Advances in Cycloaddition. Volume 5

ADVANCES IN CYCLOADDITION

Volume 5

9 1999

This Page Intentionally Left Blank

ADVANC CYCLOADDITION Editor'.

MICHAEL HARMATA

Department of Chemistry University of Missouri-Columbia

VOLUME5

9 1999

JAI PRESS INC.

Stamford, Connecticut

Copyright 91999 JAI PRESSINC 1O0 Prospect Street Stamford, Connecticut 06904

All rights reserved. No part of this publication may be reproduced, stored on a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, filming, recording, or otherwise, without prior permission in writing from the publisher. ISBN: 0-7623-0346-8 ISSN: 1052-2077 Manufactured in the United States of America

CONTENTS

LIST OF CONTRIBUTORS

vii

PREFACE

Michael Harmata

THE SYNTHESIS OF SEVEN-MEMBERED RINGS: GENERALSTRATEGIES AND THE DESIGN AND DEVELOPMENT OF A NEW CLASS OF CYCLOADDITION REACTIONS

Paul A. Wender and Jennifer A. Love

RECENT ADVANCES IN DIELS-ALDER CYCLOADDITIONS OF 2-PYRONES

Benjamin T. Woodard and Gary H. Posner

47

THE INTER- AND INTRAMOLECULAR [4+4] PHOTOCYCLOADDITION OF 2-PYRIDONES AND ITS APPLICATION TO NATURAL PRODUCT SYNTHESIS Scott McN. Sieburth

85

[3+4] ANNULATIONS BETWEEN RHODIUM-STABILIZED VINYLCARBENOIDS AND DIENES

Huw M. L. Davies

INDEX

119 165

This Page Intentionally Left Blank

LIST OF CONTRIBUTORS

Huw M.L. Davies

Department of Chemistry State University of New York at Buffalo Buffalo, New York

Jennifer A. Love

Department of Chemistry Stanford University Stanford, California

Gary H. Posner

Department of Chemistry Johns Hopkins University Baltimore, Maryland

Scott McN. Sieburth

Department of Chemistry State University of New York at Stony Brook Stony Brook, New York

Paul A. Wender

Department of Chemistry Stanford University Stanford, California

Benjamin T. Woodard

Department of Chemistry Johns Hopkins University Baltimore, Maryland

vii

This Page Intentionally Left Blank

PREFACE The development and application of cycloaddition methodology continues to be at the forefront of research in synthetic organic chemistry. This volume is a testament to the vitality of the field. Paul Wender and Jennifer Love start things off with a review of methods available for the synthesis of sevenmembered rings, before delighting us with their impressive work on metalcatalyzed cycloadditions. Benjamin Woodard and Gary Posner provide an exciting update on the cycloaddition chemistry of 2-pyrone. A unique application of photocycloaddition is detailed by Scott Sieburth in his report on 4+4 cycloadditions of 2-pyridones. Huw Davies concludes the volume with an interesting discussion of his groups latest explorations of the reaction of rhodium-stabilized vinyl carbenoids with dienes. I want to thank A1 Padwa and JAI Press, especially Fred Verhoeven, for their help. The final touches for this volume were made while I was on research leave at the Georg August Universitat in G/3ttingen. I need to thank the Alexander von Humboldt Foundation for a fellowship and Professor Reinhard Brtickner (then Gtittingen, now Freiburg) and Lutz E Tietze (Gtittingen) for their hospitality. Finally, this work is a continuing series. Though submissions are by invitation only, I would be happy to accept suggestions or nominations for contributions to future volumes. Michael Harmata Editor

This Page Intentionally Left Blank

THE SYNTHESIS OF SEVEN-MEMBERED RINGS: GENERAL STRATEGIES AND THE DESIGN AND DEVELOPMENT OF A NEW CLASS OF CYCLOADDITION REACTIONS

Paul A. Wender and Jennifer A. Love

Abstract

I~ II.

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

Introduction

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

2 3

Seven-Membered Rings from Acyclic Precursors .........

5

A.

Nucleophilic . . . . . . . . . . . . . . . . . . . . . . . . . .

6

B.

Electrophilic . . . . . . . . . . . . . . . . . . . . . . . . . .

7

C.

Radical

9

D.

Metal Carbene . . . . . . . . . . . . . . . . . . . . . . . .

10

E.

Transition-Metal

10

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

Advances in Cycloaddition Volume 5, pages 1-45. Copyright 9 1999 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0346-8

PAUL A. WENDER and JENNIFER A. LOVE III.

IV.

V.

VI.

VII.

VIII.

Seven-Membered Rings from Larger and Smaller Rings . . . . . A. One-Atom Expansions . . . . . . . . . . . . . . . . . . . . B. Two-Atom Expansions . . . . . . . . . . . . . . . . . . . . C. Three-Atom Expansions . . . . . . . . . . . . . . . . . . . D. Four-Atom Expansions . . . . . . . . . . . . . . . . . . . . E. Ring Contractions of Larger Rings . . . . . . . . . . . . . . Seven-Membered Rings from Fragmentation Strategies . . . . . A. Fragmentations of Bicyclo[3.2.0]heptanes . . . . . . . . . . B. Fragmentations of Bicyclo[4.1.0]heptanes . . . . . . . . . . Cycloaddition Strategies for Seven-Membered Ring Synthesis A. [4+3] Cycloadditions . . . . . . . . . . . . . . . . . . . . . B. [5+2] Cycloadditions . . . . . . . . . . . . . . . . . . . . . C. Other Cycloadditions Leading to Seven-Membered Rings Transition-Metal-Catalyzed [m+n] Cycloadditions . . . . . . . . A. [4+4] Cycloadditions . . . . . . . . . . . . . . . . . . . . . B. [4+2] Cycloadditions . . . . . . . . . . . . . . . . . . . . . Design and Evolution of a New Reaction: Metal-Catalyzed [5+2] Cycloadditions . . . . . . . . . . . . . . A. Intramolecular [5+2] Cycloadditions of Yne-Vinylcyclopropanes . . . . . . . . . . . . . . . . . . . B. Intramolecular [5+2] Cycloadditions of Ene-Vinylcyclopropanes . . . . . . . . . . . . . . . . . . . C. Intramolecular [5+2] Cycloadditions of Allene-Vinylcyclopropanes . . . . . . . . . . . . . . . . . D. Total Synthesis of Dictamnol . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11 12 12 13 13 15 15 15 16 . 17 18 19 . 21 23 23 26

ABSTRACT This chapter provides an overview of representative methods for synthesizing seven-membered rings with special emphasis on a new class of reactions, the [5+2] cycloadditions of vinylcyclopropanes with re-systems, a flexible, selective, and efficient homologue of the DielsAlder reaction.

29 30 32 36 39 40 40 41

The Synthesisof Seven-Membered Rings I. I N T R O D U C T I O N Organic synthesis has played a major role in the evolution of modem science, providing access to novel medicinal agents, new materials, fascinating structures of theoretical interest, and critical insights into their properties and transformations. ~From bucky balls and space-age plastics to new therapeutic leads and cures, synthetic chemistry has transformed the way scientists approach a wide range of problems and has quite literally changed their views of what is possible. In addressing many problems at the molecular level, we are no longer constrained to consider only what is available or what nature has produced, but now we can design what is desirable and, in many circumstances, synthesize such designed systems with practical efficiency. The increasing sophistication of synthesis has beneficially transformed virtually every field of science, including most notably biotechnology, medicine, and materials science. It has also enabled the emergence of fundamentally new areas of research, such as combinatorial synthesis and nanotechnology, that will shape the practice of science in the next century. The continuing evolution of organic synthesis and its role in the broader context of science are inexorably coupled to the design, discovery, and development of new reactions and strategies that enable the preparation of high technology targets from readily available materials in a simple, safe, and practical fashion. 2 In this chapter, we place special emphasis on a new class of reactions that have great potential for addressing a range of problems in seven-membered-ring synthesis, including both natural and designed systems with exceptional biological activity (Figure 1). We also illustrate how the conceptual basis for this process can be used to design other new reactions to synthesize a variety of ring systems and sizes. To establish the synthetic context for this new class of reactions, we provide first a

classification of the four generic strategiesfor synthesizing any ring system. Using this organizational backdrop, we 9focus then on the specific problem of making seven-membered rings and initially give an overview of strategies and representative methods for addressing this problem. Subsequently we describe the design and development

of a new class of cycloaddition reactionsfor seven-membered ring synthesis, namely, [5+2] cycloadditions of vinylcyclopropanes and

PAUL A. WENDER and JENNIFER A. LOVE OR .....

ilt,. / ~ ~ , / . .

H

,#r

i

o

i II

Y.,

H H

HO"HdHO#,~OH

~ON

phorbol esters

ingenol

lao,~ Ph

O

,~OMe 0 '~'~" "OH resiniferatoxin

OMe cephalotaxine

Figure 1. Seven-membered rings in natural products. various n-systems, remarkable homologues of the Diels-Alder cycloaddition. The synthesis of any ring system can be categorized in one of four strategic classes (Scheme 1): closure of an acyclic precursor, ring size alteration (expansion or contraction), fragmentation, and cycloaddition. The effectiveness of each strategy depends on the specific nature of the problem of interest. However, these strategies are based on different types of starting materials and, as such, they proceed with different changes in complexity. In its simplest form, for example, acyclic closure requires forming one new bond (+ l bd) to complete a

Acyclic Closure

~+lbd, -lbd

Ring Size Alteration

g

(C~ ",C,J

-nbd~l

Cycloaddition

Fragmentation

Scheme 1. Strategies for ring formation.

The Synthesis of Seven-Membered Rings ring. As such, the cyclic target is typically more complex than the acyclic starting material. Such increases in complexity are required for synthetic brevity because the principal objective of most syntheses is to connect simple starting materials to complex products in the fewest number of steps. Synthetic sequences that decrease complexity, increase complexity beyond the target level, or do not change complexity generally do not lead to concise syntheses. Strategies that involve ring size changes also require forming one new bond, although another bond must also be cleaved. Thus, although these transformations can be conducted serially or as part of a single operation, the complexity of the target is not necessarily greater than that of the starting material. As a result, the synthesis of the starting material can be as difficult as that of the target ring. Of course, easy access to either the larger or smaller ring precursor can compensate for the modest change in complexity attending a ring size change. In a fragmentation reaction, the target ring, already in place, is made up of two or more smaller rings. Consequently, this strategy requires cleavage of subtended-ring bonds. As with ring size alterating processes, the product of a fragmentation reaction is often less complex than the starting material. Nevertheless, fragmentation reactions are of great value in synthesis, especially when the precursors are readily available and the product is a macrocycle, i.e., a system for which other approaches are less well developed. The special significance of cycloadditions can be appreciated by this analysis of complexity because cycloadditions rely on simple starting materials, offer synthetic convergence, and utilize reactions that form two bonds, collectively representing a highly advantageous strategy for ring formation.

II.

SEVEN-MEMBERED RINGS FROM ACYCLIC PRECURSORS

The merit of each strategy for ring formation is influenced by the specific nature of the problem under consideration. The size of the ring to be formed is often a major factor. For example, closure of an acyclic precursor to form a three-membered ring is a strategy which generally benefits from favorable entropic factors because relatively few degrees of freedom in the acyclic precursor must be controlled to reach the transition state for ring formation. On the other hand, this

PAUL A. WENDER and JENNIFER A. LOVE

process is enthalpically disfavored because it proceeds with the development of strain. In comparison, when applied to six-membered rings, the same type of closure strategy is enthalpically less problematic. To form larger rings based on acyclic closure, entropic factors become more of a problem, often necessitating the use of high dilution techniques to counteract competing intermolecular reactions. Compensating for the entropic limitations encountered in some applications of the acyclic closure strategy are the number of possible procedures for effecting acyclic closure and the simplicity of the starting materials. Virtually any bond-forming reaction can be performed intramolecularly to form a ring from an acyclic precursor, as illustrated later. The approaches are classified according to the type of reactive intermediate involved. The vast majority of these bond-forming reactions fall into one or more of these classifications: nucleophilic, electrophilic, radical, carbene (or metal-stabilized carbene), and organometallic.

A. Nucleophilic Intramolecular alkylation reactions provide simple examples of the powerful utility of acyclic closure as a strategy for synthesizing seven-membered tings. A key step in the syntheses of ambrosin, damsin, and psilostachyin C (Eq. 1) illustrates how enolates have been

LDA, THF, HMPA -78 to -20 *C

B

O

(1) Bn

O

used in this approach. 3 The anionic opening of an epoxide employed by Bird to provide a heterocyclic seven-membered ring (Eq. 2) is o

-BuL,

0"

THF, -78 ~

Ho

(2)

another variant of this concept based on a less-stabilized carbanion. 4 Recently, a cascade reaction was reported by Rodriguez in which an enolate ring closure reaction is preceded by a coupling reaction to

The Synthesis of Seven-Membered Rings provide overall a convergent approach to a seven-membered ring (Eq. 3). 5 This single-operation cascade of five reactions involves an initial

C02Me 0

H

~

. ' MeOHt'BuLi :_

0

(3)

Me02C

Michael addition, followed by an intramolecular aldol condensation to provide the seven-membered ring. Subsequent retro-Dieckmann reaction, dehydration, and ester saponification provide the bicyclic product in 98% yield. A related cascade reaction was recently reported by the same research group in which the reactions of various allylic halides with cyclopentanone derivatives provide seven-membered rings. 6

B. Electrophilic Lewis acid mediated intramolecular C-C bond formations represent another major class of reactions adaptable to seven-membered ring synthesis. A superb example of this class is found in the work of Majetich, which features a titanium-induced cyclization reaction employed in the synthesis of several natural products, including barbatusol (Eq. 4). 7 Although technically this closure has a nucleophilic MeO

~

TiCI4 =, ~ ~ -780C

MeO

OMe

(4)

component, not unlike the previously described anionic closure, this component is an electron-rich aromatic ring. To compensate for this diminished nucleophilicity, a more reactive electrophilic species, a delocalized carbonium ion, must be transiently generated through titanium coordination to the dienone to effect bond formation. Home used methanesulfonic acid in an intramolecular cyclization reaction (Eq. 5) to effect a related cation-initiated closure involving an aromatic system and a cationic intermediate, s The process is

PAUL A. WENDER and JENNIFERA. LOVE

Br i ~

Br

H

H

O

N~CH

0

B.~NN

CH3SO3H rt

Br

"

H

O

I

H

(5)

commendably simple and, because it is based on acrolein and pyrroles, it is practical, although the reaction times have not yet been optimized. In studies directed toward the synthesis of ingenol, Kuwajima investigated Lewis acid catalysis for seven-membered ring formation. Initial cyclization and subsequent rearrangement provides a bridged bicyclo[4.4.1] system (Eq. 6), incorporating the rather exotic in-out

AcO "~ ~ OMe

(COO)3 "ColCO)3

MeAI(OTf)(OAr) =

(co~) ......(r-~,o(COs)

co

(CO)3 /~__:ColCO)3 '... H OMe

(6)

/

OMe

bridgehead stereochemistry that has attracted many to this synthetic problem. 9 Martin recently reported the use of Lewis acid catalysis in sevenmembered ring formation (Eq. 7), providing the tricyclic product illustrated in 58% yield and 1.3"1 diastereoselectivity. ~~

HO O

Et2AICI CH3CN 20 ~

~" O==~O~

"-(3 1.3"1

(7)

The Synthesis of Seven-Membered Rings C. Radical Radicals constitute another type of reactive intermediate that have found considerable use in synthesizing seven-membered rings. Pattenden provides a rather remarkable example of the way this process can be incorporated into a macrocyclization-transannulation cascade to prepare polycycles. Tributyltin hydride generates a radical intermediate which, upon macromolecular ring closure and two subsequent transannular processes, provides a tricyclic product (Eq. 8). ~1 Aside

~

I

I

Bu3SnH=" AIBN

~ H"

0

(8)

from its relationship to seven-membered ring formation, the increase in complexity attending this process illustrates the great potential of cascade-based transformations. Little has reported the use of diyl-trapping reactions to synthesize taxol of analogs via initial formation of a seven-membered ring species (Eq. 9). 12Further studies related to diyl-trapping reactions can

CH3CN

H

reflux

(9)

N

be found in a recent review from this group. ~3An attractive aspect of this and related chemistry is the enhanced bond-forming capability that comes from using what can be considered two reactive intermediates, the diradical. A recent report from Snider shows another variant of a radicalmediated, ring-forming reaction (Eq. 10). 14 This process technically produces both a six- and seven-membered ring product. 0

(~~'"" O TMS

Mn(OAc)3 EtOHI HOAc 90~

(10)

TMS

10

PAUL A. WENDER and JENNIFER A. LOVE

A noteworthy example of a radical-mediated transannular C-C bond forming reaction was reported by White (Eq. 11).15 Sml2,t-BuOH HMPA

H

(11)

or

Bu3SnH AIBN

0

OH

D. Metal Carbene Carbenes and carbenoids generally are not commonly used for the synthesis of seven-membered tings, in part because of their high reactivity. However, the longer-lived, metal-stabilized carbenes are increasingly valuable in the formation of seven-membered tings, in particular in ring-closing metathesis reactions (Eqs. 12 and 13). 16'17

~~

M e R e O a~

(12)

el

/ ~ ~ ~

h

2 4 moI%cat,. benzene,20 *C

C

~~.~

Ph

(13)

cat.--(PCYa)2(CI)2Ru~ /Ph \ Ph

A recent report shows the preparation of a bicyclo[5.3.0]decane in high yield from a cyclodecyne (Eq. 14), TM a reaction which putatively proceeds via a carbene intermediate.

- -o

(14) H

H

E. Transition-Metal Given the number of metal-mediated bond forming reactions, it can be expected that more will be applied to the synthesis of sevenmembered tings. A principal challenge in adapting such processes to the preparation of larger tings is the suppression of competing side

The Synthesis of Seven-Membered Rings

11

reactions, often 13-hydride elimination. A representative example of a way to achieve this goal is found in the work of Negishi, in which seven-membered rings are prepared by a palladium catalyzed cyclization (Eq. 15). 19 Pd(OAc)2 I

K2CO3 =n-Bu4NCI

(15)

DMF

III.

SEVEN-MEMBERED RINGS FROM LARGER AND SMALLER RINGS

Ring-size alteration approaches fall into two general categories: ring expansion and ring contraction. The use of this strategy in synthesis is generally more demanding from a synthetic perspective than acyclic closure because an existing ring is required and it must bear functionality suitably positioned to effect formation of the new ring with concomitant or subsequent cleavage of a bond from the original ring system. In essence, in the ring-size alteration processes, one bond must be cleaved and a new bond must be made, in contrast to acyclic closure for which only one new bond must be formed. As might be expected, precursors for ring-size alteration are often more complex than those used for acyclic closure and, as such, the synthesis of starting tings can be as demanding as that of the product. As a result, this strategy is typically employed only when the smaller (or larger) ring starting materials are readily available. For example, ten-membered rings, which are not readily available and are often difficult to synthesize by acyclic closure because of entropic factors, are connected to the abundant pool of six-membered ring precursors by a four carbon ring-size change. Not surprisingly, the Cope rearrangement of divinylcyclohexanes represents a powerful approach to the formation of ten-membered rings. Interestingly, radical-mediated transannular cyclization of the initially produced ten-membered ring allows access to seven-membered tings. This method has found use in the total syntheses of a variety of natural products. 2~ Most ring-size alteration methods are used to expand or contract rings by 1-4 units. In these instances, the new bond formed during this process is part of a 3- to 6-membered ring transition state.

PAULA. WENDERand JENNIFERA. LOVE

12

Consequently, the bond-forming reaction is favored entropically. Expansions or contractions by more than four units are rare, but noteworthy examples of such macroexpansions have been reported. 21

A. One-Atom Expansions Base-induced one-carbon homologations of cyclohexanones have found utility in the preparation of cycloheptanones because they are based on often readily available six-membered tings (Eqs. 16 and 17).22,23

O~

TolS(O)CH(Me)CI

O

O

LDA, -70 *C, t-BuLi

=

O

(16)

k.z ~

....--/~S,,~,,,.~ N. . ~

cyclohexanone,, CH2CICHCI2 110 ~

(17)

Other reactive intermediates have been used to effect one-atom expansions of six-membered tings. These approaches include the use of radicals (Eq. 18) 24 and photolysis (Eq. 19), 25 the latter involving H O

(18)

AIBN, 110 *C " I

E Ph-'~H

H [~0

Boc" N,,,.

Ph CO2Me

.~

H D

O

~,H

N,..~_,,3..,~CO,,M~

Boc"

(19)

photorearrangement of a spirocyclic oxaziridine to a heterocyclic seven-membered ring. Additional examples of one-carbon ring expansions of cyclohexanones appear in a recent review. 26

B. Two-Atom Expansions Illustrative of a two-atom expansion process, a bicyclo[3.2.2]nonane product was derived from a 1,3-shift of a norbornene derivative

The Synthesis of Seven-MemberedRings

13

(Eq. 20). 27 A more generally employed process involves the cycloaddition of enamines followed by cleavage of the cycloadduct (Eq. 21).28

%

OH

250"C _-

~

O

(20)

O

C. Three-Atom Expansions

A novel example of a three-atom expansion is found in the work of Liebeskind in which rhodium catalysis is used to expand a cyclobutenone to provide a cycloheptadienone product (Eq. 22) via ring fusion. 29

h ~

RhCI(PPh3)3" , . ~ PhCH3 60-120*C Ph

P

(22)

Research by Dowd illustrates another approach to seven-membered rings based on expansion of a cyclobutanone (Eq. 23) mediated by radical intermediates.3~

~

~.,~oC ' D.

Br Bu3SnH= AIBN

OTMS [~~ 0

(23)

Four-Atom Expansions

The expansion of a cyclopropane to a seven-membered ring can be efficiently achieved through a divinylcyclopropane rearrangement. Examples of this transformation have emerged from the groups of Wender,31 Marino (Eq. 24), 32 Piers (Eq. 25), 33 White (Eq. 26), 3~I~Harvey (Eq. 27), 35 Barluenga (Eq. 28), 36 Wulff,37 Davies, 38 and others. 39 Divinylcyclopropane rearrangements have been utilized as the key step in the synthesis of a variety of natural products, including the total

14

PAUL A. WENDER and JENNIFER A. LOVE

C02Et

- 140*C =.

(24)

LitCsHsSCu]~

(25)

I

0

(26) TMS

X

TMS

Bu C02E t r''OcHa

X

OMe

THF,65 ~

C02E t

(27)

I "OMe Bu

Cr(CO)s

o

1. ,~.cH,cN. ~co

(28)

2. 3N HCI

0

syntheses of damsinic acid and confertin (Eq. 29).40Recently, Davies reported the syntheses of tremulenolide A and tremulenediol A by this method (Eq. 30). 41 o

hv, 98*C

M.o. o c

,ooc

?

(29)

(30)

The reaction between cyclopropylcarbene-tungsten complexes and alkynes has been studied by Hemdon (Eq. 31).42 Both inter- and

15

The Synthesis of Seven-Membered Rings

[

w(co),

~O(CH2)3Cm

~',.,1*c4~ ~ CPh

"

(31)

. C

intramolecular processes have been used to generate seven-membered rings.

E. Ring Contractions of Larger Rings Contractions of larger tings to seven-membered tings have also been investigated. Funk reported the Ireland-Claisen rearrangement of a macrocyclic lactone to provide the in-out bicyclic core of ingenol (Eq. 32). 43

s,I. o..

i

i,o..

R3SiOTI, Phil :_ &,

(32)

Et3N

OSIR 3

IV. SEVEN-MEMBERED RINGS FROM FRAGMENTATION STRATEGIES Fragmentation strategies typically require precursors that are more complex than the targets. Thus their use and value in synthesis is associated with advantages arising from the ease with which some systems capable of fragmentation can be assembled and/or from favorable entropic factors, as the large ring target is prepared from a series of smaller tings.

A. Fragmentations of Bicyclo[3.2.0]heptanes Winkler employed a photochemical approach to the in-out tricyclic core of ingenol, beautifully illustrating the utility of a fragmentation strategy in complex molecule synthesis (Eq. 33). 44 Fragmentations of bicyclo[3.2.0]heptanes are commonly used to prepare seven-membered tings. The value of this process arises from

16

PAUL A. WENDER and JENNIFER A. LOVE

(e•

hv

:-

~

H H

(33) C02Me

the ease of assembling the precursors using a [2+2] photocycloaddition. Lange used a radical fragmentation strategy to elaborate the bicyclic structures of a variety of perhydroazulene natural products (Eq. 34). 45Photolytic fragmentation of related structures has also been reported (Eq. 35). 46 H

I Bu3SnH

"

OCS2Mo

A,BN

"--

(34)

o

0

B. Fragmentations of Bicyclo[4.1.0]heptanes

Marples reported radical-induced fragmentation of a cyclohexene oxide derivative to form a heterocyclic seven-membered ring (Eq. 36). 47 OCSIm 0 Ph

(36)

AIBN Ph

Paquette used a fragmentation strategy to elaborate the ring system of 18-oxo-3-virgene. 48 Upon treatment with triethylamine in warm methanol, the starting material fragments to the seven-membered ring (Eq. 37).

The Synthesis of Seven-Membered Rings

Et3N,

,~H

17

H~ ~', . . . . .

(37)

V. CYCLOADDITION STRATEGIES FOR SEVEN-MEMBERED RING SYNTHESIS Cycloadditions offer several advantages in elaborating various ring systems which no doubt account for their widespread use in synthesis. One needs only to consider the impact of the Diels-Alder cycloaddition to appreciate the intrinsic merit of this approach to cyclic systems. Cycloadditions are convergent, often based on simple starting materials, and allow two new bonds to be formed in one operation. Despite their synthetic potential, cycloaddition approaches to seven-membered tings are limited principally to isoelectronic variants of the Diels- Alder cycloaddition (Figure 2). 49

r

[5+2]

4C

2C

4e"

2e"

4C

3C

4e"

2e"

G ii 5C

2C

4e"

2e"

6-membered ring

7-membered ring

,-

0 7-membered ring

Figure 2. Cycloaddition approaches to seven-membered ring synthesis that are isoelectronic with the Diels-Alder reaction.

PAUL A. WENDER and JENNIFERA. LOVE

18

A. [4+3] Cycloadditions The reaction of a diene with a three-carbon, two-electron species in a [4+3] cycloaddition (Figure 2) has been studied extensively for the synthesis of seven-membered rings. Noyori, 5~ Hoffmann, 51 White, 52 Mann, 53 Harmata, 54 Trost, 55 Giguere, 56 and others have reported spectacular examples of these processes, a few of which are illustrated here. 57 The most common three-carbon unit utilized is the oxyallyl cation. Noyori pioneered the use of iron-promoted generation of oxyallyl cations and provided impressive examples of their reactions with dienes (Eq. 38). 50

Bt

O

o.,co,9

Br

[ Sr 1 9

o

.

(38)

Hoffmann also made pioneering contributions to the field of [4+3] cycloadditions. These contributions include the development of processes for both intra- and intermolecular cycloadditions and of a variety of methods for generating allyl cations (Eq. 39). 5]

o

Br

O

Br 0

Harmata studied several variants of the intramolecular [4+3] cycloaddition including the cycloaddition of a furan tethered to an oxyallyl cation (Eq. 40), 54 the latter generated through a clever TiC14 initiated heterolysis of an allylic sulfone. This approach very nicely circumvents problems of performing intramolecular [4+3] cycloadditions based on ct, ct '-dibromoketones as the allyl cation sources. OEt 02Ph

TiCl4 CH2CI2 -78 ~

"-

(40)

The Synthesis of Seven-Membered Rings

19

Trimethylenemethane (TMM) derivatives, such as n-allyl palladium species, are much used in [3+2] cycloadditions. Trost showed that the methodology can also be applied in certain cases to [4+3] cycloadditions (Eq. 41).55 AcO~,,~,./SiMe3 CO2Me

MeOaC;

PatoAc)= (/-PrO)aP

~~===

(41)

The reactive rc-allyl species is generated with Pd(OAc) 2. This approach requires that the diene moiety be in the more reactive s-cis conformation to preclude competing [3+2] cycloaddition and as such has been applied exclusively to intermolecular reactions.

B. [5+2] Cycloadditions Conceptually, a [5+2] cycloaddition involves the reaction of a five-atom species with a two-atom species. The most commonly encountered examples of such [5+2] cycloadditions are the reactions of oxidopyrylium and oxidopyridinium ions with various alkenes and alkynes. Originating more than 40 years ago with the investigations by Wood and Hurd, and continuing with contributions from Weeks, 5a Katritzky, 59 Sammes, 6~Wender, 61 and Williams, 62 this class of [5+2] cycloadditions has serviced a number of synthetic objectives. 63 One of the most complex examples of this process has figured in the first total synthesis of phorbol (Eq. 42), a remarkably demanding probOAc

!

OAc 0

DBU CH2CI2 rt S

Iem. 61 The

(42)

I=,

OTBS

reaction is completely selective, in accord with the illustrated transition-state model. Although this reaction has found utility in complex molecule synthesis, it is primarily restricted to the use of pyrylium and pyridinium intermediates. Acyclic pentadienyl cations,

20

PAUL A. WENDER and JENNIFER A. LOVE

required to make a nonbridged system, have received limited attention in part because such systems preferentially close to five-membered rings. An exciting alternative approach to [5+2] cycloadditions was drawn from the somewhat similar reactivities of cyclopropanes and alkenes, suggesting that vinylcyclopropanes might react with two-carbon 7zsystems analogously to dienes and two-carbon n-systems in a DielsAlder reaction. 64 The resultant homologue of a Diels-Alder reaction would utilize a vinylcyclopropane as a five-carbon unit instead of an oxidopyrylium ion and therefore would be a potentially powerful and simple process for cycloheptene synthesis. In studies on this novel [5+2] cycloaddition strategy, Sarel and Breuer reported in 1959 that the reaction between a phenyl substituted vinylcyclopropane and maleic anhydride generates a seven-membered ring product (Eq. 43). 65 However, several reports in the literature suggest that this O

Ph

O 0

PhH,A 0

(43)

0

reaction is not reproducible. 66Perhaps more importantly, this thermal [5+2] reaction has not been reported for any related systems involving the reactions of simple vinylcyclopropanes with alkenes or alkynes. Although simple vinylcyclopropanes have not proven useful, Fowler reported in 1971 that a homopyrrole, a constrained and heteroatom-activated vinylcyclopropane, reacts with alkynes to produce a seven-membered ring product (Eq. 44). 67 A zwitterionic intermediMeO2?

