectly assigned. Further work revealed that glabrescol should be derived from a squalene with at least one Z double bond. Structure elucidation by total synthesis continues.

References I 349 References 1

Reviews: a) J. K. SUTHERIAND in Comprehensive Organic Synthesis, Vol. 3 (Eds.: B. M. TROST,I. FLEMING), Pergamon Press, Oxford, 1991, 341-377; b) L. F. TIETZE,U. BEIFUSS, Angew. Chem. 1993, 105, 137-170; Angew. Chern. Int. Ed. Engl.

8

9

1993, 32, 131-63.

a) W. S. J O H N S O N , M. B. GRAVESTOCK, B. E. MCCARRY,].Am. Chem. SOC.1971, 93, 4332-4334; b) W. S. JOHNSON, Angew. Chem. 1976, 88, 33-41; Angew. Chem. Int. Ed. Engl. 1976, 15, 9-17. 3 M. BOGENSTAITER, A. LIMBERG, L. E. OVERMAN, et aI.,J. Am. Chem. Soc. 1999, 2

10

11 12

1993, 49, 1871-1878.

BARTON,J. DORCHAK, J. JASZBERENYI, Tetrahedron 1992, 48,

13 D. H. R.

121, 12,206-12,207,

R. SAKOWICZ, M. S. BERDELIS, K. RAY,et al., Science 1998, 280, 292-295. 5 a) C. L. BIACKBURN,C. HOPMANN, R. SAKOWICZ, et al.,]. Org. Chem. 1999, 64, 5565-5570; b) J. A. KALAITZIS, P. D E ALMEIDA LEONE, L. HARRIS,et al., J. Org. Chem. 1999, 53, 5571-5574; c) J. A. KAIAITZIS, R. J. QUINN,J. Nat. Prod. 1999, 62, 1682-1684; d) C. L. BIACKBURN, D. J. FAULKNER, Tetrahedron 2000, 56,

7435-7446.

4

8429-8432. 6 a) L. S.

B. GOLDSTEIN, Trends Cell Biol.

2001, 1 I, 477-482; b) R. L. KARCHER,

7

a) E. J. COREY,G. Luo, L. S. LIN,J. Am. Chem. SOC.1997, 119,9927-9928; b) E. J. COREY,G. Luo, L. S. LIN, Angew. Chem. 1998, 110, 1147-1148; Angew. Chern. Int. Ed. Engl. 1998, 37, 1126-1128. J. BURFEINDT, M. PA=, M. MULLER,et al., 1.Am. Chem. SOC.1998, 120, 3629-3634. M. MOHRI,H. KINOSHITA, K. INOMATA, et al., Chem. Lett. 1985, 451-454. J. M. SAA, M. DOPICO,G. MARTORELL, et al.,]. Org. Chern. 1998, 55, 991-995. K. MORI,M. AMAIKE, M. ITOU,Tetrahedron

14 S. ISAACS, A. HIZI, Y. KASHMAN,

Tetrahedron 1993, 49, 4275-4282. 15 A. RUEDA,E. Z U B ~ A M., ORTEGA,et

al.,

J. Org. Chem. 1997, 62, 1481-1485. 16 D. H. R. BARTON, S. W. MCCOMBIE,]. Chem. SOC.,Perkin Trans. 11975, 1574. 17 J. E. MCMURRY, W. J. SCOTT, Tetrahedron Lett. 1983, 24, 979. 18 P. SCHAEFFER, J. POINSOT,V. HAUKE, et al., Angew. Chem. 1994, 106, 1235-1238; Angew. Chem. Int. Ed. Engl. 1994, 33, 1166-1169.

S. W. DEACON, V. I. GELFAND, Trends Cell Biol. 2002, 12, 21-27; c) A. HOLZINGER, U. LUTZMEINDL, Cell. Biol. Intern. 2002, 26,

19 W. W. HARDING, P. A. LEWIS,H. JACOBS,

689-697.

20

R. J. STEWART, J. P. THALER, L. S. B. GOLDSTEIN, Proc. Natl. Acad. Sci. USA

21

1993, 99, 5209-5213.

et al., Tetrahedron Lett. 1995, 36, 9137-9140.

Z. XIONG,E. J. COREY,].Am. Chem. SOC. 2000, 122,4831-4832.

2.-X. WANG,Y. T u , M. FROHN,et al.,]. Am. Chem. SOC.1997, 119, 11,224-11,235.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Sanglifehrin A an Immunosuppressant Natural Product from Malawi Thomas Lindel

About 20 years ago, the natural product cyclosporin A was discovered. It has revolutionized the practice of organ transplantation, because it prevents rejection of solid organs and bone marrow. In addition, cyclosporin A is frequently used for the treatment of autoimmune diseases. The major problems encountered with the clinical use of cyclosporin A include its toxicity, while it would also be desirable to improve its efficacy against chronic rejection and its immunosuppressive selectivity [l].Cyclosporin A is not only an important drug, but at the same time it allows the exploration of the molecular mechanisms resulting in suppression of immune response. From this perspective, it is extremely important to identify other molecules showing similar, but not identical biological activity. Besides cyclosporin A, the natural products FK50G (tacrolimus) and rapamycin (sirolimus) show comparable effects [I,21. In 1997, scientists at Novartis characterized a novel immunosuppressive natural product from the bacterium Streptomyces Jlaveolus, isolated from soil collected in the East African state of Malawi [3]. The compound, sanglifehrin A (1,Scheme l),was named after its discoverers Sanglier and Fehr. Sanglifehrin A (1)binds strongly (ICso = 2-4 nM) to the intracellular protein cyclophilin, which also mediates the effects of cyclosporin A ( ICso = 82 nM), but not to calcineurin. Despite its greater affinity for cyclophilin, the immunosuppressive effect of sanglifehrin A (1)is about 10 times lower than that of cyclosporin A. Unlike cyclosporin A, sanglifehrin A (1)inhibits the proliferation not only of T cells, but also of B cells (ICso = 90 nM). The structure of sanglifehrin A (1) is characterized by a novel, highly substituted [ 5.51spiro-lactam moiety and a 22-membered, partially peptoid macrocycle, connected by a nine-membered chain. The natural product 1 contains 17 stereogenic centers. There are two complete total syntheses of sanglifehrin A (1):by Nicolaou et al. (1999, [4]) and by Paquette et al. (2001, [S]). They follow very similar overall strategies, as outlined in Scheme 1. The same spirolactam subunit 2, representing C2G to C41 of the natural product 1, is coupled with exactly the same protected macrocyclic moiety 3 in a Stille reaction, forming the bond between C26 and C27. The preceding macrocyclization to the 22-membered ring is achieved either by another Stille coupling between C19 and C20 (Nicolaou et al.) or by lactonization (at C1, Duan and Paquette). Scheme 1 gives the experimental conditions used for the last two synthetic steps. It is apparent that both groups observed low yields in the differently

Sanglifehrin A: an Immunosuppressant Natural Product from Malawi Stille coupling (Nicolaou, Paquette)

1: sanglifehrin A

Nicolaou: 1. Pd,(dba),,

AsPh3, Pr2NEt, DMF, 40"C, 45 %

2.2N H2S04, THF/H,O, rt, 33 %

'I

Paquette: 1. PdC12(MeCN)2, DMF, rt, 40 % 2. ~ T s O H HsBO,, , THF, rt, 30 Yo

Stille macrocyclization (Nicolaou)

2: anti aldol

4:(3:) N,Oketalization rearrangement (Nicolaou) 2

3

Endgame to the immunosuppressive natural product sanglifehrin A (1) from Streptomycespaveolus. Nicolaou et al. and Paquette et al. connect the same building blocks 2 and 3 by Stile coupling reactions, followed by ketal hydrolysis. Strategic connections for the synthesis of 2 and 3 are given (see following Schemes). Scheme 1.

performed Stille couplings (40-45%) and subsequent hydrolyses (30-33%) of the ketal portion originating from 3. The last step was originally performed at Novartis [3a] and was apparently not optimized further. The syntheses of the spirolactam part (C2GC41) of sanglifehrin A (l),outlined in Schemes 2 and 3, is discussed first. Both groups start with a stereoselective syn aldol addition to form the bond between C36 and C37. Nicolaou et al. continue with the connection of C33 and C34 by stereoselective anti aldol addition and stereoselective formation of the C39-C40 bond by an Ireland-Claisen rearrangement. Unlike Nicolaou et al., Duan and Paquette chose the formation of the bond between C32 and C33 as their second key step. The starting materials used by Nicolaou et al. (Scheme 2, above) include 3-pentanone (4), methacrolein, 3-benzyloxypropanal, and propionic acid anhydride, which together account

I

351

I

352

Sanglifehrin A: an Immunosuppressant Natural Productfrom Malawi 1, (+)-lpc2BOTf,iPr2NEt,THF, -78°C;

methacrolein; 30% H202,pH 7, MeOH, 0°C 3

34 0v

2. TESCI, imidazole, CH2C12,0°C

cypBCI, Et3N, Et20 0°C; BnO(CH2)2CH0, -78 to -10°C; *

*

39

74 Yo

w 3 4 TESO 0

LiBH4 72 Yo

5

4

\

1 . (MeOWMe2, CSA, acetone . .2. ('PrC0)20, Et3N, CHpClp ~

B n36

39

TESO

,

+

34 OH OH

3. LDA, TBSCI, THF, -78°C; HMPPJTHF, -78 to 0°C

A 7

6

-

1, toluene, 70°C

2. BHyTHF, THF, -20°C; NaB03, THF/HpO 3. TPAP, NMO, CH2CIp 39 % from 6,ds 60:lO

40

0

Bn Me2AINH2 CHpCI2

0x0

OBn

0

90 Yo 9

8

( + ) - l P c z B ~

1. Hp, Pd(OH)p/C, EtOH 2. D.-M. periodinane, pyr, CHZCIZ * 3. HF/MeCN/H20 (120:i)

11 THF, -78"C, 3 h; NaB03, THF/H20

t

67 Yo, dS 70:30

52 %, single diastereorner

TB -

1. LOA, THF, -78°C;

1 . TBSOTf, 2,6-lutidine, CHpC12, -10 to -25°C 2. 03,Me2S, CH2C12,-78 to 25°C

56 %

H2N

TMSl&N'Bu

yo

13

-78°C to 0°C 2. Hr, Lindlar, MeOH 63 %

1

1

OTBS

NH

"'8)

yh

15

1. TBAF, THF, 45°C 2. NBS, AgN03, acetone 2

3. [Pd2(dba)3]-CHC13.Ph3P, "Bu3SnH 42 %

98 Yo

17 Scheme 2. Synthesis of the spirolactam part (2) of sanglifehrin A (1) by Nicolaou et al,

Sangl3ehrin A: an Immunosuppressant Natural Productfrom Malawi Sn(OTf),, Et3N, CH,CI, then

\

I

353

-78'C;

:

TBDPSO&O 73 %,41dS 9 2 8 37

36

TBDPSOW

19

O

"

36 P

M

B

OH 0 20

18

1. Me4NBH(OAc),, HOAc, MeCN, -25 to 0°C 2. DDQ, rnol. sieves (4 A), CH,CI, 0°C

TBDPSO

1. TESCI, irnidazole, DMF, 50°C

33

*

c

OH 0-0

70 Yo

Q

21

2. DIBAL-H, THF, O'C

3. DMSO, (COCI),, -78"C, Et3N 81 %

OCH,

30% HO ,,

pH 7, MeOH, 0°C 48 %

1. (MeO),CMe,, acetone, PPTS, rt 2. TBAF, THF, rt 3. PivCI, pyr, DMAP, rt 4. TESCI; hnidazole, DMF, 50°C 5. DIBAL-H, CH,CI, -78°C

Me4NBH(OAc)3,HOAc, MeCN, -25 to 0°C

* TMS 6. Dess-Martin periodinane, CH,CI, O'C 7. NaCIO,, NaH,PO,, Me,C=CHMe, tBuOH, HO , 8. CHZN,, EtOAc 67 yo

91 %

PMB' 25

26

1. TBAF, THF

-

D.-M. periodinane, 2. CHpCI, 3. CSA, CH,CI,

26

"1'1

MeOH

74 70,dS 8O:lO Scheme 3.

pMBo 27

1. DDQ, CHzCI,, H20 2. 3. NBS, [Pd2(dba),]-CHC13, AgN03, acetone t

37 NH

2

Ph3P, "Bu,SnH, THF

41

64 Yo

Synthesis of the spirolactam part (2) o f sanglifehrin A (1) by Duan and Paquette.

354

I

Sanglgehrin A: an lmmunosuppressant Natural Product from M a h i

for the C31-C41 fragment. Chain-elongation (C26-C30) is achieved by asymmetric crotyl boration from 4 to 5 [6], by Peterson olefination of the aldehyde 13 [7] with trimethylsilyl aldimine 14, and by Ohira-Bestmann homologation [8] of 15 to 17 with the diazophosphonate 16. The enantioselective aldol addition of the chiral boroenolate of 3-pentanone (4) to methacrolein generates the stereogenic centers C36 and C37. All subsequent steps up to the synthetic intermediate 10 are performed with achiral reagents. Compound 6, with its five contiguous stereogenic centers, is obtained after treatment of 5 with dicyclohexylboron chloride/triethylamine and then with 3-benzyloxypropanal,with subsequent diastereoselective in s i b reduction with lithium borohydride, by a procedure of Paterson and Perkins [9]. The stereogenic center C40 of the synthetic intermediate 8 is generated by Ireland-Claisen rearrangement of the silyl ketene acetal 7, obtained from 6 by a desilylation/acylation/ silylation sequence. The 1,3-diolmoiety of 6 is simultaneously protected as its dioxolane. The Ireland-Claisen rearrangement results in the loss of the stereogenic centers C37 and C38, which are reintroduced by means of a moderately diastereoselective (ds 60:10), substratecontrolled hydroboration of the double bond. Ley oxidation (TPAP/NMO) of the intermediate lactol to the lactone 8 and subsequent amidation (MelAlNHZ, Weinreb method [lo]) afford the amide 9, which is converted into the C37-ketone by debenzylation and Dess-Martin oxidation. A crucial step in the sequence is the spiroketalization to 10, which was obtained in a nearly quantitative yield as a single isomer (favored, not unexpectedly, by about 20 kj.mol-' over its diastereomer). The crotylboration of the spirolactam 10 with Brown's ( Z ) crotylborane 11 generates the two stereogenic centers C31 and C30, but is of limited diastereoselectivity (ds 70:30). After ozonolysis (reductive workup) the aldehyde 13 is obtained, and is treated with the lithio derivative of the silyl aldimine 14 [7], resulting in vinylogization. Five more synthetic steps yield the vinyl stannane 2. Duan and Paquette (Scheme 3, above) assemble 2 from three larger building blocks (18 [ 111, 19 [Sa], and 23 [Sc]),stereoselectively synthesized by the Evans oxazolidinone methodology. Duan and Paquette start with the substrate-controlled aldol addition of the chiral tin(I1) enolate of the ketone 18 to the aldehyde 19, which produces the syn aldol 20 with moderate diastereoselectivity (ds 92%). The configuration at C35 is conveniently induced by the C37-hydroxy-directedreduction of 20 with Me.+NBH(OAc)3, first reported by Evans et al. [12]. Treatment with DDQ does not cleave the PMB protecting group, but gives rise to the intramolecular formation of the acetal 21, which upon reduction does not revert to the starting material, but affords compound 22, with the PMB group on the secondary alcohol function (35-0). Following Paterson et al. [13], the boron enolate of the ketone 23 was added to the aldehyde 22 in an asymmetric aldol addition, generating the stereogenic center at C33. After substrate-controlled, stereoselective ketone reduction at C31 in 24 and several protection and deprotection steps, the ester 26 is obtained and converted into the amide 27 by treatment with MeZAlNH2. One OH group of 27 (at C37) is deprotected, and is conveniently oxidized to the ketone (Dess-Martin). Now, as in Nicolaou's synthesis, the stage is set for the double, intramolecular N,O-ketalization, stereoselectively regenerating the stereogenic information at C37. In contrast to the work of Nicolaou et al., no diastereoselectivity is reported. Conversion of 28 to 2 takes three more standard steps. Schemes 4 and 5 summarize the syntheses of the macrocyclic fragment (3) of sanglifehrin A (1). At the current state of development, Nicolaou's yield for the macrocyclizing Stille reaction (62%) is superior to that of Paquette's macrolactonization (21%). At this point,

Sanglifehrh A: an Immunosuppressant Natural Product from Malawi

25

TES

OTBS 1. CrCl2,CHI,, dioxane/ THF (9:1), 0 to 25°C 2. TBAF, THF, 0 to 25'C

11

3. EDCI, 4-PPy, 'Pr NEt, CHZCIZ, 32Y;0

34

l f l

29

-

'yo'

(+)-lPCzB 1.

I

''Zc

4. (EtO),P(=O)CH,CO,Et, NaH, THF, -78°C to fl 5. DIBAL, THF, -78'C NaBO,, THF/HzO -30°C 2. TBSOTf, 2,6-lutidine, CHzCI, 6. mCPBA,CH& ds 79:21 3. 0,. Sudan 78, CHpClp; PPh3 28 %

cNSBoc !'BOC

MgBr

\

$3

Et,O/THF ( l : l ) ,-40°C

36

TBSO 1. TFA, CHPCIP(111) 2. EDCI, HOAt, 'Pr,NEt, CHzCIz,

66 %

1. PivCI, pyr 5. TPAP, NMO, 2. HF/MeCN/H,O (1:lO:l) mol. sieves (4 A), CHzCIz 3. K,C03, MeOH 6. NaCIO,, NaH2P04,Me,C=CHMe, 4. "Bu3SnH, 'BuOH, HzO [PdCIz(PhCN)z], P(@tOl),, 'Pr,NEt, CH2CIZ, from -2O"Ci 44%

3. TFA, CH,CIz (1:l)

&L./.+KI

I /

OyO "~u,Sn3

33

17 5

15 1 3 14 40 H

30

1. HATU, 'PrzNEt, DMF, rt, 51 % (three steps) 2. Pdz(dba)3,AsPh,, 'Pr,NEt, DMF, rt, 62 %

5 .

Scheme 4.

Synthesis o f t h e rnacrocyclic part (3) of sanglifehrin A (1) by Nicolaou et al.

it should be mentioned that any total synthesis plan must be treated as a hypothesis. The experiments have to be performed. Both groups use the iodovinyl aldehyde 29 [14] as precursor, accounting for the C21LC25 fragment. While Nicolaou et al. assemble the macrocycle starting from 29 "counter-clockwise'' (with reference to the representation of sanglifehrin A as in I), Paquette et al. build it up "clockwise". The Takai olefination [15] of 29 belongs to the lower-yielding steps in the synthesis by Nicolaou et al. (57%). Coupling with the Boc-protected piperazic acid derivative 30 gives the bis-iodovinyl compound 31, which is further elongated to 33 at the less hindered P-NH

355

356

I

Sanglfehrin A: an Immunosuppressant Natural Product from Malawi

0 0 k k ' ( 0 E t ) z Me0

'' 29

LiHMDS, THF, -45°C 2. DIBAL, THF, -78°C 3. MnO,, CHzCIp

'

L 25

C OTBS

H

O

Et20, -78 to -20°C 2. Me4NBH(OAc)3,MeCN,

17

HOAC,-25 to 0°C

39

54 %

50 %

-

1. Phl(OCOCF3)p, CH2CIp 2. NaBH,, THF, HO ,

1

3. D.-M. periodinane, CH,CI,

'us 4. NaCIO,,

NaHZP04, Me2C=CHMe, 'BuOH, HO , 5. TBAF, THF, 0°C 48 %

41

HO& 42

13

1. LiOH, THF,

43

HpO, 0% 2. EDCI, 4-PPy, 10-3 M CH,CI,

&0Boc

c

HATU, 'Pr,NEt, MeCN

3

3. TMSOTf, 2,6-lutidine,

CH,CI,

15 %

67 % b O B , Scheme 5.

44

Synthesis of the macrocyclic part (3) of sanglifehrin A (1) by Paquette et al

group with the dipeptide fragment 32, composed of L-rn-tyrosineand L-valine. In the C13C19 fragment, the stereochemical information is induced by treatment of the TES-protected propargylic aldehyde 34 with Brown's (E)-crotylborane, with no comment as to the stereoselectivity. Two of the newly introduced carbon atoms are retained after ozonolysis. After bishomologation and reduction, the resulting allylic alcohol is epoxidized to 35 with rnCPBA, with only moderate diastereoselectivity (ds 79:21). In the following step, the C51-C54 side chain (see Scheme 1) is introduced by Grignard opening of the epoxide 35. Pivaloyl protection of the primary hydroxy group in 37 and desilylation of the masked secondary hydroxy group (17-OH) allows the favored 1,3-dioxolane to be produced by transketalization. The carboxyl group (C13) of 38 is obtained by a two-step oxidation, first with the Ley reagent and

Sanglifehrin A: an Immunosuppressant Natural Productfrom Malawi

Tab. 1. Strategic data relating to the total syntheses of sanglifehrin A (1). Diastereoselectivities have not been taken into account in calculation of the overall yields. Nicolaou et a/.

Paquette et a/.

Longest Linear Sequence

24 steps, starting from 4

Overall Yield Selected Diastereoselectivities

0.14%, starting from 4 to 8: 60:lO to 12: 70:30 to 35: 79:21 deprotection to 1: 33% Stille coupling (2 and 3): 45% Takai olefination of 29: 57%

25 steps, starting from 18 0.16%, starting from 18 to 20: 92:8 to 28: 80:lO

Worst Yields (Single Steps)

macrolactonization: 21% deprotection to 1: 30% Stille coupling (2 and 3): 40%

then with sodium chlorite. Of the two bonds still missing for the macrocycle, the amide bond is formed first from 33 and 38. Regioselective (!) Stille macrocyclization (DMF, 1 mM) gives 3 in a yield of 62%. Paquette et al. start with the bis-vinylogation of the same compound 29 [14], by WittigHorner reaction, reduction, and oxidation (Scheme 5). For the formation of the C17-ClG bond, the anti-aldol41 (ds not reported) is obtained by treatment of the aldehyde 39 with the (Z)-boronenolate 40, bearing a dithioketal moiety that is later to be the C51-C54 side chain. 3-Hydroxy-assisted,diastereoselective reduction of the keto group at C15 gives 41, which is converted into intermediate 42 in five more steps. The dethioketalization of 41 is achieved with phenyliodine(11 I ) bis(trifluor0acetate) [ 161, As in Nicolaou’s synthesis, the N12-Cl3 amide bond is formed first, followed by a low-yielding (21%, even at a concentration of 1 mM) macrolactonization to 3. Table 1 summarizes the benchmark data of the two total syntheses of sanglifehrin A (1). An alternative, but premature, approach to the C13-Cl9 fragment of sanglifehrin A (1) uses stereocontrolled radical reactions starting from the monosaccharide chiral pool [ 171. The synthesis of structural analogues of the 22-membered, macrocyclic partial structure of sanglifehrin A (1) lacking all stereogenic centers of the C13-Cl9 fragment employs ringclosing metathesis reactions [ 181. Selective chemical transformations can also be performed on the natural product sanglifehrin A (1) itself 1191. It is surprising that C2G-C27 of 1 can be chemoselectively cisdihydroxylated (Sharpless conditions) in a yield of 70%. The natural product can afterwards be reassembled by Julia-Kocienski olefination. The success of this operation indicates that total syntheses of sanglifehrin A (1) alternative to those by Nicolaou et al. and Paquette should be worth pursuing. From the crystal structure of the cyclophilin-sanglifehrin A complex it can be concluded that the peptide portion of the macrocycle is essential for binding. If the spirolactam part (C2G-C27) is cleaved off, the binding affinity of 1 to cyclophilin is only slightly changed. Figure 1 shows the recognition and spacer domains. The structurally simplified compound 45 has been synthesized by Wagner et al. [20]. The C53-deoxo analogue of 1 shows activity similar to that of 1, while deoxygenation at the phenyl position CGl results in a tenfold decrease in activity in the mixed lymphocyte reaction (MLR) and a tenfold decrease in bind-

I

357

358

I

SanglifehrinA: an Immunosuppressant Natural Product from Malawi

spacer domain

OH

45

1: sanglifehrin A Fig. 1. Model macrolide 45 displays an affinity for the intracellular binding protein cyclophilin a thousand times smaller than that of the immunosuppressive natural product sanglifehrin A.

ing affinity to cell-free cyclophilin. The biological activity of the natural product 1 has yet to be surpassed. Studies on the exact mode of action of the unmodified sanglifehrin A (1)by Liu et al. found that 1 inhibits the T cell cycle (G1 phase), mediated by activation of the tumor suppressor gene p53 [21]. Sanglifehrin A (1)is a novel immunosuppressant, which, in addition to CsA, FKSOG, and rapamycin, represents a fourth class of immunophilin-binding metabolites with a new, as yet undefined mechanism of action [22].The structural variation now accessible through total and partial synthesis should contribute to understanding of its biological action on the molecular level.