H

CO2M [ e

,,C02Me N" ~ O 2 M e

100~ "

CO2Me CO2Me I

..,H "C02E t

(44) e?~

--

l o,liH

O2Et

The Synthesis of Seven-Membered Rings

21

ate, presumably stabilized by the nitrogen atom, has been proposed for this reaction. Subsequent cycloaddition between the reactive dipole intermediate and the dipolarophile (alkyne) provides a sevenmembered ring product. The facial selectivity of this product is consistent with the proposed intermediate. Herges and Ugi reported an analogous reaction between homofuran and tetracyanoethylene which leads to a seven-membered ring product (Eq. 45). 68 These authors, however, favor a concerted pathway for this O

c.,cl,

+

NC

CN

"~

~

c.

CN CN

(45)

reaction. Although this methodology provides access to seven-membered tings, these reactions are thus far confined to homopyrroles and homofurans, systems requiting heteroatom activation and conformational constraints. 69'7~As noted by Herges, unactivated "vinylcyclopropanes do not react even with the strongest dienophiles. ''71 This point and class of reactions is addressed further in this chapter.

C. Other Cycloadditions Leading to Seven-Membered Rings Some cycloadditions can be used to simultaneously generate two rings and one is a seven-membered ring. An example of this approach is found in the work of Rigby directed at the preparation of ingenol through an impressive [6+4] cycloaddition (Eq. 46). 72 The reaction Me

(46) Cr(CO)3

hv, 0 *C

proceeds stereoselectively and in good yield. Given the ready availability of the starting materials, this procedure is likely to have much value in synthesis. Trost employed an intramolecular [3+2] cycloaddition to form a 5,7-fused bicyclic system in quantitative yield with good diastereoselectivity (Eq. 47). 73 In this reaction, a two-bond-forming cycloaddition process produces the desired one-bond closure of an acyclic precursor.

PAUL A. WENDER and JENNIFER A. LOVE

22

O

TMS

i

OC Me

~S02Ph

5 mol% Pd(OAc)2 30tool%(/-PrO)3P dioxane, 100~ 8.2' 1

~ 2 P h

(47)

O

SO2Ph

In another example, a [3+2] cycloaddition leads to the concomitant formation of a highly substituted cycloheptane (Eq. 48). TM -

O~ N ~ ~ ~]..,,OBn HO,,...-,,,y,,,,,~OBn OBn

O.. N

....n-Bu4NF THF

~ B n ~ .0"

"~OBn

(48)

bBn

Lautens recently reported superb examples of a metal-mediated cycloaddition of norbomadienes and dienes. Although this process establishes connections which deliver an eight-membered ring, the process can also be viewed and exploited as a [4+3] cycloaddition (Eq. 49). 75 This reaction proceeds in up to 66% yield with up to 72% enantiomeric excess.

Y

2 tool%Co(acac)2 2 mol%PROPHOS 8 mol % Et~,lCl :Phil.rt

,J

(49)

West reported the reactions of pyrones with furans to generate seven-membered ring products in modest yield (Eq. 50). 76 This is a beautiful example of a reaction that allows for a great increase in complexity in a single transformation. O O

hv 9 CFsCH2OH

O

(50)

The Synthesis of Seven-MemberedRings

23

Stryker recently reported a metal-catalyzed [3+2+2] cycloaddition leading to a seven-membered ring (Eq. 51).77 This is a fundamentally new development in this area and suggests that multicomponent approaches to seven-membered tings akin to those developed for fiveand six-membered rings (e.g., Pauson-Khand, [2+2+2]) are on the horizon.

p" "OTf Ir+1~ Ph,-

Ph

Cp.lr~"'~ .'~Ph ~/~'"'Ph

(51)

Molander has reported highly selective [4+3] annulation reactions for synthesizing seven-membered tings (Eq. 52). 78 The diastereoselectivity of the reaction can be controlled by the choice of Lewis acid catalyst.

O"Ph 0

0 ricl, =

TMSO OTMS "~"~~OMe

CH2CI2

MeO=C~ 7

O

(52)

eO~O-ph

VI. TRANSITION-METAL-CATALYZED [M§ CYCLOADDITIONS

A. [4+4] Cycloadditions Prompted in part by the medicinal potential of taxol and the synthetic problems embedded in its polycyclic core, our group initiated a program in the 1980's directed at the use of transition-metal catalysts 79to effect reactions that are otherwise difficult or impossible to achieve, s~ Culminating as described here in the first examples of a metal-catalyzed [5+2] cycloaddition of alkynes and vinylcyclopropanes, this work was first directed at nickel(0)-catalyzed intramolecular [4+4] cycloadditions for the synthesis of eight-membered ring containing targets. 81 Although finding the fight catalyst initially proved challenging, it has since been shown that this reaction is general and efficient. In the presence of 11 mol% Ni(COD)2 and 33 mol% PPh 3, for example, tetraene 1 undergoes a [4+4] cycloaddition

24

PAUL A. WENDER and JENNIFER A. LOVE

to provide 2a and b in 70% yield as a 19:1 mixture of diastereomers, favoring the product with cis ring fusion (Eq. 53). Providing precedent

E~,,.~

Ni(O)catalyst

211

2b

(53)

1

E

3

~.

4

for another new class of cycloadditions, the metal-catalyzed intramolecular [4+2] cycloaddition, this study also showed that variations in conditions can be used to preferentially produce a [4+2] cycloadduct (3). The t-elimination product 4 was also obtained through variations in these conditions. Driven in design and development by the variety of natural product families that contain eight-membered rings, this methodology found immediate use in studies related to the preparation of the taxane 82 and ophiobolin s3 ring systems and in the total syntheses of asteriscanolide 84and salsolene oxide, 85among other examples. Two classes of intramolecular reactions, types I and II, were established using this methodology (Figure 3). The type I reaction provides access to fused bicycles, whereas the type II reaction generates bridged bicycles. For example, the first asymmetric synthesis of a

TypeII (

[~ (

Figure 3. Type I vs. type II [4+4] cycloadditions.

The Synthesis of Seven-Membered Rings

25

cyclooctane-containing terpenoid asteriscanolide (7) was accomplished through the use of a nickel(0)-catalyzed type I [4+4] cycloaddition, illustrating the utility of this methodology for constructing fused bicycles incorporating an eight-membered ring (Scheme 2). 84 Tetraene substrate 5 is prepared in enantiomerically enriched form in 10 steps from commercially available acrolein. Preparation of cyclooctadiene 6 is accomplished via [4+4] cycloaddition of 5 in the presence of Ni(COD)2 and PPh 3. With two additional transformations, cycloadduct 6 is converted to (+)-asteriscanolide (7). Overall, (+)-asteriscanolide was prepared in 13 steps and 3% overall yield. A type II cycloaddition was employed to synthesize (+)-salsolene oxide, 85 as depicted in Scheme 3. Upon treatment with a nickel(0) catalyst, pentaene substrate 8 is converted to bicyclic systems 9a and b (3:7) in 80% yield. The major isomer (9b) is converted in two subsequent steps to (+)-salsolene oxide 10. During the course of these studies, the broader utility of the concept of metal-catalyzed cycloadditions became apparent, particularly as it would apply to reactions that cannot be achieved at all or at least under mild conditions. Based on the [4+2] cycloadducts obtained as byproducts in our initial studies on [4+4] cycloadditions, our next studies focused on Diels-Alder cycloadditions which are difficult or impossible to effect. 0 '~"~CHO

=S 0

Ni(COD)2

O

0 O

2 steps

PPh3, 60 *C

H~

=

67% 6

H ~'H 0 " 7

Scheme 2. Synthesisof (+)-asteriscanolide via metal-catalyzed [4+4]

cycloaddition.

26

PAUL A. WENDER and JENNIFERA. LOVE Ni(COD)2 P(O-o-BiPh)3 Phil, 85"C, 80%

8

9

+

3:7 9a

9b

10

Scheme 3. Synthesis of salsolene oxide via metal-catalyzed [4+4] cycloaddition.

B. [4+2] Cycloadditions Although the Diels-Alder cycloaddition is a highly versatile process for six-membered ring synthesis, the lack of reactivity of various dienophiles, such as unactivated alkynes, has limited its synthetic scope. 86 Several examples of Diels-Alder reactions involving unactivated alkynes have been reported for which the reaction proceeds extremely slowly or is entirely unsuccessful. 87 To avoid elevated temperatures, the feasibility of using nickel(0) to catalyze the cycloaddition under milder conditions was explored. 88 The results of this investigation have been fruitful. For example, in the presence of 10 mol% Ni(COD) 2 and 30 mol% tri-o-biphenyl phosphite in THF at 55 ~ 11 undergoes efficient cycloaddition to provide 12 in 85% yield (Eq. 54). In contrast, in the absence of catalyst, 11 reacts only at 10 mol % Ni(COD)2

/ ~

/--.-OAc

30 mol % P(O-o-BiPh)3 -__

(54)

THF, 55 *C, 85% 11

12

temperatures of approximately 200 ~ and produces only decomposition products. The metal-catalyzed reaction between allenes and dienes was also investigated and was found to be highly efficient in many cases. 89 For

The Synthesis of Seven-Membered Rings

27 H fOTBS

10 mol % Ni(COD)2 10 tool % P(O-o-BiPh)a TBS

THF, 25 ~ 97%

5 mol % [Rh(COD)CI]2 13

48 mol % P(O-o-BiPh)s

.... THF, 45 ~ g0%

i=

~

(55) OTBS

15

example, in the presence of 10 mol% Ni(COD)2 and 30 mol% tri-obiphenyl phosphite in THF at 25 ~ the diene moiety of 13 reacts with the allene terminus to provide 6,6-bicyclic system 14 in 97% yield as a 2:1 mixture of diastereomers (Eq. 55). By altering the catalyst, the chemoselectivity of the cycloaddition is reversed, a situation of great significance in synthesis. Heating the same substrate (13) at 45 ~ in the presence of 5 mol% [Rh(COD)C1)2 and 48 mol% tri-o-biphenyl phosphite in THF provides the 6,5-product (15) as a single stereoisomer in 90% yield. 9~ In addition to catalyst control of chemoselectivity, catalyst control of stereochemistry was also demonstrated in this series. Treating substrate 16 with [Rh(CHE=CH2)C1] 2 and the novel ligand P[OCH(CFa)(o-CHaOPh)] 3 in toluene at 60 ~ provides a 91:9 (trans to cis) ratio of 17a and b in 87% yield (Eq. 56). In contrast, reaction of the same substrate with Rh(CHE=CH2)C1]2,AgOTf, and the novel ligand P[OCH(CFa)(2,6-(CHa)EC6H3)]3 provides a complementary 5 mol % Rh(H2C=CH2)2CI

/

10 mol % P(OCH(CF3)(o-CH3OPh)]3 PhCH3, 60 "C, 87% -91:9 trans:cis

(56) 5 mol % Rh(H2C--CH2)2CI

16

~,

5 mol % AgOTf

17a and b ==,

15 tool % P[OCH(CF3)(2,6-(CH3)2Ph)]3

PhCH3, 60 ~ 69% -5:95 trans:cis

PAUL A. WENDER and JENNIFER A. LOVE

28

to cis ratio of 17a:17b, 5:95, in 69% yield, evincing the dramatic effect of ligand modification upon the stereochemical outcome of the reaction. Recently, the utility of the nickel-catalyzed [4+2] cycloaddition was evaluated in connection with approaches to steroid and alkaloid syntheses. The synthesis of 8ct-isoestradiol, 1713-acetate, 3-methyl ether is highlighted in Scheme 4.91 The cycloaddition reaction of dienyne 19 proceeds in 90% yield to provide an intermediate (20), which contains the C and D rings of the steroid. In dramatic contrast, the corresponding thermal reaction of 19 proceeds with a half-life of 109 h at 175 ~ to provide only decomposition products. Five additional steps are required to complete the synthesis of 8ct-isoestradiol, 1713-acetate, 3-methyl ether (21). Yohimbane is synthesized via the intramolecular [4+2] cycloaddition of a nitrogen containing dienyne substrate, 22 (Scheme 5). 92 Upon treatment with a nickel(0) catalyst, 22, which had been prepared in 3 steps from commercially available tryptamine, provided an 88% yield of tetracycle 23. As before, the thermal reaction proceeds at 150 ~ providing only 45% of the 1,4-cyclohexadiene product, a telling manifestation of the advantage of metal catalysis in this case. Overall, a 1:1 mixture of yohimbane trans

~ '~OMOM 4 steps ~--MOMO 18

MeO~

19 20 mol % Ni(COD)2 40 mol % P(O-i-C3HFs)3

cyclohexane, 80 *C, 90% OTMS V

OTMS 5 steps H3CO

MeO

21

O

2O

ONON

Scheme 4. Synthesis of a steriod via metal-catalyzed [4+2] cycloaddition.

The Synthesisof Seven-Membered Rings

N I

H2

29

N

O

I

Boc

22

20 mol%Ni(COD)2 60 mol%P(O-/-C3HFs)s THF, rt, 88% J~

N~H

H~"L~ 24a: yohimbane (H = 13)

TMS

4 steps t

H 23

24b: alloyohimbane(H = ix) Scheme 5. Synthesisof yohimbane via metal-catalyzed [4+2] cyclo-

addition.

24a and its isomer, alloyohimbane 24b, is obtained in four steps from 23.

VII. DESIGN AND EVOLUTION OF A NEW REACTION" METAL-CATALYZED [5+2] CYCLOADDITIONS Given the knowledge that transition metals effect [4+4] and [4+2] cycloadditions and induce strained ring cleavage, 93 we began to explore whether such catalysts could promote the cycloadditions of vinylcyclopropanes and dienophiles, a reaction with great synthetic potential. Although as noted before, the thermal cycloaddition does not work with simple vinylcyclopropanes, it was expected that a metal catalyst would mediate initial bond formation, leading to metallacyclopentene 26a or metallocyclohexene 26b from yne-vinylcyclopropane 25 (Scheme 6). With a metal-carbon bond adjacent to the cyclopropane, 26a would be expected to undergo strain-driven cleavage of the cyclopropane to provide metallocyclooctadiene 27. Likewise, reaction of 26b with the alkyne moiety would also provide 27. Subsequent reductive elimination would give the 5,7-fused bicyclic product 28 and catalyst, representing overall a novel metal-catalyzed [5+2] cycloaddition.

30

PAUL A. WENDER and JENNIFER A. LOVE

26a

25

/~,.,~

27

28

26b

Scheme 6. Plausible mechanistic pathway for [5+2] cycloaddition. Ae

Intramolecular [5+2] Cycloadditions of Yne-Vinylcyclopropanes

The substrates selected to investigate this reaction were intended to provide the framework and substitution patterns of a variety of natural products and to establish the applicability of this process to commonly encountered synthetic problems. Toward these goals, the reaction was investigated initially with yne-vinylcyclopropane 29, the cycloadduct of which possesses the carbobicyclic core of a wide range of natural products. In our initial investigation, 29 underwent [5+2] cycloaddition in the presence of 10 mol% of commercial RhCI(PPh3) 3 in toluene at 110 ~ in 2 days and provided an 84% yield of 30 (Table 1), thefirst example of a metal-catalyzed [5+21 cycloaddition. 94 Remarkably, by increasing the polarity of the solvent, the reaction is complete within

Table 1. Metal-Catalyzed Cycloadditions of Yne-Vinylcyclopropanes

~~

RhCI(P' Ph3)=.3 ~ ~ , ~ solvent

29

30

Entry

Solvent

Additive

1 2 3

PhCH3 CF3CH2OH PhCH3

none none AgOTf

Temp.(~ 110 55 110

lime (h) 48 19 0.3

Yield (%) 84 90--95 83

The Synthesis of Seven-Membered Rings

31

19 h, even at 55 ~ Presumably the more polar trifluoroethanol assists in ligand turnover. A comparable result is achieved by adding AgOTf, which precipitates AgC1, thereby forming a cationic rhodium(I) species. The reaction of 29 in the presence of O.5 mol% RhCI(PPh3)3 and 0.5 mol% AgOTf in toluene at 110 ~ provides an 83% yield of 30 in only 20 rain. Given the success of these initial attempts, other substrates with varying substitution patterns were subsequently investigated. Cycloadditions proceed smoothly for substrates with both ether and gem-diester tethers, indicating that a Thorpe-Ingold effect is not required for efficient reaction. The reaction is relatively insensitive to substitution of the alkyne terminus. Terminal alkynes and internal alkynes with electron-rich, electron-poor, sterically demanding, and conjugating substituents all provide good to excellent yields of the 5,7-fused bicyclic products (Table 2). Only in the case of 31a is the isolated yield low because of the difficulties handling the more volatile product. The cycloaddition proceeds efficiently even with methyl substitution of the double bond of the vinylcyclopropane. Although angular alkyl substituents are commonly encountered in natural products and designed targets. 95 However, the introduction of such a group has remained a considerable synthetic challenge. Given this situation, it is noteworthy that these new reactions proceed well even when a quaternary center is developed. Cycloaddition of yne-vinylcycloTable 2. Metal-Catalyzed Cycloadditions of Yne-Vinylcyclopropanes R

31a

Entry

-

9

32a

R

Solvent

Time (h)

-

9

Yield (%)

a

H

THF

1.5

50

b

Me

PhCH3

1.5

88

c

CO2Me

PhCH3

1.25

74

d

TMS

PhCH3

3.5

83

e

Ph

PhCH3

1.5

80

PAUL A. WENDER and JENNIFER A. LOVE

32

(57)

PhCH 3, 110 ~ 30 min, 82% 33

34

Table 3. Metal-Catalyzed Cycloadditions of Yne-Vinylcyclopropanes

.,..

10 mol % RhCI(PPh3) 3 PhCH 3, 110 *C

"

""

37a - d

Entry

R

a b c d

Me H CO2Me TMS

lime (h)

48 48 16 168

I

93 7

Held (%)

3.5:1 100:0 100:0 0:100

89 82 81 71

36

propane 33 provides a cycloadduct with an angular methyl group in 82% yield (Eq. 57). In one case where the substrate bears double-bond substitution, the initially formed product undergoes further isomerization (Table 3). Despite this minor limitation, the yield of the cycloaddition still exceeds 71%, and the majority of the yields are higher than 80%.

B. Intramolecular [5+2] Cycloadditions of Ene-Vi n yl cy cl o p ro pan es Although the [5+2] cycloadditions of alkynes and vinylcyclopropanes service a number of objectives in synthesis, the [5+2] cycloaddition with alkenes also has enormous potential value and in addition presents a remarkable opportunity to address the intrinsic stereoselectivity of the process because two diastereoisomeric products can form. We began our investigation with substrate 38 (Table 4). Treating ene-vinylcyclopropane 38 with a catalyst derived from 0.1 mol% RhCI(PPh3) 3 and 0.1 mol% AgOTf after 17 h at 110 ~ gives cycloadduct 39 in 86% isolated yield as a single diastereomer. 96 The

33

The Synthesis of Seven-Membered Rings

Table 4. Metal-CatalyzedCyc!oaddition of Ene-Vinylcyclopropanes H

E4~j j~V~

RhCI(PPh3)z

E , " " ~ ~ ~

additive

110 *C

H

39

38

Mol%

Entry

RhCl(PPh3)3 Additive a

1 2b 3 4 5 6

0.1 0.1 0.1 1 5 10

Notes:

Concn (m)

AgOTf AgOTf AgOTf AgOTf AgOTf none

1.0 1.0 0.4 0.05 0.01 0.005

?ime (h)

Held (%)

15 17 17 5 2 2.5

90 86 88 93 91 91

amol%AgOTf = mol% RhC10aPh3)3. bReaction run on 1 g scale.

reaction works on a gram scale and additional scale-up appears possible. Substrate concentrations of >1 M are tolerated, although oligomeric byproducts form at higher concentrations (>5 M). The stereoselectivity of this reaction can be rationalized by the mechanistic analysis shown in Scheme 7. As delineated for only the cyclometallation mechanism, the [5+2] cycloaddition of an alkene and H

H "it.,, -- -

f H

X

'

41a

42a

H

-- X

43a

H

H

40

H 41b

"v

~

~Rh,tLn

H

H

H

x ,

42b

43b

Scheme 7. Plausible mechanistic rationale for stereochemistry.

34

PAUL A. WENDER and JENNIFER A. LOVE

a vinylcyclopropane could give two diastereoisomeric products, 43a and b. The stereochemistry of these cycloadducts originates during the initial cyclometallation process leading to 41a and 41b and is fixed by the turnover of these intermediates to products. Thus the formation of 41b reflects a kinetic preference for reaction via the cis-fused intermediates 41b and 42b, relative to their trans-fused counterparts. It is not clear yet whether the rate-determining step in this sequence is correlated with the initial cyclometallation process or the further processing of these and related metallacyclic intermediates. Computational and mechanistic studies are currently being conducted to define the relative energetics of these and related competing paths. The generality of this methodology was established with a variety of ene-vinylcyclopropane substrates as illustrated (Eqs. 58-62). As was expected on the basis of the results of the cycloaddition of substrate 38, ene-vinylcyclopropane 44 produces exclusively cisfused cycloadduct 45 in 94% yield by GC and in 70% isolated yield (Eq. 58). The isolated yield of this product is reduced because of its

C

~ 44

5 mol % RhCI(PPh3)3 5 mol % AgOTf ~

THF,65"C

70*/. (94*/.by GC)

H O ~ ~

(58)

H

45

volatility. It is noteworthy that the cycloaddition of the allyl ether substrate (44), proceeds faster than alkene isomerization, a potentially competing process also mediated by Rh(I) catalysts. 97 In accord with our previous results, 94 the efficiency of this cycloaddition also indicates that the geminal diester substitution in the tether is not required for the cycloaddition to proceed efficiently. Substrates 46 (E:Z = 5.5:1) and 48 were selected for study because of the number of naturally occurring bicyclo[5.3.0]decanes bearing an angular methyl group and because of the general difficulties associated with quaternary center formation. 76 These methyl-substituted substrates (46 and 48) react rapidly (reaction times ~ 1 h) and with high efficiency (>90%) to afford exclusively the cis-fused products 47 and 49, respectively (Eqs. 59 and 60). In these cases, silver triflate is required for clean conversion. In its absence, decomposition occurs more rapidly than cycloaddition. At higher substrate concentration and

The Synthesis of Seven-Membered Rings 10 mol % RhCI(PPh3)3 10 mol % AgOTf PhCH3, 110 *C 92%

46

~" ~~JA'~... E" '~ 48

.~

10 m~ RhCI(PPh3)3 10 mo,% AgOT, PhCH3. 110 *C "-

94*/0

35 H

(59) 47

E e % ~

(60) H

49

lower catalyst load, the cycloadditions of 46 and 48 are also successful, although the benefits associated with decreasing the catalyst load are accompanied by a slightly reduced yield. Attempted cycloadditions of substrates, which would lead to cycloadducts beating two angular methyl groups, have been unsuccessful thus far. Likewise, substrates beating substitution of the alkene terminus do not undergo efficient cycloaddition but react instead to form products primarily arising from 13-hydride elimination pathways. In contrast, methyl substitution of the alkene group of the vinylcyclopropane is tolerated, as indicated by the cycloaddition of 50 (E:Z = 6.5" 1) which provides 51 in 78% yield (Eq. 61). In this case, the cycloadduct initially produced undergoes a secondary isomerization mediated by the Rh(I) catalyst to produce 51. At lower temperatures, this isomerization is not complete and thus results in a mixture of products. 5 mol % RhCI(PPh3)3

50

PhCH3, 110 *C 78%

(61) 51

Finally, the reaction is also successful for substrates with four-atom tethers (Eq. 62), although a longer reaction time is required in this case to offset the less favorable entropy. Cycloaddition of 52 in the presence of 10 mol% RhCI(PPh3) 3 and 10 mol% AgOTf in toluene at 100 ~ provides a 77% yield of 53 in 5 days. Again a single diastereomer, tentatively assigned with trans stereochemistry, is formed, reconfirming the high diastereoselectivity of this process.

36

PAUL A. WENDER and JENNIFER A. LOVE E

~

E

52

Ce

10 mol % RhCI(PPh3)3 10 mol% AgOTf PhCH3, 100*C = 77*/.

H E E

(62)

H 53

Intramolecular [5+2] Cycloadditions of Allene-Vinylcyclopropanes

Unlike reactions with alkenes and alkynes, relatively few examples of intramolecular transition metal-catalyzed reactions of allenes have been reported so far. 98Continuing our endeavor to extend the synthetic reach of transition-metal-catalyzed reactions, we have directed our attention at the use of an allene as the =-system. 99 As with the alkene systems, two stereochemical outcomes are possible for the intramolecular [5+2] cycloaddition of allene-vinylcyclopropanes. The use of an allene moiety also presents an interesting opportunity to incorporate chirality into the substrate. Additionally, because ene-vinylcyclopropane substrates substituted at the alkene terminus are not amenable to [5+2] cycloaddition, the use of an allene allows access to the same framework that would be obtained by cycloaddition of terminally substituted alkene substrates, thereby circumventing one of the few limitations encountered with ene-vinylcyclopropane cycloadditions. The investigation began with allene-vinylcyclopropane substrate 54. In the presence of 5 mol% RhCI(PPh3) 3 and 5 mol% AgOTf in toluene at 100 ~ for 0.5 h, 54 undergoes cycloaddition to provide a 1.1:1 mixture of 55a and b in 68% yield (Eq. 63). Attempts to increase

E E

~

~

54

.//

5 mol % AgOTI ~ i~~,. ~ PhCH3,100"c 68%, 1.1 : 1

H

H

H

I~1

55a

55b

(63)

the diastereoselectivity of this cycloaddition through changes in the catalyst were only moderately successful. However, modification of the substrate has a profound effect on both the yield and diastereoselectivity of the process. The cycloaddition of 56, which differs from

The Synthesis of Seven-Membered Rings

E E

o •

5 mol % RhCI(PPh3)3 5 mol % AgOTf PhCH3,100_ C =

~

92%, 2 19

37

E~ H

E

56

H

H

(64)

I~1

57a

57b

54 only by dimethyl substitution of the allene terminus, provides a 92% yield of 57a and b in a cis to trans ratio of 2:1 (Eq. 64). Presumably, increasing the steric bulk of the allene precludes competing oligomerization processes, resulting in a higher yield of the 5,7-product. The effect of even greater substitution of the allene terminus was explored next. Allene-vinylcyclopropane 58, which bears t-butyl substitution, was chosen for this study. In the presence of 1 mol% tris(triphenylphosphine)rhodium(I) chloride in toluene at 100 ~ for 5 h, 58 undergoes efficient cycloaddition to provide a 96% yield of 59 as a single diastereomer with a cis ring fusion (Eq. 65). Thus, oJ E

t-Bu

1 mol % RhCI(PPh3)3

t-Bu~....~

(65)

96*/,

H

58

59

increasing the steric bulk of substituents on the terminal carbon of the allene moiety results in an exceptional improvement in both the yield and diastereoselectivity of the transformation. The effect of substitution at the internal carbon of the allene was examined next, driven in part by the potential use of this process in the synthesis of targets bearing an angular substituent. In the presence of a catalyst system derived from 5 mol% RhCI(PPh3) 3 and 5 mol% AgOTf in toluene at 110 ~ allene-vinylcyclopropane 60 provides 61 in 44% yield (Eq. 66). In contrast to the cycloaddition of 54, cycloaddition of 60 produces 61 as a single diastereomer. E,,./'~" E

"

~ 60

5 mol % RhCI(PPh3)3 5 mol % AgOTf PhCH3, 110 ~ 44%

(66) H

61

38

PAUL A. WENDER and JENNIFER A. LOVE

To determine whether increased substitution of the allene terminus would have a similar beneficial effect on the yield as seen with the cycloaddition of 58, allene-vinylcyclopropane 62 was selected for study. The yield of cycloaddition improved to 70% by including t-butyl substitution of the allene terminus (Eq. 67). t-Bu

.J

5 mol % RhCI(PPh3)3

mo,%A~

E

PhCH3, 100 ~

E

7O%

tBu"-a~

;

(67) H

62

63

The reaction was also tested with a substrate containing a four-atom tether (Eq. 68). Consistent with our earlier observations, the yield of the cycloaddition improves with increasing substitution of the allene (Eq. 69). Interestingly, the reaction times for substrates with both three- and four-atom tethers are comparable, in contrast to our earlier findings with ene-vinylcyclopropane cycloadditions in which a oneatom increase in tether length profoundly increases the reaction time. .~

10 mol % RhCI(PPh3)3 10 mol % AgOTf

E

PhCH3, 100 ~

E

\

,,

\

(68)

E

43%

E

64

65

10 tool % RhCI(PPh3)3 -i/~o E

.

10 tool % AgOTf PhCH3, 100 ~

E

52% 66

-__

(69)

E E

67

A point of further significance is whether the chirality of a nonracemic substrate would be transferred to the cycloadduct. Based on the high diastereoselectivity and unparalleled efficiency of the cycloaddition of allene-vinylcyclopropane 58, this substrate was selected to study chirality transfer. This substrate is prepared from ethylene glycol in 10 steps. In the presence of 1 mol% RhCI(PPh3) 3

The Synthesis of Seven-Membered Rings H ,~,,t

E

~

39 FBu

Bu 1 mol % RhCI(PPh3)s

(70)

PhCHs, 100*C

E

81% 58

H 59

in toluene at 100~ 58 (91% ee) gives an 81% yield of cycloadduct 59 (92% ee), a process which occurs with complete retention of stereochemistry (Eq. 70).

D. Total Synthesis of Dictamnol From these studies, it is apparent that this new reaction has great value in producing otherwise difficult to prepare building blocks and has enormous potential in synthesis. Our next endeavor was to evaluate the suitability of this methodology to synthesize complex molecules. Dictamnol, a new trinor-guaiane type sesquiterpene isolated from the roots of Dictamnus dasycarpus Turcz, is representative of a large number of natural and designed targets to which this cycloaddition might apply. 1~176 In 1996, the first synthesis of dictamnol was reported, 1~ and another synthesis emerged later the same year. 1~ The latter report included a revision in the originally proposed structure of dictamnol. Confirmation of this revised structure was subsequently provided in 1997 with the synthesis reported by Lange and co-workers. 103 Given the previously discussed examples of the [5+2] cycloaddition, one can imagine a variety of approaches to the synthesis of molecules like dictamnol. One which has found success is given in Scheme 8. The cycloaddition precursor is prepared in three steps from commercially available cyclopropanecarboxaldehyde. Cycloaddition of alcohol 68 proceeds in 69% yield to provide cycloadduct 70. The yield of the cycloaddition is improved to 80% by protecting the alcohol as a TBS ether (69), although the combined yield for cycloaddition and deprotection is 70%. With two additional steps from 70, dictamnol (71a) was prepared in 10% overall yield, marking the first application of the metal-catalyzed [5+2] cycloaddition in natural product synthesis.

40

PAUL A. WENDER and JENNIFER A. LOVE CHO Z

~

"

f

1 mol % RhCI(PPh3)3 PhCH3, 110 *C, 80%; TBAF, THF, 88% (70% 2 steps)

= RO

R =H (68)

R = TBS (69)

HO

s

H

Hb H

70

H

71a

- H

71b

Scheme 8. Total synthesis of dictamnol.

VIII.

CONCLUSION

After four decades of research on the potential of vinylcyclopropanes as five-carbon components in [5+2] cycloadditions, a new reaction has now been successfully developed to synthesize seven-membered tings based on the reaction of vinylcyclopropanes and dienophiles, a reaction homologous to the Diels-Alder cycloaddition, one of the most important reactions in synthesis. A wide variety of substrates can be used in this reaction that provide an array of seven-membered rings. Electron-rich, electron-poor, sterically demanding, and conjugating substituents all provide good to excellent yields of fused bicyclic products. The cycloadditions generally proceed with exceptional diastereoselectivity. Increasing the tether length provides access to 6,7-fused bicyclic compounds. This novel and efficient transformation has been applied to the total synthesis of dictamnol, an example representative of a variety of molecules of synthetic and medicinal interest. In summary, we have demonstrated that vinylcyclopropanes in the presence of a rhodium(I) catalyst react even with the weakest dienophiles, providing a new and remarkably general process for complex molecule synthesis.

ACKNOWLEDGMENTS This research was supported by a grant (CHE-9321676) from the National Science Foundation. Fellowship support from the American Chemical Soci-

The Synthesis of Seven-Membered Rings

41

ety Division of Organic Chemistry, sponsored by Eli Lilly (J.A.L.), is gratefully acknowledged.

REFERENCES 1. 2. 3. 4. 5. 6. 7.

Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765. Wender, P. A.; Miller, B. A. Org. Synth. Theory Appl. 1993, 2, 27. Grieco, P. A.; Ohfune, Y.; Majetich, G. J. Am. Chem. Soc. 1977, 99, 7393. Bird, C. W.; Hormozi, N. Tetrahedron Lett. 1990, 31, 3501. Filippini, M-H.; Rodriguez, J. J. Org. Chem. 1997, 62, 3034. Lavoisier-Gallo, T.; Charonnet, E.; Rodriguez, J. J. Org. Chem. 1998, 63,900. Majetich, G.; Hicks, R.; Zhang, Y.; Tian, X.; Feltman, T. L.; Fang, J.; Duncan, S. G. J. Org. Chem. 1996, 61, 8169. 8. Xu, Y.; Yakushijin, K.; Home, D. A. J. Org. Chem. 1997, 62,456. 9. Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J. Org. Chem. 1997, 62, 3032. 10. Martin, S. E; Bur, S. K. Tetrahedron Lett. 1997, 38, 7641. 11. Begley, M. J.; Pattenden, G.; Smithies, A. J.; Walter, D. S. Tetrahedron Lett. 1994, 35, 2417. 12. Ott, M. M.; Little, R. D. J. Org. Chem. 1997, 62, 1610. 13. Little, R. D. Chem. Rev. 1996, 96, 93. 14. O'Neil, S. V.; Quickley, C. A.; Snider, B. B. J. Org. Chem. 1997, 62, 1970. 15. Colclough, D.; White, J. B.; Smith, W. B.; Chu, Y. J. Org. Chem. 1993, 58, 6303. 16. Junga, H.; Blechert, S. Tetrahedron Lett. 1993, 34, 3731. 17. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856. 18. Curci, R.; Fiorentino, M.; Fusco, C.; Mello, R.; Ballistreri, E P.; Failla, S.; Tomaselli, G. A. Tetrahedron Lett. 1992, 33, 7929. 19. Negishi, E-I.; Ma, S.; Sugihara, T.; Noda, Y. J. Org. Chem. 1997, 62, 1922. 20. Fan, W.; White, J. B. J. Org. Chem. 1993, 58, 3557. 21. Wender, P. A.; Holt, D. A.; Sieburth, S. M. J. Am. Chem. Soc. 1983, 105, 3348. Wender, P. A.; Holt, D. A. J. Am. Chem. Soc. 1985, 107, 7771. 22. Satoh, T.; Itoh, N.; Gengyo, K.; Yamakawa, K. Tetrahedron Lett. 1992, 33, 7545. 23. Katritzky, A. R.; Xie, L.; Toader, D.; Seryduk, L. J. Am. Chem. Soc. 1995, 117, 12015. 24. Banwell, M. G.; Cameron, J. M. Tetrahedron Lett. 1996, 37, 525. 25. Wolfe, M. S.; Dutta, D.; Aube, J. J. Org. Chem. 1997, 62, 654. 26. Wovkulich, P. M. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 1, Chap. 3.3. 27. Berson, J. A.; Jones, M. J. Am. Chem. Soc. 1964, 86, 5017. Berson, J. A.; Gajewski, J. J. J. Am. Chem. Soc. 1964, 86, 5019. 28. Reinhoudt, D. N. Adv. Het. Chem. 1997, 253. 29. Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993, 115, 4895. 30. Zhang, W.; Dowd, P. Tetrahedron Lett. 1996, 37, 957. 31. Wender, P. A.; Filosa, M. P. J. Org. Chem. 1976, 41, 3490.

42

PAUL A. WENDER and JENNIFER A. LOVE

32. Marino, J. P.; Kaneko, T. J. Org. Chem. 1974, 39, 3175. 33. Piers, E.; Morton, H. E.; Nagakura, I.; Thies, R. W. Can. J. Chem. 1983, 61, 1226. 34. Chou, W-N.; White, J. B.; Smith, W. B. J. Am. Chem. Soc. 1992, 114, 4658. 35. Harvey,D. E; Grenzer, E. M.; Gantzel, P. K.J.Am. Chem. Soc. 1994,116, 6719. 36. Barluenga, J.; Aznar, E; Martin, A.; Vasquez, J. T. J. Am. Chem. Soc. 1995,117, 9419. 37. Wulff, W. B.; Bauta, W. E.; Kaesler, R. W.; Lankford, P. J.; Miller, R. A.; Murray, C. K.; Yang, D. C. J. Am. Chem. Soc. 1990, 112, 3642. 38. Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thomley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095. 39. Griesbeck, A. G. J. Prakt. Chem. 1993, 335, 489. 40. Wender, P. A.; Eissenstat, M. A.; Filosa, M. P. J. Am. Chem. Soc. 1979, 101, 2196. 41. Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1998, 63, 657. For additional examples of the scope of this reaction, see Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thomley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095. 42. Hemdon, J. W.; Chatterjee, G.; Patel, P. P.; Matasi, J. J.; Tumer, S. U.; Harp, J. J.; Reid, M. D. J. Am. Chem. Soc. 1991, 113, 7808. 43. Funk, R. L.; Olmstead, T. A.; Parvez, M. J. Am. Chem. Soc. 1988, 110, 3298. 44. Winkler, J. D.; Henegar, K. E.; Willard, P. G. J. Am. Chem. Soc. 1987, 109, 2850. Winkler, J. D.; Gretler, E. A.; Willard, P. G. J. Org. Chem. 1993, 58, 1973. 45. Lange, G. L.; Gottardo, C. Tetrahedron Lett. 1994, 35, 8513. 46. Miesch, M.; Mislin, G.; Franck-Neumann, M. Tetrahedron Lett. 1997, 38, 7551. 47. Comer, D. A.; Marples, B. A.; Dart, R. K. Synlett 1992, 987. 48. Paquette, L. A.; Wang, X. J. Org. Chem. 1994, 59, 2052. 49. In this manuscript, bracketed numbers (e.g., ([4+2]) are used to describe the number of atoms in each component of a cycloaddition reaction. Thus this notation is differentiated from electronic designations which, by convention, utilize numbers with subscripts indicating orbital type (e.g., 4p+2p). 50. Noyori, R.; Makino, S.; Takaya, H. J. Am. Chem. Soc. 1971, 93, 1272. 51. Rawson, D. I.; Carpenter, B. K.; Hoffmann, H. M. R. J. Am. Chem. Soc. 1979, 101, 1786. 52. Arco, M. J.; Trammell, M. H.; White, J. D. J. Org. Chem. 1976, 41, 2075. 53. Cummins, W. J.; Drew, M. G. B.; Mann, J.; Markson, A. J. Tetrahedron 1988, 44,5151. 54. Harmata, M.; Gamlath, C. B.; Barnes, C. L. Tetrahedron Lett. 1993, 34, 265. 55. Trost, B. M.; Higuchi, R. I. J. Am. Chem. Soc. 1996, 118, 10094. 56. Giguere, R. J.; Tassely, S. M.; Rose, M. I. Tetrahedron Lett. 1990, 31, 4577. 57. For reviews of [4+3] cycloadditions between aUyl cations and dienes, see Hosomi, A.; Tominaga, Y. In Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Vol. 5, Chap. 5.1; Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1; Mann, J. Tetrahedron 1986,

The Synthesis of Seven-Membered Rings

43

42,4611; Noyori, R.; Hayakawa, Y. Org. React. 1983, 29, 163; Harmata, M. In Advances in Cycloaddition; Lautens, M., Ed.; JAI: Greenwich, 1997, Vol. 4, p. 41; Harmata, M. Tetrahedron 1997, 53, 6235.

58. Volkmann, R. A.; Weeks, P. D.; Kuhla, D. E.; Whipple, E. B.; Chmurny, G. N. J. Org. Chem. 1977, 42, 3976. 59. Katritzky, A. R. J. Am. Chem. Soc. 1970, 92, 4134. 60. Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1983, 666. 61. Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. For the first asymmetrical synthesis of phorbol, see Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997, 119, 7897. 62. Williams, D. R.; Benbow, J. W.; McNutt, J. G.; Allen, E. E. J. Org. Chem. 1995, 60, 833. 63. For a review of oxidopyrylium cycloadditions, see Sammes, P. G. Gazz. Chim. Ital. 1986, 116, 109. 64. The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New York, 1987; Parts 1 and 2. Schleyer, Pv. R.; Buss, V. J. Am. Chem. Soc. 1969, 91, 5880-5882. Wolf, J.; Harch, P. G.; Taft, R. W.; Hehre, W. J. Am. Chem. Soc. 1975, 97, 2902-2904. 65. Sarel, S.; Breuer, E. J. Am. Chem. Soc. 1959, 6522-6523. 66. Pasto, D. J.; Chen, A. E-T., Binsch, G.J. Am. Chem. Soc. 1973,95, 1553. Pasto, D. J.; Chen, A. E-T. Tetrahedron Lett. 1973, 713. Herges, R., unpublished results. 67. Fowler, E W. Angew. Chem., Int. Ed. Engl. 1971, 10, 135. 68. Herges, R.; Ugi, I. Angew. Chem., Int. Ed. Engl. 1985, 24, 594. 69. Christi, M.; Brunn, E.; Lanzendorfer, E J. Am. Chem. Soc. 1984, 106, 373. Baldwin, J. E.; Pinschmidt, R. K., Jr. Tetrahedron Lett. 1971, 935. 70. Effenberger, F.; Podszun, W. Angew. Chem., Int. Ed. Engl. 1969, 8, 976. Langbeheim, M." Sarel, S. Tetrahedron Lett. 1978,1219. Yamaoka, H." Yamada, Y.; Ono, S.; Hanafusa, T. Chem. Lett. 1979, 523. Sarel, S.; Felzenstein, A-M.; Weisz, M. Isr. J. Chem. 1982, 22, 64. 71. Herges, R. In Chemical Structures; Warr, W. A., Ed.; Springer-Verlag: Berlin, 1988; p. 385. 72. Rigby, J. H.; Ateeq, H. S. J. Am. Chem. Soc. 1995, 117, 8275. 73. Trost, B. M.; Grese, T. A. J. Org. Chem. 1992, 57, 686. 74. Duclos, O.; Dureault, A.; Depezay, J. C. Tetrahedron Lett. 1992, 33, 1059. 75. Lautens, M.; Tam, W.; Sood, C. J. Org. Chem. 1993, 58, 4513. 76. West, E G.; Hartke-Karger, C.; Koch, D. J.; Kuehn, C. E.; Arif, A. M. J. Org. Chem. 1993, 58, 6795. 77. Schwiebert, K. E.; Stryker, J. M. J. Am. Chem. Soc. 1995, 117, 8275. 78. Molander, G. A.; Eastwood, P. R. J. Org. Chem. 1996, 61, 1910. 79. For recent reviews and lead references on transition-metal-catalyzed cycloadditions, see Hegedus, L. S. Coord. Chem. Rev. 1997, 161, 129. Dell, C. P. Contemp. Org. Syn. 1997, 4, 87. Franhauf, H. W. Chem. Rev. 1997, 97, 523-596. Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.

44

PAUL A. WENDER and JENNIFER A. LOVE

80. Wender, E A.; Natchus, M. G.; Shuker, A. J. In TAXOL Science and Applications: M. Suffness, Ed.; CRC Press: New York, 1995, pp. 123-187. 81. Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678. 82. Wender, P. A.; Snapper, M. L. Tetrahedron Lett. 1987, 28, 2221. 83. Wender, P. A.; Nuss, J. M.; Smith, D. B.; Suarez-Sobrino, A.; Vagberg, J.; Decosta, D.; Bordner, J. J. Org. Chem. 1997, 62, 4908. 84. Wender, P. A.; Correia, C. R. D.; Ihle, N. C. J. Am. Chem. Soc. 1988,110, 5904. 85. Wender, P. A.; Witulski, B., Stanford University, unpublished results. 86. Sauer, J. Angew. Chem., Int. Ed. Engl. 1966, 5, 211. Ciganik, E. Org. React. 1984, 32, 1. 87. Roush, W. R. InAdvances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, 1990; Vol. 2, p. 91. 88. Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432. 89. Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117, 1843. 90. Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem. Soc. 1990, 112, 4965. 91. Wender, P. A.; Smith, T. E. J. Org. Chem. 1995, 60, 2962. 92. Wender, P. A.; Smith, T. E. J. Org. Chem. 1996, 61,824. 93. For a review on metal-mediated cleavage of cyclopropanes, see Khusnutidinov, R. I.; Dzhemilev, U. M. J. Organomet. Chem. 1994, 1 and references therein. 94. Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720. 95. For reviews and lead references on seven-membered-ring natural products, see Fischer, N. H.; Olivier, E. J.; Fischer, H. D. Fortschr. Chem. Org. Naturst. 1979, 38, 47-390; Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Pavoac, E; White, C. T. In Total Synthesis of Natural Products; Apsimon, J., Ed.; Wiley: New York, 1983, Vol. 5, pp. 333-393; Rigby, J. H. In Studies in Natural Products Chemistry, Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 1988, Vol. 12, pp. 233-274; Fraga, B. M. Nat. Prod. Rep. 1996, 13, 307. 96. Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.J. Am. Chem. Soc. 1998, 120, 1940. Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; Pleuss, N. Tetrahedron, in press. 97. For representative examples, see Corey, E. J.; Suggs, J. W. J. Org. Chem. 1973, 38, 3224; Gigg, R.; Gent, P. A. J. Chem. Soc., Chem. Commun. 1974, 277; Gigg, R. J. Chem. Soc., Perkin Trans I 1980, 738. 98. For examples of allenes in intramolecular transition-metal-catalyzed cycloadditions, see [5+1] Murakami, M.; Itami, K.; Ubukata, M.; Tsuji, I.; Ito, Y. J. Org. Chem. 1998, 63, 4; [4+1] Murakami, M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1995, 34, 1476; Sigman, M. S.; Kerr, C. E.; Eaton, B. E. J. Am. Chem. Soc. 1993, 115, 7545; Sigman, M. S.; Eaton, B. E. J. Org. Chem. 1994, 59, 7488; [2+2+1] Kent, J. L.; Wan, H.; Brummond, K. Tetrahedron Lett. 1995, 36, 2407; [2+2+2] Aubert, C.; Llerena, D.; Malacria, M. Tetrahedron Lett. 1994, 35, 2341. 99. For comprehensive reviews on allene chemistry, see The Chemistry of Ketenes, Allenes and Related Compounds; S. Patai, Ed.; Wiley: New York, 1980; The

The Synthesis of Seven-MemberedRings

100. 101. 102.

103.

45

Chemistry ofAllenes; S. R. Landor, Ed.; Academic: London, 1982; Coppola, G. M.; Schuster, H. E AUenes in Organic Synthesis; Wiley: New York, 1984; Pasto, D. J. Tetrahedron 1984, 40, 2805. Takeuchi, N.; Fujita, T.; Goto, K.; Morisaki, N.; Osone, N.; Tobinaga, S. Chem. Pharm. Bull 1993, 41,923. Koike, T.; Yamazaki, K.; Fukumoto, N.; Yashiro, K.; Takeuchi, N.; Tobinaga, S. Chem. Pharm. BulL 1996, 44, 646. For the revised structure and second total synthesis of dictamnol, see Piet, D. P.; Orru, R. V. A.; Jenniskens, L. H. D.; Van De Harr, C.; Van Beek, T. A.; Franssen, M. C. R.; Wijnberg, J. B. P. A.; De Groot, A.; Chem. Pharm. Bull. 1996, 44, 1400. Lange, G. L.; Merica, A.; Chimanikire, M. Tetrahedron Lett. 1997, 38, 6371.

This Page Intentionally Left Blank

RECENT ADVANCES IN DIELS-ALDER CYCLOADDITIONS OF 2-PYRONES

Benjamin T. Woodard and Gary H. Posner

I~ II. III.

IV.

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . .

48 48

[4+2] Cycloadditions of 2-Pyrones with Alkynes . . . . . . . . [4+2] Cycloadditions of 2-Pyrones with Alkenes . . . . . . . . A. Aromatic Products . . . . . . . . . . . . . . . . . . . . . B. D i h y d r o b e n z e n e Products . . . . . . . . . . . . . . . . . . C. D o u b l e D i e l s - A l d e r Cycloadditions . . . . . . . . . . . . D. Isolable Bicycloadducts . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

50 52 52 54 54 56 80 80 80

Advances in Cycloaddition Volume 5, pages 47-83. Copyright 9 1999 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0346-8 47

48

BENJAMIN T. WOODARD and GARY H. POSNER ABSTRACT

This review of recent progress in [4+2] cycloaddition of 2-pyrone dienes emphasizes control of relative and absolute stereochemistry. Discussion includes the development of mild reaction conditions and electronic matching of reaction partners, allowing the isolation of bicyclic lactones with control of relative stereochemistry. Control of absolute stereochemistry in these cycloadditions features a stereochemical control element on one or more of the following: a pyrone diene, a dienophile, or a Lewis acid promoter. Applications of this methodology to synthesizing complex organic molecules are mentioned. i.

INTRODUCTION

Because of the aromatic character of 2-pyrones, they enter into [4+2] cycloadditions less readily than most cyclic conjugated dienes. Nevertheless, the ability of these heteroaromatic compounds to act as dienes in [4+2] cycloadditions was reported by Diels and Alder only three years after they first reported the [4+2] cycloaddition between dienes and dienophiles which bears their names. 1 In the decades following the first report of 2-pyrones acting as dienes, this methodology was occasionally employed by synthetic chemists, but up until the early 1970s the use of this methodology was largely confined to synthesizing aromatic products (1 and 4). This subject was the partial subject of a review in 1974. 2 More recently it has been recognized that, if isolable, the initially formed bicyclic lactones 2 themselves would provide highly functionalized, stereochemically rich building blocks from fiat, stereochemiR

ol

R~

O

R

-C02 R 1

R,,_

O

X

co2

Hx R

"

R

R

Diels-Alder Cycloadditions of 2-Pyrones

49

cally uninteresting precursors. This has frequently proved difficult because under thermal conditions these bicyclic lactones often undergo CO 2 extrusion leading to dihydrobenzene products 3. Considerable progress has been made in developing reaction conditions and electronically matching reaction partners to allow isolating these bicyclic lactones 2. Much of this work was reviewed in 1992. 3 Nucleophilic ring opening of the lactone ring in bicycloadducts of type 5 leads directly to tetrasubstituted cyclohexenes in which the relative stereochemistry of all four contiguous stereocenters is established. Thus, pyrones provide attractive synthetic equivalents to acyclic dienes of type 6 which may be difficult to prepare as pure geometrical isomers and which in many cases do not lead via DielsAlder cycloaddition to the desired stereochemical relationships. The application of [4+2] cycloaddition reactions of 2-pyrones to synthesizing functionalized cyclohexenes was the partial subject of a 1994 review. 4 The last decade has also witnessed steady progress in expanding the utility of this methodology by controlling the absolute stereochemistry of the cycloadducts. In general, three strategies have been employed to control the stereochemical outcome of these reactions. Chiral auxiliaries have been temporarily attached either to the diene or to the dienophile. Alternatively (or additionally), homochiral Lewis acids have been used to promote the cycloaddition. All three of these strategies have seen some success, and now Diels-Alder reactions of 2-pyrones reliably lead to products with greater than 90% enantiomeric excess. This chapter focuses on recent advances in the scope, stereocontrol, and synthetic utility of 2-pyrones in Diels-Alder reactions. Special attention is given to the development of new, mild reaction conditions and electronically matched reaction partners which allow isolating the initially formed bicyclic lactone adducts. Relative reactivities and selectivities of differently substituted pyrones are compared. Finally, 0

nuc

HO~~ 5 R

""x nuc, I~

" ZO"

uc 6

r~. x R

50

BENJAMIN T. WOODARD and GARY H. POSNER

the control of absolute stereochemistry is emphasized. Original papers discussed in the 1974 and 1992 reviews are mostly omitted from this discussion, except where the material is brought in to illustrate a point or to make a comparison. II.

[4+2] CYCLOADDITIONS OF 2-PYRONES WITH

ALKYNES

Since the first report of the reaction of 2-pyrones with acetylenic dienophiles in 1937,5 a wide variety of aromatic compounds has been synthesized by this method. The scope of this methodology is evident from the copious examples detailed in the 1974 and 1992 reviews. 2'3 This methodology was first applied to synthesizing carbazoles by Plieninger and co-workers in 1964,6 and it has been exploited subsequently in synthesizing a wide variety of substituted carbazoles 7 and indoles. 8 To date, no examples of isolated bicyclic dienes of type 7 have been reported, presumably because of the highly strained nature of such compounds. Arynes have functioned as dienophiles in this type of Diels-Alder reaction. The reaction of 2-pyrone with benzyne to yield naphthalene, as shown in the accompanying scheme, was first reported in 1962. 9 This methodology has since been applied to constructing [b]-annelated carbazoles, 7 and benz[f]indole, 8band the tetracyclic skeleton of the benzophenanthridine alkaloids. 1~Arynes used in this type of reaction include 3,4-didehydropyridine in the synthesis of ellipticine 8 and isoellipticine 9,11 3,4-(methylenedioxy)benzyne, 1~ and 2,3naphthalyne, l~ A recent report states that benzopyrones, such as coumarin 10, do not undergo the corresponding [4+2] cycloaddition reaction, presumably because the fused aromatic ring must lose aromaticity in the

R

III

~~0 0 R =

o

O/~R 7

R

-C02 R

Die~s-Aider Cycloadditions of 2-Pyrones

~~o ~

10

~~

.

51

-oo~ o~ ] ~ 1

Me

Me

Me '

Me

Me

Me

8

=. no reaction 10

transition state, t2 although there are examples in the literature of coumarins with pendant alkyne moieties that undergo intramolecular Diels-Alder reactions at high temperature. ~3 The intramolecular Diels-Alder reaction of 2-pyrones with alkynes has recently been exploited in synthesizing [a]-annelated carbazoles 11,14 [c]-annelated carbazoles 12,15 and lycorine alkaloids 13.16

~Jn

R-H, Me n=1,2,3

N

)n

o..o~ <~~o o~

~ 0

A

N H CO2Et R1

11

R=H, Me n=1,2

)n

H 12 CO2Et

A =R1 0

RI=R2=OMe RI+R2=OCH20

0

13

52

BENJAMIN T. WOODARD and GARY H. POSNER

Me R1

Me R1

RI=Me,Ph R2=CO2Et,Ts 14 MeO~OcN M e O ~ R M e O ~ J " ~ O z~=_M e O , - " , ~ ~ N Me Me R=CO2Et,Ts 15

Diels-Alder reactions have also been reported in which phosphaalkynes function as the dienophile component to yield phosphabenzenes. 17 An AM1 semiempirical study comparing alkynes and phosphaalkynes as dienophiles has been published recently. 18 It has also been reported that ethyl cyanoformate and p-toluenesulfonylcyanide undergo Diels-Alder reaction with some pyrones to yield pyrido[3,4-b]-indoles 14 and isoquinolines 15.19 This methodology was limited in scope, however, and it could not be extended to other nitriles (R = COPH, Me, Ph, Py, Me2N) nor to imines. III.

[4+2] CYCLOADDITIONS OF 2-PYRONES WITH ALKENES

A. Aromatic Products Although the bicycloadducts 2 resulting from the Diels-Alder reaction of 2-pyrones and alkenes are generally more stable than the diene bicycloadducts 7 formed from alkyne dienophiles, at elevated temperatures they may still undergo CO 2 extrusion to form cyclohexadienes 3. These cyclohexadienes may themselves undergo elimination of HX, either spontaneously or after the addition of a base to the reaction mixture, to yield aromatic products 4. Many examples of this reaction type are shown in the 1992 review, 3 and more examples may be found in the carbazole and indole references. 7'8 An interesting development in this area has been the in situ dehydrogenation of the cyclohexadiene products 3 (X = H) by palladium on activated carbon. 2~ This has been applied to a wide variety of substituted phenyl and biphenyl compounds, and it offers the advan-

Diels-Alder Cycloadditions of 2-Pyrones

~~O : ' ~

53

X -HX x 2

R

R

3

17 0 , ~

4

OO h

tage that further cycloaddition of the cyclohexadiene with the dienophile does not occur. A related reaction type is the high pressure (6.2 kbar) Diels-Alder reaction of 2-pyrones with cyclopropenone ketals 16 to give isolable bicycloadducts 17, which then undergo cycloreversion, electrocyclic rearrangement, and ketal hydrolysis leading to tropones. Tropolones also have been formed in this way. This tropolone annulation chemistry was the partial subject of a review in 1990, 2~ and it was exploited in the syntheses of some naturally occurring tropoloisoquinolines 18-20. 22

OMe

O 18

OMe

H

OMe

OMe

O

19

20

Me

54

BENJAMIN T. WOODARD and GARY H. POSNER

B. Dihydrobenzene Products Typically, under thermal conditions, initial bicyclolactone formation is followed by cycloreversion with loss of CO 2. The resulting cyclohexadiene then suffers elimination or dehydrogenation leading to aromatic products (vide supra) or cycloaddition of a second dienophile molecule leading to bicyclo[2.2.2]octenes (vide infra). If the dienophile is geminally disubstituted or otherwise unable to aromatize and if the cyclohexadiene does not undergo subsequent cycloaddition, dihydrobenzene products may be isolated. This reaction mode is less common than that leading to aromatic products, but some examples are detailed in the 1974 and 1992 reviews. 2'3 A more recent example of this methodology is the Diels-Alder reaction of 3-carbomethoxy2-pyrone 21 with ct-terpinene, followed by CO z extrusion leading to bicycle 22, which was subsequently elaborated to (+)-10-epijuneol. 23

.C02Me 21

/

C02Me / 64~

22

[ ~ O~]~HL (•

C. Double Diels-Alder Cycloadditions When at least two equivalents of dienophile are used and the reaction conditions are such that CO 2 extrusion spontaneously occurs, a second molecule of dienophile adds to the cyclohexadiene initially produced. A number of examples of this sort of reaction have been reported, generally in which maleic anhydride or maleimides function as the dienophile. Klemm and co-workers have applied this double Diels-Alder methodology to the synthesis of novel polymers. 24 Copolymerization of bispyrone 23 with bismaleimide 24 leads to soluble, stable polymers of number-average molecular weights between 10,000 and 34,000. The polymers are composed of coronand structure subunits 25 alternating with alkyl linkers. The structure of the coronand subunit, including the endo-selectivity of these double Diels-Alder adducts, has been elegantly demonstrated in model reactions. The orientation of the unsymmetrical

Diels-Alder Cycloadditions of 2-Pyrones

55

! 0

23

+

o -O

N, .O

I

S

R

O,,,

24 N O

25

H2) O

_

~1~

R----"" N-'~O

Un

bismaleimide linker is unknown. Continuing work in the Klemm group has shown that the nature of the polymers is controlled by changing the polymerization conditions. At high concentration, for instance, cross-linked polymers are produced rather than linear polymer 25. Other linker groups have been used both for the bismaleimide and the bispyrone. Various other nonconjugated dienes have been used as the dienophile component in tandem Diels-Alder processes. In these cases, the first cycloaddition occurs as usual. Then cycloreversion with loss of CO 2 is followed by intramolecular Diels-Alder reaction with the remaining pendant alkene to yield bicyclo[2.2.2]octene structures. For example, methyl coumalate (5-methoxycarbonyl-2-pyrone 26) reacts with 1,5-cyclooctadiene under thermal conditions to give the cage compound 27. 25

Me02C

:I 27

~

~'~ec~^~"

"v

\

/

56

BENJAMIN T. WOODARD and GARY H. POSNER

D. Isolable Bicycloadducts The initially formed Diels-Alder cycloadducts of 2-pyrones and alkenes, if isolable, provide stereochemically rich, highly functionalized, building blocks for organic synthesis. Thus, although it is often useful to cause CO 2 extrusion to form cyclohexadiene products, which then undergo elimination or dehydrogenation to form aromatic products or subsequent Diels-Alder reaction to form bicyclo[2.2.2]octene products, it is desirable to arrest the reaction before cycloreversion. Because of the aromatic character of 2-pyrones, however, these dienes do not typically enter into Diels-Alder reaction at ambient pressure without heating. Furthermore, under the high temperatures required for thermal cycloaddition, cycloreversion with loss of CO 2 is generally observed. With the goal of isolating these bicycloadducts, we began a research program in the mid-1980s focusing on 2-pyrone cycloadditions. The stereochemical richness inherent in these bicyclic lactone adducts has led also to the investigation of absolute stereochemical control in these cycloadditions.