References 1

F. J. DUMONT,Curr. Opin. Invest. Drugs

2001, 2, 357-363. 2 Reviews: a) J. MANN,Nat. Prod. Rep. 2001, 18, 417-430; b) S. L. SCHREIBER, M. W. ALBERS,E. J. BROWN,Acc. Chem. Res. 1993, 26, 412-420. 3 a) T. FEHR,L. OBERER, V. QUESNIAUX RYITEL,et al., Novartis AG, PCT Int. Appl.

1997, PIXXD2 WO 9702285 A1 19970123. 1998, PIXXDZ WO 9807743 A1 19980226;

b) 7.-J. SANCLIER, V. QUESNIAUX, T. FEHR, et al., J . Antibiot. 1999, 52, 466-473; c) T . FEHR,J. KALLEN, L. OBERER, et al., J. Antibiot. 1999, 52, 474-479; S. J. CLARKE, G. P. MCSTAY,A. P. HALESTRAP,].Bid. Chem. 2002, 277, 34793-34799.

4 a)

K. C. NICOLAOU, J. Xu, F. MURPHY,et

al., Angew. Chem. 1999, I 1 I, 2599-2604; Angew. Chem. Int. Ed. 1999, 38, 2447F. MURPHY,S. 2451; b) K. C. NICOLAOU, BARLUENGA, et al., 1.Am. Chem. SOL 2000, 122, 3830-3838. 5 a) L. A. PAQUETTE, I. KONETZKI,M. DUAN, Tetrahedron Lett. 1999, 40, 7441-7444;

b) M. DUAN,L. A. PAQUEITE,Tetrahedron Lett. 2000, 41, 3789-3792; c) M. DUAN, L. A. P A Q U E ~Angew. E, Chem. 2001, 113, 3744-3748; Angew. Chem. Int. Ed. 2001, 40, 3632-3636; L. A. PAQUETTE, M. DUAN,I. KONETZKI,C. KEMPMANN, J. Am. Chem. SOC.2002, 124, 42574270.

References I 3 5 9 6

7 8

9 10 11

12

13 14

15

a) H. C. BROWN,R. K. DHAR,R. K. BAKSHI,et a]., /. Am. Chem. SOL. 1989, 1 1 1 , 3441-3442; b) I. PATERSON, A. N. HULME, 1.Org. Chem. 1995, 60, 3288-3300. E. J. COREY, D. ENDERS,M. G. BOCK, Tetrahedron Lett. 1976, 17, 7-10. a) S. OHIFS, Synth. Commun. 1989, 19, 561-564; b) S. MULLER, B. LIEPOLD,G. J. ROTH, et al., Synlett 1996, 521-522. I. PATERSON, M. V. PERKINS, Tetrahedron Lett. 1992, 33, 801-804. A. BASHA,M. LIPTON, W. M. WEINREB, Tetrahedron Lett. 1977, 18, 4171-4174. I. PATERSON, M. DONGHI,K. GERLACH, Angew. Chem. 2000, 112,34533457; Angew. Chem. Int. Ed. 2000,39, 3315-3319. D. A. EVANS,K. T. CHAPMAN, E. M. CARREIRA,]. Am. Chem. SOC.1988, 110, 3560. I. PATERSON, J. M. GOODMAN, M. A. LISTER,et al., Tetrahedron 1990, 46, 4663. K. C. NICOIAOU,N. P. KING, M. R. V. FINLAY, et al., Bioorg. Med. Chem. 1999, 7, 665-697. a) K. TAKAI,K. NIITA,K. UTIMOTO,J.Am. Chem. SOC.1986, 108, 7401-7408; b) D. A.

16 17 18

19

20

21

22

EVANS,W. C. BLACK,].Am. Chem. SOL. 1993, 115, 4497-4513. G. STORK,K. ZHAO,Tetrahedron Lett. 1989, 30, 287-290. M. K. CURTAR, S. R. CHAUDHURI, Etrahedron Lett. 2002, 43, 2435-2438. J. WAGNER, L. M. M. CABREJAS, C. E. GROSSMITH, et al., J. Org. Chem. 2000, 65, 9255-9260. a) R. BANTELI,I. BRUN,P. HALL,et al., Tetrahedron Lett. 1999, 40, 2109-2112; b) R. MEITERNICH, D. DENNI,B. THAI, et al., /. Org. Chem. 1999, 64, 9632-9639; c) P. HALL,I. BRUN,D. DENNI,et al., Synlett 2000. 315-318; d) R. BANTELI, J. WAGNER, G. ZENKE,Bioorg. Med. Chem. Lett. 2001, 11, 1609-1612. L. M. M. CABREJAS, S. ROHRBACH, D. WAGNER, et al., Angew. Chem. 1999, 111, 2595-2599; Angew. Chem. Int. Ed. 1999, 38, 2443-2446. a) L.-H. ZHANG,J. 0. LIU,/. Immunol. 2001, 166, 5611-5618; b) L.-H. ZHANG, H.-D. YOUN,J. 0. LIU,]. B i d . Chem. 2001, 276, 43534-43540. G. ZENKE, U. STRITTMATTER, S . FUCHS, et al., J. Immunol. 2001, 166, 71657171.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Short Syntheses o f the Spirotryprostatins

Heterocyclic natural products represent particular challenges to organic synthesis, because a “building block system” of standard reactions often fails. The five so far completed total syntheses of spirotryprostatin €3 (2, Figure 1)described below have been developed by leading groups in the field and outline the difficulties involved when dealing with heterocycles. In 198G, Osada et al. reported the isolation and structure elucidation of the natural products spirotryprostatin A (1)and B (2) from the fermentation broth of the fungus Aspergillus furntgatus [l]. Both alkaloids are derived from the amino acids tryptophan and proline, and each possesses a prenyl side chain (Figure 1). Unlike the diketopiperazine demethoxyfumitremorgen C (3) from the same source organism, 1 and 2 possess a challenging spirooxindole moiety. Compounds 1 and 2 inhibit the cell cycle (G2/M block), with spirotryprostatin B (2) being more potent by about one order of magnitude (ICso 14 pM). Small molecules such as the spirotryprostatins appear especially suitable as lead structures for industrial drug design. They hold the promise that structural variation by synthesis will remain more facile than by genetic engineering. Spirotryprostatin A (1)was synthesized earlier by Edmondson and Danishefsky [ 21. The difference between spirotryprostatins B (2) and A (1)is the absence of the G-methoxy group on the indole ring and - more importantly - the presence of the C8-C9 double bond in spirotryprostatin B. Scheme 1 presents the two approaches used by Wang and Ganesan [ 3 ] and by von Nussbaum and Danishefsky [4], which employ an essentially common intermediate (9/14), with the exception of the different protecting groups. The total synthesis by Wang and Ganesan can hardly be considered complete, because only marginal yields are achieved in the last steps introducing the double bond (Scheme 1).Both syntheses start from L-tryptophan methyl ester (4) and include steps with very low diastereoselectivity,and hence the separation of diastereomers. In two steps, Wang and Ganesan convert 4 first into the aJ-unsaturated imine G and then, by an acyliminium Pictet-Spengler condensation, into the p-carboline 8 (Scheme 1) [ 51. The trans diastereomer was formed as a side product, and had to be separated. Treatment of 8 with NBS in aqueous acetic acid by a procedure described in 1969 by van Tamelen [GI results in the formation of the oxindoline 9 through a spiro ring-contraction. The intermediate bromoniurn ion is generated on the less hindered a-face, in the position opposite to the

Short Syntheses ofthe Spirotryprostatins

1: spirotryprostatin A

2: spirotryprostatin B

3:demethoxyfumitremorgin C

Fig. 1. Secondary metabolites from the fungus Aspergillusfumigatus.

unreactive prenyl side chain. A pinacol-like rearrangement follows, with inversion of the stereogenic center C3 and retention of the rearranging center C18. It should be mentioned that the spiro ring-contraction cannot be applied to every starting material: if the NBS oxidation is applied to the complete diketopiperazine frame of demethoxyfumitremorgen C (3), oxidative cleavage of the CIS-NIO bond predominates and stereochemically undefined spirooxindoles are formed in only small amounts. In the alternative Mannich route to the spiro intermediate 14, the indole ring of 4 is oxidized first. The resulting oxoindoline 11 is then converted by treatment with senecialdehyde (5, “prenal”) into a mixture of four diastereomers of compound 12, which are acetylated, as a mixture, to 14. The two total syntheses differ with respect to the formation of the diketopiperazine structure and the introduction of the C8-C9 double bond of spirotryprostatin B (2), with quite divergent overall yields. Ganesan et al. first cyclize 9 to the spirotryprostatin A analogue 10. After selenylation of 10, the natural product spirotryprostatin B (2) is formed in the marginal yield of only 2%. As the dominant reaction, the hydroxylation of the second diketopiperazine cc-carbon (C12) is observed (20% relative yield). Von Nussbaum and Danishefsky perform the steps in the opposite order. On treatment of 14 with phenylselenyl chloride, the other cc-carbon (C9) is chemoselectively attacked. Oxidation with dimethyldioxirane gives the C8-C9 double bond. Unfortunately, the undesired 3-ent diastereomer of 15 is obtained as the major product and has to be separated chromatographically. As an additional isomer, the product with opposite configurations at C3 and C18 is formed. The ring-closure of 15 to the diketopiperazine is the last step of the total synthesis of spirotryprostatin B (2). It may be of practical importance for further biological studies that 500 mg of the natural product can be obtained in one batch starting from 5.5 g of tryptophan methyl ester (4). Sebahar and Williams published a non-biomimetic approach to spirotryprostatin B (2) [7] (Scheme 2). The key reaction of their sequence is an asymmetric [1,3] dipolar cycloaddition [S] between the oxindolidene acetate 16 and the intermediate azomethine ylide 19. The intermediate 19 is itself generated from the aldehyde 17 and the chiral diphenylmorpholinone 18. The stereochemistry of the spiro compound 20 (82% yield) was confirmed by X-ray analysis. Four contiguous stereogenic centers (C9, C8, C3, C18) are generated simultaneously. After removal of the bibenzyl moiety by hydrogenation it was found that condensation with the benzyl ester of D-proline (21) gave a higher yield than with the L-isomer. It was hoped that the thermodynamically favored, correct stereochemistry of the natural product 2 could be achieved later on by epimerization. After ringclosure to the diketopiperazine

I

361

362

I

Short Syntheses ofthe Spirotryprostatins

Lo

5

1.05 eq. DMSO, 12N HCI, AcOH, 0.05 eq. PhOH, rt, 4h

HCWH/

J

6

'$ 5, NEt3,3 8, sieves, pyridine, rt, 9 h

730 ' from

separation of diastereomers

, pyridine

CH2C12, rt, 8 h 32

from 4

/"

/ 8

'

@$

12

1.2 eq. BOP-CI, CH2CI2, 2.5 eq. NEt3, rt, 2 d 90 %

CO2CH3

9: PG = Fmoc

PG

414: diastereomers PG = B ~ c ,

/ \ 1) 2.2 eq. LiHMDS, THF, O'C, 30 min; 2.2 eq. PhSeCI,

piperidine/CH2CI2, rt, 15 min quant.

diastereomers

J

38 %

&$ 2) 4 eq. DMDO, THF, O'C, 4 h

0

3.8 eq. LDA, -75"C, 40 min;

..............

3.9 eq. PhSeBr, -75'C, 1 h

2

1) TFNCH2Ch rt, 30 min * 2) NEt3, CH2C12, rt, 4 h

2 Yo

\

Boc

/ \

86 %

10 Scheme 1. Biomimetic syntheses o f spirotryprostatin

C02CH3

15

B (2), by Wang

and Canesan (2000) and by von Nussbaum and Danishefsky (2000).

Short Syntheses ofthe Spirotryprostatins

I

363

C02Et 0 Et

16

'Lo OCH3

H

b

p

h

i?"::b,f?_

*

82 %

Ph

OCH3

18

19

17

1) HP,PdC12, THFIEtOH, 60 psi, 36 h

Ph Ph

0 MeCN 3) HP,Pd-C, EtOH 4) BOP, Et3N, MeCN

1 eq. p-TsOH toluene, A

*

/r OCH3

-

85 Y' o

70 % 20

22

1 ) Lil, pyridine, A

NaOMe, MeOH

2) DCC, DMAP, BrCC13, A,

separation of diastereomers

H o - N ~

s 23 Scheme 2.

65 %

25% 24

Total synthesis of spirotryprostatin B (2) by Sebahar and Williams (2000).

22, the prenyl group was formed by elimination of methanol on treatment of 22 with one equivalent of p-TsOH in boiling toluene. The initial [ 1,3] dipolar cycloaddition had resulted in the introduction of the ethoxycarbonyl group at C8, which now had to be removed. It was found that the ethyl ester of 23 could be hydrolyzed by LiI in boiling pyridine, but not by, for example, LiOH in THF/water. Among the possible conditions for the decarboxylation, the Barton version of the Hunsdiecker reaction proved to be optimal [9]. The C12 epimer 24 of spirotryprostatin B (2) was formed in a yield of 40% and was converted into the natural product in a yield of 65%, again making the separation of diastereomers necessary. A domino total synthesis of spirotryprostatin B (2) and three of its isomers has been published by Overman and Rosen, who apply two sequential palladium-catalyzed reactions (one-pot) to assemble the two spiro-fused rings [lo] (Scheme 3). This work again makes it clear that complex heterocyclic systems may represent a harder challenge to synthetic

*

2

364

I

Short Syntheses of the Spirotryprostatins

'1 r-OTBDPS

25

Meozc\

1. LiOH 2. TBDPSCI 78 % 3. 2-iodoaniline, 1-Me9-CCpyridinium iodide

1. CO, [Pd(dppf)Clz], MeOH 2. 2-iodoaniline, AIMe3 3. SEMCI. NaH

74 %

32

SEM I . N V o T B D p s 33

1. SEMCI, NaH

1. TBAF 2. DMSO, (COC1)2, NEt3 3. 27, KOtBu, [18]crown-6

71 %

3. DMP

(MeO)zOP

1

27

SEM\ N

O

18

&IF

20

34

I

0.2 eq [Pd2(dba)3]-CHC13, R-BINAP, PMP. DMA, IOO'C

0.1 eq [Pd2(dba)3]-CHC13, 72 % P(o-tol)3, KOAc, THF, 66'C

29

/ 30 Scheme 3.

\

o

6: 1

1 31

:1 36

Total synthesis of spirotryprostatin 8 (2) by Overman and Rosen (2000). The products 30, 31, 36,and 37 are deprotected with MezAlCIl'Pr2NEt in 90-95% yields.

37

Short Syntheses ofthe Spirotryprostatins

methodology - Pd chemistry in this case - than large acetogenins. Scheme 3 gives the last steps of two approaches that were carried out to gain access to all stereoisomers with the common 12s absolute configuration and also to establish the then unknown stereochemistry of the natural product. Two precursors 28 and 34, differing in the geometry of the C3-Cl8 internal double bond, were synthesized by independent routes. From the beginning, it was not clear which stereochemistry would be obtained in the spiro-fused products 30, 31, 36, and 37, because in the second reaction step the nitrogen nucleophile might attack v n or anti to the metal center of the q3-allylpalladium complexes 29 and 35. The experiments had to be performed. The first Heck cyclizations, forming the oxindole systems, proceeded in a 5-exo manner, regioselectively generating the assumed intermediates 29 and 35. In the case of 29, diastereoselectivity (G:l, total yield only 28%) a preference for 30 over 31 could be achieved, since it was possible to use (R)-BINAPas a chiral ligand. The synthesis of the intermediate 35 was only successful when the achiral P(o-tol)3 and KOAc as base were used, providing a 1:l mixture of SEM-protected spirotryprostatin B (36) and its 3,lS-bis-epi isomer 37 in the satisfying yield of 72%. Apparently, the C3-Cl8 double bond isomerizes on heating in dimethylacetamide, because the identical product 30 is formed on exposure of 34 to the same reaction conditions as used for its double bond isomer 28. Overman's strategy for the stereoselective build-up of the quaternary spiro center and its neighboring stereogenic centers is novel. For the first time it was demonstrated that Heck insertions of conjugated trienes can be regioselective and that the reaction between diketopiperazine nitrogen atoms and q3-allylpalladium intermediates occurs with anti selectivity. Spirotryprostatin B (2) was obtained in a total yield of 976, over ten isolated intermediates starting from methyl acrylate and 3-methyl-2-butenal (not shown), again including separation of diastereomers. The worst step, until conditions are found to carry it out enantioselectively, is the final cascade reaction (3G% per diastereomer). A key advantage of the Overman/Rosen approach is that the difficult introduction of the C8-C9 double bond by functionalization of C9, as employed by the other groups, is circumvented. The most recent synthesis of spirotryprostatin B (2) has been developed by Fuji et al. (Scheme 4) and starts from the chiral oxindole 38, obtained by asymmetric nitroolefination [I11 of the indole 3-position [12]. After conversion to the aldehyde 39 by treatment with TiC13, in situ hydrolysis, and further Strecker synthesis, the protected amino acid 40 is obtained. Double N-deprotection and attachment of the proline unit yields 41. The three-step introduction of the hydroxy group into the prenyl side chain, affording 42, follows a procedure developed by Sharpless [13]. An allylic carbocation is formed on exposure to p-TsOH and undergoes nucleophilic attack by the neighboring amide nitrogen atom. Since the earlier Strecker reaction was not carried out in an enantioselective manner, two spirocyclic diastereomers are now formed, of which only 43 has the correct spirotryprostatin B (2) stereochemistry. Compound 43 is obtained in a yield of only 24%, because the reaction was stopped after 50% conversion due to increasing loss of the Boc group. Compound 43 is identical to the intermediate used by von Nussbaum and Danishefsky. Fuji et al. also reproduce the endgame to 2 (21%). Of the five completed total syntheses of spirotryprostatin B (2), four struggle with the introduction of the C8-C9 double bond and all of them include steps of very low diastereoselectivity. It is unusual for the biological activity of natural products to be surpassed by synthetic

I

365

KNoZ 4 366

I

Short Syntheses ofthe Spirotryprostatins

MeOH/H20 TiCh aq, NH40Ac, (4:1), rt, 3 h r 55 Yo

/

\

/

\ 39

30

i:~

~

~rt* ~

c

3. CbZCI, Et3N, CHpCIp, rt, 12 h 4. K2C03, MeOH, rt, 6 h 5. HCI (1N), rt, 30 min

~

$

40

38 Yo

1. Pd black, 5 O h HCOpH

COPMe

0

-

2. in CHzCIp, KBoc-L-proline, MeOH,1220h minEDCI,

1. mCPBA, CHpCIp, O'C, 6h 2. PhSeSePh, NaBH4, MeOH, 65-C, 10 h

&3
/

\

I

69 %

3. Hp02 (30%), THF, O'C, 6 h

O

85 Yo

41

1. LiHMDS, THF, O'C, 30 min; PhSeCI, THF, O'C, 2 h 2. DMDO, THF, OaC4 h

pTsOH, MeCN, lOO'C, 25 rnin

- 2 3. HCI (4N) in dioxan, O'C, 30 rnin 4. Et3N, CH2C12, 4 h

t

24 Yo SeDaration of diastereomers

42 Scheme 4.

43

21 %

Total synthesis of spirotryprostatin B (2) by Fuji et al. (2002).

analogues (Figure 2). Danishefsky et al. were fortunate in finding a few synthetic intermediates with higher biological activity than the natural products themselves [ 2b]. Replacement of the prenyl group by a benzyloxymethyl group gives compounds 44,45, and 46, with a 5000-fold higher cytotoxicity than spirotryprostatins A (1)and B (2). The IC50 of compound 46, which additionally lacks the proline part of the diketopiperazine unit and possesses only the spirooxindole moiety, is surprisingly low (2.lo-' M against the MDA MB-4G8 breast cancer cell line). The relative stereochemistry at the C 3 and C18 centers of compounds 44 and 45 has hardly any influence on their cytotoxicity.

44

45

Analogues o f the spirotryprostatins from Danishefsky's synthetic program, with cytotoxicities 5000 times higher than those of the natural products. Fig. 2.

46

~

v

References I 3 6 7

References 1 a) C.-B. CUI, H. KAKEYA, H. OSADA, ].

Antibiot. 1996, 49, 832-835; b) C.-B. CUI, H. KAKEYA,H. OSADA,Tetrahedron 1996, 52, 12,651-12,666. 2 a) S. D. EDMONDSON,S. J. DANISHEFSKY, Angew. Chem. 1998, 110, 1190-1193; b) S. EDMONDSON, S . J. DANISHEFSKY, L. SEPPLORENZINO, et al.,]. Am. Chem. Soc. 1999, 121, 2147-2155; Angew. Chem. Znt. Ed. Engl. 1998, 37, 1138-1140. 3 H. WANG,A. GANESAN,].Org. Chem. 2000, 65, 4685-4693. 4 F. V O N NUSSBAUM, S. J. DANISHEFSKY, Angew. Chem. 2000, 112, 2259-2262; Angew. Chem. Int. Ed. 2000, 39, 21752178. 5 See the synthesis of demethoxyfumitremorgen C: H. WANG, A. GANESAN, Tetrahedron Lett. 1997, 38, 4327-4328.