Control of Relative Stereochemistry Four basic strategies have been employed toward the goal of low-temperature cycloaddition of 2-pyrones. The first strategy imposes geometric constraints on either the pyrone or the dienophile to increase reactivity. The scope of this approach is restricted by the limited availability of such species and by the relatively small array of cycloadducts which could be thus formed. Examples of this approach are detailed in the 1992 review and are not treated here. 3 The second strategy has been to use high pressure reaction conditions to promote the cycloaddition, which has a negative volume of activation, while retarding the extrusion of CO 2, which has a positive volume of activation. The third strategy has been to match the pyrone and the dienophile electronically to narrow the energy gap separating the frontier molecular orbitals which interact during the cycloaddition. The fourth strategy has been the use of Lewis acids or bases also to attenuate differences in the energy levels of the frontier molecular orbitals.

Diels-Alder Cycloadditions of 2-Pyrones

57

Although we continue to use high pressure and the use of high pressures has yielded exciting results, the cost of the requisite equipment, the inherent danger in working at high pressures, and the restrictions on reaction scale all limit this approach. Thus, for over a decade, we have also been exploring the advantages of electronically matching the pyrone and dienophile components and using Lewis acids for mild Diels-Alder cycloadditions. Often these strategies have been combined with one another and combined with high pressure to achieve the desired result. For this reason, it is more convenient to arrange a discussion according to substrate type rather than according to the strategy or strategies employed to facilitate cycloaddition.

2-Pyrone. Unsubstituted and therefore unactivated 2-pyrone itself typically undergoes cycloaddition under thermal conditions so vigorous that CO 2 extrusion is spontaneous. High-pressure conditions have been employed by Mark6 and co-workers, who reported that 2-pyrone reacts with a variety of different dienes, including unactivated dienes, at very high pressure (19 kbar) and yield the initially formed bicyclic lactones as stable, isolable products. 26 Then these bicyclic lactones are smoothly converted to bicyclo[2.2.2]octene adducts shown in the accompanying figure upon heating. Dienophile

Product 0

0

BENJAMIN T. W O O D A R D and GARY H. POSNER

58

O

0

••oO•

O

CO2Me 18.5 kbar / OO~ c O2Me 28 syn-endo

O

C02Me +

C02Me C02Me

syn-exo

anti-endo

anti-exo

Subsequent work in the Mark6 group has shown that under highpressure reaction conditions, methyl acrylate reacts with 2-pyrone to yield a mixture of all four possible isomeric bicyclic lactones. The identification of the major reaction product as the syn-endo isomer 28 was established by X-ray crystallographic analysis. 27 This methodology was subsequently employed to synthesize dialdehyde 29 as an entry into the tricyclic core of gibberellic acid and zizaene. 28 Although the reaction with electron-poor dienophiles is relatively facile, unsubstituted 2-pyrone undergoes cycloaddition only sluggishly at high pressures with electron-rich vinyl ethers. Under the combined influence of pressure and Lewis acid catalysis, however, 2-pyrone reacts with benzyl vinyl ether on a gram scale in the absence O

~~O O

18.5 kbar

_CHO

I T!C~;/ 2) NalO4

O 29

=-. CHO O ~ ~ 0 0 ~+ 0 v Ph10"12kbar O'J( Ph

Lewis Acid

Yb(fod)3 Yb(NO3)3=5H20 ZnCI2

Yield 94% 90~ 92%

3O

O

Diels-Alder Cycloadditions of 2-Pyrones

59

of solvent to give excellent yields of bicyclic lactone 30 as a single stereoisomer. 29 It is noteworthy that the high pressure cycloaddition of 2-pyrone with fullerene C60, which yields isolable bicyclic lactone adducts in the absence of Lewis acid, has recently been reported. 3~

3-Carbonyl-2-pyrones. Early work in this group focused on making the pyrone component more electron-deficient and therefore more reactive toward electron-rich dienophiles. As a quantitative measure of electron density in the diene portion of the pyrone system, 13C NMR chemical shift data were recorded for a series of 3-substituted pyrones. 3~These data and comparison data for the corresponding substituted benzenes are shown in Table 1. Based on 13C NMR chemical shift data, 3-chlorocarbonyl-2-pyrone 31 is the most electron-poor pyrone diene. Thus, its reaction with electron-rich vinyl ethers was examined. It was not initially clear whether vinyl ethers would react with pyrone 31 via nucleophilic attack at the acid chloride functionality or via [4+2] cycloaddition at the diene moiety. Vinyl ethers in fact cycloadded to 31 at room temperature to give quite acceptable yields of syn-endo cycloadducts either predominantly (in the case of butyl vinyl ether 5% of the syn-exo isomer was observed) or exclusively (in the case of the TBDMS ether Table 1. z

Z

z

13C (ppm)

13C(ppm)

c1c(o)-

158.8

--

ArO2S-

157.1

133.6

MeO2C-

156.5

132.8

H-

151.7

128.5

Br-

150.9

127.0

ArS-

147.0

126.9

R3SiO-

144.0

121.4

HO-

142.1

121.4

60

BENJAMIN T. WOODARD and GARY H. POSNER

COOl 0 ~ ~ O '.~ ~) O"R 25902O~,,O ~ ~ ( oCOCILiOM..~ e . ~ C OCO2Me 2Me CH2CI HO~ ' ' v ~OR 31 "R 32 R Yield n-Bu 80% TBDMS 77% no other regioisomer or stereoisomer was observed). 4 The regiochemistry and stereochemistry of this and other bicyclic lactones were established unequivocally by 1H NMR decoupling experiments, details of which are fully discussed in the 1992 review. 3 The subsequent methanolysis of these adducts leads to trans-1,3-dioxygenated cyclohexenes 32. As might be expected on the basis of the ~3C NMR chemical shift data, 3-methoxycarbonyl-2-pyrone 33 is less reactive toward vinyl ethers than 3-chlorocarbonyl-2-pyrone. In fact, at room temperature in methylene chloride, no cycloadduct formation was observed with a number of different vinyl ethers. Mark6 and co-workers, however, coaxed these pyrone dienes into reacting with representative vinyl ethers at elevated temperatures (70~ ~ in polar aprotic solvents, leading to bicyclic lactones 34-37. 32 In all cases, each of these bicycloadducts is obtained as a single stereoisomer. Our own experience with 3-carbomethoxy-2-pyrone has shown that it can be made to react with vinyl ethers in the presence of Lewis acid catalysts, such as montmorillonite clays, silica, or zinc salts in methylene chloride at ambient pressure and room temperature or lower to give excellent yields of bicyclic lactones 38 and 39 as single regio- and stereoisomeric products. 4'33 Substituted vinyl ethers may react more sluggishly, but often they can be forced into reaction at high pressure. This strategy was employed to synthesize bicyclic lactone 40, which was prepared as an intermediate in synthesizing a novel 4'-hydroxybutyl vitamin D analog. 34 Retention of the olefin stereochemistry in the cycloadduct suggests that this reaction proceeds via a concerted rather than a stepwise mechanism. Although electron-rich vinyl ethers can be coerced into reacting with 3-methoxycarbonyl-2-pyrone under either high pressure or Lewis acid catalysis, the same is not true ofunactivated dienophiles. Thus

Diels-Alder Cycloadditions of 2-Pyrones

CO2Me f~',~O/o~ II

61

O 70g_80oC o'~CO2Me CH3NO2 ~~"~10 95%

33

34

0

CO2Me O,J(,CO ~ ~ O .O~ O v Ph 70~-80g CH3NO2 C ~:/O 2Me 65% vph CO2Me O ~ ~ O O+-~O- 70g-80gC O~t,cO2Me DMSO

~

40~

36

CO2Me

.CO2~e O+ ~ O ~ . 2 5 g

O 70~-80gC O~./CO2Me DMSO 7~7~ 46%

C = CH2CI2

O o~/CO2Me

/f~O~ 38

K-306montmorillonite 4 days 91% silicagel 1day >95% O CO2Me ZnBr2 O,J~,CO ~O ,.OTBDMS0'C+ CH2Cl2 . /~L'~O 2Me <5min TBDMS 95% 39 CO2Me ~O OTBDMS

O 11kbar = 0~ CO2Me OTBDPS40H2012 days / ~ O TBDMS 60% 40 ~./~,~OTBDPS

BENJAMIN T. WOODARD and GARY H. POSNER

62

Table 2. CO2~ e O+fR

R

0

ZnBr2 o~CO2Me 10-12kbar CH2CI2 - ~ " ~ R

syn-endo

syn-exo

anti-endo

anti-exo

74% 76% 64%

3% 9% 13%

12% 0% 0%

2% 0% 0%

CH2OTBS CH2Si(OEt)3 CH2Ph

a combination of Lewis acid catalysis and high pressure is needed to promote the [4+2] cycloaddition of this pyrone with a number of unactivated terminal alkenes leading to bicyclic lactones shown in Table 2. 35 In general, reaction with unactivated dienophiles leads to decreased levels of stereocontrol compared to reaction with activated dienophiles.

5-Methoxycarbonyl-2-pyrone. It has been reported that the [4+2] cycloaddition reactions of 5-methoxycarbony]-2-pyrone 41 0

~,~0~0 I1~ 0Q8 -0Q C / ~0'l ~~l .+0 ~ 7 CH3NO2;>95% ~ ~ O

MeO2C

41

MeO2C 42

75%

MeO2C~ . ~ O O+ ~ , O .

MeO2C

+

MeO2C' 43

~

88:12

O

~~00+ l~OvPh7 0L8OQC/~0 CH3NO2 7

MeO2C

endo'exo

~/Ph

90:10

O

70L80gC O~ . CH3NO2= ~'L"~/" 80% MeO2C~"~'O~ O CH3NO2" / X t ' ~ . . ~ >95% MeO2C 45

100:0

45:55

Diels-Alder Cycloadditions of 2-Pyrones

63

0 o

MeO2C~ ~ O

=' 7 MeO2C 46

(•

(•

with enol ethers that lead to adducts 42-45 proceed in higher yields, but with stereoselectivity lower than the corresponding reactions of 3-methoxycarbonyl-2-pyrone (vide supra). 32 This evidence parallels the higher reactivity of 5-bromopyrone relative to 3-bromopyrone (vide infra). High pressure was used to effect [4+2] cycloaddition of 5-methoxycarbonyl-2-pyrone with irida-2(7),5-diene 46 as the key step in a synthesis of (+)-shizuka-acoradienol. 36 In this case, thermal conditions alone were unsuccessful in promoting the cycloaddition, and in fact, upon heating at ambient pressure, the cycloadduct undergoes retro-Diels-Alder reaction to give starting materials.

3-SulfonyI-2-pyrones. Based on the 13C NMR chemical shift data in Table 1, 3-arylsulfonyl-2-pyrones were expected to cycloadd to electron-rich dienophiles, such as vinyl ethers. Pyrone sulfone 47 underwent cycloaddition to ethyl vinyl ether at room temperature and ambient pressure in the absence of Lewis acid to give cycloadduct 48 in excellent yield. 37 For steric and electronic reasons, it was expected Table 3. 0

TolSO2 CH2012

~~0~TO[ R R

R H H Me i-Pr

Conditions 80 ~ 12 kbar, 25 ~ 80 ~ 12 kbar, 25 ~

Yield

endo:exo

93% 100% 100% 20%

5:1 6:1 3:1 1:0

64

BENJAMIN T. WOODARD and GARY H. POSNER

T~

0

~~O O 47

25 gC =,OJ(/sO2mol

+ II~0~ CH2C12 /4-|~ 95 '~ //-..,~=/'

~ ~'0~ 48

that 1,2-dioxygenated olefins would react less readily. In fact, it was found that [4+2] cycloaddition with such olefins occurs with reasonable stereoselectivity at 60-80 ~ to yield bicycloadducts, as shown in Table 3. 38 In our experience, addition of Lewis acids does not help in the cycloaddition of 3-arylsulfonyl-2-pyrones. Elevated pressure was also necessary to force the reaction of pyrone 47 with substituted vinyl ethers 48E and 48Z. 34 Interestingly, geometric isomer 48Z reacts considerably faster and with better stereoselectivity than 48E. Thus, 48Z cycloadded to give 38% of cycloadducts 49,,do and 49~o in a ratio of 18:1. By contrast, 48E cycloadded to give a very low yield of cycloadducts 50,,do and 50,=o in a ratio of 2:1. In each reaction, the olefin stereochemistry was retained in the reaction products, indicating that these cycloadditions occur in a concerted rather than in a stepwise fashion.

3-Sulfinyl-2-pyrones. In contrast to 3-sulfonyl-2-pyrones, which do not benefit from the addition of Lewis acids, electron-poor 3-sulfinyl-2-pyrones undergo cycloaddition to electron-rich vinyl ethers under Lewis acid conditions. 39 Thus, in the presence of zinc bromide, pyrone 51 reacts with ethyl vinyl ether with reasonably good stereoselectivity to give cycloadducts 52endo and 52,=o in excellent yield. Vinyl Tol.SO2 ~~O o

+ oo"~

O 11 kbar _# ooTo, C"2Cl2- o y~,"

OT.S 47 48E ToISO2 ,,,,~_.,O .,OMe

47

48Z

OMe

49endo

O 11 kbar ...#.SO2ToI CH Ci2- u +

J

+

o,

, y " Y ~ OMe 49exo ~,.vf',....~OTBS O #SO2To I O OMe

L,~/~OTBS 50endo

O

50ex ~

Die~s-Alder Cycloadditions of 2-Pyrones

TolSO

65

0 ZnBD O,J(/SOTol

0

rile

51

97%

52enu~

Et

+

10:1

ToISO 0 ~1~00/SMe 6.8kbar O,J~,SOTol II 53

980/.

0 oEt 52ex~

"~'~S Me 54

thioethers, on the other hand, do not react under Lewis acid conditions, and high pressure is required for the cycloaddition of 53 with pyrone 51, which gives cycloadduct 54 in excellent yield as a single stereoisomer. 3-Sulfenyl-2-pyrones. As might be expected on the basis of the 13C NMR chemical shift data in Table 1, although 3-sulfonyl- and 3-sunfinyl-2-pyrones act as electrophilic dienophiles, 3-sulfenyl-2pyrone acts as a nucleophilic diene, cycloadding to a diverse array of electron-poor dienophiles. 4~ Table 4 gives results of representative cycloadditions. These data demonstrate the dramatic effects often observed because of small structural changes in the dienophile.

Table 4.

to u e n e

EWG

-NO2 --CN -CHO --CHO -COMe -CO2Me -CO2Bn -CO2Me

R

H H H Me H H H Me

T ~ (h)

25 (36) 85 (24) 88 (34) 85 (168) 85 (96) 85 (72) 85 (192) 85 (215)

Yield

EWG endo:exo

82% 53% 44% 70% 70% 65% 64% 42%

>98:2 2:1 >98:2 >98:2 >98:2 3:1 9:1 3:1

66

BENJAMIN T. WOODARD and GARY H. POSNER

3-Bromo-2-pyrone. Based on literature precedent and also on the 13CNMR chemical shift data in Table 1, our expectation was that 3-bromo-2-pyrone (55) would be unexciting as a diene in Diels-Alder reactions. We were pleasantly surprised to find that pyrone 55 undergoes [4+2] cycloadditions with both electron-rich and electron-poor dienophiles under relatively mild reaction conditions. 41 It has the additional advantage of being considerably more stable than 2-pyrone. The bicyclic lactone adducts formed typically undergo reductive debromination, therefore making 3-bromo-2-pyrone a synthetic equivalent of 2-pyrone. Based on competition experiments, 3-bromo-2-pyrone is more reactive toward both electron-poor and electron-rich dienophiles than unsubstituted 2-pyrone. It is, however, less reactive toward electrondeficient dienophiles than 3-sulfenyl-2-pyrone. More recently it was demonstrated that Lewis acid catalysis combined with high pressure coaxes 3-bromo-2-pyrone into [4+2] cycloadditions with unactivated terminal alkenes leading to cycloadducts, as shown in Table 5. 35 As in the case of 3-methoxycarbonyl-2-pyrone (vide supra), reaction with unactivated dienophiles generally leads to decreased levels of stereocontrol compared to reaction with activated dienophiles. The synthetic utility of 3-bromo-2-pyrone has been demonstrated by the conversion of bicyclic lactones 56-58 into differently functionalized A-ring fragments for a number of biologically interesting novel vitamin D analogs. 42 Table 5.

Br ~~OO+~ R R

CH2CH2CHs CH2Si(OEt)3 CH2CHEPh

ZnCI2 ;OBr 10-12kbar O VCH2CI2 ~ ~ R

syn-endo

syn-exo

anti-endo

anti-exo

74% 80% 60%

25% 0% 0%

0% 16% 4%

0% 0% 1%

Dieis-Alder Cycloadditions of 2-Pyrones

o o~Br

"T"31 =I : ~)H

(•

I

/ ~'~CHO ~ =-

O

~

o~Br,, ~CHO

(•

(•

o

o

' ~;' O T B S

(%58

H

HO""

I

OH

I

~

I

+

H

I

I

HH

I

H

7" + OH HO""

(•

",,,..

"T" I

~;-ii;;

o

67

~

25

(calcitriol)

HO""

o

OH ~

+

I

.,,,,OH H

I

+

I

H.H

I I

~

.,,~OH

(•

I ll[~

F H0""

I

o

,,w,,,,,

II

OH

F

5-Bromo-2-pyrone. Encouraged by the unexpectedly high reactivity and good stereoselectivity of 3-bromo-2-pyrone, we examined the [4+2] cycloaddition chemistry of 5-bromo-2-pyrone. Like 3bromo-2-pyrone, 5-bromo-2-pyrone reacts with both electron-rich and electron-poor dienophiles to give bicyclolactone adducts. 43 In general, the reactivity of 5-bromo-2-pyrone is two to six times greater than that of 3-bromo-2-pyrone, on the basis of competition experiments. The level of stereocontrol is lower for 5-bromo-2-pyrone relative to 3-bromo-2-pyrone, paralleling the trend observed for methoxycarbonyl substituted pyrones. Interestingly, it has been recently reported that 5-bromo-2-pyrone reacts even with unactivated dienophiles at modest pressures and temperature (i.e. pressure tube,

BENJAMIN T. W O O D A R D and GARY H. POSNER

68

Table 6.

~0 Br

Z

§

Z

0

toluene

Z

"

Br'

T ~ (days)

Yield

endo:exo

-CO2H --COCH3 --CN -OCH2CH2C1 -OSiMePh2

25 25 100 100 100

(5) (4) (2.5) (2) (2)

100% 89% 83% 100% 100%

1:0 1:0 54:46 2:1 2:1

-p-C6H4Br --CH2Br

100 90

(2.5) (5)

89% 62%

4:1 1:1

(5) (5) (5) (5) (5) (5) (5) (5) (5)

84% 86% 33% 61% 73% 49% 88% 79% 90%

1:1 1:1 45:55 1:1 55:45 40:60 30:70 <1:9 <1:9

-C4H10 --CH2CHMe2 --CH(Me)C2H5 --OCOCMe3 -OCOPh -OCHO --OCOMe -N-Pyrrolidinone -NPhth

90 90 90 90 90 90 90 90 90

90 ~ to give good yields of cycloadducts, albeit with low levels of stereocontrol (Table 6, entries 7-10). 44 Moreover, Afarinkia and co-workers 44showed that the stereochemistry of the cycloaddition is reversed with certain sterically demanding alkenes, thus favoring the syn-exo cycloadduct (Table 6, entries 15 and 16). This has been rationalized on the basis of the steric interaction between the bromine and the dienophile, as shown in the accompanying figure. o

Diels-Alder Cycloadditions of 2-Pyrones

69

Control of Absolute Stereochemistry In general, three strategies have been employed toward absolute stereochemical control in Diels-Alder reactions. A stereocontrol element may be attached to the dienophile, to the diene, or to a catalytic species, such as a Lewis acid. All three of these approaches, sometimes combined with one another, have been exploited in the Diels-Alder reactions of 2-pyrones. Each strategy is discussed. Cases in which chiral Lewis acids are employed along with chiral pyrone dienes are included in the section on chiral pyrone dienes. A brief discussion of intramolecular Diels-Alder reactions of 2-pyrones tethered to dienophile moieties with homochiral tethers is included as a separate section.

Stereochemical Control Element on the Dienophile. Pyrone sulfone 47 undergoes asymmetrical cycloaddition with a number of homochiral dienophiles at room temperature and gives modest to good diastereomeric excesses. 45 The results, shown in Table 7, were best with benzylic vinyl ethers. This methodology was employed to synthesize (-)-methyl triacetyl-4-epishikimate 46 and an A-ring precursor to lt~,25-dihydroxyvitamin D3.47

TolS02

R*

47

2-octyl endo-2-bomyl 8-phenylmenthyl menthyl 1-naph(Me)CH Ph(Me)CH 2,4,6-MeaPh(Me)CH Ph(i-Pr)CH Ph(t-Bu)CH

Table 7.

0 ~OR* Yield

>90% >90% >90% 89% 95% 75% >90% 94% 90%

%de

0 5 5 54 64 66 80 84 90

BENJAMIN T. W O O D A R D and GARY H. POSNER

70

Table 8. 0

Br

Br z

02R*

R*

Yield

%de

Ph(t-Bu)CH MeOOCCH(Me) endo-2-bomyl

95% 40% 85%

20 40 85

Modest to good levels of diastereoselectivity were also observed in the [4+2] cycloaddition reactions of 5-bromo-2-pyrone with homochiral acrylate esters, as shown in Table 8. 43 This strategy was recently used in a key step in the asymmetric total synthesis of (-)-podophyllotoxin. 48 In this case, high endo-selectivity and high facial selectivity were observed, and only one Diels-Alder product is formed.

0 ~ 0

~..,,,Omenth

< r

r,,

.~

.....~~..,,Omenth __.

o

O1'-.%/~O +1~ Me& O~/t'~~' ~ O .__,,.< o ~ O Ar

O

Ar

O

QH :

~,r O (-)-podophyllotoxin

Another recent application of this methodology to synthesis is the diastereoselective [4+2] cycloaddition of pyrone 59 to (R)-t-butylbenzyl vinyl ether in the presence of dimethylaluminum chloride which yields bicyclic lactone 60 in modest diastereomeric e x c e s s . 49 The major isomer is subsequently elaborated to a C-ring fragment of taxol.

CO2Me O..o,. Ph Me2AICI -~1CO2Me "-r~~..,, ~ ~ O'+11i" YB "78-~0 . C ~ . ~ O R " ==,..L..J~._'/~ - u CH2CI2 TM~' ' ' v "OH

59

60

Diels-Alder Cycloadditions of 2-Pyrones

71

TolSO 0 ~~0 0 ?eOyOMe 2590 _~SOTol .. ., ,-Io y~Y ,,OMe toluene >97% ~/. -'*OMe 76%de~v 51 OMe Ofl"~Okbaro Ph+~oEt 85%' 13 2590 " .-iJ"-~ 04~0__~0OMeph 10"/,de ~s 61

More recently, chiral BrCnsted bases have been employed along with chiral dienophiles in the Diels-Alder reaction of 3-hydroxy-2pyrone and give good levels of diastereoselectivity (vide infra). 5~

Stereochemical ControlElement on the Pyrone Diene. Early work in our group showed that the chiral sulfinyl group of pyrone 51 provides a measure of stereochemical control in Diels-Alder reactions. 5~ Diastereomeric excesses as high as 76% are obtained. Unfortunately, subsequent efforts to prepare enantiopure 51 have been unsuccessful. An early report by Thornton and co-workers indicates low levels of diastereocontrol in the reaction of pyrone 61 with ethyl vinyl ether. 52 To improve stereoselectivity, pyrone lactate methyl and ethyl esters 62 and 63 were synthesized. 53 Early experiments with a variety of achiral Lewis acids produced modest levels of diastereocontrol (3360%). Reaction of methyl lactate ester 63 with benzyl vinyl ether in the presence of zinc bromide at -50 ~ that yields the bicylic lactone adduct in 80% diastereomeric excess 53 encouraged us to pursue the possibility of double asymmetric induction. In fact, we discovered that (S)-lactate ester 64 cycloadds to benzyl vinyl ether in the presence of the chiral lanthanide promoter (-)-

EtO2Cv.0,~.0 MeO2Cv.ON~.O ~,,~o

62

~./o

63

72

BENJAMIN T. WOODARD and GARY H. POSNER

MeO2CTOi"i~O

(.).Pr(hfc)3

~,,,,,O 64

96%de

A/CO2R* Bn

65

Pr(hfc)3 to give bicyclic lactone 65 in excellent yield with very good diastereocontrol (96% de). 54When the same chiral Lewis acid is used with the opposite pyrone ester antipode, the diastereocontrol decreases (89% de). A similar decrease in asymmetric induction was observed when achiral Pr(fod)3 is employed as the promoter species (88% de). Mark6 and co-workers also have explored the use of chiral derivatives of 2-pyrones to induce asymmetry. 55Chiral pyrones 66-69 were studied in their reactions with ethyl vinyl ether. As the data in Table 9 indicate, the pantolactone auxiliary is the most useful of those studied. Most intriguing is the fact that catalysis with either antipode of the europium Lewis acid, or even an achiral europium Lewis acid, yields the same stereochemically impressive results.

Table 9.

CO2R. ~ ~ O O fOEt cat. + R=

1......

~ /~OEt

I \ Cat.

66 67 68 69 69 69

(+)-Eu(hcf)3 (+)-Eu(hcf)3 (+)-Eu0acf)3 (+)-Eu(hcf)3 (-)-Eu(hcf)3 Eu(fod)3

O OJ(/CO2R*

.....

0

t 67

68 Yield

83% 85% 82% 97% 91% 94%

69 %de

28 8 61 >95 >95 >95

Diels-Alder Cycloadditions of 2-Pyrones

73

Table 10.

O~ Z

OEt OBu OBu SBu SPh

o?CO2R* O+ I~Z cat" /~Z

Cat.

Yield

%de

Eu(fod)3 (+)-Eu(hcf)3 Eu(fod)3 (+)-Eu(hcf)3 (+)-Eu(hcf)3

94% 84% 95% 87% 91%

>95 >95 >95 >95 75

This methodology was extended to butyl vinyl ether and to thioethers (Table 10). When dihydrofuran is used as the dienophile, however, diastereometic excesses drop to around 5%. The facial selectivity of these cycloadditions has been rationalized by invoking the chelated structures 70, 71, and 72. The authors note that ~H NMR evidence indicates that the major complex in solution is the six-membered chelate 72, but they propose a dynamic equilibrium with the seven-membered chelates. The seven-membered chelate, it is proposed, is more reactive than the corresponding six-membered chelate, thus providing the dominant reaction pathway. This proposed

H --O L '~O,,.l~u'.L o.,ro"L

o

70 0

*RO2C,~ O

zC&

H H '~~l~O,,,i~u, O -- 0,... ~.L~ L'

~ ~ ~,,f.v

,rz

o

~... _ o. -

71 0

o'~CO2R~

....L:'

~..o'~.

72 0

*RO2Ck,O~

L

74

BENJAMIN T. WOODARD and GARY H. POSNER

enhanced reactivity is based on higher reaction rates of pantolactone containing pyrone 69 relative to 3-methoxycarbonyl-2-pyrone 33, which cannot form an analogous seven-membered chelate. Facial selectivity results from the axial t~-methyl group which shields the Si face of the pyrone in complex 71. It is proposed that the seven-membered chelate 70 is disfavored because of dipole-dipole repulsions. This model accounts for the observed unimportance of the chirality of the Lewis acid employed because the sole function of the europium species is to promote formation of the seven-membered chelate.

Stereochemical Control Element Tetheringthe Dienophile and Pyrone. The r advantage of intramo]ecu]ar [4+2] cyc]oaddi-

tion reactions is well established. Therefore we synthesized unsymmetrical enol silaketals 73 and 74 in which the enol group was tethered to the carboxylate group of 2-pyrone-3-carboxylate. 56 It was found that these tethered species undergo intramolecular Diels-Alder cycloaddition under Lewis acid conditions to give cycloadducts 75 and 76 in good chemical yields and with outstanding diastereocontrol. It is noteworthy that in both cases shown the e x o cycloadduct predominates. Also, surprisingly, we found that the exclusively E-stereochemistry of the dienophile was not retained in the cycloadducts, suggesting that a stepwise mechanism is operative in these cases. By contrast, high-pressure reaction conditions produced cycloadducts which retain olefinic stereochemistry (albeit in low yield). Cycloadduct 76,~o was employed subsequently to synthesize a novel 2-fluoroalkylvitamin D analog. o

o

-

0, " J ~ ~ O " ~

ZnBr2

~L~ o ) 43d0:~ s ,,,~,,v,~~O,, Si(/-Pr)2 73 o

o

o5

Zn r,

, 10days F~o,,Si(/-Pr)2~ 74

=-~p ~

-

0~0

J-]

(-)75endo 15% 0

~

=

0"~0~0 + "~Si r ) 2 ~ , pr)2 (+)75e x o 74%

0 "J NI

0 'm"S'

- Pr)2 v "F " F (')76exo (+)76~do 46% 12%

Diels-Alder Cycloadditions of 2-Pyrones

75

Stereochemical Control Element on the Promoter Species. The strategy of using a chiral promoter species to direct the absolute stereochemistry of [4+2] cycloaddition has several advantages over employing chiral auxiliaries attached to either the pyrone diene or the dienophile: (1) the steps required to attach and to remove the auxiliary are avoided; (2) the chiral catalytic species can often be recovered and reused; and (3) in some cases less than a stoichiometric amount of the chiral species may be used. Moreover, from an experimental viewpoint, the increasing number of commercially available homochiral ligands which may be employed along with any one of a number of Lewis acidic species offers a plethora of potential chiral catalysts for the organic chemist. TADDOL Lewis Acids Initial work in this group focused on using C2-symmetric TADDOL (tetraaryldioxolane dimethanol) ligands derived from enantiomerically pure tartrate esters to prepare titanium complexes as homochiral Lewis acids. As shown in the scheme following, 3-methoxycarbonyl-2-pyrone reacted with a number of different benzylic vinyl ethers (benzyl vinyl ether, 1-naphthylmethyl vinyl ether, fluorenyl vinyl ether, diphenylmethyl vinyl ether) to give cycloadducts in reasonable yields and with modest levels of stereochemical control. Best results were obtained with naphthylmethyl vinyl ether as the dienophile and with 4/~ molecular sieves in the reaction mixture. 57 Benzylvinyl ether gives slightly lower levels of enantiocontrol under the same conditions. 5s

Ph Ph OH

.C02Me Ph/ 'Ph ,~ .CO,Me Ar ~ ~ 0 0+ ~ O~/ArTiCI2(Oi'Pr) O ~ b v - "708 g C 4 A mol.sieves ,~r.. %ee Ph 55 1-naph 65 Mark6 and co-workers reported low levels of stereocontrol in the cycloaddition of 3-methoxycarbonyl-2-pyrone and butyl vinyl ether when TADDOL ligands are used in conjunction with Yb(OTf)3 .55b

76

BENJAMIN T. WOODARD and GARY H. POSNER

• .C02Me ~ ~ 0 0 ./O,.B u + II

Ph Ph 0~,,. OH L"Ph~Ph ~ .CO,Me Yb(OTf)3 , O. I'J~ .bBu CH2CI2 R %ee Ph <5 Me <5

This illustrates the large changes in selectivity caused by subtle differences in the diene, dienophile, and Lewis acid.

Binaphthol Lewis Acids. In search of Lewis acids which might provide better stereocontrol in these cycloadditions, we turned our attention to 1,1'-bi-2-naphthol as a potentially useful ligand for the titanium promoter complex. For synthetic reasons, we continued to use benzylic vinyl ethers and silyl vinyl ethers so that these protecting groups could be cleaved to provide the free alcohol later. Considerable experimentation finally provided reaction conditions which lead to high levels of enantiocontrol in these cycloadditions. 59 A lack of reproducibility of high levels of stereocontrol, however, was troubling. This led us to investigate the subtle variables which might be operative in determining absolute stereocontrol. 6~ It was determined relatively early that the molecular sieves exhibit substantially different characteristics from batch to batch. Unexpectedly, we also found that the moisture content of the sieves is critical to good levels of stereocontrol, and moisture contents between 15 and 17% provide optimal results. Unexpectedly, we also found that, to achieve consistently high levels of stereocontrol in this reaction, the temperature at which the binol-titanium complex and the pyrone are mixed must be carefully maintained at 50 ~ Thus, with these conditions of 15-17% moisture content of the molecular sieves used in the formation of the binol-titanium complex and 50 ~ maintained during the coordination of this complex with the pyrone ester, reproducibly high chemical yields and excellent levels of enantiocontrol are achieved. This methodology suffers from the disadvantage that more than a stoichiometric amount of the Lewis acid complex is used in the reaction, although

77

Die~s-Aider Cycloadditions of 2-Pyrones .C02Me

~ .CO,Me

~0.0TBS (R)-(+)-binol-TiCI ~ , ~ ~ E)TBS ~L~./o+~ -30,0,toluene2(O/-Pr)? 59%,92%ee

.C02Me

~0/0

~1.~.~$+11

77

z1 ~ C O ~

v naph(,R)-(+)-binoI-TiCI2(O/-Pr)aONN.[.~Ovnaph -30'C, toluene 0/~ 83%,93%ee 78

the chiral ligand can be recovered and reused. Both cycloadducts 77 and 78 have been elaborated to give A-ring synthons for vitamin D 3. Mark6 and co-workers also explored the use of binol complexes as Lewis acid catalysts for [4+2] cycloadditions of 3-methoxycarbonyl2-pyrone. Mark6 reported modest to excellent levels of stereocontrol in the cycloadditions of a variety of vinyl ethers with this pyrone (Table 11). 55b-d'61 Still better results are reported when vinyl thioethers function as the dienophile. It is important to note that these impressive stereochemical results are obtained with catalytic amounts (0.1-0.2 equivalents) of Lewis acid.

Table 11.

C02Me 0 ~D /'Z Yb(OTf)3-(Ft)-(+)-binol g'ff~CO2Me + CH2CI2 ='~~Z Z

Held

OEt OBu OBn OC(Me)2Ph OCyclohexyl OAdamantyl SEt SBu SBn SCyclohexyl SPh

90% 95% 95% 93% 91% 97% 96% 70% 93% 88% 91%

%ee

27 36 49 71 82 85 30 57 72 86 >95

78

BENJAMIN T. WOODARD and GARY H. POSNER

Table 12.

CO2Me O ~O ~ Z Yb(OZf)3-(R)-(+)-binol O'J(/CO2Me + 5-10eq.THFCH2Cl2 ~ Z Z

Yield

OBu OCyclohexyl SBu SCyclohexyl SPh

81% 90% 85% 67% 92%

%ee

65 96 74 >95 >95

It has been noted that reaction solvent choice is crucial to obtain good stereoselectivity in these cycloadditions. Nonpolar solvents, such as toluene, give inferior results, presumably because of low catalyst solubility, whereas polar solvents, such as nitromethane or acetonitrile, may coordinate to the ytterbium complex, generating an achiral catalytic species. Best results were obtained in carefully purified methylene chloride because any traces of alcohols in the solvent lower the levels of stereocontrol. More recently, it has been reported that the addition of species which act as basic ligands improves the stereocontrol in these cycloadditions. 6z Thus, water, t-butanol, and tetrahydrofuran all improve the observed enantioselectivity in the reaction of 3-methoxycarbonyl-2pyrone with butyl vinyl ether. Optimized reaction conditions include 5-10 equivalents of THF per ytterbium. These conditions were applied to other dienophiles and gave improved results (Table 12). It has been proposed that the basic additives function to expand the coordination sphere of the catalyst and to displace one or more triflate ligands, thus generating a cationic ytterbium complex. This exciting work again illustrates the subtle changes which produce large effects in levels of stereocontrol. It is noteworthy that although the focus of attention in chiral catalysis has been on Lewis acidic species, naturally occurring alkaloids present the opportunity for highly enanBrCnsted Base Catalysis.

Die~s-Aider Cycloadditions of 2-Pyrones

79

tioselective base-catalyzed Diels-Alder reactions. Although basecatalyzed Diels-Alder reactions are rare, a recent report by Okamura and co-workers provides exciting preliminary data which suggest that in some cases this strategy may be employed to good effect. 63 Thus N-methylmaleimide reacts with 3-hydroxy-2-pyrone in the presence of different cinchona alkaloids to give cycloadducts with modest to good levels of stereocontrol. Two of the more impressive examples are shown in the scheme following. The authors propose that the aminoalcohols coordinate to hydroxypyrone, as indicated.

0 OH

0 base

o

O base cinchonidine cinchonine

yield 91% 95%

endo:exo

7.8:1 7.1:1

0

endo %ee

74(+) 71 (-)

Base

Yield

endo:exo

endo %ee

cinchonidine cinchonine

91% 95%

7.8:1

74 (+)

7.1:1

71 (-)

-6

*,N'~':" H o H'

In an effort to improve asymmetrical induction, Okamura and co-workers investigated the cinchona-alkaloid-promoted reaction of 3-hydroxy-2-pyrone with enantiomerically pure N-acryloyloxazolidinone dienophiles: ~ These cycloadditions proceed smoothly at 0 ~ to give bicyclic lactone adducts in good yields and with good to excellent levels of diastereocontrol. The diastereoselectivities depend

80

BENJAMIN T. WOODARD and GARY H. POSNER

OH

O

O

o

cinchonidine/~i ~

~ -~"COR* 94% 95%de OH O O O~OH ~~O O ~ .~ocinchonineO=O ~'~J~ COR* -"~"""

100% 95%de

on the solvent and on matching the substrate and BrCnsted base. Two particularly impressive examples are shown in the accompanying figure. IV. C O N C L U S I O N S

The last several years have seen substantial advances in the DielsAlder cycloaddition chemistry of 2-pyrone and its derivatives. Most of these advances have come in developing mild reaction conditions and electronic partnering of components and in controlling the relative and absolute stereochemistry of the cycloaddition. This is an area which is clearly not yet mature. Although this methodology is clearly useful as it stands, we expect that the future will bring still more advances in expanding reaction scope and stereocontrol. With these advances, we expect to see continued application of this methodology to synthesizing complex organic molecules. ACKNOWLEDGMENTS

We thank the NSF and the NIH for support of our research at Johns Hopkins University on fundamental aspects and synthetic applications of pyrone cycloadditions.

REFERENCES 1. Diels, O.; Alder, K. Ann. 1931, 490, 257. 2. Shusherina, N. P. Russ. Chem. Rev. 1974, 43, 851. 3. Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48, 9111.

Diels-Alder Cycloadditions of 2-Pyrones

81

4. Posner, G. H. In Stereocontrolled Organic SynthesisuChemistry for the 21st Century; Trost, B. M.; Beletskaya, I. P., Eds.; Blackwell Scientific: Oxford, U. K., 1994; pp. 177-191. 5. Alder, K.; Rickert, H. Ber. 1937, 70, 1354. 6. Plieninger, H.; MUller, W.; Weinerth, K. Chem. Ber. 1964, 97, 667. 7. For a separate review on this subject, see Pindur, U.; Urfanian-Abdoust, H. Chem. Rev. 1989, 89, 1681. For more recent references, see reference 3. 8. (a) Andrews, J. E P.; Jackson, P. M.; Moody, C. J. Tetrahedron 1993, 49, 7353. (b) Harrison, C.-A.; Jackson, P. M.; Moody, C. J.; Williams, J. M. J. J. Chem. Soc., Perkin Trans. 1 1995, 1131. 9. Wittig, G.; Hoffmann, R. W. Chem. Ber. 1962, 95, 2718. 10. (a) P&ez, D.; Guiti~in, E.; Castedo, L. J. Org. Chem. 1992, 57, 5911. (b) Escudero, S.; P6rez, D.; GuitiAn, E.; Castedo, L. J. Org. Chem. 1997, 62, 3028. 11. May, C.; Moody, C. J. J. Chem. Soc., Chem. Commun. 1984, 926. 12. Escudero, S.; P6rez, D.; Guitifin, E.; Castedo, L. Tetrahedron Lett. 1997, 38, 5375. 13. Kraus, G. A.; Pezzanite, J. O.; Sugimoto, H. Tetrahedron Lett. 1979, 853. 14. Moody, C. J.; Shah, P. J. Chem. Soc., Perkin Trans. 1 1988, 3249. 15. Moody, C. J.; Morrell, A. I. J. Indian Chem. Soc. 1994, 71,309. 16. P&ez, D.; Bur6s, G.; Guitifin, E.; Castedo, L. J. Org. Chem. 1996, 61, 1650. 17. MarE, G.; Jin, G. Y.; Silbereisen, E. Angew. Chem., Int. Ed. Engl. 1982, 21, 370. 18. Jursic, B. S. J. Mol. Struct. (Theochem) 1995, 342, 121. 19. Van Broeck, P.; Van Doren, P.; Hoomaert, G. Synthesis 1992, 473. 20. Matsushita, Y.-i.; Sakamoto, K.; Murakami, T.; Matsui, T. Synth. Commun. 1994, 24, 3307. 21. Boger, D. L.; Brotherton-Pleiss, C. E. Advances in Cycloaddition Chemistry; Curran, D. P., Ed.; JAI: Greenwich, CT, 1990; Vol. 2, pp. 147. 22. Boger, D. L.; Takehashi, K. J. Am. Chem. Soc. 1995, 117, 12452. 23. Hatsui, T.; Hiram, N.; Takeshita, H. Chem. Express 1993, 8, 449. 24. (a) Klemm, E.; Alhakimi, G.; Schtitz, H. Makromol. Chem. 1993, 194, 353. (b) Alhakimi, G.; Klemm, E. Polymer. Bull. 1994, 33, 183. (c) Klemm, E.; Kottner, N.; Alhakimi, G. Angew. Makromol. Chem. 1994, 223, 193. (d) Alhakimi, G.; Grids, H.; Klemm, E. Macromol. Chem. Phys. 1994, 195, 1569. (e) Alhakimi, G.; Klemm, E. J. Polym. Sci. Part A: Polym. Chem. 1995, 33,767. (f) Alhakimi, G.; Klemm, E.; G6rls, H. J. Polym. Sci. Part A: Polym. Chem. 1995, 33, 1133. (g) Kottner, N.; Bublitz, R.; Klemm, E. Macromol. Chem. Phys. 1996, 197, 2665. 25. (a) Harano, K.; Aoki, T.; Eto, M.; Hisano, T. Chem. Pharm. Bull. 1990, 38, 1182. (b) Eto, M.; Harano, K.; Hisano, T. J. Chem. Soc., Perkin Trans. 2 1993, 963. 26. Swarbrick, T. M.; Mark6, I.; Kennard, L. Tetrahedron Lett. 1991, 32, 2549. 27. Mark6, I.; Seres, P.; Swarbrick, T. M.; Staton, I. Tetrahedron Lett. 1992, 33, 5649.

82

BENJAMIN T. WOODARD and GARY H. POSNER

28. Mark6, I.; Seres, P.; Evans, G. R.; Swarbrick, T. M. Tetrahedron Lett. 1993, 34, 7305. 29. Posner, G. H.; Ishihara, Y. Tetrahedron Lett. 1994, 35, 7545. 30. Mori, S.; Karita, T.; Komatsu, K.; Sugita, N.; Wan, T. S. M. Synth. Commun. 1997, 27, 1475. 31. Imagawa, T.; Haneda, A.; Kawanisi, M. Org. Magn. Resonance 1980, 13, 244. 32. Mark6, I.; Evans, G. R. Tetrahedron Lett. 1993, 34, 7309. 33. B. T. Woodard and G. H. Posner, unpublished results. 34. Posner, G. H.; Johnson, N. J. Org. Chem. 1994, 59, 7855. 35. Posner, G. H.; Hutchings, R. H.; Woodard, B. T. Synlett 1997, 432. 36. Hatsui, T.; Hashiguchi, T.; Takeshita, H. Chem. Express 1993, 8, 581. 37. Posner, G. H.; Wettlaufer, D. G. Tetrahedron Lett. 1986, 27, 667. 38. Posner, G. H.; Nelson, T. D. Tetrahedron 1990, 46, 4573. 39. Posner, G. H.; Haces, A.; Harrison, W.; Kinter, C. M. J. Org. Chem. 1987, 52, 4836. 40. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. J. Org. Chem. 1992, 57, 4083. 41. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Afarinkia, K. Tetrahedron Len. 1991, 32, 5295. 42. (a) Posner, G. H.; Nelson, T. D. J. Org. Chem. 1991, 56, 4339. (b) Posner, G. H.; Nelson, T. D.; Guyton, K. Z.; Kensler, T. W. J. Med. Chem. 1992, 35, 3280. (c) Posner, G. H.; Dai, H. Bioorg. Med. Chem. Lett. 1993, 3, 1829. (d) Posner, G. H.; Dai, H.; Afarinkia, K.; Murthy, N. N.; Guyton, K. Z.; Kensler, T. W. J. Org. Chem. 1993, 58, 7209. (e) Posner, G. H.; Lee, J. K.; White, M. C.; Hutchings, R. H.; Dai, H.; Kachinski, J. L.; Dolan, P.; Kensler, T. W. J. Org. Chem. 1997, 62, 3299. 43. Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33, 7839. 44. Afarinkia, K.; Daly, N. T.; Gomez-Farnos, S.; Joshi, S. Tetrahedron Lett. 1997, 38, 2369. 45. Posner, G. H.; Wettlaufer, D. G. Tetrahedron Lett. 1986, 27, 667. 46. Posner, G. H.; Wettlaufer, D. G. J. Am. Chem. Soc. 1986, 108, 7373. 47. Posner, G. H.; Kinter, C. M. J. Org. Chem. 1990, 55, 3967. 48. (a) Bush, E. J.; Jones, D. W. J. Chem. Soc., Chem. Commun. 1993, 1200. (b) Bush, E. J.; Jones, D. W. J. Chem. Soc., Perkin Trans. 1 1996, 151. 49. Kusama, H.; Mori, T.; Mitani, I.; Kashima, H.; Kuwajima, I. Tetrahedron Lett. 1997, 38, 4129. 50. Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani, M. Tetrahedron Len. 1998, 39, 1211. 51. Posner, G. H.; Harrison, W. J. Chem. Soc., Chem. Commun. 1985, 1786. 52. Prapansiri, V.; Thornton, E. R. Tetrahedron Lett. 1991, 32, 3147. 53. T. E. N. Anjeh and G. H. Posner, unpublished results. 54. Posner, G. H.; Carry, J.-C.; Anjeh, T. E. N.; French, A. N. J. Org. Chem. 1992, 57, 7012.

Diels-Alder Cycloadditions of 2-Pyrones

83

55. (a) Mark6, I. E.; Evans, G. R. Tetrahedron Lett. 1994, 35, 2767. (b) Mark6, I. E.; Evans, G. R.; Declercq, J.-P. Tetrahedron 1994, 50, 4557. (c) Mark6, I. E.; Evans, G. R.; Declercq, J.-P.; Tinant, B.; Feneau-Dupont, J. Acro. Org. Acta 1995, 1, 26. (d) Mark6, I. E.; Evans, G. R.; Seres, P.; Chell6, I.; Janousek, Z. Pure Appl. Chem. 1996, 68, 113. 56. Posner, G. H.; Cho, C.-G.; Anjeh, T. E. N.; Johnson, N.; Horst, R. L.; Kobayashi, T.; Okano, T.; Tsugawa, N. J. Org. Chem. 1995, 60, 4617. 57. H. Dai, E Eydoux, and G. H. Posner, unpublished results. 58. Posner, G. H.; Carry, J.-C.; Lee, J. K.; Bull, D. S.; Dai, H. Tetrahedron Lett. 1994, 35, 1321. 59. Posner, G. H.; Eydoux, E; Lee, J. K.; Bull, D. S. Tetrahedron Lett. 1994, 35, 7541. 60. Posner, G. H.; Dai, H.; Bull, D. S.; Lee, J. K.; Eydoux, E; Ishihara, Y.; Welsh, W.; Pryor, N.; Petr, S. J. Org. Chem. 1996, 61,671. 61. (a) Mark6, I. E.; Evans, G. R. Tetrahedron Lett. 1994, 35, 2771. (b) Mark6, I. E.; Evans, G. R. BulL Soc. Chim. Belg. 1994, 103, 295. 62. Mark6, I. E.; Chell6-Regnaut, I.; Leroy, B.; Warriner, S. L. Tetrahedron Lett. 1997, 38, 4269. 63. Okamura, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M. Chem. Lett. 1996, 193.

This Page Intentionally Left Blank

THE INTER- A N D I NTRAMOLECULAR [4+4] PHOTOCYCLOADDITION OF 2-PYRI DON ES AN D ITS APPLICATION TO NATURAL PRODUCT SYNTHESIS

Scott McN. Sieburth

II.

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Background and Basic Photochemistry . . . . . . . . . . . . . 87 A. Isomerization, [4+4] Dimerization, and [2+2] Cycloaddition 87 Model Intramolecular Cycloadditions . . . . . . . . . . . . . . 98 A. N,N'-Tethered 2-Pyridones . . . . . . . . . . . . . . . . . 98 B. Head-to-Tail Tethered 2-Pyridones . . . . . . . . . . . . . 98 C. Head-to-Head and Tail-to-Tail Tethered 2-Pyridones . . . 102

Advances in Cycloaddition Volume 5, pages 85--118. Copyright 9 1999 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0346-8

85

SCOTT McN. SIEBURTH

86

III.

Application to the Synthesis of Natural Products . . . . . . . . A. Taxol (Paclitaxel) . . . . . . . . . . . . . . . . . . . . . . B. Fusicoccin A . . . . . . . . . . . . . . . . . . . . . . . . IV. Synthetic Transformations of the [4+4] Photoproduct . . . . . A. Paquette's Work at Upjohn . . . . . . . . . . . . . . . . . B. Dissolving Metal Reduction . . . . . . . . . . . . . . . . C. Hydrolytic and Reductive Opening of the Amides . . . . . IV. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . References and Notes . . . . . . . . . . . . . . . . . . . . . .

105 105 108 111

111 112 112 115 116 116

ABSTRACT The photochemistry of 2-pyridone is dominated by a [4+4] dimerization that proceeds via a short-lived singlet excited state. This intermolecular cycloaddition of two achiral aromatic molecules yields a 1,5-cyclooctadiene product with four stereogenic centers. Product formation is highly regiospecific, yields only head-to-tail products, and is moderately stereoselective, favoring t r a n s isomers. Substitution of the pyridone ring is tolerated at all positions, although an 4-alkoxy group prevents dimerization. The presence of the 4-alkoxy group allows other photochemical reactions, including [4+4] cycloaddition with other pyridones. Intramolecular reactions of a pair of 2-pyridones readily accommodates both three- and four-atom tethers. This tethering is also used to overcome the natural regioselectivity to give head-to-head [4+4] photoproducts. An excellent overlap of the 2-pyridone photoproduct with terpenoid natural products, exemplified by fusicoccin A and taxol (paclitaxel), leads to synthetic approaches to these targets. In each case, complete stereocontrol and quantitative yields are observed for the cycloaddition step. Transformations of the photoproducts generally proceed with high stereoselectivity. The amides of the polycyclic photoproducts have been hydrolytically and reductively opened for the first time.

2-Pyridone Photocycloadditions

87

I. BACKGROUND AND BASIC PHOTOCHEMISTRY AO

Isomerization, [4+4] Dimerization, and [2+2] Cycloaddition

The origin of 2-pyridone photochemistry dates only to 1960 and a short communication from Taylor's group at Princeton describing a new [2+2] photodimerization product resulting from irradiation of 2-pyridone solutions. ~Although corrected later and amplified in several ways, 2-4 this communication proved to be a catalyst for investigations of 2-pyridone photochemistry. Within a year, the second report from Taylor's group, 2 a joint publication from the Ayer and de Mayo groups at Alberta and Western Ontario, 5and one from Slomp, MacKellar, and Paquette at Upjohn, 6 elucidated the photodimerization product of 1-methyl-2-pyridone (1) as the trans, head-to-tail [4+4] cycloaddition adduct 3. This reaction proved to be quite general for 2-pyridones with varying substitution (see Table 1 for examples). There has been no review of the photoreactions of 2-pyridones, and so we begin with an overview of the area, emphasizing the [4+4] reactivity. Isomerization of pyridone 2 to Dewar-pyridone 1 is an alternative photoreaction competing with [4+4] cycloaddition, not observed in the initial studies (Figure 1). The crystallinity of the [4+4] product and dominance of the [4+4] reaction pathway obscured this reaction mode until the 1964 report by Corey and Streith describing it and a similar isomerization of 2-pyrone. 7 The key reaction condition for achieving the Dewar-pyridone product 1 instead of dimerization product 3 was dilute solutions. With an initial concentration of 2-pyridone below 0.01 M, the unimolecular isomerization to give 1 dominates the product mixture, whereas above 0.1 M the [4+4] dimer 3 is the major product, a The partitioning ratio of 1 and 3 is solvent independent (Figure 2). Naturally, for intermolecular reactions, the selectivity for 3 diminishes in favor of 1 as the reaction progresses and the concentration of 2-pyridone falls. Nevertheless, good yields of [4+4] dimers are routinely obtained (see Table 1). Despite substantial synthetic work with 2-pyridone photochemistry, few studies have addressed the photochemical details of the reaction. A study by Sharp and Hammond in 1972 describes the effect of singlet and triplet quenchers on the reaction outcome. 9 These

SCOTT McN. SIEBURTH

88

NNH

H

~

~

1

/PO

_~

2

3

N

3

Figure 1. An initial concentration above 0.1 M results primarily in the [4+4] photodimerization reaction pathway. experiments found no evidence for a triplet intermediate, and characterized a rather short-lived singlet excited state that has an estimated lifetime of 0.2 ns. Recent measurements with N-methyl-2-pyridone 2 and a tethered bis-2-pyridone (40, Figure 15), arranged by Boyd

Table 1.

Selected Examples of Dewar Pyridones 5 and [4+4] Dimers 6

~'.,,

hv

4

5

6

4,

4,

H

H

H

H CH3 H

H H CH3

H H H

CH3

H

H

CH3

f

CH3

H

H

g h

CH3 H

H Cl

t-Bu H

Entry

,I,

a

H

H

b c d

CH3 CH3 CH3

e

,.,O

Yield(tel.) 5

6

H H H

95(15) 20 (7) X 100 (15)

40 (4) 43 (3) 14(3) 19 (3)

H

X

58 (3)

H

CH3

X

52(16)

H H

H H

100(15) 35 (15) X 24(19)

i

H

H

C1

H

H

X

13(19)

j

H

H

H

CI

H

22(19)

42(19)

k

H

H

H

l In

CH3 CH3

H H

-(CH2)4-(CH)4H OCH3 H H

X X 82 (21)

60(17) 65(18) X

n

CH3

CN

OCH3

H

H

89(22)

X

2-Pyridone Photocycloadditions

89

100 80

WATER

-o- 3 "~1

60 "~

40

s

-"

~ s

BENZENE

s % s

J

"

~ ~

20 0 10

-

-

-'

.

.

.

.

.

,

1~

.

-*

3

"~"

1

.

.

.

.

, , , ~ . .

Initial Concentration of 2 (mM)

d

1000

Figure 2. Isolated yields of Dewar pyridones (outlined shapes) and

[4+4] dimers (filled shapes) as a function of the initial concentration of 1-methyl-2-pyridone. Note the absence of a solvent effect. Data from reference 8. (Loyola University of Chicago), found that Hammond's estimate is accurate, and the fluorescent lifetime of 2 and 40 are 180 ps. I~ Triplet-sensitized reactions of 2-pyridones have not been extensively studied. However Sharp and Hammond found no evidence for 2-pyridone photoproducts when xanthone is used as a photosensitizer. 9 Using tethered pyridones, Nakamura found [2+2] and [4+2] cycloaddition products with benzophenone sensitization (see Figure 14). ~ This is consistent with 2-pyrone photochemistry, ~2-14but the generality of these results await further experimentation. Both the [4+4] photodimerization reaction (4 ~ 6) and the isomerization to give Dewar-pyridone products (4 ~ 5) tolerates substitution at every position (Table 1), but certain combinations of substituent and position are notable exceptions. The parent 2-pyridone 4a and Nmethyl 4b are typical, yielding either 5 or 6 depending on the starting concentration. 3'4"7 1 5 A single additional alkyl substituent, represented by 1,n-dimethyl examples 4c-4f, all yield at least the [4+4] dimer. 3'16 Even a t-butyl substituent at C4 (4g) which presents a possible steric impediment, is compatible with the dimerization reaction. ~5Fusion of a cyclohexyl ~7at C5/C6 (4k) or a Cy C lohexadienyl 18 ring at C4/C5 (41) leads to acceptable yields of the photodimer 6. Chlorine substitution

90

SCOTT McN. SIEBURTH

H

- "

CI

7

8

~"~.,~.-CO2CH3~..1CO2CH3 IN * N 9

10

Figure 3. Chloropyridone 7 undergoes an unusual photoreaction for 2-pyridones. 2~ has also been systematically studied. ~9 At positions C3, C4, or C5 (4h-4j) normal [4+4] photoreactions have been reported. At C6, however, at least in methanol as solvent, a completely different pathway is followed 2~(see Figure 3). Substitution with an alkoxy group at C4 (4m, 4n) is incompatible with the dimerization reaction, 21 for reasons that have not been fully addressed. This effect was first observed by De Selms and Schleigh at Kodak with the natural product ricinine 4n, finding that this compound gave an excellent yield of the Dewar pyridone product. 22 Photoreaction of 6-chloro-2-pyridone 7 in methanol is the unique example of an apparent six-electron electrocyclic rearrangement that produces an intermediate ketene/chloroimine 8 which undergoes loss of HC1 and addition of methanol to yield a mixture of three isomeric unsaturated nitrile esters 9 and 10. 20 The observation that 4-alkoxy-2-pyridones do not photodimerize, 21'22but lead only to the Dewar-pyridone products, has provided a novel route to 13-1actams such as those shown in Figure 4. 23 Photoisomerization of 12 to give 13 is accomplished with a pyrex-filtered, high-pressure mercury lamp. Without the 4-alkoxy substituent, the Dewar-pyridone synthesis requires rather dilute reaction conditions to avoid dominance of the [4+4] dimerization reaction. Additional examples of 13-1actam synthesis, based on photoisomerization of 2-pyridones, have been published. 24

11

OM~o hv~ H ~"OCH3 I"TBSCIH ~2" Oa HO~r-I,"'~OH HN'N'NO~ 3.NaBH4 TBs,N-~o 12 13 14

Figure 4. The efficient photoisomerization of 4-alkoxy-2-pyridones provides ready access to 13-1actams.23'24

2-Pyridone Photocycloadditions

91 NC

H

+

hv

CN

H

15

H 16 41%

O 17 4%

Figure 5. Photocycloaddition of acrylonitrile with 2-pyridones yields two new products. 26 Photo-[2+2] reactions of 2-pyridones have been studied, particularly the intramolecular versions. 25Intermolecular reactions, unbiased by the constraints of tethering are less well studied, in part because of the dominance of the [4+4] cycloaddition. In one simple system, however, acrylonitrile reacts with 2-pyridone to form two products 16 and 17 (Figure 5). 26 The latter has been extensively characterized by both X-ray and NMR techniques. 27 The inability of 4-alkoxy-2-pyridones (e.g., 12, Figure 4) to photodimerize makes them a valuable substrate for other photochemistry. Electron-donating and electron-withdrawing alkene substituents lead to different sites of reaction. The major products are shown in Figure 6.28

Nondimerization [4+4] Cycloadditions Whereas a 4-alkoxy group (e.g., 12) prevents the photodimerization of 2-pyridones, it does not prevent a photo-[4+4] cycloaddition with other pyridones, such a s 20, 29 a typical 2-pyridone dimerization substrate. 8 In this reaction of 2-pyridone mixtures, a simple 1"1 mixture of the two substrates (Figure 7, each 0.25 M in methanol) yields two major products. The yield of dimer 21 dominates that of cross product

.OCH3

H 1 8 380

0CH3

hv

H 12

O'CH3

hv

-N" "-(3 H 1 9 80~

Figure6. Photocycloaddition of electron-rich or electron-poor alkenes leads to addition at two different sites.28

SCOTT McN. SIEBURTH

92 OMe

~N

O

N

H

12

20

1:1

Isolated yield 22%

4:1

12%

ratio

0

21

m, )lar rj ti1 1.8 1 7.2

7:1

8%

1 13

9:1

6%

1 16

~O

OMe 22 isolated yield 6% 42% 47*/.