6

7 8 9

10

11

12 13

E. E. VAN TAMELEN, J. P. YARDLEY,M. MIYANO,et al., ]. Am. Chem. SOC.1969, 91, 7333-7341. P. R. SEBAHAR, R. M. WILLIAMS,].Am. Chem. SOC.2000, 122, 5666-5667. For a review, see: K. V. GOTHELF.K. A. J O R G E N S E N , Chem. Rev. 1998, 98, 863-909. D. H. R. BARTON,D. CRICH,W. B. MOTHERWELL, Tetrahedron 1985, 41, 3901. L. E. OVERMAN, M. D. ROSEN,Angew. Chem. 2000, 112,4768-4771; Angew. Chem. Znt. Ed. 2000, 39,4596-4599. a) K. FUJI,T. KAWABATA, T. OHMORI, et al., Synlett 1995, 367; b) K. FUJI, T. KAWABATA. T. OHMORI,et al., Heterocycles 1998, 47, 951. T. D. BAGUL,G. LAKSHMAIAH, T. KAWABATA, et al., Org. Lett. 2002, 4, 249-251. K. B. SHARPLESS, R. F. L A U E R ,Am. ~. Chem. SOC.1973, 95, 2697-2699.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

The Chemical Total Synthesis o f Proteins Oliver Seitz Introduction

The incredible amount of sequence data being produced by the different genome projects is revealing the primary structures of thousands of new proteins. It is one of the foremost challenges of the “post genome era” to unravel the functions of these newly discovered protein molecules. Understanding of the molecular details of protein function is particularly important for the development of diagnostically or therapeutically active agents. In the acquisition of knowledge about the “active residues”, the most useful approaches have proven to be systematic variation of the target protein at defined positions and protein crystallography. In the last two decades, modified proteins were predominantly produced by making use of recombinant DNA techniques, which enabled molecular biologists to modify cells genetically. The variability of a protein generated by biosynthesis is limited, however, and, with a few exceptions, restricted to the exchange of the 21 proteinogenic amino acids. In contrast, chemical synthesis allows for the introduction of almost any kind of modification, both in the protein backbone and in the protein side chains. The chemical total synthesis of proteins, even of small proteins, is a tedious and by no means trivial enterprise. The following consideration might give some idea of the difficulties associated with the synthesis of a protein molecule. At present, solid-phase synthesis, introduced by the pioneering work of Merrifield, is the most powerful method for the synthesis of small to medium-sized peptides (5-50 amino acids). The solid-phase approach relies on iterative steps involving coupling of a N-protected amino acid building block with a polymer-bound amino acid- or peptidenucleophile and subsequent removal of the amino-protecting group. In order to obtain a theoretical overall yield of 90%, each coupling step of a linear synthesis of a 100-mer peptide must proceed with 99.9% yield. With a coupling/deprotection yield of 97%, a yield that would honor any preparative chemist, a 100-mer would be obtained in only 5% overall yield. It is not only the low yields that complicate the solid-phase synthesis of large peptides but also the need for an intricate purification procedure. The desired protein, produced in 5% yield, requires to be separated from 95% of formed by-products, a task difficult to accomplish even by modern separation techniques. Convergent methods avoid the “cumulative disaster” of linear synthesis. Access to large peptides can be provided by use of medium-sized peptide segments, easily available by solidphase synthesis. There are two distinct approaches. One involves the synthesis and puri-

Chemoselective Ligation of Unprotected Peptide Fragments

fication of protected peptide fragments to be joined in a fragment condensation strategy. Collected data indicate that protected peptides often show poor solubility in commonly used solvents, thereby complicating both purification and usage in peptide couplings. It adds to the difficulties that fragment couplings of the relatively unreactive segments suffer from undesired racemization of the activated amino acid. As a solution to these problems, protein chemists have developed new techniques based on the ligation of water-soluble unprotected peptide segments. In view of the multitude of functional groups present in an unprotected peptide (see Scheme l),it seems hopeless that a selective peptide bond formation could be feasible. Over the last 10 years, however, dramatic progress has been achieved in this field and it is now possible to obtain proteins made up of up to 200 amino acids by chemical protein synthesis. The current state of the chemical synthesis of proteins is presented here. It should be emphasized that this article focuses on fragment ligation techniques. The examples presented in the following sections have been selected with the aim of outlining some principles of current synthetic methodology and serving for instructive purposes rather than comprehensiveness. For more detailed information the reader is referred to some excellent review articles [ 1-71.

N-terminal fragment

H

C-terminal fragment

OH

J

chemo- and regioselective ligation

COOH

H

OH

Scheme 1. Fragment ligation o f two unprotected peptide segments.

Chemoselective Ligation of Unprotected Peptide Fragments

The ligation of two unprotected peptides is a challenging problem to the synthetic chemist (Scheme 1). The solubility of unprotected segments decreases with increasing molecular weight, and productive encounters between the reactive ends become less likely to occur. In order to compensate, the rate constant of the bimolecular reaction must be high. Despite

I

369

370

I

The Chemical Total Synthesis of Proteins

such high reactivity, though, the presence of the many potentially reactive functional groups must be tolerated. Reactions that meet these demands of chemoselectivity are classified into two categories, involving the formation of peptidic and non-peptidic bonds. Formation of Non-peptidic Bonds

Selective conjugation can be achieved by the introduction of functional groups not normally present in biopolymers 181. Figure 1 shows a selection of reactions for which the required chemoselectivity has been demonstrated. For example, the reaction between a thiocarboxylate and a bromoacetyl group proceeds at pH 5-6 without concomitant alkylation of the thiol groups of the cysteine side chains (Figure 1, entry A). As a trade-off for the high chemoselectivity, an alteration of the natural peptide backbone has to be accepted. Given that the ligation site has been carefully selected, proteins normally tolerate small structural alterations, particularly when introduced within flexible loop regions. As early as 1992 Schnolzer and Kent demonstrated that a synthetic HIV-1 protease, produced by the thioester-forming ligation of a 51-mer peptide-thiocarboxylate with a 48-mer bromoacetyl peptide, exhibited a proteolytic activity equal to that of the natural protein [ 91. The formed thioesters are sensitive to hydrolysis at pH values over 7, but alkylation of thiol groups furnishes ligation products of high stability. Under aqueous conditions, thiol groups selectively react with bromoacetyl or maleoylimido groups by forming thioethers (Figure 1, entries B and C). Rau and Hahnel made use of this reaction for the synthesis of a de novo designed cytochrome b model made up of 122 amino acids 110, 111. Following Mutter’s TASP (template-assembled synthetic protein) concept [ 121, four N-terminally bromoacetylated peptide helices were attached to a structured cyclopeptide template that contained four cysteine thiol groups. An illustrative example showing how biotechnology and chemical synthesis can be combined is shown in Scheme 2. An E. Coli-based expression system was used to produce a truncated version of the oncogenic H-Ras G12V protein 1, which serves as a central switch in the signal transduction cascade [13]. The omission of the C-terminal octapeptide segment, which normally anchors two lipid moieties and governs the insertion into the cell membrane, rendered the truncated protein biologically inactive. Restoration of H-Ras activity was achieved by appending the synthetic maleoylimide-modified lipoheptapeptide 2, which selectively reacted with the C-terminal cysteine side chain of the H-Ras protein 1. A highly chemoselective ligation of unprotected peptide segments can be accomplished by use of aldehyde and keto groups, which react with hydroxylamines, hydrazides, and phenylhydrazides to form oximes, semicarbazones, and hydrazones (Figure 1, entries D, E, and F) [ 14-16]. The reaction with 1,2-aminothiols, as present in N-terminal cysteine, furnishes thiazolidines (Figure 1, entry G, see also Scheme G). Particularly attractive is the orchestrated use of orthogonal conjugation techniques, as illustrated in Scheme 3. For the total synthesis of a 20 kDa transcription factor, Canne and co-workers combined thioester ligation with an oxime-forming ligation [ 171. The goal was to link the transcription factors cMyc and Max covalently and to study the DNA-binding of the resulting conjugate. Firstly, the N-terminal segments of the cMyc- (4) and Max-proteins (5) were synthesized in the forms of the thiocarboxylates. In preparation for the oxime-ligation, the C-terminus of the C-terminal cMycsegment was fitted with a hydroxylamino group (6-7). A keto group was introduced at the

Chemoselective Ligation of Unprotected Peptide Fragments

N-terminal fragment

C-terminal fragment

I

371

ligation product

0

0 R A S 7 w

0

B

RH S ,

C

RS ,H

0

D

R

R

1

R"

RA , . O . R

0

E

R

KR.

R

H

y R'

H

RAN.NyR

HzN"

0

0

"""q.. '9r H

F

R

iH

R-

R

N=N

0

0

G

Fig. 1.

R

1,

H2N

R"

H

Examples of chemoselective ligation partners.

C-terminal Max-segment by attaching a levolinic acid group at a lysine side chain (6+9), and segments 7 and 9 were equipped with N-terminal bromoacetyl groups required for the thioester ligation. Upon thioester ligation, the cMyc-segments 4 and 8 were joined together (Scheme 4),as were the Max-segments 5 and 10. The final condensation of the formed cMyc- and Maxproteins 11 and 12 proceeded chemoselectively under weakly acidic conditions (pH 4.7), providing the desired oxime 13 in 21% overall yield (based on 10).

Chemoselective Ligation of Unprotected Peptide Fragments

0 Solid phase synthesis 4

I

H N

BOC

CIZ-HN . 0 2 0 S ~ J

--

----)

CO-MBHA

5

6

HzN (CH~COCH~CHZCO)~~

BOC

0

CIZ-HN ‘

>&I4

iY Co-MBHA 4

a) TFA

Scheme 3.

Solid-phase synthesis o f brornoacetylated peptide fragments containing either an oxirne group (8, 10% overall yield) or a levulyl group (10, 14% overall yield).

strategy (Scheme 5, 16+17) [19].The process commenced with the synthesis of a templated peptide ester such as the dibenzofuran ester 16. This template contains a mercapto group, which captures the N-terminal cysteine of the segment to be coupled. After formation of the disulfide, it is possible to induce an O+N-acyl transfer, which effects the coupling of the two unprotected segments. An elegant means of pursuing a chemoselective peptide bond-forming reaction can be achieved by taking advantage of integral structural elements of the peptide. In this approach it is the peptide itself that aligns the reactive ends, thereby avoiding the need for specially designed template molecules. The thiol group of an N-terminal cysteine offers a suitable combination of functional groups. An additional advantage is that the 1,2-aminothiol structure is not normally present in proteins, which facilitates specific “targeting” of this entity. Liu and Tam developed a ligation method that produces a pseudoproline structure (Scheme 6 ) [20]. The carboxylic acid ester of glycolaldehyde 18 reacts with the 1,2-aminothiol com-

I

373

374

I

The Chemical Total Synthesis of Proteins

8

S-

+ 4

+

Br

Br

O

1

I

0.1 M NaH2P04, 8M urea, pH 4.7, 4"C, 24h

0

5

0.1M NaH2P04, 8M urea, pH 4.7, 4"C, 24h

0.1 M NaH2P04,

12

peptide 4) S

21%

0

0

0

0 13

= N-terminal fragment of the cMyc protein

(peptide)

= C-terminal fragment of the Max protein

= Gterminal fragment of the cMyc protein

(peptide)

= Kterminal fragment of the Max protein

Scheme 4. Convergent chemical ligation for the chemical synthesis o f the transcription factor-related protein conjugate cMyc-Max 13.

pound 19 to form the thiazolidinyl ester 20. This sets the stage for a subsequent O+N-acyl shift, which transfers the acyl group to the secondary amino group of the thiazolidine ring. As the net result, the amide-linked conjugate 21 is formed. The application of this method allowed the synthesis of a modified HIV-1 protease through the joining of an unprotected 38-mer with a deblocked GO-mer. At present, it appears that the most powerful method for the coupling of two unprotected peptide segments is the "Native Chemical Ligation (NCL)" developed by Dawson and Kent [21]. As indicated by its name, NCL gives rise to the formation of a natural peptide bond. This reaction was described in principle as early as 1953, by Wieland, who reported that the reaction between the (S)-valinethiophenyl ester 22 and cysteine 23 proceeded by transfer of

Chemoselective Ligation of Unprotected Peptide Fragments

DMSO d

16

I

HO

17

Brenner’s “Acyleinlagerung” ( 1 4 i l 5 ) and Kemp’s thiolcapture strategy (16-17) as examples of template-assisted fragment condensations.

Scheme 5.

0

0

18 0

HS

20

0

Scheme 6.

0

The thiaproline ligation.

the valyl group to the thiol side chain (Scheme 7, Ar-Ph) [22].This thiol exchange is the rate-limiting step. The formed (S)-valyl-cysteine24 underwent a spontaneous S-N-acyl shift, thereby forming the dipeptide 25. Dawson and Kent perfected this methodology and developed a highly efficient technique for the ligation of large, unprotected peptide seg-

I

375

376

I

The Chemical Total Synthesis of Proteins

1

thiol exchange

intramolecular acyI transfer

Wieland: R = Val; R' = OH

0

Kent: R = 30mer-peptide; R' = 18mer-peptide

SH

25 Scheme 7.

Native Chemical Ligation.

ments. Since their landmark paper in 1994, the NCL has allowed the synthesis of numerous proteins. Several recent reviews give an idea of the tremendous impact the development of the NCL has had on protein chemistry [2, 4, 61. The application of solid-phase synthesis techniques enables rapid and efficient total synthesis of a desired protein molecule. In analogy to convergent solid-phase peptide synthesis, in which protected peptide fragments are coupled to polymer-bound peptides, fragment condensation can be accomplished by employing the NCL coupling strategy, with the advantage that unprotected peptides of higher solubility can be used [ 231. The choice of solid support is a key issue for the success of NCL-mediated solid-phase fragment condensations. Conventional polystyrene-based resins were optimized for the linear Merrifield synthesis in organic solvents and show limited swelling properties in aqueous media. It is therefore advantageous to attach the unprotected peptides to a water-swellable polymer such as agarose. Dawson and co-workers have presented a powerful approach [ 241. The synthesis of a 71-mer peptide was begun by using the resin-bound mercaptopropionic acid amide 26, known as the TAMPAL (trityl-associated mercaptopropionic acid leucine) support, for the assembly of the peptide thioester 27 and segments 30 and 32 (Scheme 8). During the subsequent attachment of thioester 27 to the cysteine-functionalized agarose resin it was essential to block the N-terminal cysteine with an acetamidomethyl (Acm) protecting group in order to avoid undesired oligomerization reactions. The C-terminal end of peptide thioester 28 was anchored through the SCAL (safety-catch acid-labile) linker [25]. This safety-catch anchor is stable during all protecting group manipulations performed during a protein synthesis, but is rendered acid-labile upon SiCl4-mediated reduction of the sulfonyl groups (see inset in Scheme 8). Treatment with Hg(r1) salts removed the Acm protecting group, thereby

Chemoselective Ligation of Unprotected Peptide Fragments

I

377

a) Boc-SPPS b) HF .--.t

Ttt-S H

H2N

SCAL-Gly2-S H

26

0

HzN

Hg(0Ac)2, pH

SCAL-Glyz-Cys

H2N

29

SCAL-Gly,-Cys

SCH2NHCOCH3

28

E - SR

H-CyS I

30

Acm

pH 7, 2% BnSH

Acm

J.

31

pH 7,2% BnSH

33

\S

0

RCO-SCAL

0

1 M TiCI4 TFA, 0°C

SiCl.,

1

TFA

0

= polystyrene resin

R-CONH2

Scheme 8. Solid-phase synthesis of a 71-mer vMIP-1 protein segment 3 4 (Acrn, acetamidomethyl; BnSH, benzyl mercaptan; Boc-SPPS, solidphase peptide synthesis by t h e Boc strategy).

= agarose resin

-0

378

I

The Chemical

Total Synthesis of Proteins

preparing resin-bound segment 29 for the NCL with peptide 30. This procedure was repeated for the introduction of fragment 32. The final detachment of the 71-mer peptide 34 was accomplished by reduction of the SCAL-sulfonyl groups in 33 and subsequent TFA treatment. By using the convergent strategy elaborated by Dawson and co-workers, the total synthesis of a protein can be accomplished within a few days, with the additional advantage of being automatable. The concept of NCL has recently been applied in the synthesis of selenocysteinecontaining proteins [26-28]. The rate-limiting step in NCL is the thiol exchange, which is induced by the attack of a cysteine thiolate. The pK, value of selenols is lower than that of thiols. Since selenolates are also more nucleophilic than thiolates, it was expected that selenocysteine should provide more rapid NCL than cysteine, especially at low pH. Indeed, kinetic analysis of the model reaction shown in Scheme 9 revealed that at pH 5 the reaction with the selenocysteine 36 is lo3 times faster than with cysteine [26]. It might therefore prove possible to combine cysteine- and selenocysteine-mediated NCL in the ligation of three segments, omitting the need for the employment of protecting groups.

yk,,

0

s. Ar

+

0

35

HzNYoo-

H-Se

36

J

coo0

37

intramolecular acyl transfer

38 Scheme 9.

Native Chemical Ligation with selenocysteine 36

Extending the Applicability of Native Chemical Ligation

The high chemoselectivity of NCL relies upon the distinct reactivity of an N-terminal cysteine. The requirement for cysteine at the ligation, however, restricts the applicability of NCL. It is possible to subject the ligation product to desulfurization, resulting in the net formation of a more commonly found X-Ala bond [ 291. The presence of cysteines other than that needed for ligation is not tolerated, however, since desulfurization would occur at both protected and unprotected cysteine thiols.

Chemoselective Ligation of Unprotected Peptide Fragments

In order to extend the principles of NCL to allow connection of any peptide fragment at ligation sites other than X-Cys, it is necessary to introduce an auxiliary containing a thiol group (Scheme 10). Canne and co-workers appended N-oxyethanethiol groups at the amino groups of glycine and alanine (43in Scheme 10)[30].In these cases NCL proceeded through a six-membered transition state and the rate of product formation was low. As a result, only the sterically less demanding Gly-Ala- or X-Gly-bonds were formed in significant yields. The N-oxyethanethiolgroups were reductively removed by treatment with Zn dust, furnishing an auxiliary-freepeptide. Canne and co-workers also investigated the use of N-(2-mercaptoethyl) groups 44 [301.This auxiliary showed useful rates of amide bond formation, but its subsequent removal was not possible. Offer and Dawson suggested the use of N-mercaptobenzylpeptides such as 45 [ 311. The mercaptobenzyl auxiliary allowed chemoselective ligations at Gly-Gly, Gly-Ala, and Ala-Gly sites, although cleavage of the benzyl amide was not demonstrated. The authors proposed to induce cleavability by attaching electron-donating substituents to the phenyl ring. Indeed, the 4,5-dimethoxy-2-mercaptobenzyl amide 46 can be cleaved with strong acids such as TFMSA in TFA, as shown by Aimoto and co-workers [32]. The groups of Botti and Kent [33] and of Dawson [34]drew on a similar principle and 2-mercapto-l-phenylethyl)-group 47 as a removable auxiliary. The effecintroduced the N-( 0

H

0

SH

39

40

HS

L i

auxiliary-mediated coupling

HS.X

removal

HS-X

43

Zn, AcOH

44

none

45

none

46

TFMSA. TFA

0

O

R

41

J

auxiliary removal

Me0

Jy OMe

O

R

42 Scheme 10. Auxiliaries for Native Chemical Ligation without cysteine (TFMSA, trifluorornethane sulfonic acid).

47

I

379

380

I

The Chemical Total Synthesis of Proteins

tiveness of this moiety was demonstrated in the total synthesis of cytochrome b562 (54),a 106-mer metalloprotein (Scheme 11) 1351. To arm a peptide segment with the 2-mercapto-lphenylethyl group, a resin-bound bromoacetyl peptide 48 is allowed to react with phenylethylamine 49, with subsequent acid cleavage. The 1-phenyl substitution in 50 gives a benzyl amine that is stable under the acidic conditions required for detaching peptide 51 from the solid phase. In the ligation event, the secondary amino group is converted into a tertiary amide group (51+53), which renders the benzyl protecting group acid-labile. The degree of acid-lability can be fine-tuned by altering the substitution pattern on the phenyl ring. For example, the presence of an additional methoxy group in the 2’,4’-dimethoxy-substituted auxiliary 47 induced lability towards weaker acids such as TFA.

PG

H

Br

0

s OMe

PG

~

I

50

48

2

-

R

HN

2% PhSH, pH 7, 5mM peptide

53

Scheme 11.

S

OMe

51

The phenylethyl auxiliary in the total synthesis of cytochrome b562 (54)

New Peptide Bondforming Reactions

So far, the methods that have been shown to enable chemoselective peptide bond formation have relied upon the particular reactivity between thioesters and aminothiols. Almost simultaneously, Raines [36] and Bertozzi [ 3 7 ] reported a new method for the formation of a peptide bond with high chemoselectivity: the so-called Staudinger ligation. This reaction had

Chemoselective Ligation of Unprotected Peptide Fragments

already been used by Bertozzi (381 in order to modify cell surfaces and represents a strategy applied by Goff and Zuckermann [39] in a benzodiazepinedione synthesis. The key feature is a Staudinger reaction between the phosphine 55 and the azide 56 (Scheme 12). An azaylide intermediate 57 is formed, and normally is subjected to hydrolysis in order to obtain the amine, together with the phosphine oxide as by-product. In the Staudinger ligation, the aza-ylide structure in 57 is located in a position y or 6 to the activated carboxyl group, thereby aligning the functional groups so that an intramolecular 0 - N - or S-iN-acyl transfer is facilitated. As a result, the ligation product 58 can form by ejecting the phosphine oxide 59. Various phosphinoesters 55 have been evaluated. When examining the acetylation of azidoadenine, Saxon, Armstrong, and Bertozzi noted that the use of the phenol 55b gave higher product yields than the use of thiophenol 55a [37]. Recently, Raines demonstrated an efficient variation in which the phosphinomethanethiol 55c mediated a high-yielding Staudinger ligation [40]. It should be emphasized that azido-amino acids are easy to prepare. The Staudinger ligation could therefore become a viable alternative to Native Chemical Ligation, provided that its general utility is demonstrated.

55

Ac-Phe-S

56

PPh2

+

35%

N3CH2CONHBn NH2 I

8

Ac-0

55b

PPh2 N

95%

+ OH

Ac-Phe-S

PPh2

+

N3CH2CONHBn

55c Scheme 12.

The Staudinger ligation.

92%

I

381

382

I

The Chemical Total Synthesis of Proteins

Conclusion

The examples presented illustrate that the chemical total synthesis of proteins is not only possible, but also workable. Large unprotected peptide fragments can be joined with high chemoselectivity by forming oximes, hydrazones, thioesters, or thioethers. As long as the ligation site has been carefully selected, proteins can tolerate small structural alterations, particularly when introduced within flexible loop regions. The need to select suitable loop regions can be circumvented by employing ligation strategies that allow the chemoselective formation of natural peptide bonds, thereby widening the scope of protein synthesis. At present it appears that the “Native Chemical Ligation” (NCL) developed by Dawson and Kent is the most powerful method for such a fragment condensation of two unprotected peptide segments. The requirement for cysteine at the ligation site, however, restricts the applicability of this technique. It is in this field that the development of new peptide bond-forming reactions is rapidly progressing. One promising example has been demonstrated with the use of a phenylethylamine auxiliary in the synthesis of cytochrome b562. The Staudinger ligation is an interesting reaction with the potential to be applicable to any kind of ligation site. However, neither its scope nor its limitations have been described yet, and Native Chemical Ligation therefore remains the most versatile and reliable means for synthesizing proteins by fragment ligation. Numerous proteins have already been synthesized, and it is no exaggeration to state that chemical synthesis has the potential to give a new impetus to the study of protein function and protein modification. References

J. P. TAM,Q. T. Yu, 2.W. MIAO, Biopolymers 1999, 51, 311-332. 2 G. G. KOCHENDOERFER, S . B. H. KENT, C u r . Opin. Chem. Biol. 1999, 3, 665671. 3 G. J. COITON,T. W. MUIR,Chem. Biol. 1999, 6, R247-R256. 4 J. A. BORGIA, G. B. FIELDS, Trends BiotechnoL 2000, 18, 243-251. 5 D. M. COLTART, Tetrahedron 2000, 56, 3449-3491. 6 P. E. DAWSON, S. B. H. KENT,Annu. Rev. Biochem. 2000, 69, 923-960. 7 S. AIMOTO,Cur. Org. Chem. 2001, 5, 45-87. 8 G. A. LEMIEUX,C. R. BERTOZZI, Trends Biotechnol. 1998, 16, 506-513. 9 M. SCHNOLZER, S. B. H. KENT,Science 1992, 256, 221-225. 10 H. K. RAU,W. HAEHNEL, J . Am. Chem. SOC.1998, 120,468-476. 11 H. K. RAU, H. SNIGUIA,A. STRUCK, et a1 Eur. J . Biochem. 2001, 268, 3284-3295. 12 M. MUTTER,S. VUILLEUMIER, Angew. Chem. Int. Ed. 1989, 28, 535-554. 1

B. BADER, K. KUHN, D. J. OWEN,et al., Nature 2000, 403, 223-226. 14 H. F. GAERTNER, K. ROSE,R. COTTON,et al., Bioconjugate Chem. 1992, 3, 262-268. 15 K. ROSE,J . Am. Chem. SOC. 1994, 116, 30-33. 16 H. F. GAERTNER, R. E. OFFORD, R. COTTON,et al., J . Biol. Chem. 1994, 269, 7224-7230. 17 L. E. CANNE, A. R. FERR~-D’AMARB, S. K. BURLEY, et al., J . Am. Chem. SOC.1995, 11 7, 2998-3007. 18 M. BRENNER,J. P. ZIMMERMANN, J. WEHRMULLER, et al., Experientia 1955, 11, 397-399. 19 D. S. KEMP,R. I. CAREY,].Org. Chem. 1993, 58, 2216-2222. 20 C. F. LIU, C. RAO,J. P. TAM,]. Am. Chem. SOC. 1996, 118, 307-312. 21 P. E. DAWSON, T. W. MUIR,I. CIARKLEWIS, et al., Science 1994, 266, 776-779. 22 T. WIELAND, E. BOKELMANN, L. BAUER,et al., Ann. Chem. 1953, 583, 129-149. 23 L. E. CANNE, P. B O T ~ IR. , J. S I M O Net , al., ]. Am. Chem. SOC.1999, 121,8720-8727. 13

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27 28 29 30 31 32

A. BRIK,E. KEINAN,P. E. DAWSON, J. Org. Chem. 2000, 65, 3829-3835. M. PATEK,M. LEBL,Tetrahedron Lett. 1991, 32, 3891-3894. R. J. HONDAL,B. L. NILSSON,R. T. RAINES,J. Am. Chem. SOC.2001, 123, 5140-5 141. M. D. GIESELMAN, L. L. XIE, W. A. VAN D E R DONK,Org. Lett. 2001, 3, 1331-1334. R. QUADERER, A. SEWING,D. HILVERT, Hela. Chim. Acta 2001. 84, 1197-1206. L. 2. YAN, P. E. DAWSON,].Am. Chem. SOC.2001, 123, 526-533. L. E. CANNE,S. J. BARK,S. B. H. KENT,]. Am. Chem. Soc. 1996, 118, 5891-5896. J , OFFER,P. E. DAWSON,Org. Lett. 2000, 2, 23-26. T. KAWAKAMI, K. AKAJI,S. AIMOTO,Org. Lett. 2001, 3, 1403-1405.