Figure 7. Intermolecular [4+4] cycloaddition of 4-methoxy-2-pyridones with N-butyl-2-p~idone depends on the relative concentrations. Yields are based on 20. 22 by nearly a factor of four. These reactions, like virtually all of those described in this review, utilized a medium-pressure mercury lamp and a pyrex filter. The pyrex filter is opaque to wavelengths below 290 nm. The methoxy substituent on 12 attenuates the extinction coefficient (e = 3750, ~'m~x= 278 rim) relative to 20 (e = 5,600, ~'max -" 302 nm) and shifts the absorption to lower wavelengths. Therefore, in photoreactions of 12/20 mixtures it is assumed that the primary reaction path involves excitation of 20 and subsequent cycloaddition to another molecule of 20 or the desired reaction with 12. Altering the relative concentration of the two substrates dramatically alters the ratio of products and their isolated yields. For mixtures of 12 and 20, the optimum ratio is approximately 7:1. This ratio results in a good isolated yield of 22 and a modest yield of undesired dimer 21. At the higher 9:1 ratio of starting reagents, a slowing of the reaction rate is observed and after 72 h of irradiation starting 20 is not fully consumed. Notably, in each case the excess 4-methoxy-2-pyridone is recovered in high (> 90%) yield and only in the 9:1 case was any Dewar-pyridone 13 observed (2%). The absence of substantial amounts of Dewar-pyridones in the reaction mixture may result from the use of a mediumrather than a high-pressure mercury lamp for the irradiation (see Figure 4). Selective modification of 22 with its four distinct functional groups is described in Figures 31 and 32.

2-Pyridone Photocycloadditions

Oao" I

23

Figure 8.

93 \

.~o

o

\

67%

(lO: 1) 2

24

(5:2)

25

1,3-Dienes undergo [4+4] cycloaddition with 2-pyridones. 3~

Photo-[4+4] cycloaddition of 2-pyridone is not restricted to reaction with other pyridones. Sato, Ikeda, and Kanaoka found that cyclic and acyclic-l,3-dienes photoreact with 2-pyridones (Figure 8), 30 reactions similar to the [4+4] photocycloaddition of 1,3-dienes with other aromatic molecules. 3~Cyclopentadiene is a better substrate than cyclohexadiene, as it is for the Diels-Alder reaction. 32 A mixture of trans (24) and cis (25) isomers is formed in all cases. Use of acyclic 1,3-dienes is more complicated and yields strained trans-alkene products, presumably formed by reaction of 2 with the lowest energy s-trans conformation of the 1,3-diene. These strained products undergo further spontaneous reactions, consistent with the reactions of 1,3-dienes with benzene 33 and anthracene. 34 Triazolo-pyridine 26 is structurally related to 2-pyridones and also to 2-aminopyridines. The latter also undergo photo-[4+4] cycloadditions. 2'35 Photodimerization of 26 is reversible 36 because the product contains a triazole chromophore, in contrast to 2-pyridone photodimers (3) which are photostable. The reversibility of the [4+4] dimerization of 26 allows a competitive photocycloaddition of 26 with 1-methyl-2-pyridone (2) to yield cross product 27. The cross product 27 contains a triazole and is presumably also photoreactive. Photoreaction of 2 with a tenfold excess of 26 gives a high yield of photoproducts that have acceptable selectivity for 27 (Figure 9). 37 "N ,

26

N (10"1)

~O

\

~O

91% 2

/27

(11 "4)

3

Figure 9. Cross-cycloaddition reaction of a 2-pyridone with tria-

zolopyridine 26. 37

SCOTT McN. SIEBURTH

94

Regio- and Stereoselectivity With the possible exception of Sharp and Hammond, who isolated but did not identify other dimeric products from the photoreaction of 2-pyridones in 1972, 9 it was not until 1978 that the first attempt was made to isolate and identify isomers other than the heretofore discussed trans head-to-tail photodimers like 3. In a detailed study, Nakamura investigated the chromatographically isolable products and their yields as a function of solvent and concentration effects. 8'38These results, partially summarized in Figures 2 and 10, were the first to show the significant levels of the cis head-to-tail isomer 28 that was formed in all solvents. This study remains the only instance where regiochemical fidelity has been violated and head-to-head products 29 and 30 have been isolated. This occurs only in aqueous solution. It is noteworthy that the three very different solvents all give a similar mixture of cis and trans head-to-tail 3 and 28. The absence of cis isomers in earlier studies can be attributed to their instability and the generally higher crystallinity of the trans

\

head-to-taih

~ 0 hv 12

trans

~o

O~~. .

0//

3

91%

cis

\

/~o

N\ 28

head-to-head: 29 solvent water ethanol benzene

3

28

30 29

30

67% 22%

1%

10%

56%

44%

0%

0%

60% 40%

0%

0%

Figure 10. Two head-to-tail products 3 and 28 are normally formed. The head-to-head isomers 29 and 30 have been observed only in water. 8

2-Pyridone Photocycloadditions

95

head-to-tail product 3. This isomer often crystallizes directly from the reaction mixture. Trans isomers, such as 3, can be thermally cleaved to the starting 2-pyridone, but this normally requires temperatures higher than 100 ~ In contrast, Nakamura found that the cis isomers 28 and 30 undergo Cope rearrangement at the very modest temperature of 60 ~ For head-to-tail 28, the two possible Cope rearrangements each yield the same cyclobutane product (see Figure 12). Cis head-to-head isomer 30 gives two different cyclobutane products when thermally rearranged. These transformations give structural proof for the four isomeric products isolated from photoreactions run in water, s Photodimerization of 2-pyridones has also been effected in other media. Nakamura reported the result of reactions in micelles and reverse micelles using pyridones bearing aliphatic chains on nitrogen. A high level of "abnormal" cis and head-to-head photoproducts were observed. 39 Productive photodimerization and photoisomerization reactions of 2-pyridones in the solid state have been achieved by Toda and Tanaka using asymmetrical hosts (Figure 11). In many cases, the 2-pyridones isomerize to Dewar-pyridone products with complete enantiomeric purity. The symmetrical [4+4] products are achiral and are formed only in what one might anticipate to be the rare circumstances of a crystal structure with the appropriate orientation and distance between pyridones. Nevertheless, this has been accomplished with the two complexes depicted in Figure 11.4~

2:1 "CH3 O CH3

Ph~ /Ph NO , , . . Ph , ~ Ph OH 1 19

o~o

Figure 11. Cocrystallization of substituted 2-pyridones with the indicated hosts and irradiation leads to the formation of 2-pyridone photodimers. 4~

SCOTT McN. SIEBURTH

96

Reactivity of the [4+4] Adduct Cope rearrangement at modest temperatures is a general phenomenon of cis 2-pyridone dimers, such as 28 (Figure 12), and was also reported for 1,3-diene/2-pyridone adduct 25 (Figure 8). In some cases, the rearrangements have even been observed at or near ambient temperature (see Figure 27). This rearrangement is an easy method for identifying the cis isomer in 2-pyridone photoproduct mixtures. Facile rearrangements of related polycyclic structures, some derived from [4+4] cycloaddition reactions, are well k n o w n . 41 Without the polycyclic ring system, the thermodynamics of the Cope equilibrium between cis-l,2-divinylcyclobutane and 1,5-cyclooctadiene are reversed, favoring the latter. 42 The Cope rearrangement yields a product with a conjugated ~system (see 31), a structure that photocleaves to the starting 2-pyridones (see Figure 15). 43 Therefore it is likely that isolation of only trans products could result from an inadequately cooled mercury vapor lamp destroying cis isomers through a combination of Cope rearrangement and photocleavage. Note that only trans pyridone dimers were reported for the 2-pyridone photoreactions studied before Nakamura's work in 1978. 38

\N 0

~0

Figure 12. Cis [4+4] products undergo a facile Cope rearrangement.38

2-Pyridone Photocycloadditions

97

One factor leading to the very facile Cope rearrangement of 2pyridone dimers and related structures can be seen in their X-ray crystal structures. In the earliest crystallographic report, 44it was noted that the two new C - C bonds of 3 were significantly longer than a normal single bond between t w o sp 3 hybridized carbons (1.54/~). The same long bond length has been seen in every subsequent structure, including the dimer of the tetrahydro-2-quinolone 45 and intramolecular products 32 and 33. 46,47Models of four of the structures are shown in Figure 13, and the crystallographically determined bond lengths are indicated. These long bonds have generally been attributed either to the strain of nonbonding interactions in the photoproducts or to a - n orbital interactions. 48

1.623 (3)

.

I

0 dimer

1.63(2)A(~~

~

[~0 H

dimer

(2)A

1.591 (6)A

1.644

(6)A

0

32 trans-anti

o-

N

33 cis-syn

Figure 13. Structures of [4+4] adducts with crystallographically determined carbon-carbon bond lengths.44-47

SCOTT McN. SIEBURTH

98

II. MODEL INTRAMOLECULAR CYCLOADDITIONS A. N,N -Tethered 2-Pyridones The first intramolecular photochemistry between 2-pyridones was reported by Nakamura using bis-2-pyridones 34 tethered with varying chain lengths. 11 Coupling of the pyridones at nitrogen in this way prevents the "normal" head-to-tail [4+4] photocycloaddition. The cis head-to-head product is possible (see 38). However the direct (unsensitized) irradiation of 34 was not reported. The benzophenone-sensitized reactions of 34 produce only [2+2] and [4+2] products, shown in Figure 14. In the case of 34a with a two-carbon tether, only the [4+2] product 35 was isolated. For 34b and 34c, a single [2+2] product was found in each case (36 and 37). Interestingly, the four-atom tethered product 37 is unstable and with modest heating undergoes a Cope rearrangement to give the [4+4] product 38. This too is unstable and rearranges to give the alternative divinylcyclobutane 39 at higher temperature.

B. Head-to-Tail Tethered 2-Pyridones Intramolecular tethering of 2-pyridones at the 3- and 6 -positions, as shown in Figure 15, reinforces the "normal" head-to-tail [4+4]

o

o 34,, n = O b n: I r n=2

37 (unstable) from 34r (2 + 2)

35 (64%) from 34a (4 + 2)

36 (60%) from 34b (2 + 2)

38 (60%)

Figure 14. Intramolecular photocycloaddition of 34 using benzophenone as a sensitizer gives a single product, depending on the chain length. 11 Product structures are shown with molecular models.

2-Pyridone Photocycloadditions

99

hv

I

o 40

conditions 41,,:42, ~ hv 2"1 (84%) hv,&,hv 7"1 hv,A,hv,&,hv 18"1 (76%)

41

42

| 6o oc

hv 43

Figure 15. Intramolecular photocycloaddition of a three-atom tethered bis-2-pyridone and the thermal/photochemical transformation of cis [4+4] product 42 into trans product 41.43 cycloaddition (compare to 3 and 28, Figure 10). 43,46 When the chain is three atoms long (40), the intramolecular cycloaddition proceeds smoothly and gives a mixture of trans and cis products 41 and 42 similar to intermolecular cases, and the former dominates by a factor of 2. Unlike intermolecular dimerization reactions, of course, the photoreaction of 40 is not affected by concentration. Like the intermolecular reactions (see Figure 12), the cis isomer undergoes a facile Cope rearrangement to give 43. With the expectation that 43, containing an t~,13-unsaturated amide, might be photoreactive, it was subjected to the photochemical conditions used with 40 (methanol, pyrex-filtered medium-pressure mercury lamp). Photoreaction of 43 is slower than for 40. However, within 12 h 43 is converted to the same 2:1 mixture of 41 and 42. This is consistent with photofragmentation of 43 and subsequent photocycloaddition of the resulting 40. Under the same thermal and photochemical conditions, the trans isomer 41 is stable. 43 As a consequence of the thermal and photochemical stability of 41, the mixture of photoproducts 41 and 42 can be simply heated and then irradiated, transforming about two-thirds of the cis isomer 42 into trans isomer 41. Two cycles of heat and light transform the initial 2:1 mixture to nearly 20:1, with only a small decrease in the isolated yields of products 41 and 42.

1 O0

SCOTT M c N . SIEBURTH R hv......~

TBS

/L " ,b

44

pro-trans-anli

J

.J

pro-trans-syn

.PR 4-

4.

+

O// trans-anti 45

_

i n

i

cis-anti 47

trans-syn 46

substrate R

solvent _

N\

45

trans : 46

i

I

II

9

cis-syn 48 cis 47 : 48

iii

I

I

ii

s

OH

CH2CI2

5

4.8

1

2.8

a

OH

methanol

13

1.8

2.5

1

b

OTBS

CH2CI2

2.9

"

1

"

b

OTBS

methanol

2

-

1

-

Figure 16. A bulky tether substituent (R = OTBS) yields exclusively anti products 45b and 47b. 47

A stereogenic center on the tether (44a), composed of a relatively small hydroxyl substituent, results in the four possible product isomers shown in Figure 16. The designations anti and syn isomers refer to the orientation of the tether substituent and the adjacent carbonyl group in the product. Alcohol 444 yields all four possible products, and trans is preferred over cis by a factor of 2.5 or 4.2, depending on the solvent. The primary difference in the product ratios comes from the solventdependent syn/anti ratio. In the protic solvent methanol, the anti isomers comprise 85% of the product whereas in the aprotic methylene chloride the syn isomers are 56% of the mixture. The syn selectivity may result from an intramolecular hydrogen bond of the alcohol to the nearby carbonyl (see pro-trans-syn conformation). Steric enhancement of the alcohol as a t-butyldimethylsilyl ether (44b) results in a solvent independent anti-selective photoreaction. The amount of syn isomers produced with a t-butyldimethylsilyloxy substituent is less than 1%.47

2-Pyridone Photocycloadditions

101

\N H0 hv"-~O; ~ ,~0 49

50 only

"~00~ \N H 51 not formed

Figure 17. Photocycloaddition of 39 does not yield cis products. 46 Whereas a three atom tether yields a mixture of cis and trans isomers, a four-atom chain connecting the pyridones is highly transselective (Figure 17). One of the first substrates of this type is 49, irradiation of which gives a mixture of two products 50 that can be oxidized, after hydrogenation of the alkenes, to the same ketone. 46The two products that differ only in the orientation of the hydroxyl group, are formed in a ratio of 3:2 (configuration undetermined). Trans-selectivity of 49 most likely originates from product strain, an aspect that was more fully appreciated after studies of the photocycloaddition of 52, part of a projected taxol synthesis (see Figure 23). Photocycloaddition of 52 gives a single product isomer 53. 49Although compound 53 is readily prepared and handled, chromatography on silica gel results in cleavage of the photoproduct and isolation of starting bis-2-pyridone 52. The trans-anti configuration of 53 was tentatively assigned based on our experience with the stereoinduction of a t-butyldimethylsilyloxy group (see Figure 16) and the general dominance of the trans isomer in photocycloaddition reactions. This stereochemistry was confirmed by X-ray crystallography after hydrogenation of the disubstituted alkene to give 54. 50 The most surprising aspect of the crystal structure of 54 is the boat conformation of the cyclohexane derived from the tether, especially with the bulky silyloxy group held in the most difficult flagpole position (Figure 18). The rigid tetracyclic photoproduct holds four of the carbons of the cyclohexane in a planar arrangement, much like a cyclohexene but with smaller internal bond angles. For a cyclohexene, the half-chair conformation is more stable than a boat by more than 6 kcal/mol. The asymmetry of 54 allows four possible boat and halfchair conformations. Molecular mechanical calculations were performed, and the most stable of each is shown in Figure 18.

102

SCOTT McN. SIEBURTH OMe

"N" "-0 ~. 52 \

I Si02

/

O/~"ol"~'e I~\ only

53

_~-_rZ-

0

OMe x 54

i

X-ray structure of 54

~ "-"

air

> ;kcal/mol

Figure 18. Photoadduct 53 is formed exclusively as the trans-anti isomer. X-ray crystallography and calculations revealed the greater stability of a boat conformation for the cyclohexane derived from the tether. 49-51

Surprisingly, the lowest energy boat conformation is more stable than the lowest energy half-chair by more than 4 kcal/mol. This inversion of conformational preference is a direct consequence of the sp 3 hybridization of the cyclohexane carbons where they join the polycyclic ring system, hold the prow and stern of the boat in close proximity, and raise the energy of the half-chair conformation. 51

C. Head-to-Head and Tail-to-Tail Tethered 2-Pyridones Nakamura's isolation of head-to-head photoproducts from photodimerizations in water s (Figure 10) suggested that symmetrical tethering of 2-pyridones at the 3 and 3' positions (head-to-head, 55, Figure 19) or 6 and 6' positions (tail-to-tail, 58, Figure 20), while reversing

2-Pyridone Photocycloadditions

0 "N- "-O I

O-" "N" I

hv

103

.O

\N

0

\O ~i +

/

55 head-to-head

0

/ 56

1 1 "

57

Figure 19. Head-to-head photocycloaddition is not stereoselective.

52

normal regioselectivity, should be compatible with [4+4] photocycloaddition. This proved correct but the stereoselectivity of the cycloaddition is altered. When head-to-head ether 55 is irradiated in the standard solvent methanol, the cis and trans products 56 and 57 are formed in equal amounts. 52 A full reversal of stereoselectivity occurs for the tail-to-tail case 58 (Figure 20) and favors the cis isomer 60 by a large margin. 53 For both the head-to-head 55 and the tail-to-tail 58, the photochemistry is extremely clean and gives only the two products indicated. The cis isomer in both cases is readily identified by warming the mixture to 50-60 ~ to induce Cope rearrangement of 57 and 60, each cleanly giving a single Cope product. It is interesting to compare the results in Figures 19 and 20 with Nakamura's results (Figure 10). The intermolecular reaction in water yields head-to-head (which can also be called tail-to-tail) product wherein the cis isomer is favored over trans by a factor of 11. This is close to the result found for reaction of tail-to-tail 58 but quite different from the results for head-to-head 55 (Figure 19). For comparison, the non-ether tail-to-tail 61 was prepared. In contrast to ethers 55 and 58, cycloaddition of 61 gives a normal mixture of trans and cis isomers, and the trans dominates by a factor

h ""o 58

tail-to-tail

§

O

59

\

5 "95

o

60

Figure 20. Tail-to-tail photocycloaddition strongly favors the cis iso-

mer. 53

SCOTT McN. SIEBURTH

104

N .OTI3S

0

61 tail-to-tail

0

\

62

o//O.• N/ OTBS

2" 1

63

Figure 21. Tail-to-tail photocycloaddition of all-carbon tethered 61 results in a typical mixture of trans and cis products. 54

of 2 (Figure 21).54 Clearly, a full understanding of the factors determining the trans- and cis-selectivity for all of these 2-pyridone photocycloadditions awaits additional experimentation. Extension of the head-to-head and tail-to-tail orientation to the four-carbon homologues 64 and 65 encountered one of the first significant limitations to these intramolecular [4+4] cycloadditions (Figure 22). Both of these substrates are converted to photoproducts much more slowly than any of the head-to-tail analogs (days instead of hours). Head-to-head 64 gives a complex mixture from which isolation of pure products proved difficult. Analysis by IR indicated that the mixture included 13-1actams.55 In contrast to 64, tail-to-tail 65 produces a clean isomerization to the bis-Dewar-pyridone 66. 54 It is likely that this is a mixture of two diastereomers although this could not be ascertainedby NMR or chromatography. hv

complex mixture

head-to-head

h

65 tail-to-tail

N

/N

66 only

Figure 22. A four-carbon tether symmetrically attached to 2-pyridones does not allow useful [4+4] cycloaddition, s4'ss

2-Pyridone Photocycloadditions

105

III. APPLICATION TO THE SYNTHESIS OF NATURAL PRODUCTS

A. Taxol (Paclitaxel) The most prominent natural product with an eight-membered carbocyclic ring is taxol (paclitaxel) 67. 56 Synthetic approaches to taxol using a [4+4] cycloaddition strategy have been pursued by a number of g r o u p s . 31 A 2-pyridone cycloaddition strategy for taxol is outlined in Figure 23. A four-carbon tethered reaction yields 68, and the B and C tings are formed simultaneously. This strategy creates both quaternary carbons of taxol, places the carbonyl carbons where methyl groups are required, and locates alkenes at oxidized carbon centers in the natural product. The six-membered A ring cannot be incorporated directly with this approach but must be introduced after cycloaddition. Two photosubstrates were considered, 69 and 52, representing initial attachment of ring A carbons via route i or route ii, respectively. Photosubstrate 69 was an intriguing and optimistic approach with all but two carbons of the tetracyclic taxol target. Unfortunately, this bis-2-pyridone did not photocyclize to 70 but only slowly decomposed photochemically. We speculated that the obstacle to this cycloaddition was the requirement that four fully substituted sp 3 carbons be created in a single step. Molecular modeling reinforced this view. 5~ A conformational search of the parent four-carbon tethered bis-2pyridone (71) that holds the incipient bonding carbons within 5/~, gives a number of closely related structures: ~Two views of the lowest energy conformation are pictured in Figure 23 (71 and 72). In all of the lower energy conformations, the hydrogens on the ring opposite the tether (see 72) are constrained to approach closely by the conformation of the tether. Carbon substituents replacing these hydrogens, as in 69, would experience substantial steric compression, thereby preventing the cycloaddition. Based on these results, removal of the A-ring carbons as in 52, it was hoped, would allow the cycloaddition to proceed. As described in Figures 18 and 24, cycloaddition of 52 yields a single photoproduct 53 that has both quaternary centers of taxol. 5~The lone stereogenic center in 52 controls formation of the adjacent stereogenic center and the associated amide nitrogen. Then the t r a n s -

SCOTT McN. SIEBURTH

106

AcO O OH

o

Ph"~NH 0 ph~,~.

&H

\N

~1OR'

.o~

67

HO ~)Z--OAt

:O ii

taxol (paclitaxel)

68

OH HO

690)

52 (ii)

H3CO \N

0 OH

O~"-'~-N\

70

<2.9A 1

2

Figure 23. Application OfsP0Yridone photocycloaddition to taxol and photosubstrates 69 and 52. selectivity of the four-carbon tether controls the remaining two stereogenic centers. In addition, one pyridone of 52 carries a methoxy group that differentiates the alkenes in the photoproduct and forms a point at which the A-ring carbons will be attached. Purification of 53 proved difficult because silica gel chromatography resulted in cleavage of 53 to give 52. 49 The stereochemistry of this product was confirmed by X-ray crystallography of a dihydro derivative (see Figure 18). Elaboration of 53 to introduce taxol functionality involved initial treatment with osmium tetroxide. This step relies on the approach of the reagent from the sterically accessible face of each olef'm (see model of 53, Figure 24) because one face of each alkene is blocked by an amide group. The resulting trihydroxyketone 74 is formed as a

2-Pyridone Photocycloadditions

N•-•TBS ~~/'~

52

\ ?

O OCH3 53

H3CO

0504

HO O

107

I

53

MgBr \HO HOO

_~...~-~.

_,1-~-~.

O'JOHC)H" / / 73

O O ~)H~ 74

~zr ~

74

HO O

o ~ ( Z ~ o ." ,

// 7s / ~x,c.:., I'

,o'Koo o~g.o " , / / 76

X-ray

OCH3

~ ~ ~

~,

o,

Figure 24. Cycloaddition route to taxol and elaboration of the photoproduct. 5~ single isomer. Treatment of 74 with an excess of allyl magnesium bromide gratifyingly gives a single diastereomeric product, presumably 73, and subsequent treatment with dimethoxypropane forms a single acetonide. 57 The allylic anion was expected to approach the ketone of 74 from the least hindered face, just as the osmium reaction had with 53, to set the correct stereogenic center at C1 of taxol and give 73. X-ray crystallography of the allyl Grignard addition product confirmed that the osmium tetroxide had delivered three hydroxyl groups

108

SCOTT McN. SIEBURTH

with the expected stereochemistry. However, the allyl nucleophile reagent had been cleanly delivered from the unexpected direction to give 75! 55,58Two possible explanations for this contrasteric delivery of the allyl group are the blockage of one carbonyl face by the ~-alkoxy group and prior coordination of the allyl group with the amide carbonyl that was expected to play a steric blocking role. Investigation into these possibilities continues. B. Fusicoccin A

Before the intensive investigation of taxol and related natural products as anticancer agents, fusicoccins, ophiobolins, and ceroplastols were the major classes of cyclooctanoid natural products, all with a similar 5-8-5 fused ring system. 59Application of 2-pyridone photochemistry to the synthesis of fusicoccin A 77 is depicted in Figure 25. The two methyl substituents on the cyclooctene ring would be derived from the amide carbonyls. Ideally, the cis relative configuration of these methyl groups would derive directly from a cis-selective cycloaddition. A silyloxy substituent on the three-atom tether would set the stereochemistry at C l l (see Figure 16). The additional fused cyclopentane ring with its C3 methoxymethyl substituent presents HO 0 ",.,__. H ~ O A

c

**o

R'

,

cis O~----x

9

~OTBS BS

IL-..OCH3

~Ip

I~~

OTBS OCH3 78

'~"OCH3 77 fusicoccinA O

O. 0

79

H~I~'OCH3~ oneface 80

Figure 25. Retrosynthetic approach to fusicoccin A via a cis-[4+4] cycloaddition.

2-Pyriclone Photocycloadditions

109

another steric influence on the cycloaddition step. As depicted in conformation 80, the methoxymethyl group would be expected to direct the other pyridone ring away from that face. Thereby, the natural configuration at C3 would reinforce the effect of the tether silyloxy group (C 12) on the photochemically set stereochemistry at C11. If a cis-selective cycloaddition were achieved, the epoxide stereochemistry shown in 78 would originate from epoxidation of the disubstituted alkene from the least hindered face. The desired cis-selective cycloaddition of 79, however, was unprecedented. Some degree of cis-selectivity was initially anticipated on the basis of a possible steric interaction between the cyclopentane in 79 (and 81) and a solvated carbonyl of the approaching pyridone. Therefore, it was inexplicable that the cycloaddition is extraordinarily trans-selective (Figure 26)!60 This trans-selectivity is solvent-independent for the N,N'-dimethyl (entries 1,2) and also for a monomethyl analog (entries 3, 4). Only when both N-methyl groups are absent does the cis/trans-selectivity of the cycloaddition become solvent-dependent. This dramatic effect is illustrated with eleven solvents in reference 60. With benzene (or toluene) as solvent, the stereochemistry is completely reversed and yields the cis isomer 77 exclusively. The cis-

O

hv ~

%

O ~ . . . _ . ,R1 . ~ _ . ~ .N =~--~-~

, RI N

+ BS R ~,

TBS

81

82

83

entry

R1

1

CH3

CH 3 methanol

>99 : 1

2

CH3

CH3

>99 : 1

4

6

R2

solvent

C6H6

82 : 83

H

CH 3 methanol

>99 : 1

H

CH 3

C6H6

>99"1

H

H

methanol

H

H

C6H6

9:1 1 :>99

Figure 26. Solvent-dependent cycloaddition of 81 is observed only when both pyridones lack N-substitution. 6~

110

SCOTT McN. SIEBURTH o

NH

o

NH

o

<* ~0

k.~NH 84

8s 85

~

%orBs 86

Figure 27. Cis isomer 85 undergoes Cope rearrangement to give 84 at ambient temperature. Treatment of 85 with dimethyldioxirane at 0 ~ yields a single epoxide 86. 58 Molecular models of 84-86 are shown. selectivity in benzene may result from a pair of hydrogen bonds between the two pyridones that hold the molecule in a pro-cis conformation (Figure 26). An alternative hydrogen-bonded assembly involving association of two molecules, similar to the self-assembling pyridone arrays of Wuest 61 but leading to cis cycloadducts, cannot be excluded. The cis-selective reaction to give 83 is complicated by an extremely facile Cope rearrangement (Figure 27). At ambient temperatures, quantitative rearrangement of 85 to 84 takes place in a matter of hours. Several attempts to intercept 85, such as irradiation of 81 under an atmosphere of hydrogen in the presence of a catalyst, failed. 58 Peracids, such as MCPBA, were insufficiently reactive. However dimethyldioxirane proved reactive with 85 and both site- and stereoselective. Irradiation of 81 followed by treatment with dimethyldioxirane, keeping both reactions near or below 0 ~ gives isolated yields of 86 as high as 90%. The selectivity of the dimethyldioxirane for the less substituted alkene may result from the steric shielding of the trisubstituted alkene in 85 by the silyloxy group because dimethyldioxirane is sterically sensitive. 62 Approach of dimethyldioxirane from the least hindered face accounts for the stereochemistry of the epoxide. The oxirane in 86 is ideally positioned for introduction of the trans-diol in fusicoccin A 77. 58

2-Pyridone Photocycloadditions Nail

$s

111

o

~ No.

0

.~

R.N.,~

RNCO R"NH _~/~ObT BB 0

0 ~ }A,N,.

O~/

87

~'obTBSH 88

Figure 28. Carbamoylation of the least hindered amide in 86 allows for reductive opening of the lactam under mild conditions. 58 This model study would be ideally completed by hydrolysis of the lactams, and this is most easily accomplished by activating the amide nitrogens. Here the steric congestion of the photoproduct 86 (compare to Figure 31) presents challenges. Attempts to derivatize 86 with Boc or sulfonyl groups uniformly failed. Treatment with sodium hydride and isocyanates however, leads to acyl urea product 87 (Figure 28). Reduction of 87 with lithium borohydride at ambient temperature leads to hydroxymethyl derivative 88. Mesylation of 88 proceeds smoothly and treatment of the mesylate with an iodide/zinc/acetic acid mixture leads to reduction of the mesylate to a methyl group. 58 IV.

SYNTHETIC T R A N S F O R M A T I O N S OF THE [4+4] PHOTOPRODUCT

A. Paquette's Work at Upjohn Paquette's work at Upjohn generated many examples of photodimerization and also subsequent reactions of the photoproducts, primarily hydrogenation, lithium aluminum hydride reduction, and quatemization of the resulting amines to give 90 and related products (Figure 29). 3 Much of this chemistry can be found in the patent

1. H2, PtI2 O//

9

3

N\

CH3I

2. LiAIH4

N\

89

130 "C autoclave

" --

90

Figure 29. Photodimerization products are transformed to amines and quaternary ammonium salts, several of which were discovered to have bioactivity at Upjohn.

112

SCOTT McN. SIEBURTH

literature. 16'63-66One other attempt to transform 2-pyridone photodimer products was frustrated by the high crystallinity (insolubility) of the dimers. 17

B. DissolvingMetal Reduction The rigid polycyclic photoproduct derived from the [4+4] cycloaddition is resistant to simple hydrolytic ring opening of the amide bonds, presumably caused by the limited conformational mobility of the ring system and the steric crowding that occurs when the tetrahedral intermediate of amide hydrolysis is formed. Dissolving metal reduction of amides has been successfully used for sterically hindered amides, 67 and this reaction has proven to be a powerful method for transforming the pyridone photoproducts. The simplest intramolecular [4+4] product 41 was initially hydrogenated to give 91. Reduction of the alkenes lends flexibility and stability to the molecule by preventing reversion to pyridones. Treatment of 91 with an excess of lithium in ammonia for several minutes results in the complete consumption of 91 and formation of two products. One has been tentatively identified as the expected bisaminal 92. However the second product 93 (isolated in 25% yield) retains two amides, but now one is secondary. Only one isomer was found for this product, and the structure was solved by X-ray crystallography (Figure 30). A multistep mechanism has been advanced to account for the formation of 93. 68 Interestingly, the three stereogenic centers in 93 maintain the relative orientation of the substituents. Protonation of two enolates (94) from the least hindered face accounts for the stereochemistry.68

C. Hydrolytic and Reductive Opening of the Amides Intermolecular cycloaddition of n-butyl-2-pyridone and 4methoxy-2-pyridone gives 17 in 51% yield (Figure 7). 29 This has provided a platform to explore the reactivity of the photoproducts. A combination of the n-butyl substituent and an absence of symmetry results in good solubility properties for 17 compared with many simple pyridone photodimers. Some initial transformations of 17 are shown in Figure 31. In all cases the yields exceed 70% and in most cases are nearly quantitative. 69 The simplest reaction is hydrogenation. The close analogy of 17 to the core of taxol intermediate 53 (Figures 18

2-Pyridone Photocycloadditions

H2'Pd'C \Nj ~ ~ . "90

41

113

~

H

91

i

o\N~ ~ N ~ .OH + M

92

93

(~c,,

LiNI OLi

..

=4

LiO/

\

94

a

o,

0

H N ~.H

X-raystructureof 93

Figure 30. Lithium-ammonia reduction yields an eleven-membered carbocycle. 68

n-Bu "N~~~" O

O NH

n-Bu,N

O

Bu

N

95

=t4h

n-Bu,

.0

~

96

n-Bu

.0

n-Bu, -'~,0

NO:~NINH Ra-Ni "No:~H 98 CSA 17

n-Bu, N

0/~0l-l~IH 99

.,~O

NO:~~

N-

,

o o lO, T

"1<:

Figure 31. Reduction and hydrolysis of the alkene groups in 17 and Boc-derivatization of the secondary amides. 69

114

SCOTT McN. SIEBURTH

and 24) led to the expectation that selective reduction of the disubstituted alkene over the enol ether would be straightforward. Nevertheless, platinum oxide and one atmosphere of hydrogen rapidly reduced both alkenes to give 96 as a single isomer. Raney nickel is much more selective, however, and yields only the dihydro derivative 98. 69,70 Hydrolysis of the enol ether also proved to be very facile. Exposure of 17 to aqueous hydrochloric acid in THF at 0 ~ for ten minutes gives ketone 101 (or 99 from 98). With methanol as solvent, the acetal 100 is isolated. If the hydrolysis is allowed to run for several hours at ambient temperatures, however, a new product 95 forms in high yield, resulting from cleavage of a carbon-carbon bond attached between the enol ether and the amide carbonyl. 69

n-Bu,

0

n-Bu,

/)-/I---N._

K2CO3 MeO~,C....

O O 97

uoc

N aBH4 ~ -20 "C

n-Bu "N

~O

NHBoc

~

0 0-~="

/~0 LiBH4

.0

MeO2C

NHBoc O

104

-~ 25 "C .,,~O

~

~ 25 0~ HOPOIH"--I~I" Goc 106

n-Bu, ,~O I~.,, HO\ ..... HO

n-Bu, .O I~..., HO~..... HO

m

n-Bu,

O 103

n-Bu N "

"Boc 105 n-Bu, N

.0

NHBoc 108

aT/mm:::~'-'u'l~ ",~ al m cu

~lWdk

0' X-ray structure of 104c"

Figure 32. Facile hydrolysis of Boc-activated amide. 69

NHBoc 107

2-Pyridone Photocycloadditions

115

When treated with di-t-butyl dicarbonate, triethylamine and DMAP, ketones 99 and 101 lead to a rapid (10 min), quantitative coupling of the secondary amides to give 97 and 102, respectively. 69 The Boc-activated amide in 97 proved reactive under very mild conditions. In methanol with potassium carbonate at ambient temperature, a mixture of 13-keto esters 103 and 104 forms. The product in which the ester group had epimerized (104) crystallized and an X-ray structure confirmed that hydrolysis occurs and identified the product isomer (Figure 32). Alternatively, treatment of 97 with sodium borohydride reduces the ketone. At 0 ~ and above, a mixture of two alcohols forms, but a t - 2 0 ~ only 105 was detected. Lithium borohydride proved more reactive and reduces the activated amide carbonyl. Interestingly, at 0 ~ this gave the aminal 106 as a single (unidentified) diastereomer that could be isolated and characterized. Continued reaction with lithium borohydride at ambient temperature gives the diol amide 107 in high yield and as a single isomer. Reduction of 97 directly to 107 is easily accomplished with lithium borohydride, beginning at -20 ~ and warming to room temperature. Similarly, enone 102 reduces to yield enediol 108 in high yield and as a single diastereomer. 69 IV. CONCLUSIONS During nearly forty years of study, the photocycloaddition of 2-pyridones has consistently exhibited versatile and reliable [4+4] reactivity. When dimerization is not desired, intramolecular reactions efficiently steer two pyridones to react. Altematively, intermolecular cross reaction with an excess of another four-electron reactant can be extended to other heterocycles and to simple 1,3-dienes. It is perhaps surprising how few photoreactions of 2-pyridone fail to yield [4+4] products. Failure of the [4+4] reaction can result from a tethering unit that prevents the normal head-to-tail reactivity and introduces strain (Figures 14 and 22) or from steric hindrance caused by excessive substitution at the reacting carbons (Figure 23). A 4-alkoxy substrate shuts down the normally dominant photodimerization reaction and provides opportunities for other [4+2] or [4+4] reactions (Figures 6 and 7). Postphotochemistry manipulation of the photoproduct's dense functionality presents challenges and opportunities, and these studies

116

SCOTT McN. SIEBURTH

are still young. Nevertheless, the level of predictable diastereomeric control (see Figures 24 and 27) and straightforward amide manipulation (Figures 31 and 32) bodes well for future applications.

ACKNOWLEDGMENTS Virtually all of the work described here and not attributed to other labs was performed by the talented cadre of postdoctoral associates (Taleb H. A1-Tel and Jian-long Chen), graduate students (Jianhao Chen, Nick T. Cunard, Christina B. Madden-Duggan, Gary Hiel, Pramod V. Joshi, Cherrilyn Keaise, Dora P. Kuan, Chao-Hsiung Lin, Kevin F. McGee, Jr., Zhilei Qiu, K. Ravindran, David Rucando, Brian Siegel, Yuanzan Ye) and undergraduate students (Zhigang Cheng, Fareed Fareed, David Gallagher, E. Alex Justell, Lori Morrow, Anthony Nguyen, and Ting T. Yin) with whom I have been privileged to explore the fascinating chemistry of pyridones. The generous support by the National Institutes of Health (GM45215) is also gratefully acknowledged.

REFERENCES AND NOTES 1. 2. 3. 4. 5.

Taylor, E. C.; Paudler, W. W. Tetrahedron Lett. 1960, 25, 1. Taylor, E. C.; Kan, R. O.; Paudler, W. W. J. Am. Chem. Soc. 1961, 83, 4484. Paquette, L. A.; Slomp, G. J. Am. Chem. Soc. 1963, 85, 765. Taylor, E. C.; Kan, R. O. J. Am. Chem. Soc. 1963, 85, 776. Ayer, W. A.; Hayatsu, R.; de Mayo, P.; Reid, S. T.; Stothers, J. B. Tetrahedron Lett. 1961, 648. 6. Slomp, G.; MacKellar, E A.; Paquette, L. A. J. Am. Chem. Soc. 1961, 83, 4472. 7. Corey, E. J.; Streith, J. J. Am. Chem. Soc. 1964, 86, 950. For photoisomerization of 2-aminopyridine, see Taylor,E. C.; Paudler, W. W.; Kuntz, I., Jr. J. Am. Chem. Soc. 1961, 83, 2967. 8. Nakamura, Y.; Kato, T.; Morita, Y. J. Chem. Soc., Perkin Trans. 1 1982, 1187. 9. Sharp, L. J., IV; Hammond, G. S. Mol. Photochem. 1970, 2, 225. 10. Boyd, M. K., Loyola University of Chicago, personal communication. 11. Nakamura, Y.; Zsindely, J.; Schmid, H. Helv. Chim. Acta 1976, 59, 2841. 12. Van Meerbeck, M.; Toppet, S.; De Schryver,E C. Tetrahedron Lett. 1972, 2247. 13. Pirkle, W. H.; Eckert, C. A.; Turner, W. V.; Scott, B. A.; McKendry, L. H. J. Org. Chem. 1976, 41, 2495. 14. West, E G. In Advances in Cycloaddition; Lautens, M., Ed.; JAI: Greenwich, CT, 1997; Vol. 4; pp. 1-40. 15. Matsushima, R.; Terada, K. J. Chem. Soc., Perkin Trans 2 1985, 1445. 16. Paquette, L. A., U.S. Patent 3 562 252, 1971. Chem. Abstr. 1971, 75, 20454c. 17. Meyers, A. I.; Singh, P. J. Org. Chem. 1970, 35, 3022. 18. Jones, D. W. J. Chem. Soc. (C) 1969, 1729.

2-Pyridone Photocycloadditions

117

19. Dilling, W. L.; Tefertiller, N. B.; Mitchell, A. B. Mol. Photochem. 1973, 5, 371. 20. Kaneko, C.; Fujii, H.; Kato, K. Heterocycles 1982, 17, 395. 21. Kaneko, C.; Shiba, K.; Fujii, H.; Momose, Y. J. Chem. Soc., Chem. Commun. 1980, 1177. 22. De Selms, R. C.; Schleigh, W. R. Tetrahedron Lett. 1972, 3563. 23. Kametani, T.; Mochizuki, T.; Honda, T. Heterocycles 1982, 19, 89. 24. Furrer, H. Chem. Ber. 1972, 105, 2780. Begley, W. J.; Lowe, G.; Cheetham, A. K.; Newsam, J. M. J. Chem. Soc., Perkin Trans. 1 1981, 2620. Kaneko, C.; Katagiri, N.; Sato, M.; Muto, M.; Sakamoto, T.; Saikawa, S.; Naito, T.; Saito, A. J. Chem. Soc., Perkin Trans. 1 1986, 1283. Katagiri, N.; Sato, M.; Yoneda, N.; Saikawa, S.; Sakamoto, T.; Muto, M.; Kaneko, C. J. Chem. Soc., Perkin Trans. 1 1986, 1289. For a lipase resolution of the Dewar pyridones, see Nakano, H.; Iwasa, K.; Kabuto, C.; Matsuzaki, H.; Hongo, H. Chem. Pharm. Bull. 1995, 43, 1254. For solid state photoisomerization to yield enantiomerically pure products, see Wu, L.-C.; Cheer, C. J.; Olovsson, G.; Scheffer, J. R.; Trotter, J.; Wang, S.-L.; Liao, E-L. Tetrahedron Lett. 1997, 38, 3135. 25. Kaneko, C.; Uchiyama, K.; Sato, M.; Katagiri, N. Chem. Pharm. Bull. 1986, 34, 3658. Kaneko, C.; Suzuki, T.; Sato, M.; Naito, T. Chem. Pharm. Bull. 1987, 35, 112. 26. Somekawa, K.; Shimou, T.; Tanaka, K.; Kumamoto, S. Chem. Lett. 1975, 45. 27. Somekawa, K.; Kumamoto, S.; Matsuo, T. J. Org. Chem. 1982, 47, 1564. 28. Fujii, H.; Shiba, K.; Kaneko, C. J. Chem. Soc., Chem. Commun. 1980, 537. 29. Sieburth, S. McN.; Lin, C.-H. Tetrahedron Lett. 1996, 37, 1141. 30. Kanaoka, Y.; Ikeda, Y.; Sato, E. Heterocycles 1984, 21,645. Sato, E.; Ikeda, Y.; Kanaoka, Y.Heterocycles 1989, 28,117. Sato, E.; Ikeda, Y.; Kanaoka, Y. Liebigs Ann. Chem. 1989, 781. 31. Sieburth, S. McN.; Cunard, N. T. Tetrahedron 1996, 52, 6251. 32. Fringuelli, E; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley-Interscience: New York, 1990. 33. Gilbert, A.; Griffiths, O. J. Chem. Soc., Perkin Trans. 1 1993, 1379. 34. Saltiel, J.; Dabestani, R.; Schanze, K. S.; Trojan, D.; Townsend, D. E.; Goedken, V. L. J. Am. Chem. Soc. 1986, 108, 2674. 35. Taylor, E. C.; Spence, G. G. Org. Photochem. Synth. 1971, 1, 46. 36. Nagano, T.; Hirobe, M.; Itoh, M.; Okamoto, T. Tetrahedron Lett. 1975, 3815. 37. Nagano, T.; Hirobe, M.; Okamoto, T. Tetrahedron Len. 1977, 3891. 38. Nakamura, Y.; Kato, T.; Morita, Y. J. Chem. Soc., Chem. Commun. 1978, 620. 39. Nakamura, Y.; Kato, T.; Morita, Y. Tetrahedron Lett. 1981, 22, 1025. Kato, T.; Nakamura, Y. Heterocycles 1981, 16, 135. Kato, T.; Nakamura, Y.; Morita, Y. Chem. Pharm. Bull. 1983, 31, 2552. 40. Toda, E; Tanaka, K. Tetrahedron Lett. 1988, 29, 4299. 41. For examples, see Yang, N. C.; Libman, J. J. Am. Chem. Soc. 1972, 94, 1405; Eaton, P. E.; Chakraborty, U. R. J. Am. Chem. Soc. 1978, 100, 3634; Paquette, L. A.; Doecke, C. W.; Klein, G. J. Am. Chem. Soc. 1979, 101, 7599; Tobe, Y.;

118

42. 43. 44. 45. 46. 47. 48.

49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

SCOTT McN. SIEBURTH Hirata, E; Nishida, K.; Fujita, H.; Kimura, K.; Odaira, Y. J. Chem. Soc., Chem. Commun. 1981, 786. Vogel, E. Liebigs Ann. Chem. 1958, 615, 1. Sieburth, S. McN.; Lin, C.-H. J. Org. Chem. 1994, 59, 3597. Laing, M. Proc. Chem. Soc., London 1964, 343. Brown, J. N.; Towns, R. L. R.; Trefonas, L. M. J. Am. Chem. Soc. 1971, 93, 7012. Sieburth, S. McN.; Chen, J.-1. J. Am. Chem. Soc. 1991, 113, 8163. Sieburth, S. McN.; Hiel, G.; Lin, C.-H.; Kuan, D. P. J. Org. Chem. 1994, 59, 80. Dougherty,D. A.; Choi, C. S.; Kaupp, G.; Buda, A. B.; Rudzifiski, J. M.; Osawa, E. J. Chem. Soc., Perkin Trans 2 1986, 1063. Baldridge, K. K.; Battersby, T. R.; Vernon Clark, R.; Siegel, J. S. J. Am. Chem. Soc. 1997, 119, 7048. Sieburth, S. McN.; Ravindran, K. Tetrahedron Lett. 1994, 35, 3861. Sieburth, S. McN.; Chen, J.; Ravindran, K.; Chen, J.-1. J. Am. Chem. Soc. 1996, 118, 10803. Sieburth, S. McN. J. Chem. Soc., Chem. Commun. 1994, 1663. Sieburth, S. McN.; Siegel, B. J. Chem. Soc., Chem. Commun. 1996, 2249. Yin, T. Y.; Madsen-Duggan, C. B. SUNY Stony Brook research notes. A1-Tel,T. H. SUNY Stony Brook research notes. Qiu, Z. SUNY Stony Brook research notes. Kingston, D. G. I.; Molinero, A. A.; Rimoldi, J. M. Prog. Chem. Org. Nat. Prod. 1993, 61, 1. Chen, J. SUNY Stony Brook research notes. McGee, K. E, Jr. SUNY Stony Brook research notes. Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. Sieburth, S. McN.; McGee, K. E, Jr., A1-Tel, T. H.J. Am. Chem. Soc. 1998,120, 587. Persico, E; Wuest, J. D. J. Org. Chem. 1993, 58, 95. Curci, R.; Dinoi, A.; Rubino, M. E Pure Appl. Chem. 1995, 67, 811. Paquette, L. A., U.S. Patent 3 321 482, 1967. Chem. Abstr. 1968, 68, 49577m. Paquette, L. A., U.S. Patent 3 318 899, 1967. Chem. Abstr. 1968, 68, 49579p. Paquette, L. A., U.S. Patent 3 466 292, 1969. Chem. Abstr. 1970, 72, 12781e. Paquette, L. A., U.S. Patent 3 432 507, 1969. Chem. Abstr. 1969, 70, 96834u. Evans, D. A.; Illig, C. R.; Saddler, J. C. J. Am. Chem. Soc. 1986, 108, 2478. Garner, P.; Ho, W. B.; Shin, H. J. Am. Chem. Soc. 1993, 115, 10742. Sieburth, S. McN.; A1-Tel,T. H.; Rucando, D. Tetrahedron Lett. 1997, 38, 8433. Rucando, D. SUNY Stony Brook research notes. Lin, C.-H. SUNY Stony Brook research notes.

[3+4] ANNULATIONS BETWEEN RHODIUM-STABILIZED VINYLCARBENOIDS AND DIENES

Huw M. L. Davies

Abstract

I. II.

III.

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

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . I n t e r m o l e c u l a r [3+4] A n n u l a t i o n s of V i n yl carbenoi ds with D i e n e s . . . . . . . . . . . . . . . . . . . . . . . . . A. C y c l o p e n t a d i e n e . . . . . . . . . . . . . . . . . . . . B. A l k y l - S u b s t i t u t e d Acyclic Dienes . . . . . . . . . . . . . C. H e t e r o a t o m - S u b s t i t u t e d Dienes . . . . . . . . . . . . . . . D. M e c h a n i s t i c A n a l y s i s of V i n y l c a r b e noi d Cyclopropanations . . . . . . . . . . . . . . . . . . . I n t e r m o l e c u l a r R e a c t i o n s with A r o m a t i c S y s t e m s . . . . . . . . A. B e n z e n e s . . . . . . . . . . . . . . . . . . . . . . . . B. F u r a n s . . . . . . . . . . . . . . . . . . . . . . . . . . C. Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . .

Advances in Cycloaddition Volume 5, pages 119-164. Copyright 9 1999 by JAI Press Inc. All r i o t s of reproduction in any form reserved. ISBN: 0-7623-0346-8

119

120

. .

120

. . . .

122 122 128 133

. .

142 143 143 145 149

. . . . . .

120 IV.

H UW M. L. DAVI ES

Intramolecular [3+4] Reactions of Vinylcarbenoids with Dienes and Aromatic Compounds . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154 160 160

ABSTRACT The [3+4] annulation between rhodium-stabilized vinylcarbenoids and dienes is a general method for the stereoselective synthesis of highly functionalized seven-membered tings. The methodology can be carried out inter- or intramolecularly and is applicable to a wide range of vinylcarbenoids and dienes, including furans, pyrroles, and even benzene derivatives. The annulation occurs in a two-step sequence, cyclopropanation followed by a Cope rearrangement of the resulting cis-divinylcyclopropane intermediate. The success of this chemistry results from the high stereoselectivity of vinylcarbenoid cyclopropanations, which strongly favor the formation of cis-divinylcyclopropane intermediates. The asymmetric version of the [3+4] annulation can be readily achieved by using methyl (S)-lactate or (R)-pantolactone as chiral auxiliaries or by using dirhodium tetraprolinates as chiral catalysts. I.

INTRODUCTION

Because a number of important natural products contain densely functionalized seven-membered rings, general methods for constructing these ring systems have been actively pursued. ~ In recent years, annulation processes, such as [4+3] annulations between dienes and allyl cations 2 or a nucleophilic vinylcarbene, 3 or [5+2] annulations between heterocyclic betaines and alkenes 4 have been shown to be particularly versatile. 5 In this chapter, the advances made in developing a general method for constructing seven-membered tings by a [3+4] annulation between rhodium(H) stabilized vinylcarbenoids and dienes are described. 6 The critical step is a stereoselective cyclopropanation of a diene by a vinylcarbenoid followed by a Cope rearrangement of the resulting divinylcyclopropane (Scheme 1).7 The major advantage of this method compared with traditional reaction sequences using the Cope rearrangement of divinylcyclopropanes 7'8 is the ease of forming the divinylcyclopropane. Typically, the stereoselective synthesis of the

Annulations of Vinylcarbenoids and Dienes

R9 R8'~R10

N2/ ~

R1

121

Rh(ll) R9-'-'~ 910| R96 4

R.9 ,,R10 ,.-,1 R 8 ~ r~

R5 k 6 Scheme 1.

cis-divinylcyclopropanes has been very demanding, even though a number of elegant methods have been developed to overcome this problem. 7,8 Because the Cope rearrangement of cis-divinylcyclopropanes 7'8 occurs through a boat transition state under mild conditions with very predictable stereochemistry, the success of the [3+4] annulation depends on a highly regioselective and stereoselective cyclopropanation between the vinylcarbenoid and the diene. As becomes apparent later, vinylcarbenoids functionalized with an electron-withdrawing group adjacent to the carbenoid undergo highly stereoselective cyclopropanations. Furthermore, the cyclopropanation can be made highly enantioselective by using a chiral auxiliary or a chiral catalyst, which means that the seven-membered rings are formed with excellent control of diastereoselectivity and enantioselectivity. The general feasibility of [3+4] annulations between vinylcarbenes and dienes was originally demonstrated by Franck-Neumann and co-workers. 9 The vinylcarbenes were generated through photolysis of (3H)-pyrazoles in the presence of various dienes as solvent. The chemistry was complicated because vinylcarbenes are prone to rearrangement, and moreover, the triplet state of the vinylcarbene is generally the ground state. An illustratory example from Franck-Neumann's work is shown in Scheme 2. Photolysis of the 3H-pyrazole 1

1

2

Scheme 2.

3

122

HUW M. L. DAVIES

in furan resulted in the formation of a 2"1 mixture of the [3+4] annulation product 2 and the cyclopropene 3. Thus, even when furan is used as a solvent, rearrangement of the vinylcarbene to the cyclopropene competes favorably with the intermolecular reaction with furan. A reasonable approach to temper the reactivity of vinylcarbenes would be to use metal-stabilized vinylcarbenoids derived from the decomposition of vinyldiazoalkanes instead of the free vinylcarbenes. Even though such an approach has been extensively used for numerous carbenoid systems, 1~ there were very few examples of the metalcatalyzed decomposition of vinyldiazomethanes before our studies began ~1and none leading to [3+4] annulations with dienes. Intermolecular cyclopropanations using various copper catalysts had been achieved in poor to moderate yield (6-40%) and stereoselectivity (E/Z ratios up to 2:1).1 la-c One notable early reaction was an intramolecular example reported by Corey (45% yield) that was used to synthesize sirenin, 11e'g and has since been achieved asymmetrically by using a chiral copper catalyst. 12For us to develop efficient [3+4] annulations between vinylcarbenoids and dienes, a major improvement in the yields of vinylcarbenoid transformations was needed. This was achieved by decomposing the vinyldiazomethanes using rhodium(II) carboxylates as catalysts, which, it had been shown by the early 1980s, are superior to the traditional copper catalysts in many carbenoid reactions. ~~ !1. INTERMOLECULAR [3+4] A N N U L A T I O N S OF

VINYLCARBENOIDS WITH DIENES A. Cyclopentadiene

An interesting feature of vinyldiazomethanes, the precursors to vinylcarbenoids, is that they are prone to rearrangement to 3H-pyrazoles. 13 Kinetic studies by Pincock and co-workers 14 on some very elaborate vinyldiazomethanes indicated that electron-withdrawing groups on the vinyldiazomethanes hinder this rearrangement. Consequently, we began our studies with the vinyldiazomethane 4, which contains two ester groups and is indefinitely stable at ambient temperature in the absence of catalyst. ~5'16Rhodium(II) acetate catalyzed

Annulations of Vinylcarbenoids and Dienes

,C02Et

123

Rh2(OAc)4 ,=~

C02Et

98%yield C02Et

5

4

C02Et

Scheme 3.

decomposition of 4 in the presence of cyclopentadiene results in a remarkable reaction. The [3+4] annulation product 5 is formed in essentially quantitative yield, exclusively as its endo diastereoisomer (Scheme 3). 17 The [3+4] annulation product 5 could conceivably arise by a [4rc+2n] cycloaddition in which the vinylcarbene acts as a 2re system, or by a tandem cyclopropanation Cope rearrangement. To test which mechanism is operative, the reaction was repeated using the bulky vinyldiazomethane 6 (Scheme 4). 17 The Cope rearrangement of divinylcyclopropanes is sensitive to steric effects, 7'8 and so, if the second mechanism was operative, it should be possible to observe the sterically crowded cyclopropane. Rhodium(II) acetate catalyzed decomposition of the vinyldiazomethane 6 in the presence of cyclopentadiene results in the formation of the cis-divinylcyclopropane 7. Even though 7 is isolated by chromatography, it slowly rearranges to the [3+4] annulation product 8 on standing, and this rearrangement is achieved in quantitative yield by heating 7 at 110 ~ for 1 h. To expand the synthetic utility of the [3+4] annulation, the study was extended to a range of vinyldiazomethanes. Examples of the type

~+

C02Et

~

,,~H

,/2 89%yield ~ ' ~ X ~ MeO-~ Et020~ ~ .....'C02Et C02Et 7

6 /~~...CO2E t 110gC, 1 h. "~-OMe quantitative

8

CO2Et Scheme 4.

HUW M. L. DAVIES

124

Table 1. Diastereoselective Synthesis of

Bicyclo[3.2.1 ]octa-2 6-dienes 91

O Entry

1 2 3 4 5 6 7 8 9 10

+

R1

N2~/ R2

Rh2(O2CR)4 ~R~ F:I12R -

R2 R3

CO2Et H CO2Et H CO2Et H CO2Me H COMe H CO2Me H CO2tBu H CO2Et H COMe H COMe OTBDMS

R3

Catalyst/Solvent

CO2Et CH=CHPh SO2Ph Ph Ph H H CH=CH2 H H

Rh2(OAc)4/CH2C12 Rh2(OAc)4/CH2C12 Rh2(OAc)4/cn2c12 Rh2(OAc)4/CHEC12 Rh2(OAc)4/CH2C12 Rh2(OPiv),dpentane RhE(OAc)4/pentane Rh2(OAc)g/pentane Rh2(OAc)4/pentane Rh2(OAc)4/pentane

Yield (%)

98 72 80 73 66 86 72 83 75 88

of vinyldiazomethanes that can be used in this chemistry are shown in Table 1.17-19 In each case that has a stereochemical issue, the e n d o product is exclusively formed because of the stereochemical requirement of the Cope rearrangement of divinylcyclopropanes. The reaction of vinyldiazomethane derivatives, such as 9, 20that contain a single electron-withdrawing group (~ to the diazo and unsubstituted at the vinyl terminus is more complex than 4 (Scheme 5). TMThe rhodium(II)

CO2MeRh2(O2CR)4 , - I ~ 7CO2MeF ~ 9

10

Rh2(OAc)4/CH2CI2 Rh2(TFA)4/CH2CI2 Rh2(OPiv)4/pentane

ratio (10"11) 67:33 32:68 98"2

Scheme 5.

11~~"CO2Me

125

Annulations of Vinylcarbenoids and Dienes

acetate catalyzed decomposition of the vinyldiazoacetate 9 in the presence of cyclopentadiene results in the formation of two products, the [3+4] annulation product 10 and the bicyclo[2.2.1 ]heptene 11. The ratio of the two products, 10 and 11, critically depends on the nature of the catalyst and solvent. The use of an electron-deficient catalyst and a moderately polar solvent, such as CH2C12, favors the formation of 11 whereas an electron-rich catalyst, such as rhodium pivalate, and a hydrocarbon solvent strongly favors formation of the [3+4] annulation product 10. The dichotomy in the chemistry of the vinylcarbenoid derived from 9 arises because this carbenoid undergoes electrophilic reactions at two sites, unlike the 1,3-disubstituted vinylcarbenoids. 2~ Reaction at the carbenoid site leads to cyclopropanation whereas attack at the vinyl terminus leads to zwitterionic intermediates and ultimately 11. Therefore, to enhance the formation of [3+4] annulation products, it is necessary to disfavor zwitterionic intermediates by using electron-rich carboxylates as ligands on the rhodium and nonpolar solvents. 18 The formation of the bicyclo[3.2.1]octadienes in Table 1 in such high yields implies that the cyclopropanation step occurs with very high diasteroselectivity because only cis- divinylcyclopropanes are expected to undergo a Cope rearrangement under the mild reaction conditions. 7,s Such stereoselectivity is very unusual in the carbenoid

Table 2.