33

34 35

36 37

38 39 40

P. BOTTI, M. R. CARRASCO, S. B. H. KENT,Tetrahedron Lett. 2001, 42, 18311833. C. MARINZI,S. J. BARK,J. OFFER,et al., Bioorg. Med. Chem. 2001, 9, 2323-2328. D. W. Low, M. G . HILL,M. R. CARRASCO, et al., Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 6554-6559. B. L. NILSSON,L. L. KIESSLING, R. T. RAINES,Org. Lett. 2000, 2, 1939-1941. E. SAXON,J. I. ARMSTRONG, C. R. BERTOZZI,Org. Lett. 2000, 2, 21412143. E. SAXON,C. R. BERTOZZI,Science 2000, 287, 2007-2010. D. A. GOFF,R. N. ZUCKERMANN, ]. Org. Chem. 1995, 60, 5744-5745. B. L. NILSSON,L. L. KIESSLING, R. T. RAINES,Org. Lett. 2001, 3, 9-12.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Solid-Phase Synthesis of Oligosaccharides Ulf Diederichsen and Thomas Wagner

While automated solid-phase synthesis of peptides and oligonucleotides is well established, the preparation of oligosaccharides on solid support still remains challenging. The first two biooligomer families are based on linear backbones and are composed of monomers that differ only in their side chains or nucleobases, and no formation of a stereogenic center is involved in the coupling step. Oligosaccharides, in contrast, are usually branched, since sugar units with varying functionalization are linked at different positions, in a linear or branched manner, and with alternating stereochemistry. The advantages of solid-phase chemistry, such as the improvement of yield made possible by the use of excess of reagents, or the separation of reactants and side products, should also be of interest in oligosaccharide synthesis. Important for a successful oligosaccharide solidphase synthesis are the choice of the appropriate resin and linker, a suitable protecting group strategy, and the provision of a high-yielding, stereospecific coupling reaction. The sugar donor or acceptor can be applied either as the resin-bound component, or in excess as the reagent. The detection of successful coupling on solid support is of particular importance for the development of a solid-phase synthesis. Coupling of oligosaccharides remains more difficult to analyze than chain-elongation of peptides or oligonucleotides, because the coupling yield can not be determined simply from the concentration of cleaved protecting groups. In addition, the newly established stereocenter has to be considered. The use of enzymes for coupling of sugar units on solid support is especially valuable for control of regioselectivity and stereochemistry. Some further examples of promising approaches towards the solid-phase synthesis of oligosaccharides are reported in [ 11. Trichloroacetimidatesas Sugar Donors

Trichloroacetimidates are widely used in oligosaccharide syntheses as anomeric leaving groups. They can also be applied under solid-phase conditions when the acceptor is attached to the resin. Glucose is bound to the solid support by functionalization of the anomeric center with a propanedithiol linker [ 2 ] . (l,G)-Glycosylationis achieved by selective deprotection of the primary hydroxyl group and coupling of the obtained polymer-bound acceptor 1

Tn'chloroacetirnidates as Sugar Donors

rp

S : & .Q + BnO

BnO

Donor (2)

+

BnO H 0 BnO

S

s

Y

S

BnO

O Y N H CCI,

Acceptor (1)

TMSOTf (0.2 eq.) CH2CI2,r.t.,1 h

- P

BnO Fig. 1. 1,6-Clycosylation with a glucose acceptor attached t o a polymer support (P = solid support) and a trichloroacetimidate donor.

with the trichloroacetimidate donor 2 (Figure 1). In the absence of neighboring group participation a 1:l mixture of anomers is obtained, which might be useful for combinatorial approaches. Linear oligosaccharides are produced by multiple repetition of the glycosylation step. Monitoring of the progressing solid-phase synthesis is achieved by partial cleavage of small samples from the resin and analysis by MALDI-TOF mass spectrometry. Controlledpore glass (CPG),well established in oligonucleotide chemistry, can be used as an inert solid support to avoid problems with different swelling behavior according to solvent and temperature [ 31. Trichloroacetimidates are similarly used for CI-( 1,2)-mannoside oligomerization, with an CIdiastereoselectivity arising from neighboring group participation [4]. The synthesis of mannosyl pentamer 3 with trichloroacetimidates was chosen to introduce a new alternative regarding the solid support (Figure 2) [S]. The anomeric center of the mannopyranosyl trichloroacetimidate donor 4 is attached to the polyethylene glycol-wmonomethyl ether (MPEG) through an cc,cc'-dioxyxylyl (DOX) diether linker and can be elongated by subsequent reaction cycles. With this resin, the advantages of coupling in homogeneous solution are thus combined with the separation of reagents by filtration, since the resin is soluble in CHzClz under glycosylation conditions and can be precipitated with ethanol [GI. Furthermore, analytical methods such as NMR spectroscopy and mass spectrometry can easily be applied [ 71. Solid-phase synthesis of branched oligosaccharides requires a specific protecting group strategy [8]. This is shown by the synthesis of branched lacto-N-neohexanose, occurring in human milk (Figure 3). The oligosaccharide is constructed by sequential glycosylation of trichloroacetimidates: starting with the resin-bound lactosyl donor 5, elongation of the saccharide with lactosamine G is followed by branching with glucosamine 7. Finally, attachment of galactose 8 provides the branched hexasaccharide [ 91.

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Hy* HO BnO

*oG : Donor (4)

O Y N H

I'

H HO F

q

CCI,

H k HO * t

*

HF*oH HO

0-DOX-MPEG

3

Fig. 2. Application of the polyethylene glycol-w-monomethyl ether (MPEC) solid support with an cc,cc'-dioxyxylyl (DOX) diether linker for oligosaccharide synthesis in solution.

At this point it may be mentioned that the use of different protecting group strategies has recently enabled numerous linkers to be synthesized [ 101, and automated syntheses of longer oligosaccharides performed [ 111. Oligosaccharide Synthesis with Clycosyl Phosphates

Together with trichloroacetimidates, glycosyl phosphates have proven to be easily availabie and effective glycosyl donors. The driving force in the phosphate activation is considered to be the stoichiometric release of silyl phosphate, initiated by addition of TMSOTf. The acceptor is generated by cleavage of the respective silyl protecting group with tetrabutylammonium fluoride (TBAF). As an example, the /?(l,G)-linked triglycoside 10 was synthesized on solid support with octenediol as a linker (Figure 4). This allows the release of the trisaccharide 11 simply by cross metathesis with Grubbs' catalyst [ 121. Glycosyl phosphates have also been applied in automated solid-phase synthesis, enabling the first automated synthesis of a branched oligosaccharide on a peptide synthesizer [ 131. As regards other anomeric leaving groups, further progress has been obtained with the recently published DISAL (methyl dinitrosalicylate) group, which allows Lewis acidpromoted glycosylations [ 141. Solid-phase oligosaccharide synthesis conditions have also been applied with analogues based on azasugars [15].

Solid-Phase Synthesis of Carbohydrate Libraries

AcO AcO OAc AcO

OAc OAc

OAc

Lacto-N-neohexanose

AcO

OAc

NDMM FmocO

AcO ~

o yOAcc c l .

+

+

OBn

NH

8

7

'n? /

6 Fig. 3.

OLev OBn

5

Retrosynthesis o f the branched lacto-N-neohexanose occurring in human milk.

Solid-Phase Synthesis of Carbohydrate Libraries

Glycosylation conditions are highly sensitive to structural differences in the glycosyl donors and acceptors, which is a particular problem in combinatorial chemistry; glycosylation methods with reliable yields and stereochemistry would be required. In this regard, glycosylation with anomeric sulfoxides is especially remarkable [ 161. Sulfoxide glycosyl donors are activated between -30 and -78 "C, to couple in nearly quantitative yield to sugar acceptors attached to a Merrifield resin. It is even possible to achieve stereochemical control, through participation by a neighboring C2 protecting group (Figure 5). The benzyl-protected glycosyl sulfoxide 12 is activated with trifluoromethanesulfonic acid and treated with a suspension of the polymer-bound sugar acceptor 13 in CHIC12 to yield disaccharide 14 with high Mselectivity. The yield can be increased by repeated coupling, an important advantage of solidphase syntheses. The high reactivity at low temperatures, even with a secondary alcohol, is remarkable and most probably due to the low polarity of reagents and resin. The completely protected pentapivaloyl galactosyl sulfoxide 15 yields the P-configured disaccharide 16 thanks to neighboring group participation in the coupling step. Overall, this approach allows access

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6,

p

I . TBAF 2. TMSOTf

TIPSOY

BnO 10

BnO

OPiv

TIPSO

V

11 Fig. 4. Synthesis o f a tetrasaccharide with glycosyl phosphates as sugar donors; cleavage of the oligomer from solid support by Crubbs' cross-metathesis.

both to the c( and to the p anomer, ensuring high yields even with less reactive acceptors in the heterogeneous environment of the solid support. New resins more suitable for the preparation of libraries have recently been reported [ 171. Polystyrylboronic acid can be prepared with high loading capacity; even more importantly, a solvent mixture of acetone and water can be used to reduced the amount of impurities after the cleavage step. Polystyrylboronic acid has proven to be especially useful for coupling of thioglycosides, for which trichloroacetimidates give only modest results. Orthogonal Clycosylation

In the oligosaccharide syntheses described so far, the glycosyl acceptors have been attached to the solid phase. In a second approach, the glycosyl donor is linked to the solid support

Orthogonal Clycosylation

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Bno@OBn OBn BnO

OBn

12

BnO

*

14

phT*s. p

N3

PivO

13

PivO

Ph

15 Fig. 5.

OPiv

N3

OPiv

s’

16

Clycosylation with anorneric sulfoxides as donors for an efficient and stereocontrolled synthesis.

[18]. The problems with this strategy are the accumulation of poorly separable side products on the resin and the need to activate the anomeric position before each coupling step. Orthogonal glycosylation and exclusively hydrophobic labeling of the desired sequence are used to overcome these problems (Figure 6). Orthogonal glycosylation is based on the alternating coupling of a thioglycoside 17 under Suzuki conditions ([ Cp2HfC12]-AgOS02CF3/ CH2C12) and a glycosyl fluoride 18 with MeOS02CF3and MeSSMe in CH2C12. The different reaction conditions ensure stepwise single glycoside coupling. Furthermore, there is no need for activation of the anomeric center by use of additional reagents. Hydrophobic labeling is provided by linkage of 2-(trimethylsily1)ethyl(SE) glycoside 19 in the final step, which facilitates the isolation of the desired oligomer 20. Subsequent conversion of the SE residue to a trichloroacetimidate is possible.

/ p

P

$;o q MeOSO,CF, MeSSMe

O ’

SMe

Fig. 6. Orthogonal glycosylation: the glycosyl donor is attached t o the solid support; alternating coupling with a thioglycoside and a glycosyl fluoride acceptor.

P

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Glycals in the Solid-Phase Synthesis of Oligosaccharides

In general, polymer-bound glycals are versatile building blocks that also offer interesting constitutional and configurational alternatives in oligosaccharide synthesis [ 191. This method provides the donor linked to the resin and needing to be activated for each coupling step. Side reactions are reduced by hydrolysis of the activated intermediates. Activation of the glycals, to generate appropriate donors, can be achieved either by epoxidation with 2,2dimethyldioxirane or by aminoglycosylation (Figure 7). Glycal 21, linked to a polystyrene support, is first oxidized to the epoxide 22, which then is opened in the presence of ZnClz by the glycal acceptor 23. This elongation step diastereoselectively yields the /3 anomer 24. Simultaneously, an oligosaccharide with a /I(1,6)-linkage and a new secondary hydroxyl group with further /I-galactosylacceptor reactivity is established. The glycal method therefore appears especially useful for the preparation of branched oligosaccharides. Donor activation by aminoglycosylation allows the simultaneous formation of /I(1,3)-, /I 1,4)-, ( or p( 1,6)-linked oligosaccharides and the introduction of a /I-amino functionality, OH

0’

0’

CHzCIz

21

24

Aminoglycosylation

P

P

P’ BnO& BnO

0’

0’ I(coll)zcIo, PhSOflH, I

-

LHDMS, EtSH, DMF

*

BnO 26

25

BnO

I

NHSOQh

NHSOPh

27 MeOTf,

Ten

0’

I

B 0n -0- BnO

BnO NHSOQh

Fig. 7.

BnO I

28

Activation o f resin-bound glycals by epoxidation followed by ring-opening or aminoglycosylation.

Enzyme-Catalyzed Solid-Phase Synthesis of Oligosaccharides

I

often found in oligonucleotides at position C2 [20]. The polymer-bound glycal 25 is treated with I( Coll)2C104 and PhSOzNHz to generate the diaxial iodosulfonamide 26, which rearranges after substitution with ethanethiolate to give the glycosyl donor 27. The b(1,4)linkage is selectively formed with glycal 28 in high yield. Furthermore, the glycal strategy is advantageous as the reductive end can easily be functionalized. N-Glycoproteins can be obtained if tetrabutylammonium azide is used instead of ethanethiolate in the aminoglycosylation. After reduction to the b-aminal, peptides can be attached via the side chain of the aspartic acid. Finally, the glycal strategy has been used to develop an analytical method for the characterization of reaction products and intermediates during oligosaccharide synthesis on solid support without the need to cleave small samples from the resin [21]. High-resolution magic-angle spinning (HR-MAS) N M R spectroscopy provides a line-width sufficient for the characterization of a trisaccharide glycal. The synthesis is performed on a polystyrene resin, which allows a high loading density. The constitution and configuration of the resin-bound oligosaccharide are confirmed by ‘H and 13C NMR and HMQC N M R correlation spectra. Enzyme-Catalyzed Solid-Phase Synthesis of Oligosaccharides

The combination of solid-phase synthesis and enzymatic catalysis still remains a challenge in the preparation of oligosaccharides [22]. The major advantages of enzymatic glycosylations are their high regio- and stereoselectivities, as well as the possibility of working without protecting groups. Possible problems arise from the limited availability of substrates and enzymes, the high substrate-specificity of enzymes, and compatibility with the solid support. The kind of polymer and its properties in aqueous solvents are as crucial as the linkage of the first saccharide unit and its enzyme accessibility. Furthermore, there seems to be an optimal loading density of the resin in order to obtain good yields from enzymatic conversions [22e]. As an example, the enzymatic elongation of glycopeptide 29 (tripeptide Boc-Asp-GlyPhe-OH with N-acetyl-D-glucosamine(GlcNAc) connected to the Asp-side chain) linked to a silica gel matrix is presented (Figure 8) [ 22al. A glycine heptapeptide functions as a linker, to which the glycopeptide is bound as an ester. Uridine 5’-diphosphogalactose (UDP-Gal) and ~-1,4-galactosyltransferase are applied for the elongation of the GlcNAc unit by one galactosyl monomer. In a second cycle, cytidine 5’-monophospho-N-acetylneuraminic acid (CMP-Neu-Ac)and a-2,3-sialyltransferase proved to be suitable to attach a neuraminic acid unit to disaccharide 30. Both enzymatic glycosylation steps are performed with satisfying yields and selectivities. Finally, glycopeptide 31 is released by cleavage of 32 with achymotrypsin. With a( 1,4)-galactosyltransferase (LgtC), an oligosaccharide with a &-a( 1-4) linkage, usually difficult to obtain, can be prepared chemoenzymatically on solid support (Figure 9) [ 231. A lactosyl derivative attached to a poly(ethy1ene glycol) support through a dioxyxylene linker (33) can be stereoselectivelylinked to a galactosyl donor to form the problematic cis linkage. The advantage of a stereoselective enzymatic reaction is combined with simple purification methods. This chemoenzymatic synthesis afford the resin-bound trisaccharide 34, which is of special interest because of its potential binding to verotoxin-1 [24]. Further progress has recently been reported in the fields of solid supports in chemoenzymatic synthesis [22, 251 and of the use of enzyme-labile linker groups for the prepara-

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,)i,

BocNH

~

HOHO

7iJo7

NH-(Gly),-NH-Silica

NH

O

NHAc

H

O

W

:

&

o

i

&

29

'0"

H

YO NH

AcNH

HO HO

bH

NHAc

OH

YO NH

AcNH OH

Fig. 8. Enzymatic glycosylation i n the solid-phase synthesis of oligosaccharides: elongation of the glycopeptide with /J'-1 ,4-galactosyltransferase and a-2,3-sialyltransferase. The glycopeptide i s finally released by cleavage with wchymotrypsin.

tion of oligosaccharides [ 261. However, it remains uncertain whether the availability and the applicability of enzymes can keep up with the large diversity of synthetic problems in oligosaccharide synthesis. The use of enzymes in solid-phase synthesis opens a viable and efficient alternative to well known classical procedures and adds to the arsenal of synthetic methods.

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Solid-Phase Synthesis of Oligosaccharides Synlett 1999, 1802-1804; d) SeleniumH. J. based linker: K. C. NICOLAOU, MITCHELL, K. C. FYLAKTAKIDOU, et al., Angew. Chem. 2000, 112, 1089-1093; e) Y. NAKAI, Ether-type linker: K. FUKASE, K. EGUSA,et al., Synlett 1999, 1074-1078. X. W u , M. GRATHWOHL, R. R. SCHMIDT, Org. Lett. 2001, 3, 747-750; f ) Wang-type Y. NAKAHARA, Y. ITO, linker: S. MANABE, Synlett 2000, 1241-1244. S . MANABE, Y. ITO, Chem. Pharm. Bull. 2001, 49, 1234-1235; g) Amine-type linker: N. DRINNAN,M. L. WEST,M. BROADHURST, et al., Tetrahedron Lett. 2001, 42, 11591162. 1 1 a) J. RADEMANN, R. R. S C H M I D T ,Org. ~.

12

13

14 15 16

17

18

Chem. 1997, 62, 3650-3653; b) L. G. MELEAN, W.-C. HAASE,P. SEEBERGER, Tetrahedron Lett. 2000, 41, 4329-4333; c) 0. J. PLANTE,E. R. PALMACCI, P. H . Science 2001, 291, 1523SEEBERGER, 1527. a) R. B. ANDRADE, 0. J. PLANTE,L. G. MELEAN, et al., Org. Lett. 1999, I , 18111814; b) for general review see: E. R. PALMACCI, 0. J. PLANTE,P. H. SEEBERGER, Eur. J. Org. Chem. 2002, 595-606. a) M. C. HEWITT,P. H. S E E B E R G E ROrg. ,~. Chem. 2001, 66,4233-4243; b) M. C. HEWITT,P. H . SEEBERGER, Org. Lett. 2001, M. C. 3, 3699-3702; c) E. R. PALMACCI, Angew. Chem. HEWITT,P. H . SEEBERGER, 2001, 113, 4565-4569. L. PETERSEN, K. J . JENSEN,J.Chem. Soc., Perkin Trans. 12001, 2175-2182. B. RUITENS,J.VAN D E R EYCKEN, Tetrahedron Lett. 2002, 43, 2215-2221. a) R. LIANG,L. YAN,J. LOEBACH, et al., Science 1996, 274, 1520-2522; b) L. YAN, C. M. TAYLOR, R. GOODNOW, JR., et al., J. Am. Chem. SOC.1994, 116, 6953-6954; c) D. KAHNE,Curr. Opin. Chem. Biol. 1997; 1, 130-135. a) G. BELOGI,T. ZHU, G.-J. BOONS,Tetrahedron Lett. 2000, 41, 6965-6968; b) G . BELOGI,7.ZHU, G.-J. BOONS,Tetrahedron Lett. 2000, 41, 6969-6972. a) Y. ITO, 0. KANIE,T. OGAWA,Angew. Chem. 1996, 108, 2510-2512; b) 0. KANIE, Y. ITO,T. OGAWA,].Am. Chem. SOC.1994, 116, 12,073-12,074.

19 a) S. J.DANISHEFSKY, K. F. MCCLURE, J. T.

RANDOLPH,et al., Science, 1993, 260, 1307-1309; b) J. T. RANDOLPH, K. F. MCCLURE,S. J. DANISHEFSKY, /. Am. Chem. SOC.1995, 117, 5712-5719; c) P. H. SEEBERGER, S. J. DANISHEFSKY, Acc. Chem. Res. 1998, 31, 685-695; d) S. J. DANISHEFSKY, M. T. BILODEAU, Angew. Chem. 1996, 108, 1380-1419; e ) P. H . SEEBERGER, M. T . BILODEAU, S. J. DANISHEFSKY, Aldrichimica Acta 1997, 30, 75-92; f ) C . Z H E N G ,P. H . SEEBERGER, S. J. DANISHEFSKY, /. Org. Chem. 1998, 63, 1126-1130. 20 C. ZHENG,P. H . SEEBERGER, S. J. DANISHEFSKY, Angew. Chem. 1998, 110, 786-789. 21 P. H . SEEBERGER, X. BEEBE,G. D. SUKENICK, et al., Angew. Chem. 1997, 109, 491-493. 22 a) M. SCHUSTER, P. WANG,J. C. PAULSON, et al.,J. A m . Chem. SOC.1994, 116, 1135H. HUANG,C.-H. 1136; b) R. L. HALCOMB, WONG,J. Am. Chem. SOC.1994, 116, 11,315-11,322; c) S.-I. NISHIMURA, K. MATSUOKA, Y. C. LEE, Tetrahedron Lett. 1994, 35, 5657-5660; d) S.-I. NISHIMURA, K. B. LEE, K. MATSUOKA, et a]., Biochem. Biophys. Res. Commun. 1994, 199, 249254; e) K. YAMADA,E. FUJITA,S.-I. NISHIMURA, Carbohydrate Res. 1998, 305, 443-461; f ) M. MELDAL,F.-I. AUZANNEAU, 0. HINDSGAUL, et al.,J. Chem. SOC.Chem. Commun. 1994, 1849-1850; g) N. BRINKM A N NM. , MALISSARD, M. RAMUZ,et al., Bioorg. Med. Chem. Lett. 2001, 11, 25032506; h) for a review of enzymes in glycoL. L. KIESSLING, biology, see C. R. BERTOZZI, Science 2001, 291, 2357-2364. 23 F. YAN,M.GILBERT, W. W. WAKARCHUK, et al., Org. Lett. 2001, 3, 3265-3268. 24 a) P. I. KITOV,J. M. SADOWSKA, G. MULVEY, et al., Nature 2000, 403, 669; b) E. FAN,E. A. MERRITT,C. L. M. J. VERLINDE, et al., J. Curr. Opin. Struct. Biol. 2000, 10, 680-686. 25 S. NISHIGUCHI, K. YAMADA, Y. FUJI,et al., Chem. Commun. 2001, 1944-1945. 26 For general review, see R. REENTS,D. A. JEYARAJ, H . WALDMANN, Advan. Synth. Catal. 2001, 343, 501-513.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I395

Polymer-Supported Synthesis o f Non-Oligomeric Natural Products Stefan Sommer, Rolf Breinbauer, and Herbert Waldrnann

Introduction

The continued quest for new medicines to cure discomfort and diseases coupled with man’s intrinsic curiosity to reveal nature’s hidden secrets provide a powerful motivation for research in the life sciences. The last decades have produced a tremendous gain in understanding the cell at its molecular level, which has led to the identification of a great number of new biological targets (in most cases proteins), that are involved in numerous diseases, including cancer, Alzheimer’s disease, AIDS, and heart failure. In order to cure these diseases new drugs, preferentially small organic molecules, are needed which inhibit or promote the target’s biological function and, in the ideal case, avoid side effects with perfect selectivity [ 11. The chemists’ solution for these demands is combinatorial chemistry, which has become an invaluable tool to meet this challenge. Solid-phase synthesis techniques applied either in a parallel fashion in automated synthesis or in split-pool-synthesis enable the rapid production of compound libraries containing thousands of members. But the original expectation that new hits will be discovered solely by the creation of a large quantity of library members was not fulfilled. Some of the libraries contained hardly any hit, because the underlying structures therein were not biologically relevant. Thus an old question returned Where in the almost indefinite space of thinkable chemical compounds are the structures which are of biological relevance [2]? Natural products have been identified as the active principle of herbs and extracts used in folk medicine [ 11. The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 50G) or derivatives thereof [ 31. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. Despite this proven record of biological significance there had been some doubts if natural products are suitable and accessible lead structures for combinatorial libraries by solid-phase synthesis. In contrast to the diversity-oriented approach of library design, which is driven by the underlying chemistry of reliable reactions with broad substrate scope [4], natural product

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library synthesis requires multi-step sequences requiring careful optimisation, which ultimately lead to the chosen target structure (focused library). This extra-mile in synthetic effort should be rewarded by a higher hit rate in biological screens and what would be even more significant: biologically validated hits. Recent results of protein sequencing, structural biology and bioinformatics have revealed an interesting pattern. Proteins can be regarded as modularly built biomolecules assembled from individual building blocks. These building blocks are called ‘domains’, parts of the proteins that fold independently from the rest of the structure to a compact arrangement of secondary structures and that are connected via linker peptides [S]. Although the estimate for the number of different proteins in humans range between 100,000 and 450,000, there is a common agreement that the number of domains and - even more - of topologically distinct folds will be much smaller. At present approximately 600 folds are known [ 6 ] ,and it is estimated that the number of existing folds are between 600 and 8000 distinct folds, and 4000-GOO00 sequence families [7]. Up to the present day it is unknown if the limited number of folds is due to physico-chemical constraints on stable folds or a result of the evolutionary process which has not fully explored all possible sequence combinations. Natural products have been selected by evolution to bind to these distinct protein domains. Considering that the small molecule has been biosynthesized by enzymes and that it exerts its biological function by addressing a specific target protein, most natural products have interactions with at least two different proteins. Considering that nature uses these protein domains for different biological purposes over and over again, there is a significant probability that natural products are privileged structures [ 8 ] . This term has been coined by medicinal chemists for small molecule scaffolds which bind to several proteins but with different biological functions [ 91. Benzodiazepines are a foremost example for such structures. Based on these assumptions one can reason why one should not only synthesise the natural product itself but a library thereof: the fine-tuning of substituents and variation of the molecular framework will allow for the requirements of different binding pockets and the desired selectivity to distinguish between similar protein domains. Additionally, it should be taken into account that natural products which are descended from marine or tropical sources are not optimised by nature for human cells, i.e. the fine work for getting better selectivity and less side reactions is due to pharmacological and combinatorial chemistry. Paramount to the success of this approach is that efficient and reliable methods and multistep sequences for the total synthesis of natural products and analogues thereof on polymeric supports are available. The corresponding transformations must proceed with a degree of selectivity and robustness typical of related classical solution phase transformations, irrespective of the stringencies and differing demands imposed by the anchoring to the polymeric support. Only recently the progress in solid-phase synthesis has met the demands of the intrinsic complexity of natural product library synthesis on solid support [lo]. The aim of this chapter is to describe the different approaches followed in this science and to highlight these with notable examples demonstrating the current state of the art. Solid-Phase Synthesis o f Natural Products

Two strategies have emerged for the synthesis of natural-product-like libraries on solid. The first involves building the entire core structure on solid support, a very challenging proposi-

Solid-Phase Synthesis of Natural Products

tion, since it often requires a multi-step synthesis applying a large range of organic reactions and often leads to the demand for the development of new methods. However, it allows maximum diversity in the core structure (e.g. ring size, chain length), by both variation of stereochemistry as well as the introduction and derivatisation of functional groups. In the second approach, a natural product skeleton is immobilised onto a solid support to facilitate installation of diversity. While the scaffold remains unchanged, building blocks are attached to already existing functional groups. Therefore, the core structure must already be validated by the biological target and the precursor molecule should be easily accessible either from natural sources, degradation chemistry or solution phase total synthesis. Furthermore, an appropriate site on the scaffold for attachment onto solid support must be identified to facilitate reliable loading and release, as well as installation of the most possible structural diversity. While the second strategy provides the advantage that nearly each step on solid support leads to diversification, the first one often requires considerable effort just to build up the scaffold. Modification of Core Structures

For building up a library around a given core structure many examples have been given, e.g. an Indolactam library by Waldmann et al. [ll],a Sarcodictyin-basedlibrary by Nicoloau et al. [ 121 and a Taxoid library by Xiao et al. [ 131

R3

Sarcodictyin - library

Indolactam - library

OBz

OAc

Taxoid - library Fig. 1. Examples of natural product libraries by modification of core structures

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Polymer-Supported Synthesis of Non-Oligomeric Natural Products

A recent example for this strategy is the combinatorial synthesis of macrolide analogues based on Erythromycin A by Akritopoulou-Zanze et al. which is outlined below [ 141. Erythromycin A is an important antibiotic used for the treatment of gram-positive bacteria; however, it is partially deactivated in the stomach due to the strongly acidic conditions. As a result, efforts have been made to improve the acid stability and hence increase the bioavailability by means of combinatorial chemistry. The synthesis by Akritopoulou-Zanze et al. is the first synthesis of a macrolide library on solid support (Scheme 1). The precursor molecule 1 was made in solution employing a 6-step synthetic sequence starting from 6-0-Allyl-Erythromycin.Macrolide 1 was attached to solid support with reductive amination to a pre-bound aminoacid ( R l ) (2). The resulting amine was then condensed with a second aldehyde (R2) to afford an intermediate tertiary amine. Deprotection of the side chain primary amine off the oxazolidinone moiety and reductive amination with another aldehyde (R3) afforded compound 3. Acidic cleavage from the solid support delivered the macrolide analogues (4) in high purity with reasonable to good yields. This synthesis can be considered as classical for the core functionalization strategy since only a limited number of methods are applied several times affording a good ratio of number of synthetic steps compared to the number of building blocks brought in. Thus, high yields and high purity are achieved through well optimised reactions. Another classical aspect is the choice of building blocks, which are readily available in a large variety. Synthesis of Scaflolds

Epothilones are natural products isolated from myxobacteria, which have been found to exhibit cytotoxic activity against Paclitaxel-resistent tumor cell lines, by inducing tubulin polymerisation. The successful synthesis of epothilone A by the Nicolaou group, represents a landmark in the solid-phase synthesis of complex molecules on solid support [15]. A polymer-bound Wittig ylide 5 was further elaborated by reaction with building blocks 6 , 7, 8 via an olefination reaction, an aldol reaction, and an esterification (Scheme 2). In the next step the macrocyle 9 was formed from the acyclic precursor through a ring-closing olefin metathesis reaction mediated by Grubbs’ catalyst liberating the substrate from solid support. This cyclorelease strategy pioneered by Rapoport offers the additional advantage that only molecules which undergo the desired transformation will be found in the cleavage solution [ 161. After deprotection and epoxidation of the less substituted double bond in solution epothilone A (10) was isolated. It deserves special attention that this example demonstrated for the first time the principal feasibility of multi step natural product synthesis on solid support. In a subsequent paper Nicolaou et al. prepared a library of further analogues, which helped to establish structure-activity relationships of this compound class [15b]. Prostaglandines play a prominent role in a wide variety of physiological processes and exhibit a very subtle structure-activity relationship, which make them a target for combinatorial chemistry of highest interest and significance. The group of J. A. Ellman has disclosed the solid-phase synthesis of a 26-member library of prostaglandin E l analogues (11).After modification of the core structure 12 via Suzuki-coupling with building block 13, the relative stereochemistry of the two carbons bearing the side chains was set by a diastereoselective Michael addition of a higher order cuprate 14 across the enone 15 (Scheme 3) [ 171.

Solid-Phase Synthesis of Natural Products

E

5

I

399

400

I

Polymer-Supported Synthesis of Non-Oligomeric Natural Products

no '

TBSO

ow

6

pph3

- woT H

THF, 0 "C, 3 h

5

OTBS

1) HF*pyridine, RT, THF 0 OTBS

2) Swern-oxidation

0

OH *& ' OH

8

\\+'

DCC. DMAP. RT 0 OTBS

r T

0

0 OTBS

Hog,

0

\\\+

0

I H

O

\\\"

Grubbs catalyst CH2C12, RT

W

0

1) 20% TFNDCM

OH

0

0 OTk

10

epothilon A Scheme 2.

0

:

&

0

9

+ 3 Isomers

Total synthesis of epothilon A on solid-phase by Nicolaou et al.

Waldmann et al. have synthesised a library of analogues of the anti-tumor active phosphatase inhibitor dysidiolide (16) [18]. A notable feature of this 11-step reaction sequence on solid-phase is that a wide range of transformations with vastly differing requirements could successfully be developed. Key transformations of the synthesis include an asymmetric

Solid-Phase Synthesis of Natural Products

OTMT

OTMT Y

&

Et

Pd[PPh&

I

Na2C03,THF

Et

si - 0" Et

12

1) 1 M HCOOH, DCM 2) Dess-Martin-oxidation

0

1) HF*pyridine

2) TMSOMe

11

26 prostaglandin El analogs Scheme 3.

Synthesis o f a prostaglandine library by Ellman et al.

Diels-Alder reaction with chiral dienophile 17, and an oxidative elaboration of furan 18 with singlet oxygen on solid-phase, as well as the traceless cleavage of the products via olefin-metathesis from the support (Scheme 4).The sequence rapidly yielded access to eight analogues of the natural product and led to the identification of a potent inhibitor of the cell-cycle-controlling phosphatase cdc25c which displays a very promising selectivity pattern. Shair et al. have produced a 2527 membered libarary based on the alkaloid natural product galanthamine using an elegant biomimetic oxidative cyclisation reaction (Scheme 5) [ 191. Starting from a tyrosine-derivative (19) attached onto solid support via an acid labile silylether linkage, adduct 21 was synthesized after coupling of building block 20 via reductive amination. In the following key step a PhI(OAc)2 mediated oxidative cyclisation produced the spiroazepine. The newly generated dienone 22 was further elaborated via two Michaeladditions involving an internal phenolate- and external S-nucleophile. Further 0- and Nalkylation, and imine formation of the keto-group enabled the introduction of four different

I

401

402

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Polymer-Supported Synthesis of Non-Oligomeric Natural Products

THF, RT

1) PTSA, acetone, DCE 2) (Ph3PCH20Me)CI

KOt-Bu. THF

17

3) n-BuLi

TMSOTf, DCM, -78 "C 0

c"

-; i 1) 02,DIPEA, bengal rose

O

-

7

2) Grubbs' hv, -78 "C catalyst

= H

HO

OH

0

0 16

6-epi-dysidiolide (9 analogs) Scheme 4.

Synthesis of a library of analogs of 6-epi-dysidiolide by Waldmann et al.

diversity elements. After cleavage from solid support and biological screening of library 23, a library member was identified that perturbs the secretory pathway in mammalian cells - a process unrelated to the acetylcholine esterase inhibitory activity of the lead structure galanthamine. By its clever combination of scaffold building and subsequent modification, in which each synthetic step contributes to the overall diversity of the library, the galanthaminelibrary by the Shair group has set a benchmark for future library design.

Solid-Phase Synthesis of Natural Products

I

OH

1 CH(OCH& then NaBH3CN, MeOHflHF 2) allylchloroformate, DIPEA 3) piperidine, THF

si

?

OH

I \

ip;

+

iPr

-0

19

CHO

IP

20

1

hl(O A C ) ~

k 1) R%H 2) R3CH0, AcOH then NaBH3CN or R3COCI, 2,6-lutidine

Br&y 0

22

N

P

R4

1) R4NH2,AcOH 2) HF*pyridine

0I

OH \

R'

R3

R3

23 Scheme 5.

Synthesis o f a library of galanthamine analogues by Shair et al.

403

404

I

Polymer-SupportedSynthesis of Non-Oligomeric Natural Products

Privileged Structures

The concept of privileged structures is based on common structural motifs that are capable of interacting with a variety of seemingly unrelated biomolecular targets. Many successful libraries based upon structural types such as these have been made, e.g. libraries of benzodiazepines, benzoazepines, benzamidines, biphenyltetrazoles, spiropiperidines, indoles and benzylpiperidines. This concept was applied in a recent work by Nicolaou et al. constructing a 10,000-membered natural-product-like library based on the 2,2-dimethylbenzopyran [ 201. The benzopyran motif can be found in more than 4000 compounds including many bioactive natural products and pharmaceutically designed compounds, and it is therefore an excellent choice for combinatorial derivatisation.

R4 R3

25

[6-endo-frig]

1

Elaboration

R4

J

26 H202

27 Scheme 6. Cycloloading and elaboration strategy for benzopyran synthesis according to Nicoloaou et al.

Solid-Phase Synthesis of Natural Products

For the synthesis of the 2,2-dimethylbenzopyran loading and cleavage steps were chosen in a way that they already contribute to the complexity of the target structure, i.e. operations which do not serve the complexity built up of the structure are reduced (usually loading and cleavage) and the efficiency of the combinatorial synthesis is increased (Scheme G).

R4

R4

I

R4

Glycosidation

Annulation

Addition

$-

R4

Scheme 7.

Functionalisation of a benzopyran scaffold.

I

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Polymer-Supported Synthesis of Non-Oligomeric Natural Products

Nicoloau used a polystyrene-based selenyl bromide resin (24), which can be used to load substrates by electrophilic cyclisation reactions. In this case ortho-prenylated phenol 25 reacted with the selenyl bromide (24) to form the benzopyrane scaffold (26) via a 6-endo-trig cyclisation. The high chemical stability of the pyran linked via the seleno ether bridge allowed further elaborations on all four possible positions on the aromatic ring such as annulations, condensations, aryl/vinyl couplings, glycosidations and organornetallic additions (Scheme 7). Finally, the benzopyran analogues were released by oxidation of the selenide followed by syn-elimination furnishing the benzopyrans 27. Since certain chalcones are known to interrupt mitochondria1 electron transport by inhibition of NADH:ubiquinone oxidoreductase (complex I) a chalcone-based library was synthesised by parallel synthesis (Scheme 7). Among the first round 39 library members there were already 4 natural products and several compounds with high potency in inhibition of NADH:ubiquinone oxidoreductase. Encouraged by this success a 10,000-membered natural product-like library was constructed by directed split-and-pool techniques employing the NanoKan optical encoding platform. Such an advanced encoding technique allowed the whole project to be automated. But still all applied reactions needed a high degree of optimisation and building blocks were especially chosen to couple to the attached scaffold in high yield and to reach the goal of high purity (often >go%). An automated cleavage protocol employing hydrogen peroxide furnished 2-3 mg quantities of each library member. Biological testings in 96-well microtiter plates led to the identification of a novel structural class of antibacterial agents and a series of potent inhibitors of the NADHxbiquinone oxidoreductase enzyme. It should be mentioned that the Nicolaou group applied the libraryfrom-library concept which implied the construction of a second library from cleaved 2,2dimethylbenzopyrans by solution phase combinatorial chemistry. Conclusion

The ongoing progress in the development of solid-phase techniques, including reaction design and automation, has enabled the multi-step synthesis of complex synthetic targets on solid-phase. The examples above illustrate the structural complexity of natural product molecules which is already accessible by current methods. It can be anticipated that in the future even more challenging and demanding synthetic goals will be successfully accomplished. Considering the proven biological relevance of natural products these structures should be paid more attention for the design of future combinatorial libraries. New genome and proteome sequence data combined with the tool of bioinformatics will assist the chemist in the selection of both the synthetic and biological target [21].Future libraries will also be measured by their design, in which as many steps as possible in the multi-step-sequence should contribute to the diversity of the library. References J. DREWS,Science 2000, 287, 1960-1964; b) G. WESS, M. U R M A N NB. , SICKENB E R G E R , Aagew. Chem. Int. Ed. 2001, 40, 3341-3350.

1 a)

2

R. S. BOHACEK,C. MCMARTIN,W. C. GUIDA,Med. Res. Ren 1996, 16, 3-50; b) H. C. KOLB,M. G. F I N N , K. B. SHARPLESS, Angew. Chem. Int. Ed. 2001, 40, 2004-

References I 4 0 7

2021. For a discussion about the problem of diversity in combinatorial libraries, see S. R. KLOPFENSTEIN, c) A. GOLEBIOWSKI, D. E. PORTLOCK,Curr. Opin. Chem. Biol. 2001, 5, 273-284; d) J. S. MASON,M. A. Cur. Opin. Chem. Biol. HERMSMEIER, 1999, 3, 342-349; e) J. M. BLANEY, E. J. MARTIN,Curr. Opin. Chem. Biol. 1997, 1, 54-59; f ) R. W. SPENCER,Biotechnol. Bioeng. 1998, 61, 61-67. 3 a) For an outstanding analysis of the role of natural products in pharamceuticals, see C. M. CRAGG,D. J. NEWMAN,K. M. SNADER, /. Nat. Prod. 1997, 60, 52-60; b) T. H E N K E LR., M. BRUNNE,H. MULLER, F. REICHEL,Angew. Chem. lnt. Ed. 1999, 38, 643-647; c) Y.-Z. SHU,/. Nat. Prod. 1998, 61, 1053-1071; d) D. G. I. KINGSTON in “The Practice of Medicinal Chemistry”, C. G . WERMUTH(Ed.), Academic Press: London, 1996. 4 For an excellent account of this concept and its conceptual difference to targetoriented synthesis, see a) s. L. SCHREIBER, Science 2000, 287, 1964-1969. For some notable examples of this approach, see b) D. S. TAN,M. A. FOLEY,B. R. STOCKWELL, M. D. SHAIR,S. L. SCHREIBER, /. Am. Chem. SOC.1999, 121,9073-9087; c) D. LEE,J. K. SELLO,S. L. SCHREIBER, /. Am. Chem. SOC. 1999, 121, 10648-10649; recent review article: d) R. ARYA,M.-C. BAEK, CUT. Opin. Chem. Biol. 2001, 5, 292-301. 5 a) M. WEIR,M. SWINDELLS, J. OVERINGTON, Trends Biotechnol. 2001, 19, S61-S66; b) C. P. PONTING,J . SCHULTZ, R. P. COPLEY,M. A. ANDRADE, P. BORK, Adu. Protein. Chem. 2000, 54, 185-244. 6 SCOP database: A. G . MURZIN,S. E. BRENNER, T. HUBBARD, C. CHOTHIA,/. Mol. Biol. 1995, 247, 536-540. 7 a) C. CHOTHIA,Nature 1992, 357, 543544; b) P. GREEN,D. LIPMAN,L. HILLIER, R. WATERSTON, D. STOBES,J. M. CLAVERIC, Science 1993, 259, 1711-1716; c) Y. I. WOLF,N. V. G R I S H I NE. , V. KOONIN,J . Mol. Biol. 2000, 299, 897-905. 8 R. BREINBAUER, I. R. VETTER,H. WALDMANN, Angew. Chem. Int. Ed. 2002, 41, 2878-2890 9 B. E. EVANS,K. E. RITTLE,M. G. BOCK, R. M. DIPRADO,R. M. FREIDINGER, W. L. WHITTER,G. F. LUNDELL, D. F. VEBER, P. S. ANDERSON, R. S. L. CHANG,V. J.

L o r n , D. J. CERINO,T. B. CHEN, P. J. KLING,K. A. KUNKEL,J. P. SPRINGER, J. HIRSHFIELD, /. Med. Chem. 1988, 31, 2235-2246. 10 For a recent and comprehensive review of solution-phase and solid-phase synthesis of natural product libraries, see a) D. G. HALL,S. MANKU,F. WANG,]. Comb. Chem. 2001, 3, 125-150; b) L. WESSIOHANN,Curr. Opin. Chem. Biol2000, 4, 303-309; c) L. J. WILSONin “Solid-Phase Organic Synthesis”, K. BURGESS (Ed.), Wiley-Interscience: New York, 2000 d) C. WATSON,Angew. Chem. Int. Ed. 1999, 38, 1903- 1908. 11 B. MESEGUER, D. ALONSO-DIAZ, N. GRIEBENOW, T. HERGET,H . WALDMANN, Angew. Chem. Int. Ed. 1999, 38, 29022906. 12 K. C. NICOLAOU, N. WINSSINGER, D. VOURLOUMIS, T. OHSHIMA,S. KIM, J. PFEFFERKORN, 1. Y. Xu, T. LI,J. Am. Chem. SOC.1998, 120, 10814-10826. 13 Y.-X. XIAO, Z. PARANDOOSH, M. P. NOVA, /. Org. Chem. 1997, 62, 6029-6033. 14 I. AKRITOPOULOU-ZANZE, T. J. SOWIN,/. Comb. Chem. 2001, 3, 301-311. 15 a) K. C. NICOLAOU, N. WINSSINGER, J. PASTOR,S. NINKOVIC,F. SARABIA, Y. H E , Z. YANG,T. LI, P. D. VOURLOUMIS, GIANNAKAKOU, E. HAMEL,Nature 1997, 387, 268-272; b) K. C. NICOIAOU,D. VOURLOUMIS, T. LI, J. PASTOR,N. WINSSINGER, Y. H E , S. NINKOVIC,F. SARABIA, H. VALLBERG, F. ROSCHANGAR, N. P. KING, M. R. V. FINLAY,P. GIANNAKAKOU, P. VERDIER-PANARD, E. HAMEL,Angew. Chem. lnt. Ed. 1997, 36, 2097-2103. 16 a) J. I. CROWLEY, H. RAPOPORTJ. Am. Chem. SOC.1970, 92, 6363-6365; notable applications: b) K. C. NICOLAOU,N. WINSSINGER, J. PASTOR,F. MURPHY, Angew. Chem. Int. Ed. 1998, 37, 25342537; c) S. C. SCHURER,S. BLECHERT, Synlett 1999, 879-1882; review: d) 0. SEITZ,Nachr. Chem. 2001, 49, 312-316. 17 a) L. A. THOMPSON, F. L. MOORE,Y.-C. MOON,1. A. ELIMAN,/. Org. Chem. 1998, 63, 2066-2067; b) D. R. DRAGOLI,L. A. THOMPSON, J. O’BRIEN,J. A. ELLMAN, /. Comb. Chem. 1999, 1, 534-539; for a soluble supported synthesis of a prostanoid library and the screening

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thereof for antiviral activity, see c) K. J. LEE,A. ANGULO,P. GHAZAL,K. D. JANDA, Org. Lett. 1999, 1, 1859-1862. 18 D. BROHM,S. METZGER, A. BHARGAVA, 0. MULLER,F. LIEB,H. WALDMANN, Angew. Chem. Int. Ed. 2002, 41, 307-311. 19 a) H. E. PELISH,N. J. WESTWOOD, Y. FENG,T. KIRCHHAUSEN, M. D. SHAIR, J . Am. Chem. SOC.2001, 123, 6740-6741; b) for an earlier beautiful example of a biomimetic heterodimerization in the synthesis of carpanone library; see C. W. LINDSLEY, L. K. CHAN,B. C. GOES, R. JOSEPH,M. D. SHAIR,J . Am. Chem. SOC. 20

2000, 122,422-423. A discussion to the concept of natural product-like combinatorial libraries based on privileged structures and an impressive experimental proof of concept has been disclosed by the Nicolaou group: a) K. C.

NICOLAOU, J . A. PFEFFERKORN, A. J. ROECKER, G.-Q. CAO, S. BARLUENGA, H. J. MITCHELL, J . Am. Chem. Soc. 2000, 122, 9939-9953; b) K. C. NICOLAOU, J. A. PFEFFERKORN, H. J. MITCHELL,A. J . ROECKER, S. BARLUENGA, G.-Q. CAO, R. L. AFFLECK, J. E. LILLIG,1.Am. Chem. SOC. 2000, 122, 9954-9967; c) K. C. NICOLAOU, J. A. PFEFFERKORN, S. BARLUENGA, H. J. MITCHELL,A. J. ROECKER, G.-Q. CAO,/. Am. Chem. SOC. 2000, 122, 9968-9976; for a review see: K. C. NICOLAOU. J. A. PFEFFERKORN, Biopolymers 2001, 60, 171-193. 21 For an excellent review of chemogenomic approaches to drug discovery, see P. R. CARON,M. D. MULLICAN,R. D. MASHAL, K. P. WILSON,M. S. Su, M. A. MURCKO, Curr. Opin. Chem. B i d . 2001, 5, 464470.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions Rijdiger Faust

Why would anyone attempt to synthesize fullerenes from elaborate precursors if all it takes is graphite and a suitable energy source like a strong electric field or laser power? One of the answers to this somewhat unfair question bears a certain philosophical charme reminiscent of the motto that the way is the goal. And indeed, only in 2002, twelve years after its initial isolation [ 11, Scott et al. reported on a rational chemical synthesis of buckminsterfullerene c 6 0 in twelve steps from commercially available 1-bromo-4-chlorobenzene [ 21. Of course, the benefit of the synthetic methodology developed to obtain carbon-rich materials in a rational fashion is multitudinous and undisputed [3-6]. But there is more. Firstly, research on endohedral fullerene complexes and metal-filled nanotubes [7, 81, in many ways the most exciting and the most unprecedented aspect of fullerene chemistry and physics, is severely limited due to the low yields encountered in their preparation. A promising approach to improve this situation lies in the development of synthetic strategies towards these molecules. Secondly, knowledge about crucial stages of the fullerene formation process and about the rules that govern the observed product distribution remains rather sketchy [9, lo]. The design of more sophisticated fullerene precursors may allow the investigation of this process under conditions that are more controllable than the chaotic plasma of carbon atoms at ca. 3000 K. Strained cycloalkynes are attractive starting materials for the energy-induced transformation of carbon-rich materials to fullerenes or related structured forms of carbon. In ideal cases, the high energy content of a given cycloalkyne can lead to the coalescence of the cyclic structure to a thermodynamically more stable carbon sphere. Furthermore, incorporation of benzenoid substructures into cycloalkynes offers the opportunity to coordinate metal fragments, thereby providing a synthetic entry to endohedral fullerene complexes. Significant progress towards these goals has been made and a selection of the (therm0)chemistry of new dehydrobenzoannulenes and alkyne-based cyclophanes is highlighted in the following. First evidence for the feasibility of a cycloalkyne-to-fullereneconversion has been produced by Diederich et al. [ 11-13] shortly before macroscopic quantities of buckminsterfullerene c60 1 were available [ 1, 141. In Fourier-transform laser-desorption mass spectrometric (FTLD-MS) experiments they observed that cations of cyclo-C30 2 undergo an efficient ionmolecule coalescence to give fullerene ions such as 1+ (Scheme 1).

410

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

I

0

0

T

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

In a related series of experiments, cyclic cationic carbon structures like 3 (depicted in symmetry, Scheme 1)were also shown to rearrange to spherical C60 ions [15-171. However, the preparation of bulk quantities of the neutral cyclocarbons and hence that of the fullerenes from these precursors remains elusive [ 181. More recent developments exploit the energy content of readily accessible cycloalkynes based on phenyl-alkynyl structural motives, albeit not always with fullerene formation in mind. For example, the strained dehydrobenzoannulene 4 [ 191 could be converted by light, heat (145 “C), or pressure (20000 psi) in a topochemical polymerization reaction typical for butadiynes to a deeply coloured polymer. A similar thermochemical behaviour (strongly exothermic transformation around 200 “C) was observed for compounds 5 and 6 [20]. However, none of the systems 4-6 shows any tendency to produce spherical forms of carbon under the conditions investigated.

4

5

6

The situation is drastically different when the thermochemistry of cycloalkyne 7 [21] is considered (Figure 1).The high energy content of 7 becomes apparent when the compound is heated to 245 “C. At this temperature 7 “explodes violently with a flash of orange light” [ 211. An investigation of the black, carbonaceous residue by transmission electron microscopy (TEM) revealed the presence of not only amorphous carbon and graphite, but also of closed-shell carbon particles, namely buckytubes and buckyonions in yields between 1-2% (by TEM) [22]. It is not unlikely that the molecular structure of 7 as observed in the crystal (Figure 1) supports its explosive transformation to these fullerenoid carbon allotropes. While 7 is commonly and deceivingly depicted as a planar rectangle, the X-ray structural analysis

I

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors t o Fullerenes, Buckytubes and Buckyonions

7 Fig. 1. The structure o f 7 in the crystal deviates considerably from that suggested by the graphical representation.

reveals that 7 adopts a non-planar, twisted D2-symmetric conformation in the crystal, in which two butadiynyl linkages are crossing on top of each other. Vollhardt and coworkers further advanced their concept of acetylenic starting materials for the synthesis of carbon nanostmctures by exploring a metal-mediated version of the thermolytic transformations of oligoalkynes into carbon nanostructures [ 231. Thus, separate pyrolyses of the cobalt complexes 8 and 9 at temperatures around 800 "C led to the formation of large amounts (up to GO% by TEM) of buckyonions and multi-walled carbon nanotubes. In addition, some graphitic and very little amorphous carbon was produced. Thermal analysis of this transformation reveals that exothermic CO extrusion 153 "C signals the onset of the reaction, and is followed by an endothermic polymerisation process at 188 "C, possibly induced by initial Co--Co bond breaking. Interestingly, pyrolysis of a mixture of 7 with 5% C02(C0)8 produceed only soot with little graphitised carbon. Again, there appears to be a clear structural predisposition in 8 and 9 that favours the thermal production of carbon nanostructures. Structural analysis of the starting materials by X-ray crystallography, however, were inconclusive in this respect. The fate of the metal during the pyrolysis of 8 and 9 is intriguing. Whereas most of the metal is deposited amorphously in discrete domaines, some of it is trapped during the thermolysis process in carbon-coated nanorods or even in crystalline form inside the carbon tubes and onions. The thermal decomposition of 7, 8 and 9 into fullerenic substructures is a milestone in fullerene formation and represents the first example of a macroscopic preparation of closedshell carbon particles from acetylenic precursors. However, molecular allotropes of carbon, such as C ~ or O higher fullerenes were not found among the decomposition products. It is interesting to note in this context that 10 [24], a structural isomer of 7 with a saddle-shaped solid state conformation, also shows thermal transformations, but in this case they occur at temperatures ca. 50 "C lower than those of 7 and are accompanied by a release of 50 kJ mol-' more energy. Although an insoluble carbonaceous material is formed during this process, further details of its nature are currently not known.

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to fullerenes, Buckytubes and Buckyonions

H

H

8

9

10

Cyclophanes have previously been envisioned as precursors to the fullerenes [ 251 and alkynyl-based cyclophanes ("cyclophynes") are beginning to play an eminent role in this field. Two experimental results may serve to demonstrate the substantial energy content of these molecules. Firstly, belt-shaped [ blparaphenylacetylene 11 [2G] explodes when heated to 80 "C in the presence of oxygen. Under inert gas, temperatures of ca. 240 "C are needed to induce the decomposition. No attempts have been made to characterize the decomposition products that are described as a brown, polymeric mixture. Secondly, [8.8]paracyclophaneoctayne 12 [27] could only be prepared in a protected form in which four of the eight acetylenic units arc complexed by bridging ( p-acetylene dicobalt) moieties. Efforts to release the highly strained hydrocarbon from its octacobalt complex resulted in large amounts of insoluble material. In light of the constitutional similarities between 8, 9 and the octacobalt complex of 12 an investigation of the pyrolytic behaviour would be very informative. Major steps towards the transformation of acetylenic cyclophanes into fullerenes have recently been made by Rubin et al. At the center of their promising approach [28-301 lies a preformed sixty carbon cyclophyne cage which is meant to be brought by appropriate acti-

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors t o Fullerenes, Buckytubes and Buckyonions

11

12

vation techniques to coalesce to buckminsterfullerene CGO.The prototypical cyclophyne 13 [ 311 (C60H18), skillfully assembled in only four steps from 1,3,5-triethynylbenzene,is stable for weeks in dilute solutions in the dark. The cyclophyne 13 adopts a chiral, helical D3conformation in the solid state, and, according to calculations, racemizes rapidly even at low temperatures. Disappointingly, 13 was shown to be very reluctant to loose hydrogen in matrix-assisted LD-MS experiments and does not collapse under dehydrogenation to fullerene c 6 0 . The most abundant ion (negative ion mode) corresponds to the parent ion of 13 and only partial dehydrogenation to C6OH14- is observed. The authors speculate that the reasons for the failure of 13 to produce fullerenes are the pronounced flexibility of the system, and, more importantly, the bad leaving group properties of the remaining hydrogens of the c60 H 18 hydrocarbon. 0

0

0

0 13

14

(C60H18)

[C60H6(C0)121

In a straightforward refinement of their concept Rubin et al. have turned to cyclophyne 14 [32] in which the vinylic hydrogens of 13 are replaced by 1,2-dioxocyclobutenogroups. This cyclic diketone moiety has been used previously [18, 33, 341 as a synthetic equivalent for alkynyl groups which can be generated from the dione by thermally or photochemically induced CO expulsion. Successive decarbonylation of 14 should ultimately lead to cyclophyne 15 with the composition C6&.

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

In contrast to the synthesis of cyclophyne 13, the preparation of 14 is a more tedious multistep (eight) procedure that furnished a sensitive material that is stable in CH2Clz solution for only two hours. The instability of 14 notwithstanding, the mass spectrometric behaviour of the compound under FT-ICR-LD (ICR = ion cyclotron resonance) conditions proved to be intriguing. The parent ion of 14, C ~ O H ~ ( C can O ) ~neither ~ , be observed in the positive nor in the negative ion mode, but fragments thereof resulting from loss of eight, nine, ten, and eleven CO groups are detectable. The most abundant ions observed in the negative ion mode are c60'- and C60H6'~-.The anion of the carbon cluster c 6 0 was unambiguously identified as a fullerene, since its fragmentation pattern shows the successive loss of Cz-units typical for spherical carbon particles. C6OH6'- on the other hand does not lose C2 fragments, suggesting that its structure is not fullerene-like. It may be speculated that C60H6'- is best represented by structure 15. It is noteworthy that the formation of fullerene ions from acetylenic 14 is observed in the negative ion mode, which is considered to be "milder" than the positive ion mode which was previously used to detect ionized carbon spheres. It thus appears that 14 is structurally predisposed for fullerene formation. However, attempts to perform the exhaustive decarbonylation on a macroscopic scale by irradiating dilute THF solutions of 14 with pulsed laser light did not lead to the formation of buckminsterfullerene c 6 0 . A n alternative strategy for fullerene production through the intermediacy of 15 was adopted (and pursued independently and simultaneously to the work described above) by Tobe et al. [35] Their attempt to overcome the difficulties encountered in the exhaustive dehydrogenation of 13 led to design of a similar cyclophyne 16, in which six alkynyl groups are masked by so-called [4.3.2]propellatrienes. Laser-induced [ 2+2]cycloreversion [ 36-38] will cleave the bicyclic substructures to generate six equivalents of indane and will furnish cyclophyne 15. Consequently, the LD-mass spectra (positive ion mode) of 16 feature an intense signal for c60 cations with a C2-fragmentation pattern. In the negative ion mode, c60 anions are formed only to a minor extent, and the spectrum is dominated by C6OH6'anions. Again, upon photolysing solutions of 16 no indication for the macroscopic formation of fullerenes was observed, despite the promising confirmation that indane had been produced.

I

415

416

I

Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions

16: X = Y = Z = CH 17: X = Y = N,Z = CH 18: X = Z = N. Y = CH

Tobe and coworkers have extended their work to the pyridine-based cyclophynes 17 and 18 in efforts to detect the incorporation of heteroatoms into the fullerene structure [ 391. Similar to the behaviour of the hydrocarbon 16, heterocyclic 17 and 18 show the successive loss of indane units and hydrogen under the conditions of LD mass spectrometry (negative ion mode) culminating in the observation in both cases of the formation of the anion CssNz-. The relative low intensity of the diazafullerene anion observed can be attributed to the kinetic and thermodynamic instability of the heterocage formed.

19:R=H 20: R = CI

Tobe’s group also succeeded in applying the [ 2+2]cycloreversion process to the formation of smaller carbon cages, notably c36 [40]. Macroscopic quantities of cj6 have been produced before [41,42]and were shown to contain carbon cages that are covalently connected to form polymeric clusters of overall D6h-symmetry. In their efforts to obtain c 3 6 from acetylenic precursors, Tobe et al. prepared cyclophynes 19 and 20 [40]. LD time-of-flight mass spectra of 19 depict a signal for the anion of cyclophyne C36H8, generated from 19 by four-fold

References

cycloreversion of its propellatriene units, can be clearly observed. However, anionic fragments arising from the subsequent dehydrogenation of C36H8- could not be detected. Replacement of the benzenoid C-H bonds in 19 with the weaker C-C1 bonds in 20 and investigation of the latter with LD-TOF MS methods not only allowed the observation of the corresponding c36cl8- anion, but also showed the stepwise loss of chlorine atoms to produce c36-, for which the authors also assume D6h-symmetry.

21

22

23

In light of the mass spectrometric results described above, a rational fullerene synthesis from cyclophyne precursors appears to be within reach. Since superphane 21 [43] and superferrocenophane 22 [ 441 are established structural precedences, it may well be that reports about a successful synthesis of “superphyne” 23, an acetylenic isomer of buckminsterfullerene, or even a corresponding “superrnetallophyne” are only a short time away. References W. KFL~TSCHMER,L. D. LAMB,K. FOSTIROPOULOS, D. R. HUFFMANN, Nature (London) 1990, 347, 354-358. L. T. SCOTT,M. M. BOORUM,B. J. MCMAHON,S. HAGEN,J. MACK,J . BLANK, H. WEGNER, A. D E MEIJERE, Science 2002, 295, 1500-1503.

F. DIEDERICH, Y. RUBIN,Angew. Chem. 1992, 104, 1123-1146; Angew. Chem. Int. Ed. Engl. 1992, 31, 1101-1123. F. DIEDERICH, Nature (London) 1994, 369, 199-207.

U. H. F. BUNZ,Y. RUBIN,Y. TOBE,Chem. SOC.Rev. 1999, 28, 107-119. A. J. BERRESHEIM, M. MULLER,K. MULLEN,Chem. Rev. 1999, 99, 1747-1785. F. BANHART,N. GROBERT, M. TERRONES, I. C. CHARLIER, P. M. AJAYAN, Int. ]. Mod. Phys. B 2001, 15, 4037-4069. M. TERRONES, W. K. Hsu, H. W. KROTO, D. R. M. WALTON,Top. Cum. Chem. 1999, 199, 189-234.

9

H. SCHWARZ, Angew. Chem. 1993, 105, 1475-1477; Angew. Chem. Int. Ed. Engl. 1993, 32, 1412-1415.

10

P. M. AJAYAN, Chem. Rev. 1999, 99, 1787-1799.

11

Y. RUBIN,M. KAHR,C. B. KNOBLER,F.

DIEDERICH,C. L. WILKINS,]. Am. Chem. SOC.1991, 113, 495-500. 12 S. W. MCELVANY, M. M. Ross, N. S. GOROFF,F. DIEDERICH, Science 1993, 259, 1594-1596. 13 N. S. GOROFF,Acc. Chem. Res. 1996, 29, 77-83. 14

For an account of the developments leading to the isolation of CGO,see H. W. KROTO,Angew. Chem. 1992, 104,113-133; Angew. Chem. Int. Ed. Engl. 1992, 31, 111129. See also R. F. CURL,Angew. Chem. 1997, 109, 1636-1647; Angew. Chem. Int. Ed. Engl. 1997,36, 1566-1577; H. W. KROTO,Angm. Chem. 1997, 109,16481664; Angew. Chem. Int. Ed. Engl. 1997, 36,

I

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418

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Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes and Buckyonions 1578-1593; R. E. SMALLEY, Angew. Chem. 1997, 109, 1666-1673; Angew. Chem. Int. Ed. Engl. 1997, 36, 1594-1603. 15 J. HUNTER,J.FYE,M. F. JARROLD, Science 1993, 260,784-786. 16 D. E. CLEMMER, M. F. JARROLD, J. Am. Chem. SOC.1995, 117,8841-8850. 17 G. VON H E L D E NN. , G. Gorrs, M . T . BOWERS,Nature (London) 1993, 363, 60-63. 18 F. DIEDERICH, Y. RUBIN,0. CHAPMAN, N. S. GOROFF,Helv. Chim. Acta 1994, 77, 1441-145 7. 19 K. P. BALDWIN, A. J. MATZGER,D. A. SCHEIMAN, C. A. TESSIER,K. P. VOLLHARDT, W. J. YOUNGS,Synlett 1995, 1215-1218. 20 M. M. HALEY,S. C. BRAND,J. J. PAK, Angew. Chem. 1997, 109, 864-866; Angew. Chem. Int. Ed. Engl. 1997, 36, 836-838. 21 R. BOESE,A. J. MATZGER, K. P. C. VOLLHARDT, J. Am. Chem. SOC.1997, 119, 2052-2053. 22 M. S. DRESSELHAUS, G. DRESSELHAUS, P. C. EKLUND,Science ofFullerenes and Carbon Nanotubes, Academic Press, San Diego, USA, 1996. 23 P. I. DOSA,C. ERBEN, V. S. IYER,K. P. C. VOLLHARDT, I. M. WASSER, J. Am. Chem. SOC.1999, 121, 10430-10431. 24 M. M. HALEY,M. L. BELL,J. J. ENGLISH, C. A. JOHNSON, T. J . R. WEAKLEY, ]. Am. Chem. SOC.1997, 119, 2956-2957. 25 R. FAUST,Angew. Chem. 1995, 107, 15591562; Angew. Chem. Int. Ed. Engl. 1995, 34, 1429-1432. 26 T. KAWASE, H.R. DARABI,M. ODA,Angew. Chem. 1996, 108, 2803-2805; Angew. Chem. Int. Ed. Engl. 1996, 35, 2664-2666. 27 M. M. HALEY,B. L. LANCSDORF, Chem. Commun. 1997, 1121-1122. 28 Y. RUBIN,Chem. Eur. J. 1997, 3, 1009-1016. 29 Y. RUBIN,Chimia 1998, 52, 118-126. 30 Y. RUBIN,Top. Curr.Chem. 1999, 199, 67-91.

31 Y. RUBIN,T . C. PARKER, S. I. KHAN,C.

L.

HOLLIMAN, S. W. MCELVANY, 1.Am. Chem. SOC.1996, 118, 5308-5309. 32 Y. RUBIN,T. C. PARKER, S. J. PASTOR,S. JALISATGI, C. BOULLE,C. L. WILKINS, Angew. Chem. 1998, 110, 1353-1356; Angew. Chem. Int. Ed. 1998, 39, 12261229. 33 Y. RUBIN,C.B. KNOBLER, F. DIEDERICH, J. Am. Chem. SOC.1990, 112, 1607-1617. 34 Y. RUBIN,S. S. LIN, C. B. KNOBLER, J. ANTHONY,A. M. BOLDI,F. DIEDERICH, J. Am. Chem. SOC.1991, 113, 6943-6949. 35 Y.TOBE,N. NAKAGAWA, K. NAEMURA, T. WAKABAYASHI, T. SHIDA,Y. ACHIBA,]. Am. Chem. SOC.1998, 120,4544-4545. 36 Y. TOBE,T. FUJII,H. MATSUMOTO, K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, J. Am. Chem. SOC.1996, 118, 2758-2759. 37 Y. TOBE,H . MATSUMOTO, K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, Angew. Chem. 1996, 108, 1924-1926; Angew. Chem. Int. Ed. Engl. 1996, 35, 1800-1802. 38 Y. TOBE,T. F U ~ I IH. , MATSUMOTO, K. TSUMURAYA, D. NOGUCHI,N. NAKAGAWA, M. SONODA,K. NAEMURA, Y. ACHIBA,T. WAKABAYASHI, J. Am. Chem. SOC.2000, 122, 1762-1775. 39 Y. TOBE,H . NAKANISHI, M. SONODA,T. WAKABAYASHI, Y. ACHIBA,Chem. Commun. 1999, 1625-1626. 40 Y.TOBE,R. FURUKAWA, M. SONODA, T. WAKABAYASHI, Angew. Chem. 2001, 113, 4196-4198; Angew. Chem. lnt. Ed. 2001, 40,4072-4074. 41 C. PISKOTI,J. YARGER, A. ZETTL,Nature (London) 1998, 393, 771-774. 42 P. G. COLLINS, J. C. GROSSMAN, M. COTE, M. ISHIGAMI, C. PISKOTI,S. G. LOUIE,M. L. COHEN,A. ZETTL,Phys. Rev. Lett. 1999, 82, 165-168. 43 Y. SEKINE,M. BROWN,V. B O E K E L H E I D E , ~ . Am. Chem. SOC.1979, 101, 3126-3127. 44 M. HISATOME, J. WATANABE, K. YAMAKAWA, Y. IITAKA, J. Am. Chem. SOC. 1986, 108, 1333-1334.

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co I419

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis Henning Hopf

By connecting double and single bonds, formally five classes of hydrocarbons can be constructed which differ considerably from one another not only chemically and physically but also in terms of their practical significance [l]:the linear polyenes 1, the annulenes 2, which consist exclusively of endocyclic “double bonds”, the radialenes 3, polyolefins which are characterized by semicyclic double bonds, the fulvenes 4, hybrids containing endoand semicyclic double bonds, and finally, the dendralenes 5 [2] which are acyclic crossconjugated polyenes

01.

1

2

[A1 3

4

5

Scheme 1.

Of these n-systems, the first two are by far the most thoroughly investigated and also play the greatest practical role, be it in the form of vital molecules such as 8-carotene or as key substances in organic syntheses, such as benzene and its numerous derivatives. Of the remaining three classes, which are all cross-conjugated, fulvenes and their derivatives have been studied most extensively; however, in the last few years radialenes have gradually come out of the shadows as well [3, 41. Although von Auwers had obtained the first dendralene derivatives at the beginning of the 20th century already, and this class of hydrocarbons was later studied by Staudinger, among others, who described them as “open fulvenes” [ 21, there

420

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

have practically been no in depth studies of the chemistry of the parent dendralene systems. The reason for this is simple: Except for compounds 5 with n = 1 ([3]dendralene 7, Scheme 2) and n = 2 ([4]dendralene 15, Scheme 3), higher vinylogs were not known until the recent investigations by Sherburn et al., details of which are given below. A considerable number of processes have been described for the preparation of the two simplest dendralenes; however, most of them are rather means of formation than efficient preparative methods. As Scheme 2 shows for [ 3ldendralene 7, thermal methods of preparation predominate (1,2-eliminations and periyclic processes); however, these methods do not always start from readily accessible precursors (51. The most effective procedure - which can hence be employed in subsequent reactivity studies (see below) - consists in the cheletropic decomposition of 11 carried out by Cadogan and Gosney et al. [GI although the preparation of the sulfolene derivative also requires several steps.

AcO

R

OAc 6

H,, Lindlar-cat.

100%

11

12

Scheme 2.

The situation was even more critical for [41] dendralene 15 [2, 71, especially since the thermal decompositions shown in the lower half of Scheme 3 have all been carried out in connection with mechanistic studies. Before the first general synthetic concept for the preparation of the dendralenes is presented, it will be shown that these n-systems are interesting not only preparatively but also from a structural point of view. The application of dendralenes in Diels-Alder additions holds particular promise in synthetic chemistry. This is demonstrated in general form in Scheme 4 for the two simplest dendralenes. The [2+4]cycloaddition of 7 with a dienophile 20, not only leads to the expected 1:l-adduct 21 but also generates a new conjugated diene system which

Dendralenes: From a Neglected Class ofPolyenes to Versatile Starting Materials in Organic Synthesis I 4 2 1

=*-c* 13

i

Mg, (MeOCH,O)&H,

0.1 450”c Tom,

AcO

> 23%

14

15

16

> 100 “C

110 “C

.-

-~

(I.= 17

18

19

Scheme 3.

is available for a second addition with 20 to give 22 (Scheme 4, a). In principle, dienophiles containing a triple bond (see below) and heteroorganic compounds are also suitable as dienophiles. Tsuge and co-workers - building on work by Bailey and Blomquist [5] - have already made extensive use of the preparative potential of these so-called “diene transmissive” DielsAlder additions (DTDA additions) [ 81. Clearly, the dienophile does not have to be identical in the two stages of the reaction, which increases the preparative potential of these double cycloadditions considerably. The adducts of type 22 can be further processed in various ways, naphthalene derivatives as for example by dehydrogenation to give 1,2,6,7-tetrasubstituted will be discussed below. Consecutive reactions of this type with their excellent atom economy are of considerable interest particularly in view of the current efforts to increase the efficiency of organic transformations. As expected, the possibilities for [4]dendralene 15, which until now has only been used occasionally in diene-transmissive additions [ 7c], to participate in [ 2+4]cycloadditions are much greater (Scheme 4, b). Two possibilities arise for the first addition step, depending on whether 20 adds to a terminal diene unit (formation of 23) or to the central diene unit (formation of 25). For 23, two further alternatives are possible, which could either lead via 24 to

422

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

7

21

15

23

I

+20

25

I

+2x20

26

22

I

+20

27

Scheme 4.

the 3:l-adduct 27 or - by consecutive additions of two equivalent dienophiles - to the trisadduct 26 (which displays a quaternary carbon atom). Depending on the type of substituents in the dienophile, the adducts 27 could also be used again for aromatization experiments. New types of products are also expected in many other reactions of the dendralenes. Practically nothing is known so far about the photochemistry, metal complexation, ionic additions etc. of these cross-conjugated hydrocarbons, to name but a few directions for further study. As far as the structure of the dendralenes is concerned the early work concentrated on the analysis of their UV spectra - not surprising if one considers that the cross-conjugation motif occurs in many dyes (triphenylmethane dyes, indigo ete.). The electronic spectra show, for instance, that the dendralenes cannot exist in coplanar form. Their absorption maxima are very similar to those of simple 1,3-dienes; they are not shifted to longer wavelengths as one would expect for extended n-electron systems. This is confirmed by detailed structural investigations accompanied by various computational methods. According to electron diffraction measurements, 7 has the anti-skew-conformation 28 shown in Scheme 5 with a dihedral angle of 40" between the planes of the anti-butadiene fragment and the remaining

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

x 28

I

29

Scheme 5.

vinyl group [9]. In 15 this dihedral angle is 72" and again the anti-butadiene halves are practically planar (see structure 29, Scheme 5) [lo]. The unsatisfactory situation that a promising class of compounds could not be studied in greater detail has recently been rectified by the groups of Fielder, Rowan, and Sherburn who have developed a general route to the dendralenes [ I l l . In planning the corresponding sequences, the well known instability and tendency of the dendralenes to polymerize - as demonstrated by 7 and 15 - were taken into consideration from the very beginning, in that a synthetic route was designed in which the dendralene n-system is not released until the very end. In particular the butadiene fragment was transported in capped form, as a sulfolene ring, to the end of the synthesis, following the approach of Cadogan and Gosney et al. [6] for the simplest dendralene 7 (see Scheme 1). AS Scheme 6 shows, the Sherburn route begins with the vinyl stannane 30, which is initially converted by iodolysis to the vinyl iodide 31. The actual building process then took place by Stille cross-couplings; the mild reaction conditions used prevented the premature release of sulfur dioxide from the masked dendralene intermediates. The sulfolenes 11, 33, and 34 were obtained readily in the presence of [PdC12(CH3CN)z]in DMF under argon at temperatures up to 40 "C. The coupling of 31 with the bis-stannane 32, not only gave the bissulfolene 35, but also the [8]dendralene precursor 38. The masked dendralenes 36 are crystalline compounds, stable at room temperature, from which, as hoped, the hydrocarbons 37 could be released on demand in good yields by hightemperature pyrolysis. No solvent is required in these cheletropic reactions which facilitates the work-up. The dendralenes 37 obtained, up to [ 8]dendralene, have been completely characterized by the usual spectroscopic and analytical methods and can, although they tend to polymerize, be handled under the usual laboratory conditions (see below). The sulfolene decomposition route has recently been applied to the synthesis of many other cross-conjugated compounds, among them the hydrocarbons 39-42 (Scheme 7) [ 121. Having sufficient amounts of these novel dienes in hand opens the field for further study. Cycloaddition of acetylenedicarboxylic acid dimethyl ester (ADDE) to [ 3ldendralene 7 in toluene first afforded the 1:l-adduct 43, which by a second addition of ADDE provided the expected 21-adduct 44. After this had been aromatized by treatment with DDQ to the naphthalene derivative 45, a double benzannulation could be carried out as described in Scheme 8 [ 131. By reduction of the ester groups with lithium aluminum hydride the corresponding tetraalcohol was obtained which was converted to the tetrabromide 46 by treatment with phosphorus tribromide. Debromination with zinc in the presence of maleic anhydride (MA) furnished the bis anhydride 47, which, after esterification and aromatization, provided the

I

423

424

I

Dendralenes: From a Neglected Class of Polyenes t o Versatile Starting Materials in Organic Synthesis

SnBu,

I,, CH,C1,

Stille

80%

Bu,SnCH=CH,

30

31

I

Stille H,C=CBr,

Stille

M

so2

so2

0,s

I

11 (92%)

+ 30\+,

o

2

# 502

33 (1 1%)

34 (95%)

35 (43%)

+

38 (30%) 52 Scheme 6.

39 (63%)

40 (32%)

41 (25%)

42 (12%)

Scheme 7.

-

Dendralenes: From a Neglected Class ofPolyenes t o Versatile Starting Materials in Organic Synthesis

+ ADDE

C02Me

toluene

C02Me

7

+ADDE toluene

43

C02Me Me02C

DDQ toluene

C02Me

*

C02Me 44 \

Me02Cm

\

C 0 2 C02Me

M

1. LiA1H4

“ZMe

e

2. PBr3

BrH2C CH2Br

46

45

Zn

MA, dioxane

1. MeOH/H+

2. DDQ, toluene

47

C02Me Me02CP

C

O

2

M

e

C02Me 48 Scheme 8.

tetraester 48, set up for another cycle of the annulation process. The 4G-47 reduction step most likely involves o-xylylene intermediates, presumably generated in succession rather than in one step. A similar sequence was carried out with [4]dendralene 14 and via the expected cycloaddition products 49 and 50 the tetraester 51 was isolated after aromatization, again a compound which can be employed for further extension of its aromatic core (Scheme 9) [ 131.

I

425

426

I

Dendralenes: From a Neglected Class of Polyenes to Versatile Starting Materials in Organic Synthesis

Me0,C

C0,Me

15

49

+CHC1, ADDE

-

M

e

0

2

C

~

C

Me0,C

O

z

M

s

C02Me 50

toluene DDQ

Me02C&C02Me -

-

Me02C

C0,Me 51

Scheme 9.

In principle an [nldendralene can undergo [ n- 11 cycloaddition reactions. To test whether this potential is actually used by these multi dienes Sherburn and co-workers have treated various dendralenes with 4-phenyl-l,2,4-trizoline-3,5-dione (PTAD) [ 121. Since this is one of the most reactive dienophiles known, chances are high that indeed the full addition [5]-,and [bldendralene added PTAD 3, 4, potential of the dendralene is used. Indeed [4]-, and 5 times, as expected. With [8]dendralene the cycloaddition process stopped after fivefold PTAD-addition, very likely because the lower mass cycloadducts were too poorly soluble to engage in further cycloaddition steps. References

Overview: H. HOPF,Classics in Hydrocarbon Chemistry, Wiley-VCH, Weinheim, 2000, Chap. 2, pp. 5-18. 2 At present only one review article exists on dendralenes: H. HOPF,Angew. Chem. 1984, 96, 947-958; Angew. Chem. Int. Ed. Engl. 1984, 23, 947-959; see also ref. [ I ] , Chap. 11, pp. 251-300. 3 Review: H. HOPF,G. MAAS,Angew. Chem. 1992, 104,953-977; Angew. Chem. Int. Ed. Engl. 1992, 31,931-954. 1

H. HOPF,G. MAAS in The Chemistry of Dienes and Polyenes, Vol. I (Ed.: 2. RAPPOPORT), J. Wiley, Chichester, 1997, Chap. 21, pp. 927-977. 5 a) A. T. BLOMQUIST, J. A. VERDOL,].Am. Chem. Soc. 1955, 77,81-83; b) W. J. BAILEY, J. ECONOMY, J. Am. Chem. SOC. 1955, 77, 1133-1136; c) A. T. BLOMQUIST, J. A. VERDOL, ]. Am. Chem. Soc. 1955, 77, 1806-1809; d) W. J. BAILEY, C. H. CUNOV, L. NICHOLAS, /. Am. Chem. Soc. 1955, 77,

4

References I 4 2 7

2787-2790; e) H.PRIEBE, H. HOPF,Angew. Chem. 1982, 94, 299-300; Angew. Chem. Int. Ed. Engl. 1982, 21, 286-287. 6 J. I. G. CADOGAN, S. CRADOCK, S. GILIAM, I. GOSNEY, J . Chem. SOC.Chem. Commun. 1991, 114-115. 7 a) K. GREINER, Dissertation, Universitat Erlangen, 1960; b) C. A. AUFDERMARSH, US Patent 3264366, 19GG IChem. Abstr. 1966, 65, 20 003gl; c) W. J. BAILEY, N. A. NIELSEN,J. Org. Chem. 1962, 27, 30883091; d) L. K. BEE,J. W. EVERETT,P. J. GARRATT, Tetrahedron, 1977, 33, 21432150; e) L. SKATTEBaL, s. SOLOMON, /. Am. Chem. SOC.1965, 87,4506-4513; f ) W. Angew. Chem. GRIMME, H:]. ROTHER, 1973, 85, 512-514; Angew. Chem. rnt. Ed. Engl. 1973, 12, 505-507; g) W. R. ROTH, B. P. SCHOLZ, R. BREUCKMANN, K. JELICH, H.-W. LENNARTZ, Chem. Ber. 1982, 115, 1934-1946.

8

9

10

11

12 13

0. TSUGE, E. WADA,S. KANEMASA,Chem. Lett. 1983, 239-242; 0. TSUGE,E. WADA, S. KANEMASA, Chem. Lett. 1983, 15251528. A. ALMENNINGEN, A. GATAIL, D. S. B. GRACE,H.HOPF,P. KLAEBOE,F. LEHRICH, C. J. NIELSEN, D. L. POWELL, M. TRAETTEBERG, Acta Chem. Scand. Ser. A , 1988, 42, 634-650. P. T. BRAIN,B. A. SMART,H. E. ROBERTSON, M. J. DAVIS,D. W. RANKIN, W. J. HENRY, I. GOSNEY, I.Org. Chem. 1997, G2, 2767-2773. S. FIELDER, D. D. ROWAN,M. S. SHERBURN, Angew. Chem. 2000, 112, 4501-4503; Angew. Chem. Int. Ed. 2000, 39,4331-4333. M. S. SHERBURN, private communication to H. Hopf, March, 2002. H. HOPF,S. YILDIZHAN, unpublished work.

Fascinating Natural and Artificial Cyclopropane Architectures Rudiger Faust

The various facets of the chemistry of cyclopropane derivatives are amazingly diverse and continue to fascinate scientists from a broad range of backgrounds, among them theoreticians, synthetically or structurally inclined chemists, and researchers with interests in natural product and/or medicinal chemistry. The challenges posed by the intriguing cyclic arrangement of only three tetravalent carbons are multitudinous, ranging from fundamental aspects of bonding, over the synthesis of highly strained molecules to an understanding of the mode of action of biologically active cyclopropyl derivatives. Selected examples of cyclopropane architectures encountered in compounds either derived from natural sources or prepared for the first time in the laboratory are highlighted together with key steps of their syntheses in the following. The fact that nature has chosen to use a cyclopropane skeleton to design a defense mechanism for certain pyrethrum flowers against insect attack has been known since 1924, when Staudinger and Ruzicka isolated and characterised (+)-trans-chrysanthemic acid 1 from the petals of these plants [ 11. The active insecticidal ingredients in these plants are in fact esters of 1,which can be easily modified and which have been commercially exploited to give birth to one of the most successful classes of biomimetic insecticides, the pyrethroids. In 1997, the market value of this class of insecticides amounted to a staggering 1.5 billion US$ [ 2 ] .

H T C O O H H3C ‘CH3 1

IxcooH NH2 2

But chrysanthemic acid derivatives are by far not the only examples of cyclopropanecontaining structures in nature. In fact, the highly strained threemembered carbocycle is virtually ubiquitous. It occurs, for example, in every green plant in the form of 1aminocyclopropanecarboxylic acid (ACC) 2, a direct precursor to the plant hormone ethylene [ 3 ] . In addition, the cyclopropane unit is found in a variety of other natural products, inter alia in terpenes and in various cyclopropanated fatty acids [4]. The biochemical precursors of the latter are unsaturated fatty acids, and in view of the existence of polyunsaturated fatty

Fascinating Natural and Art$cial Cyclopropane Architectures

acids it is perhaps not too surprising that poly cyclopropanated analogues occur also in nature. And indeed, in 1990 Yoshida et al. were able to isolate the potent antifungal agent FR900848 (3) from the fermentation broth of Streptouerticillium feruens [ 51. The unusual architecture of 3, ultimately proven by total synthesis and X-ray crystallographic analysis [ G , 71, consists of four contiguous and one isolated cyclopropane unit, all of which are arranged on the same face of an all-trans-configurated carbon backbone. But the amazing array of five cyclopropane units in 3 is not unique. Shortly before the structure of 3 was unequivocally established, chemists at the chemical company Upjohn isolated U-1OG305 (4) from Streptomyces sp. [8]This latter compound had aroused the scientist's interest because it acts as an effective inhibitor of the cholesteryl ester transfer protein in the blood and can thus be envisioned to slow the progression of atherosclerosis. 0

3

1/

"

H

s

I

'

0 4

The remarkable structural similarity between compounds 3 and 4, the latter endowed with five contiguous out of a total of six cyclopropane units, suggests that they are synthesised along the same biochemical pathway. As with 3, the structure and the absolute configuration of 4 was established by a total synthesis [9, 101 that made use of an enantioselective cyclopropanation reaction of allylic alcohols developed by Charette et al. (Scheme 1) [ll].This method uses the preformed [Zn(CH212)].DMEcomplex 5 and capitalises on the asymmetric induction from the chiral dioxaborolane 6 which coordinates to the intermediate zinc alkoxide, formed by the reaction of 5 with the allylic alcohol [ 111. Following this protocol,

0

O H, , - / , - , HO

0 7

Scheme 1.

6

Zn(CH2I2)*DME 5 91% (89% ee)

*

H

O

T

o 8

Enantioselective cyclopropanation developed by Charette.

H

I

429

430

I

Fascinating Natural and Artificial Cyclopropane Architectures

2(E)-butene-1,4-diol7 , for example, is enantioselectively cyclopropanated to 8 in 91% yield (89% ee). The power of Charette's cyclopropanation method is aptly demonstrated by key steps in the synthesis of 4, during which the six cyclopropane units in its backbone were assembled by iterative cyclopropanations as outlined in Scheme 2 [lo]. Hence, periodinane oxidation of diol 8 to the corresponding dialdehyde, followed by Wittig olefination with Ph3 P=CHC02Et and DIBAL-H reduction to the bis-ally1 alcohol 9 sets the stage for a second, double Charette cycloprocyclopropanation to generate 10. The oxidation/olefination/reduction/two-fold panation cycle is then repeated to furnish the quinquecyclopropane 11. With five of the six cyclopropane units of 4 in place, the last one is implemented after oxidation of mono-silyl protected 11, extension of the carbon chain by a Wadsworth-Emmons-Horner homologation with (Me0)2P(0)CH2CH=CHC02Me,NaH and DBU, and reduction of the intermediate ester with DIBAL-H to give 12. The fourth Charette cyclopropanation, regioselective on the ally1 alcohol moiety then generates 13, from which U-106305 (4) is readily prepared in a few steps.

Me2NY:B-B~ 1. Dess-Martin periodinane 8

-

h"'" 0

Me2N HO

2. PhsPCH=C02Et 3. DIBAI-H

*

Zn(CH2I2)*DME 9

1. Oxidation

OH 2. Wittig olefination

* H

H O -

O

3. Reduction 4. Charette Cyclopropanation

10 1. Oxidation 2. Wadsworth-ErnrnonsHorner olefination

m

o

11 R=H R = TBSJ

HO

R

TBSCI, irnidazole

OTBS

3. Reduction 12

Charette Cyclopropanation

-

OTBS

HO 13

Scheme 2.

Synthesis of a quinquecyclopropane en route to U-106305.

Shortly after Barrett's publication of the successful approach to U-106305, Charette and Lebel reported the enantioselective synthesis of its non-natural enantiomer [ 121, and thereby further emphasised the power and the generality of their method. The same methodology was used to make the unnatural, all-trans septicyclopropane derivative 14 [ 101, the most highly cyclopropanated linear structure prepared to date.

Fascinating Natural and Artificial Cyclopropane Architectures

H

O

I

o

H

14

Multiple cyclopropyl groups can also be arranged in a spiro-fused fashion around a core carbocycle, giving rise to the structurally fascinating classes of the so-called rotanes and triangulanes [ 131. These hydrocarbons have been investigated extensively by the groups of Conia and de Meijere. In 1973, Fitjer and Conia prepared the smallest system in this series, the highly strained [3]rotane 15 [14]. More recently, de Meijere’s team presented a succession of highlights in this area, including the first synthesis of an enantiomerically pure [4]triangulane 16 [ 151, the stunning perspirocyclopropanated [ 3lrotane 17 [ 161, or even the [ 15ltriangulane 18 [ 171, a record-breaking arrangement of fifteen spiro-linked cyclopropane rings.

15

16

18

17

Compound 16, prepared to test the hypothesis that chiral, unfunctionalised and completely saturated hydrocarbons can show optical activity if sufficiently rigid, was found to have a remarkably high specific rotation = -648.2), which the authors attribute to the helical arrangement of the CT-CC bonds in 16. It was therefore suggested that 16 is a CTbond analogue of the aromatic [ nlhelicenes, a class of compounds with similarly large optical rotations due to a helical arrangement of their n-bond backbone [ 181. Most recently, de Meijere and coworkers have climbed yet another mountain in cyclopropane architecture and prepared tetracyclopropylmethane 19 (Scheme 3) [ 191. Many organoelement derivatives with the maximum number of cyclopropyl groups are known, and in fact the heavier (and larger) homologues of 19, namely tetracyclopropylsilane, -germane

S

O

H

MeC(OEt), * 3 C 0 2 E t ~

2. PBr3

3. f-BuOK

20

22

21

CH2N2 (10 equiv.) Pd(OAc)2 repeated 10 times 19 Scheme 3.

23

Synthesis of tetracyclopropylmethane and tetraisopropylrnethane.

I

431

432

I

Fascinating Natural and Artificial Cyclopropane Architectures

and -stannane had been made before [20]. However, the corresponding hydrocarbon has remained elusive, and earlier attempts to generate the compound using standard cyclopropanation methods failed. One of the key steps in the synthesis of 19 [19, 211 is the formation of its quaternary carbon centre, which is implemented by an orthoester Claisen rearrangement of the allyl-vinyl ether generated by heating a mixture or allylic alcohol 20 together with triethyl orthoacetate in diphenylether to 150 " C (Scheme 3). Manipulations of the ester group in 21, i.e. reduction, bromination of the intermediate alcohol and baseinduced dehydrobromination leads to the diolefin 22, which is then doubly cyclopropanated with diazomethane in the presence of palladium acetate to give 19. The difficulties encountered in the final step become apparent when one considers that 22 had to be subjected up to six times to the cyclopropanation conditions in order to maximise the yield. The large steric crowding around the methane carbon in 19 gives rise to dynamic conformational effects that have been investigated by variable temperature N M R spectroscopy [21].Furthermore, the accumulated ring strain in 19 makes this compound a suitable starting material for the preparation of one of the most sterically congested methane derivatives prepared to date: palladium-catalysed, regioselective hydrogenolysis of the least substituted cyclopropane bonds in 19 furnishes tetraisopropylmethane 23 in almost quantitative yield. The elegance of the synthetic route to a highly crowded molecule like 23 can be fully appreciated when one ponders the fact that the sterically even more fraught tetra-tertbutylmethane remains elusive. Further progress in the area of sterically congested cyclopropylmethanes has recently been made in the work of Ramana et al., who prepared a higher homologue of 19, namely tetrakis(cyclopropylmethy1)methane28 (Scheme 4) [ 221. Simmons-Smith cyclopropanation of the allylic alcohol 24 and transformation of the resulting alcohol 25 into its corresponding xanthate 26 generates an activated system, in which two allyl units can be introduced by a radical allyl transfer from allyltributyltin and AIBN to give 27. The target hydrocarbon 28 was then generated using a two-fold palladium-catalysed cyclopropanation with diazomethane and palladium acetate.

24

Scheme 4.

25

Synthesis of tetrakis(cyclopropylmethyl)rnethane.

26

References

This short excursion into the diverse field of natural and artificial cyclopropane architectures highlights the fact that cyclopropanes continue to provide stimuli for and challenges to current concepts of synthesis, structure and theory. It’s amazing what three carbons can do. References 1 H . STAUDINGER, L. RUZICKA,Helu. Chim. 2

3

4

5

6

7

8

9

10

11

12

Acta 1924, 7, 177-235. R. FAUST,G. KNAUS,U. SIEMELING, World Records in Chemistry, ( E d H.-J. QUADBECKSEEGER), Wiley-VCH, Weinheim, 1999, p. 95. S. F. YANG,N. E. HOFFMAN, Annu. Rev. Plant Physiol. 1984, 35, 155-189. J. MANN,Secondary Metabolism, Clarendon, Oxford, 1987, p. 42. M. YOSHIDA,M. EZAKI,M. HASHIMOTO, N. SHIGEMATSU, M. M. YAMASHITA, OKUHARA,M. KOHSAKA,K. HORIKOSHI, /. Antibiot. 1990, 18, 748-754. A. G. M. BARRETT,K. KASDORF,].Am. Chem. SOC.1996, 118, 11030-11037. J. R. FALCK,B. M E K O N N E N J.,Yu, J:Y. LAI,/. Am. Chem. SOC.1996, 118, 60966097. M. S. Kuo, R. J. ZIELINSKI, J. I. CIALDELLA, C. K. MARSCHKE, M. J. DUPUIS,G . P. LI, D. A. KLOOSTERMAN, V. P. MARSHALL, /. Am. C. H. SPILMAN, Chem. SOC.1995, 117, 10629-10634. A. G. M. BARRETT,D. HAMPRECHT, A. J. P. WHITE,D. J. WILLIAMS, /. Am. Chem. SOC. 1996, 118, 7863-7864. A. G.M. B A R R E D. ~ , HAMPRECHT, A. J. P. WHITE,D. J. WILLIAMS, /. Am. Chem. SOC. 1997, 119, 8608-8615. See also: A. G. M. BARRETT,D. HAMPRECHT, R. A. JAMES,M. M. A. TOLEDO, OHKUBO,P. A. PROCOPIOU, A. J. P. WHITE, D. J. WILLIAMS, /. Org. Chem. 2001, 66, 2187-2196. A. B. CHARETTE,H . JUTEAU, H. LEBEL,C. MOLINARO,/. Am. Chem. SOC.1998, 120, 11943-11952. A. B. C H A R E ~HE., L E B E L ,Am. ~ . Chem. SOC.1996, 118, 10327-10328.

13 A.

D E MEIJERE, S. I. KOZHUSHKOV, Chem. Rev. 2000, 100, 93-142. 14 L. FITTER,J. M. CONIA,Angew. Chem. 1973, 85, 349-3501; Angew. Chem. In&.Ed. Engl. 1973, 12, 334-335. 15 A. D E MEIJERE, A. F. KHLEBNIKOV, R. R. P. R. KOSTIKOV,S. 1. KOZHUSHKOV, A. WITTKOPP,D. S . YUFIT, SCHREINER, Angew. Chem. 1999, 111, 3682-3685; Angew. Chem. Int. Ed. 1999, 38, 34743477. 16 S. J. KOZHUSHKOV; T. H A U M A N NR.. BOESE,A. D E MEIJERE, Angew. Chem. 1993, 105,426-429; Angew. Chem. Int. Ed. 1993, 32, 401-403. 17 M. VON SEEBACH, s. I. KOZHUSHKOV, R. BOESE,J. BENET-BUCHHOLZ, D. S . YUFIT,J. A. K. HOWARD,A. D E MEIJERE, Angew. Chem. 2000, 112, 2617-2620; Angew. Chem. Int. Ed. 2000, 39, 24952498. 18 R. H. MARTIN,Angew. Chem. 1974, 86, 727-738; Angew. Chem. Int. Ed. 1974, 13, 649-660. 19 S. I. KOZHUSHKOV, R. R. KOSTIKOV, A. P. MOLCHANOV, R. BOESE,J. BENETBUCHHOLZ, P. R. SCHREINER, C. RINDERSPACHER, I. GHIVIRIGA, A. DE MEIJERE,Angew. Chem. 2001, 113, 179182; Angew. Chem. In&.Ed. 2001, 40, 180-183. 20 B. BUSCH,K. DEHNICKE, /. Organomet. Chem. 1974, 67, 237-242. 21 J. E. ANDERSON, A. D E MEIJERE,S. I. KOZHUSHKOV, L. LUNAZZI,A. MAZZANI, /. Am. Chem. SOC. 2002, 124, 6706-6713. 22 C. V. RAMANA, S. M. BAQUER,R. G. GONNADE, M. K. GURJAR,Chem. Commun. 2002,614-615.

I433

Organic Synthesis Highlights V Edited by Hans-Gunther Schmalz and Thomas Wirth Copyright02003 WILEY-VCH Verlag GmbH & Co

I435

Index

a acetals 252 N-acetylaminoacrylicacid 195 acetylenedicarboxylicacid dimethyl ester 423 acyclic stereocontrol 75 acyloxyborane 173 - chiral 173 1,4-addition 73 - Gilman cuprates 73 adociasulfate 342ff - synthesis 342ff aldol condensation 4 aldol reaction 8, 49, 168, 174, 179, 180, 307, 328ff, 351 - asymmetric 49, 179 - catalytic 174, 179 - diastereoselective 168 aldolase type I 181 alkane 36ff alkene 210ff alkene formation 40 alkene metathesis 31 alkylation 283 - of secondary amines 283 alkyne metathesis 27ff allenes 56ff, 59, 63, 64 - carboxylic esters 63 - cyclopropyl 57 - neighbouring functional groups 64 - neighbouring OH- or NH 59 -vinyl 57 allenyl ketones 62 allenyl sulfones 65 allyl silanes 138 allyl stannanes 138 allyl transfer 432 - radical 432

allylic substitution 79 - organocopper reagents 79 amines 134, 218 - homoallylic 134 - medium ring size 218 amino acids and derivatives 126, 134, 178ff - r-amino nitriles 136 - p-amino acids and derivatives 136, 183 - 8-amino esters 137 - unnatural 126 - synthesis 187 1,2-aminoalcohol 118 aminoalkylations 134ff, 138 aminocyclopropanecarboxylic acid 428 aminoglycosylation 390 aminohydroxylation 118ff, 298 p-amino ketones 182 1,2-aminothiols 370 annulation 425 annulenes 419 anomeric center 5 anti-skew-conformation 422 arene synthesis 54 Arndt-Eistert reaction 336, 339 aryl triflate 344 - Pd-catalyzed reduction 344 arylation 15 -phenols 15 asymmetric 127, 130 - alkylation 94, 125ff - - glycine derivatives 125 - - of benzaldehyde 94 - aminohydroxylation (AA) 118 - catalysis 187 - - Strecker-type reactions 187

cyclopropanation 130 epoxidation 127 - induction 71 - - directed hydroformylation 71 - Michael reactions 127 atropisomers 298ff AUC13 5Off - as catalyst 5Off azasugars 120, 386 aziridines 60 azomethine ylide 361 -

-

b Barbier-type cross coupling 90 Barton deoxygenation 344 Baylis-Hillman reaction 89, 119, 165ff - asymmetric 165ff benzopyran 404 Biginelli reaction 89 BINOL 94, 170, 189ff - fluorous 94 BINOL complex 213 Biphen-Mo catalysts 212 BMIM 105ff boron enolate 309, 354 - chiral 309, 354 boronic acids 19 - aryl ether formation 19 borylation 45 - of alkanes 45 brucin 169 bryostatin 307ff - analogues 312 buckyonions 409 buckytubes 409 Burgess-reagent 310

436

I

Index C

Cao 409 calcimycin 74 carbene complex 112 carbocycles 3, 7, 216 - medium ring size 216 - ring-contracted 7 carbocyclic polyols 1 - biosynthesis 1 carbocyclization 3 carbohydrates 237, 387 - solid phase synthesis 237, 387 carbonylation 42, 100 - ofolefins 50 - - gold-catalyzed 50 - radical 100 carbonylative cyclization 60 - ruthenium-catalyzed GO (+)-carvone 317 catalyst immobilisation 114 catalyst-directing group 69ff catalysts - amino acid 178ff - immobilization 93 - metal-free 178 - peptide 178 C-H activation 36, 53 chalcones 406 Charette cyclopropanation 430 chiral DMAP 152 chiral N-oxide 191 chirality 64 chirality transfer 59 - axial-to-central 59 - central-to-axial 64 chloroarenes 22 chromium 17 - n-complexes 17 chrysanthemic acid 428 cinchona alkaloids 170, 202 cinchonidinium and cinchoninium salts 125 - phase transfer catalysis 125 citronellol 293 civetone 29 Claisen rearrangement 9, 110, 432 - orthoester 432 cleavage 251, 255, 256, 261 - carbon-nitrogen bonds 255 - carbon-selenium bonds 261 - carbon-sulfur bonds 256 - of carbon-phosphorus 256

cyclophanes 409 cyclophilin 350, 358 organogermanium 251 cyclophynes 413ff - radical-mediated 261 cyclopropanation 130, 429, 432 - silanes 251 - asymmetric 130 [COZCO,] 58 - diazomethane 432 combinatorial chemistry 286, - enantioselective 429 319 - [Zn(CH212)].DME 429 combinatorial synthesis 242 cyclopropanes 428ff n-complexes 17 cyclotriveratrylene 111 -chromium 17 cytochrome b562 380 -iron 17 cytostatic agents 317 - manganese 17 - ruthenium 17 d compound libraries 319, 395, DABCO 166 387, 397 - Baylis-Hillman-reaction 1G6 condensation 8 Danishefsky’s diene 90, 289 copper(I ) triflate 18 decarbonylation 414 copper(I1) acetate 19 decarboxylation 363 - aryl ether formation 19 Degussa process 37 Corey-Bakshi-Shibata dehydrogenation 38, 146 reagent 310 - of alkanes 38 coupling 17, 22ff, 42, 64 - of aldehydes and - C-C-bonds 42 ketones 146 - Heck 22 dehydrohomoancepsenolide 31 - palladium 17 dendralene 419ff, 423 - - - catalyzed 64 deoxymannojirimycin 120 - Stille 23 deracemization 174 - Suzuki 22 - palladium 174 CP-225,917 326ff Dess-Martin oxidation 317, CP-263,114 32Gff [CP~H~CI~I-A~OSO 389 ~ C F ~ 344 Dess-Martin periodinane 144, - glycosylation 389 310, 329ff, 354 cross metathesis 222 - intermolecular 222 desymmetrization 214 1,2-diamine 293 cross-coupling 97 - palladium 97 (1S,2S)-diaminocyclohexane 295 cross-metathesis 244 diaminosuberic acid 31 Cu(0Tf)z 295 - as isostere of cystine 31 cyclic peptides K 15 diary1 ethers 15ff cyclisation 406 diazomethane 432 - electrophilic 406 - cyclopropanation 432 cyclitols 1 Dieckmann cyclization 337 cycloadditions 90 [2+2] cycloadditions 63, 91, 328 Diels-Alder reaction 328, 331, 336,401,420f [ 3+2] cycloadditions 8, 10 - diene transmissive 421 [4+1] cycloadditions 57 1,G-dienes 212 [4+2] cycloadditions 57, 420 1,7-dienes 214 [4+4+1] cycloadditions 57 1,x-dienes 210ff [5+1] cycloadditions 57 diethyl zinc 89, 160, 293, 295 cycloalkynes 409 dihydrofuran 61 - strained 409 dihydropyrroles GO cyclogeranyllithium 344 diketopiperazine 361 cyclohexa-l,4-dienes 121 dimethyldioxirane 390 cyclopentanes 223

- organoboron 251 -

lndex I 4 3 7

anti-diols 180 dioxirane 348 [ 1,3]-dipolar cycloaddition 154, 363 discodermolide 322 dithiane 331 DMAP 266 - polymer-bound 266 domino reactions 52, 77, 168, 173, 328 - hydroformylation-Wittig olefination 77 - Michael-aldol 173 - Michael-aldol-retroMichael 168 dysidiolide 400

e electron-rich arenes 52 - functionalization 52 a$-unsaturated carboxylic esters 119 electrophilic selenium 261 eleutherobin 317ff -total syntheses 317 eleuthosides 317 elimination 38 - /I-hydride 38 1,2-eliminations 420 EMIM 106ff enamine 181 enantioselective alkylation 131 enantioselective synthesis 210ff endo-brevicomin 216 enol-ethers 3 enzymatic catalysis 391ff - glycosylations 391ff enzymatic glycosylation 392 enzyme 152 - rhodococcus 152 enzyme-catalyzed reactions 84, 391ff epilachnene 29 epothilone 322 epothilone C 32 epoxidation 86, 127, 184 - asymmetric 127, 184 epoxide opening 86, 206 - nucleophilic enantioselective 206 a$’-epoxy ketones 184 erythromycin A 398 EtzZn 89, 160, 293, 295 Evans oxazolidinone 338, 354

explosions 409 - as synthetic tool 409

f

farnesyl transferase 326 inhibition 326 FeC13.6 H20 88 Ferrier (11) cyclization 3 Finkelstein reaction 91 fluorination 201ff, 206 - enantioselective 201 - transition metal catalysed 206 N-fluorobenzosulfonimide 201 fluoronium cations 201 fluorous solvents 93ff fluorous-phase 93ff Fmoc-strategy 231 FR-900848 429 Friedel-Crafts acylation 109 fullerenes 409 fulvenes 419 functional polymers 266 furans 50 - from allenyl ketones 50 - from propargyl ketones 50 -

g

galactosyltransferase 393 galanthamine-library 402 garsubellin A 273 Gilman cuprates 73 - 1,4-addition 73 glycals 390 glycine derivatives 125 - asymmetric alkylation 125 glycosidation 302ff glycosides Iff glycosyl phosphates 386ff - oligosaccharide synthesis 386ff glycosylation 237ff, 317ff, 384ff, 388 - orthogonal 388 gold 48ff - catalysis 48ff green chemistry 107 Gmbbs’ catalyst 31, 211, 398 guanidines 190

h hafnium 389 Hajos-Eder-Sauer-Wiechert reaction 182

Heck reaction 22, 112, 328ff, 365 heterocycles 146, 216, 273 - as scaffolds 273 hetero-Diels-Alder reaction 90, 289 HOBT 267 homoepilachnene 29 homogeneous catalysis 86 homometathesis 215 Horner-Wadsworth-Emmons olefination 73 Hunsdiecker reaction 276 hydride elimination 37 hydroaminomethylation 75 hydroboration 94 - Rh catalyzed 94 hydrocarbons 256 - synthesis 256 hydrocyanation of 188ff hydroformylation 69ff - diastereoselective 69 hydrogenation 76, 194ff, 196 - enantioselective 194, 196 - imine 76 hydrogenolysis 432 - palladium 432 y-hydroxy lactol 331 hydroxymercuration 3 hypervalent iodine reagents 144ff

i IBX 144ff immobilization 93 - of catalysts 93 indium trichloride 89 indolactam library 397 In(0Tf)j 168 ionic liquids 105ff Ireland-Claisen rearrangement 351, 354 iridium complexes 39 iron 17 - n-complexes 17 isatoic anhydride 290 itaconic acid 195

j

Jones oxidation 339 Julia olefination 309 Julia-Kocienski olefination 357 Julia-Lythgoeolefination 311

438

I

Index (R,R)-DIOP 195 (S,S)-DIOP 162 - sulfonamide 293 - tri-teit-butyl-phosphane 22 linkers 251ff lipase 85, 152 - Candida antarctica 85 - crosslinked 152 Luche-reduction 313

k

-

(-)-kallolide B 59 ketimines 136 kinetic resolution 151ff, 157, 162,217 - divergent 157 -dynamic 162 - parallel 151ff

-

motuporamine 29 (-)-mycestericin E 171

n Nagata reagent 331 nakadomarin A 31 nanostructures 412 native chemical ligation (NCL) 374ff natural products 396 I - solid-phase synthesis 396 m lactams 29 nickel 24 macrocycles 29, 307, 350 - macrocyclic, by alkyne macrocyclization 33, 298ff, 313 - catalysis 24, 63 metathesis 29 nicotine 169 - macrotransacetalization 313 lactones 29 macrolactonization 42, 308, 354 y-nitro ketone 183 - macrocyclic, by alkyne nitroolefination 365 macrolides 307 metathesis 29 nonataxel 322 magireol 347 y-lactones 160 Nozaki-Kishi cyclization 318 MALDI-TOF mass spectroLa(OTf)3 166 nucleic acids 237 - Baylis-Hillman-reaction 166 metry 385 - solid phase synthesis 237 Lewis acids 110, 136, 166, 168, manganese 17 - n-complexes 17 295, 342, 343 nucleophilic substitution 201 Mannich bases 134, 137 Ley reagent 356 - fluoride anion 201 LiA1H(OtBu)3 3 Mannich reaction 182 - three-component 182 LiEtjBH 344 0 ligands 22, 23, 24, 38, 40, 60, manumycin C 130 (o-DPPB) 70 86, 90, 122, 135, 137, 157, 160, manzamine alkaloids 120 - as a catalyst-directing 162, 194ff, 213, 293, 295 mCPBA 339 group 70 - alkaloid 122 Ohira-Bestmann MeAlClz 342 - alkaloid (DHQD)zAQN 157 N-mercaptobenzyl-peptides homologation 354 - anthraphos 40 379 olefin-metathesis ZlOff, 401 - BINAP 162, 195 Merrifield resin 319, 387 - asymmetric 210 - bis(diary1)phosphoms 198 Merrifield peptide oligonucleotides 230ff - bis(oxazoline) 60 synthesis 230, 376 - solid phase synthesis 230ff - 2,2’-bispyrimidine 38 metathesis 27ff, 210ff, 219 oligosaccharides 230ff, 384ff - chiral Schiff base 295 - alkynes 27ff - solid phase synthesis 230ff, 384ff - (DHQ)zPHAL 122 - asymmetric 210 - 2-dimethylamino-2’-di-(tee.- ring-closing 210 Oppolzer-sultame 167 buty1)-biphenyl 24 - ring-opening 210 organocopper reagents 79 - (dimethy1)phenylimido 213 - tandem reaction 219 - allylic substitution 79 - diol 90 metathesis catalysts 211ff, 225 organozinc reagents 173 - diphosphanes 196 - Mo-based 211ff - copper-catalyzed 173 - diphosphites 196 - Ru-based 211, 225 ortho-quinones 149 - diphosphonites 196 methyl-ephedrine 169 osmium 118ff methylprolinol 169 -DuPHOS 195 oxazolidinone 398 - imino peptide 135 Michael acceptors 167 oxidations 82, 144ff, 148, 149 - monodentate - chiral 167 - aromatics 82 monophosphoms 194 Michael addition 88, 127, 182f, - benzylic position 148 - 0-(di-teitbutyl-phosphino). 398,401 - hydrocarbons 82 biphenyl 23 - asymmetric 127, 182f - of alcohols 144ff - phosphinooxazoline 86 - diastereoselective 398 -phenols 149 - phosphoramidites 160, 197 Mitsunobu reaction 273 oxy-Cope rearrangement 328, - (R)-2,2‘-DiphenylMo-alkylidenes 212 336 [ 3,3’]biphenanthrenyl-4,4’- Mo(CO), 28 - silyloxy-Cope variant 328 diol = (R)-VAPOL 137 - alkyne metathesis 28 oxygenation 37

-methane 37 ozonolysis 356

pincer complexes 40 platinum 38 - catalysis 38 P,N-ligands 174 P paditaxel 322 - C2-symmetric 174 palladacycles 25 poly-amino acids as 184 palladium 17, 22ff, 97, 99, 112, polycarbonates 83 113, 174, 365,432 polyene cyclization 342ff - catalysis 22ff, 64 polyenes 419ff - - amination 24 polyketide 73, 307 - - reduction 64 polymeric scavenger - cross-coupling 17, 64, 97 reagents 280ff - cyclopropanation 432 polymerization 411 - deracemization 174 - topochemical 411 - dimerisation of polymer-supported catalyst methylacrylate 113 224 - Heck reaction 112, 365 polymer-supported - Stille cross-coupling 99 reagents 144, 265ff - IBX 144 [PdClz(CH3CN)2] 423 polymer-supported WdPPP) 344 Pd(0Ac)z-catalyzed synthesis 395ff carboxymethylation 331 polypropylene processes 83 pentadecalactone 85 L-proline 134, 179 peptides 178ff, 230ff, 369, 372 prostaglandin EZ 32 protecting groups 230ff - chemoselective bond - activating 230ff formation 372 - chemoselective ligation 369 proteins 368ff - solid phase synthesis 230ff - chemical total synthesis - - Merrifield synthesis 230 368ff - template-mediated 372 - solid-phase synthesis 368 pericyclic reactions 420 pyrans 222 perrottetines 15 pyridine-N-oxides 121 Peterson olefination 354 pharmacophore 322 9 phase transfer catalysis 125ff quaternary carbon atoms 136 - asymmetric 125ff r (-)-a-phellandrene 318 racemization 414 phenols 15, 149 radialenes 419 - arylation 15 radical reactions 36, 84, 99ff - oxidation 149 - fluorous phase 99ff phenyliodine(II1) bis(trifluor0acetate) 357 R-BINAP 36df 4-phenyl-l,2,4-trizoline-3,5- reactions in supercritical dione 426 coz 101 reagent-directing group 68ff PhI(0Ac)z 401 - substrate control 68ff phomoidrides 326 phosphitylation of alcohols 274 rearrangements 8, 48, 58 phosphonium salts 256 - of hydrocarbons 48 - vinyl cyclopropane/ PhSeLi 168 Pictet-Spengler cyclopentenc 58 reduction 64 condensation 360 - palladium-ca:alyzed 64 pinacolborane 45 reductive amination 283 pinacol-like rearrangement - primary amine 283 361

resin-capture-release 265 Rh2(4S-MEOX)4 157 [ RhCl(PPh3)3] 194 rhazinilam 42 rhodium - catalysis 42, 69ff, 194, 198 - hydroformylation 69ff rhodium-complex 45 riccardin B 15 ring-closing alkyne metathesis 28 rotanes 431 Rw(CO)IZ 87 ruthenium 17,43,60, 86, 87 - catalysis 43, 60, 86 - x-complexes 17 - carbonylative cyclization 60 S

safety-catch linker 376 saframycin A 267 Sakurai addition 328 salen complex 188 sanglifehrin A 350ff sarcodictyin 319, 317 - libraries 319, 397 Sc(OTf), 110, 343 scalarenedial 346 scavenger resins ZSlff, 265 Schiff base catalysts 188 Schrock-catalyst 210ff selectfluor 203 L-selectride 289 selenium-derived reagents 271ff, 328 - polymer-supported 271ff selenocysteine 378 SeO2 oxidation 328 sequential transformations 75, 363 Shapiro olefin synthesis 270 Sharpless asymmetric dihydroxylation 118, 357 [ 3, 31 sigmatropic rearrangement 9 silver ammonium nitrate 252 silver(I)-catalysts 60 Simmons-Smith 432 single-electron transfer [SET) 146 Srnlz 8 SN2’reaction 61, 173 - copper-catalyzed 173 - palladium-catalyzed 61

440

I

Index

SNAr 301 macrocyclization 301 - reactions 270 sodium periodate 336 solid phase synthesis 230ff, 251, 280, 265ff, 384ff - oligonucleotides 230ff - oligosaccharides 230ff, 384ff - peptides 230ff - traceless linkers 251 solvent-free organic syntheses 82 sophorolipid lactone 33 spiroisoxazolines 8 [ 5.51 spiro-lactam 350 spirotryprostatins 360ff - total synthesis 360ff squalene hexaepoxide 347 squalene synthase 326 - inhibition 326 squalene 2,3-epoxide 342 Staudinger ligation 380 Staudinger reaction 381 Stille coupling 23, 99, 270, 318. 350, 354,423 Strecker reaction 135, 137, 365 Strecker-typereactions 187ff - catalytic asymmetric 187ff structure/activity relationship 320 - sarcodictyin IibraDj 320 substrate control 68ff - reagent-directing group 68ff sulfoxide glycosyl donors 387 superferrocenophane 417 superphane 417 -

Suzuki coupling 22, 252, 256, 275ff, 290, 328. 398 t

TADDOL 206ff Takai olefination 355 tamoxifen 276 tandem Mo-catalyzed metathesis 219 taxoid library 397 teicoplanin 304 tertiary alcohols 217 tetramethylguanidine 89 teurilene 347 thiazolidines 370 thiazolidinyl ester 374 thioethers 256 thioglycosides 241, 275 TiClZ(0iPr)z 308 Tic13 365 Ti(OiPr)C13 5 tipranavir 220 titanium 189 - Strecker reaction 189 Tl(NO,)3 15 TMSOTf 386 toxicol A 344 traceless linkers 251 transesterification 94 transition metal catalysis 111 - in ionic liquids 111 triangulanes 431 triazenes 255 tricarbonylchromiurn complexes 168 trichloroacetimidates 240, 384ff triene 214 triisobutylaluminium 4

triphenylarsine 87 L-tryptophan methyl ester 360 tubulin 323 tubulin polymerization 320 U

U-106305 429 Ullmann reaction

15

vw valdivones 317 vanadium-catalyzed 61 vancomycin 15, 297ff - total syntheses 297 vinyl epoxides 60, 160 Wadsworth-Emmons-Horner homologation 430 Weinreb amides 270, 354 Wieland-Miescher ketone 182 Wilkinson catalyst 94 - fluorous analogue 94 Wittig olefination 72, 319, 430 Wittig ylide 398 - polymer-bound 398 Wittig-Horner reaction 357 Wolff rearrangement 336

Y

Yamaguchi macrolactonization 309, 311 ytterbium triflate 89 Z

(2)-N-acetylaminocinnamic acid 195 - esters 195 Ziegler-Natta process 83 zirconium catalysts 136