Diastereoselectivity of Vinylcarbenoid Cyclopropanations

R3 ~ ~ . , - R1 N2 Entry

1 2 3 4 5 6 7

R~

R 2 " , ~ ~ R 1 R2 " ~ ~ . .''R1

Rh2(OAc)4 / CH2CI2 "

R

Ph Ph Ph p-MeOC6H4 AcO BuO nBu

R1

CO2Et CO2Et CO2Me CO2Et CO2Et CO2Et COEEt

RV R2

CO2Et CH=CHPh Ph CO2Et CO2Et CO2Et CO2Et

+ Yield (%)

96 94 94 80 79 61 66

R" E/Z ratio

8.3 >20 >20 18 >20 >20 5.7

126

H U W M. L. DAVIES

field, and indeed, the poor diastereoselectivity has been a long standing problem with cyclopropanation using the ethyl diaozacetate system. ~~ The limited studies on cyclopropanation with vinyldiazomethane also resulted in low diastereoselectivity. T M We have carried out extensive studies on the diastereoselectivity of vinylcarbenoid cyclopropanations, some representative examples of which are illustrated in Table 2. 22 Ironically, the vinyldiazomethane 4 results in the least stereoselective cyclopropanations, but even so, stereocontrol with 4 is impressive (entries 1, 4-7). Cyclopropanation of styrene occurs with an E/Z ratio of 8.3"1 (entry 1). When the vinyl substituent is changed from an ester to a phenyl or a vinylphenyl group (entries 2 and 3), the diastereoselectivity increases dramatically, so that only a single cyclopropane is observed in the 1H NMR of the crude reaction mixtures. Considering that ethyl diazoacetate ~~ or v i n y l d i azomethane TM results in styrene cyclopropanation with very low diastereoselectivity, it seems that the combination of an electron-withdrawing group and an electron-donating group on the carbenoid is a critical element for the highly diastereo-selective cyclopropanations shown in Table 2. Cyclopropanation of more electron-rich alkenes occurs with higher diastereoselectivity (entries 4-6), so that only a single stereoisomer is seen in the 1H NMR spectrum of crude material from the reaction of 4 with butyl vinyl ether. Conversely, the reaction with electron neutral alkenes such as 1-hexene (entry 7) results in cyclopropanation with diastereoselectivity lower (5.7:1) than styrene. Because the [3+4] annulation is a tandem cyclopropanation/Cope rearrangement sequence, the asymmetric synthesis of the bicyclo[3.2.1]octadienes would be possible if the original cyclopropanation were achieved with asymmetric induction. The traditional chiral copper catalysts or the rhodium amide catalysts are not effective in this chemistry because the catalysts such as rhodium(II) carboxylates, need to be very active kinetically, or the vinyldiazomethane would cyclize to a pyrazole rather than undergo decomposition to a vinylcarbenoid. TM Consequently, two strategies were developed to induce asymmetric induction into vinylcarbenoid cyclopropanations, as illustrated in Schemes 6 23 and 7. 24 The first approach used t~-hydroxy esters as stoichiometric chiral auxiliaries. The highest asymmetric induction was obtained using (R)-pantolactone as the chiral auxiliary. Scheme 6 illustrates the reaction of the vinyldiazoacetate 12 with styrene at 0

Annulations of Vinylcarbenoids and Dienes

127

O CH2C1210gO Ph

N~

o" ~ d

12

9

Ph"~

H

,"

97% de 84% yield

SO2C6H4RJ4 Ph~ICO2Me

13a R =tBu (Rh2(S-TBSP)4) Phph, p~,~CO2Me 13b R =012H25(Rh2(S-DOSP)4) ~_

N2 14

Ph~

pentane

catalyst

temp, gC

ee, %

Rh2(S-TBSP)4

25

90

Rha(S-DOSP)4

25

92

Rh2(S-DOSP)4

-78

98

Scheme 6.

~ which resulted in cyclopropanation in 97% de. 23 Even though the chiral auxiliary approach was very satisfactory, it was deemed prudent to develop a second approach based on a chiral catalyst. Rhodium(II) prollnate derivatives are extremely effective, and because the asymmetric inductions are highest in nonpolar solvents, the hydrocarbon soluble catalysts Rh2(S-TBSP)4 (13a) and Rh2(S-DOSP)4 (13b) are the most successful. For example, Rh2(S-DOSP)4 catalyzed decomposition of the vinyldiazoacetate 14 in the presence of styrene at -78 o C results in cyclopropanation in 98% ee. 24 Rh2(S-TBSP)4 and Rh2(SDOSP)4 perform similarly under identical reaction conditions, but Rh2(S-DOSP)4 has the advantage of solubility in hydrocarbons at -78 ~ the optimum conditions for asymmetric induction, whereas Rh2(STBSP)4 has very limited solubility in hydrocarbons at low temperature. 24b Having developed highly effective asymmetric cyclopropanation protocols for vinylcarbenoids, the extension to the [3+4] annulation of dienes was evaluated. Rhodium(II) acetate catalyzed decomposi9

25

9

HUW M. L. DAVIES

128 0

O Rh2(OAc)4 . ~ . ~ L ~ o 0 ~ CH2CI2 35 gC 76% de 87% yield

Ph" 12

Ph 15

,C02Me Rh2(S-DOSP)4 penlane Ph

25 gC 75% ee -78 gC 93% ee

Ph 16

CO2Me

14

Scheme 7.

tion of the vinyldiazoacetate 12 in the presence of cyclopentadiene at 35 ~ results in the formation of the [3+4] annulation product 15 in 76% de (Scheme 7). 23 Alternatively, Rh2(S-TBSP)4 catalyzed decomposition of 14 in the presence of cyclopentadiene at 25 ~ results in the formation of [3+4] annulation product 16 in 75% ee. 26 Subsequently, it was found that Rh2(S-DOSP)4 is such an active catalyst that decomposition of 14 takes place even at -78 ~ and under these conditions, 16 is formed in 93% ee. 27 The asymmetric synthesis of bicyclo[3.2.1]octadienes is a general process that can be applied to a range of vinyldiazomethanes, as shown in Table 3. 27 Very high levels of asymmetric induction (greater than 90% ee) are obtained with 1,3-disubstituted vinyldiazomethanes (entries 1-4), whereas the enantioselectivities range from 60 to 74% ee for vinyldiazoacetates with other substitution patterns (entries 5-9).

B. AlkyI-Substituted Acyclic Dienes The reaction of vinylcarbenoids with alkyl-substituted acyclic dienes is an effective method for stereoselectively constructing highly functionalized cycloheptadienes. Unlike the cyclopentadiene reaction, trans-divinylcyclopropanes in addition to the [3+4] annulation products can be formed in some cases. 19 For example, rhodium(II) acetate catalyzed decomposition of 4 in the presence of 4-methyl- 1,3pentadiene results in a 4"1 mixture of the [3+4] annulation product 17 and the trans-divinylcyclopropane 18 (Scheme 8). The regiochemistry

129

Annulations of Vinylcarbenoids and Dienes

Table 3. Asymmetrical Synthesis of Bicyclo[3.2.1]octa-2,6-dienes CO 2Me

R3

Entry

R2

R3

Me H Ph H CH=CHPh H CH=CH2 H H Me H OTBDMS H cyclo-(CH2)3 cyclo-(CH2)4

1

H

2 3 4 5 6 7 8 9 Note:

pentane, -78 ~

~

2Me

Yield (%)

ee (%)

47 77 80 58 70 74 95 61a 66a

93 90 92 63 60 74 73 74

91

was carried out at 0 ~

in the reaction, however, is excellent, resulting in cyclopropanation of the least substituted double bond. As illustrated earlier in Table 2, cyclopropanation of styrene with the vinyldiazomethane 4 displays the worst diastereoselectivity of the vinyldiazoacetates, 22 and indeed highly stereoselective cyclopropanations of the acyclic dienes are

,C02Et

~]

J

~02E

,C;02Et

t

4

02E 17 (58%)

,C02Et

19

,C02Et

20

Scheme 8.

C02Et

18 (14%)

130

HUW M. L. DAVIES

~02Et C02Et 4

......j,,.~CO2Et

21

C02Et

22 C02Et 02Et 23 C02Et

Scheme 9. possible with other vinylcarbenoid systems. ~9 Reaction of the vinyldiazoacetate 19 with 4-methyl-1,3-pentadiene results in the formation of the [3+4] annulation product 20 in 80% yield without any evidence of the formation of the trans-divinylcyclopropane. ~9 The importance of achieving stereoselective cyclopropanations in these [3+4] annulations is readily seen in the example illustrated in Scheme 9.19 Typically, cis-divinylcyclopropanes undergo the Cope rearrangement at ambient temperatures or below, whereas the transdivinylcyclopropane would need to isomerize to the cis-divinylcyclopropane before the Cope rearrangement can occur. Isomerization between cis- and trans-divinylcyclopropanes usually requires heating to about 200 ~ and depending on the structure of the trans-divinylcyclopropane, competing rearrangement pathways to the Cope rearrangement may preferentially occur. In the reaction shown in Scheme 9, a mixture of the [3+4] annulation product 21 and the trans-divinylcyclopropane 22 is formed. 19 Under thermolysis or chromatographic conditions, 22 fails to rearrange to the [3+4] annulation product 21, but instead, undergoes a 1,5-homodienyl rearrangement to the ringopened triene 23. The reaction of vinylcarbenoids is feasible with a range of acyclic alkyl dienes, as summarized in Table 4.19 In addition to the formation of the cycloheptadienes with full relative stereochemical control, the regioselectivity in most cases is excellent. Vinylcarbenoids are very sensitive to steric effects around the diene and preferentially cyclopropanate a geminally unsubstituted alkene over a cis disubstituted

131

Annulations of Vinylcarbenoids and Dienes

DiastereoselectiveSynthesis of Cyclophepta-l,4-dienes

T a b l e 4.

Rs

R9 =.. CO 2Et

CO2Et

R8

R5

R3

R

R3

R5

R6

R7

R8

R9

1 2 3 4 5 6 7

CO2Et CH=CHPh CO2Et CH=CHPh CO2Et CH=CHPh CH=CHPh

Me Me Me Me H H H

Me Me Me Me H H H

H H H H Me Me H

H H Me Me Me Me Me

H H H H H H H

80 63a 73 49 a 42 72b

8 9

CH=CHPh CH=CHPh

Me H

H Me

H H

H H

H H

75 68

10

CH=CHPh

Me

H

H

H

Me

53

Notes:

a10-15% of the trans-tfivinylcyclopropane is also formed. b6:1 mixture with the regioisometric cycloheptadiene.

R

Entry

R6

+

R5"R6 R3 Yield (%) 58 a

alkene w h e r e a s no c y c l o p r o p a n a t i o n o f a t r a n s alkene occurs. 28 A n impressive e x a m p l e o f regiocontrol is seen in the reaction o f 19 with 2 ( E ) , 4 ( Z ) - h e x a d i e n e ( S c h e m e 10). 19 A single i s o m e r o f the [3+4] annulation p r o d u c t 24 is f o r m e d which is derived f r o m initial cyclo-

===~/CO2Et ~ Me N2 Rh2(OAc)4=_ Me

k 53% yield . ; CH=CHPh Me "CH=CHPh 19

Me,(

CO2Et

24

O2Me Rh2(OAc)4

N2

,CO2Me + Me CH=CHPh

CH=CHPh 19

/CO2Me

25

Scheme 10.

CH=CHPh 26

6"1 ratio

132

HUW M. L. DAVIES

CO2Me+OAc ~ O A c O~~x, ,~N2 i Rh2(OOct)4 1. H2,ClRh(PPh3)3 (490/,)

M

27

2

""

-

28

J

(66%)

"~ \ ~ "

29

30

Scheme 11.

propanation of the cis double bond of the diene. Reasonable regiochemistry is seen even in the reaction of 19 with isoprene where a 6:1 mixture of [3+4] annulation products, 25 and 26, is formed. The synthetic utility of the [3+4] annulation was demonstrated in a short stereoselective synthesis of (+)-tremulenolide A (30, Scheme 11). 19 Rhodium(II) octanoate catalyzed decomposition of the cyclopentenyldiazoacetate 27 in the presence of the E,Z diene 28 results

Enantioselective Synthesis of Cyclohepta-l,4-dienes CO2Me a CO2Me

T a b l e 5.

R7~~RRsR6 + Entry

R3

R2

Rh2(S-DOSP)4 -78~ - rt

R T / ~

a

RS~R6 R

R2

R3

R5

R6

R7

Rg

Yield (%) ee (%)

1

H

Me

Ph

H

H

H

87

98

2

H

Ph

Ph

H

H

H

83

98

3

H

CH-CHPh

Ph

H

H

H

84

93

4

H

CH-CH2

Ph

H

H

H

55

96

5

H

H

Ph

H

H

H

41

73 94

6

cyclo-(CH2)3

Ph

H

H

H

62

7

cyclo-(CH2)4

Ph

H

H

H

60

81

Me

H

H

H

47

96

8

H

Ph

9

H

Ph

H

Me

H

H

52

98

10

H

CH=CHPh

Me

H

H

H

62

98

11

H

CH=CHPh

H

Me

H

H

82

95

12

H

CH-CHPh

Me

Me

Me

H

87

97

13

H

CH-CHPh

Me

H

Me

Me

45

91

14

H

CH-CHPh

Me

H

H

C1

69

82

133

Annulations of Vinylcarbenoids and Dienes

~ N 2 ~ CO2Me ~i O2Me Rh2(S-DOSP)4= ' ~ + ~ pentane,-78QC e Ph i 980 ee ! Me Ph 14 I,52%yield ] 31 CO2Me CO2Me N2==~ Rh2(S'DOSP)4.l~,.~p ~l,~,/Me +/~ pentane,-78gC

ph i 47%yield 96,/,ee I 14

~

32

h

Scheme 12.

in the formation of the bicyclic product 29 in 49% yield, with full relative stereochemical control at the three stereogenic centers. Selective hydrogenation of the most accessible double bond in 29, using Wilkinson's catalyst followed by aqueous potassium carbonate induced lactonization, results in the formation of tremulenolide (30) in 66% yield for the last two steps. Highly enantioselective synthesis of cycloheptadienes is obtained when Rh2(S-DOSP)4 is used as the catalyst (Table 5). 26,27 Examples of the control possible in this chemistry is seen in the reactions with cisand trans-piperylenes. Rh2(S-DOSP)4 catalyzed decomposition of the vinyldiazoacetate 14 in the presence of trans-piperylene results in the formation of the cis-cycloheptadiene 31 in 98% ee, whereas reaction with cis-piperylene results in the formation of the trans-cycloheptadiene 32 in 95% ee (Scheme 12). In both of these reactions, there is full control of relative stereochemistry due to the stereochemical demands of the Cope rearrangement, and the regiochemistry results from preferential cyclopropanation of the least substituted double bond.

C. Heteroatom-Substituted Dienes In contrast to the reaction of vinyldiazoacetates with alkylated dienes, the reaction of vinyldiazoacetates with oxygenated dienes proceeds with excellent stereoselectivity. In no instance was the formation of a trans-divinylcyclopropane observed. An example of this is seen in the reaction of the cyclopentenyldiazoacetate 33 with dienes, which is a direct method for synthesizing the hydroazulene

HUW M. L. DAVIES

134

Table 6. Diastereoselective Synthesis of Bicyclo[5.3.0]decane

Derivatives

COOMe N2

O

Entry

COOMe +

R

R7

Rh2(OAc) 4 =

R8

R5

33

R5

R6

R7

R8

1

H

H

2 3 4 5 6 7

OAc H OTMS H H OMe

H OAc H H H H

Me H H H H H H

Me H H H OTMS OTBDMS OTMS

Notes:

Yield (%)

41a 67 62b 86 53 94 59

a20%of the trans-cfivinylcyclopropane is also formed. bOveraU yield for cyclopropanation followed by heating at 220 ~

skeleton (Table 6). 32In the reaction of 33 with 2,3-dimethylbutadiene, a 2:1 mixture of the [3+4] annulation product and the trans-divinylcyclopropane is formed (entry 1), but in the reactions with the oxygenated dienes, the [3+4] annulation products are cleanly formed, without any evidence for trans-divinylcyclopropanes (entries 2-7). It is well established that steric effects hinder the Cope rearrangement of divinylcyclopropanes. 7'8'31 An interesting example of this steric effect is seen in the reaction of 33 with cis- and trans- 1-acetoxybutadiene (Scheme 13).3~The reaction of 33 with trans- 1-acetoxy- 1,3butadiene leads cleanly to the [3+4] annulation product 34 in 67% yield. In contrast, the product from the reaction of 33 with cis-1-acetoxy- 1,3-butadiene is the cis-divinylcyclopropane 35 (80% yield), and high temperatures (220 ~ are required to convert 35 to the [3+4] annulation product 36. The effect of alkene geometry on the stereochemistry and the rate of reaction is readily explained by considering the boat transition state for the Cope rearrangement of divinylcyclopropanes 6 (structure 37). A trans diene substituent (Y) would generate a trans product (34), whereas a cis substituent (X) would lead to a cis

Annulations of Vinylcarbenoids and Dienes

/~02Me .~ N2 HOAc

135

.C02Me

Me Rh2(OAc)4/40 0 33 Rh2(OAc)4 ,~ 40gC AcO H 220gC

34 .C02Me

M~(~ ~,,leAcO , 35 H

,H X

36

H

.H X

"~ 7._~1~.~, Cope ~'~_~ey MeO~ O M e o ~ O O O 37 Scheme 13.

product (36). Furthermore, a cis substituent (X) would exert a much greater steric crowding ~8than a trans substituent, which explains why 35 is isolable. The [3+4] annulation approach to the hydroazulenes is achieved with high asymmetric induction (greater than 90% de) by using (R)-pantolactone as a chiral auxiliary (Table 7). TM The nature of the catalyst has a considerable effect on the level of asymmetric induction. A sterically crowded catalyst, such as rhodium pivalate, results in much lower diastereoselectivity than rhodium(II)acetate or rhodium(II) hexanoate. Consequently, even though the enantiomers of rhodium(II) mandelate exhibit double stereodifferentiation with the (R)-pantolactone auxiliary (entries 5,6), both catalysts are bulky and result iinferior asymmetric induction compared to that obtained with an uncrowded achiral catalyst (entries 1-3). The chiral catalyst approach for asymmetric [3+4] annulations of oxygenated dienes is also likely to be very feasible, although these substrates have not been extensively studied. The only example to date is the reaction of the vinyldiazoacetate 14 with the 1-(tertbutyldi-

136

HUW M. L. DAVIES Table 7. Effect of Catalyst on Asymmetric Induction Using (R)-Pantolactone as Chiral Auxiliary

Rh2O ( 2C 4R o) ~ 0

~_N2 0

+

O,

0

~

0

OTMS 0

Entry

I~TMS

OTMS

Reaction Conditions

0

Yield (%)

de (%)

1

Rh2(OAc)4, CH2C12, reflux

60

+91

2

Rh2(Onex)4, CH2C12, reflux

80

> +90

3 4

Rh2(Onex)4, CH2C12, 0 ~ Rh2(OPiv)4, CH2C12, 0 ~

58 63

> +90 +68

5 6

(-)-RhE(mandelate)4, CH2C12, reflux (+)-RhE(mandelate)4, CH2C12, reflux

60 56

+38 -4

methylsilyloxy)-l,3-butadiene catalyzed by Rh2(S-TBSP) at 25 ~ which results in the formation of the cis-cycloheptadiene 38 in 85% ee (Scheme 14).26 De Meijere and co-workers have reported on the reactions of the parent vinyldiazomethane and chlorinated vinyldiazomethanes with oxygenated dienes. 32Rhodium(H) acetate catalyzed decomposition of these vinyldiazomethanes in the presence of 2-siloxydienes proceeds in good overall yields (Scheme 15). Because the vinylcarbenoid does not contain the donor/acceptor combination of the carbenoids derived from vinyldiazoacetates, the stereoselectivity of the cyclopropanation is poor and mixtures of the [3+4] annulation products and the transdivinylcyclopropanes are formed.

C . O2Me ~~ N2I=~kR I~ +I+~he2sS % I~ooTBSP4)= ~CO2Me OTBDMS "ph 167% yield I ' Ph TBDMSO 14 38

Scheme 14.

Annulations of Vinylcarbenoids and Dienes

137

OTMS

OTUS

44% 0

N2~

II

"

,I

39%

~-~TMSO,

CI

20%

33%

Scheme 15.

A related [3+4] annulation between the stable chromium vinylcarbene complex 39 and 1-methoxy-3-(dimethyltert-butylsiloxy)-l,3butadiene has been reported by Wulff and co-workers (Scheme 16). 33 This reaction also displays poor stereoselectivity in the cyclopropanation step. The cycloheptadiene 40 is formed in 23% yield whereas the major product is the trans-divinylcyclopropane 41 (40% yield). Barluenga and co-workers extended the scope of [3+4] annulations of chromium vinylcarbenes by using 2-amino-l,3-butadienes as the diene component. 34In most cases the reaction with this diene is highly diastereoselective and favors the formation of cis-divinylcyclopropanes that rapidly rearrange to the cycloheptadienes. Furthermore, the amino functionality can be a chiral auxiliary such that an asymmetric [3+4] annulation is achieved. Examples of this approach are shown in Scheme 17. Reaction of the chromium vinylcarbene complex 43 with the dienes 42 results in the formation of the cycloheptadienes 44 which are readily hydrolyzed to the cycloheptane-1,3-diones 45 in moderate overall yields and in 55-86% ee.

TBDMSO

OMe (CO)sCr==( + OMe

.OMe MeO. 5gC2d~

3g

,.

TBDMSO Me(~ H ~ ' 40 23%

Scheme 16.

41

40%

138

H U W M. L. DAVIES

~ N N ~ OMe OMe / ~ f ~ O M e OMe O ~CO'5Cr==~~ MeCN,R T % N - . . . ] ~ 3N HC, "R1~ R1 42

43

2

2

O

44

R1

R2

yield, %

CH3 CH3

CH2OMe CH2OBn (CH2)4

45 52 40

O O

45 ee,

%

86 81 55

Scheme 17.

Extension of the [3+4] annulations to more highly oxygenated dienes results in a very effective synthesis of tropones 35 and tropolones. 36For example, decomposition of the vinyldiazomethane 4 in the presence of 1-methoxy-l-trimethylsiloxy-l,3-butadiene (46) resuits in the formation of the cycloheptadiene 47 in 87% yield (Scheme 18). 35 Mild hydrolysis of 47 with citric acid followed by DDQ oxidation results in a very short synthesis of the tropone 48 in 92% yield. The [3+4] annulation with 1-methoxy-l-trimethylsiloxybutadiene is applicable to a range of vinyldiazomethanes, as shown in Table 8. The major limitation is that because of the extremely electron-rich character of the diene, the formation of side products derived from zwitterionic intermediates dominate over the [3+4] annulation. In general, the side reactions are eliminated by carrying out the reactions in a nonpolar solvent. An alternative entry to the tropone system would be by eliminating an exocyclic substituent on the cycloheptadiene. This approach is CO2Et Me + OTMS 46

0H2CI2 4

CO2Et

.CO2Et CO2Et " DDQ TMSO OMe 47 (87%)

Scheme 18.

~O2Et ~

CO2Et

O 48 (92%)

139

Annulations of Vinylcarbenoids and Dienes Table 8.

Synthesisof Tropones R1 R2

O

MeO

~

R3

R2 MeO OTMS 3

46 Entry

1 2 3 4 5 6 7 8 9 10 Note:

R1

CO2Et CO2Me CO2Et CO2Et SO2Ph CO2Et COMe CO2tBu CO2Me CO2Et

Yield R2

H H H H H OMe H H H H

R3

COzEt Ph CH=CHPh SO2Ph CO2Et COzEt Ph H H CH=CH2E

Catalyst~Solvent

Rh2(OAc)dCH2C12 Rh2(OAc)4/CH2C12 RhE(OAc)4/CH2C12

Rh2(OPiv)a/pentane Rh2(OAc)4/pentane Rh2(OAc)a/pentane Rh2(OAc)a/pentane Rh2(OPiv)4/pentane Rh2(OPiv)a/pentane Rh2(OAc)4/pentane

(%)

87 73 89 79 58 79 71 74 67 89

a Combinedyieldfrom diazo

illustrated in a brief synthesis of nezukone (51, Scheme 19). 35 The cycloheptadiene 49, generated in 67% yield from the reaction between 15 and 46, is treated with methyllithium. On exposure to strong acid, the resulting alcohol 50, undergoes deprotection, dehydration, and double bond isomerization to form 51 in 59% yield. The reaction is readily extended to more highly oxygenated dienes, such as 52, leading into a short synthesis of methyl tropolones. 36 Reaction of the vinyldiazomethane 53 with 52 generates a 68% yield of the fused cycloheptadiene 54a, which is readily converted to the tropolone 55a in 80% yield (Scheme 20). Methylation of tropolones usually generates a mixture of regioisomers, and so a notable feature of this [3+4] annulation approach to methyl tropolones is that the methyl group is introduced in a defined position. A range of methyl tropolones 55 can be made using this methodology, and these are summarized in Table 9. The chemistry can also be extended to synthesizing 3-methoxytropones, as illustrated in Table 10. 36 The range of successful substrates

140

H U W M. L. DAVIES

.CO2Me ~ CO2Me OCH3+N2:::::~ Rh2(OAc)4 OTMS / / CH2CI2 CH30 OTMS 46

9

49 (67%)

OH

MeLi

HCI

CH3 OTMS 50

O

51(59%)

Scheme 19.

in this case is limited because the [3+4] annulations of vinylcarbenoids with diene 56 are prone to side reactions involving zwitterionic intermediates, even when hydrocarbons are used as solvent. An example of the competing reaction pathways is shown in Scheme 21. Rhodium(II) pivalate catalyzed decomposition of 57 in the presence of 56 followed by DDQ oxidation under acidic conditions results in the formation of the [3+4] annulation product 58 in 11% yield. The major product in this reaction is the cyclopentenone 59, derived from a [3+2] annulation via zwitterionic intermediates.

.CO2Me .,CO2Me . , ~ +N2=='(k Rh2(OPiv)~4 L ~,~ /~ MeO" "~ , , ~ h?ane MeO" X v MeOOTMS~,,~(68~ yield) MeOOTMS 52

53

54a

H§ "-"- O ~ (80%yield) Me O

55a

Scheme 20.

.CO2Me

141

Annulations of Vinylcarbenoids and Dienes Table 9.

Synthesisof Methyl Tropolones 55 R1

R1

+ N2

MeO

MeO OTMS

52 Entry

R2 R3

Rh2(OPiv))4 ~MoO/~R~ hexane

MeO OTMS

H+/DDQ O 55

54

R1

R2

R3

CO2Et

1

CO2Et

H

2

CO2tBu

H

Ph

3

CO2Et

H

SPh

4

CO2Me

cyclo-(CH2)3

5

CO2Et

cyclo-(CH2)4

6

CO2tBu

H

7

CO2Me

H

Note:

2

54, Yield (%) 55, Yield (%) 91

67

91

91

--

46 a

68

80

62

59

H

60

60

Me

--

67 a

aCombinedyieldfrom diazo.

Table 10.

Synthesisof 3-Methoxytropones R1

+ N2=,~ MeO OTMS Entry

Rh2(OPiv)4 ~ " R2

H+/DDQ

R3

O

R1

OMe

R2

R3

3 Yield(%)

CO2Me

H

Ph

64

CO2Et

H

SEt

38

CO2Et

H

SPh

11

CO2Me

H

Me

59

0

~SPh+

SPh

I~OTMS ~ 1. Rh2(OPiv)4 + MeO,~ N2==~' 2 DDQ/T~ 9 56

R2

MeO

57 CO2Et

58, 11% C02Et

Scheme 21.

0 -sPh 59, 77O/o

142

HUW M. L. DAVIES

D. Mechanistic Analysis of Vinylcarbenoid Cyclopropanations The success of the [3+4] annulation of vinylcarbenoids results primarily from the remarkable stereoselectivity of vinylcarbenoid cyclopropanations. A reasonable model to explain the stereoselectivity in these reactions is shown in Scheme 22. 23,24The model has many similarities to that proposed by Doyle for the stereoselectivity of diazoacetate cyclopropanations. ~~ Structure 60 represents a model to explain the remarkable E/Z stereoselectivity exhibited in vinylcarbenoid cyclopropanations. 24b Because vinylcarbenoids do not react with trans-alkenes, it is considered that the alkene/diene approaches the carbenoid in a side-on mode with bulky functionality pointing away from the "wall" of the catalyst (represented as the bold horizontal line in structure 60). The cyclopropanation is considered nonsynchronous, and the alkene/diene approach occurs preferentially on the side of the electron-withdrawing group (EWG). If the alkene is very electron-rich (for example, dienes 46 and 56) and the carbenoid is very electron-deficient (for example, vinylcarbenoids with two electronwithdrawing groups), formation of side products via zwitterionic intermediates rather than the nonsynchronous cyclopropanation can occur. 36'37 Generally, it is possible to control these side reactions by using hydrocarbons as solvents or by avoiding electron-withdrawing carboxylates as ligands. The asymmetric induction in vinylcarbenoid cyclopropanations can also be rationalized according to these models. Structure 61 represents the model for the asymmetric induction with the (R)-pantolactone auxiliary. TM Using the same trajectory for the alkene apR1

H

H ~

R2

R2

.._ Rh

, Rh

60

Scheme 22.

HEWGH ' Rh

R2

Annulations of Vinylcarbenoids and Dienes Me

ir

0

H

143

Rh

"" "

Rh--I-I

61

62

Si face open

Re face open

proach to the carbenoid, considered above, the lactone carbonyl preferentially blocks the Re face of the carbenoid because this would limit unfavorable steric interactions between the auxiliary and the wall of the catalyst. Structure 62 represents the working hypothesis for the asymmetric induction with the (S)-prolinate catalysts. 24b In this predictive model, it is considered that the catalyst behaves as if it had D 2 symmetry. Because of the D 2 symmetry, only one face of the catalyst needs to be considered. The arylsulfonyl groups align in an up-downup-down arrangement, and the two groups on the top face of the catalyst are shown in structure 62. A similar alkene approach, as in structure 60, would result in the Re face of the carbenoid to be open. For a detailed explanation of the stereochemical models, see references 23a and 24b.

!!!. INTERMOLECULAR REACTIONS WITH AROMATIC SYSTEMS A. Benzenes

The reaction of vinylcarbenoids is not limited to dienes but may also be extended to a variety of electron-rich aromatics. 37Rhodium(II) trifluoroacetate catalyzed decomposition of 4 in the presence of benzene results in the formation of the unstable bicyclo[3.2.2] system 63 (Scheme 23). 37 Direct hydrogenation of 63 results in the formation of 64 from 4 in 29% overall yield. Similar reactions occur with other alkyl benzenes, although these reactions are not of practical utility because mixtures of unstable isomeric products are formed. In contrast to the reactions with benzene, the reactions of 4 with 1-methoxybenzene, 1,2-dimethoxybenzene, and 1,2,3-trimethoxybenzene result in the formation of the alkylation products 65 in

144

H U W M. L. DAVIES

O

CO2Et ~._~CO2Et +N2'~ Rh2(TFA)4=-/'~~ CO2Et

CO2Et

4

63

H2/Pd ~, ~

CO2Et CO2Et 64 (29%)

Scheme 23.

,CO2Et Rh2(OAc)4 49-70% CO2Et 4

: 'tco,,t 65

a: RI=OMe, R 2 = H , R 3 = H b: RI=OMe,R2=OMe,R3=H c: R1= OMe,R2=OMe,R3=OMe

Scheme 24.

49-70% yield (Scheme 24). 37 The formation of 65 rather than [3+4] annulation products is not unexpected because these aromatic tings are electron-rich and form well-stabilized zwitterionic intermediates on reaction with the vinylcarbenoid from 4, leading to alkylation products rather than cyclopropanation. The reaction of vinylcarbenoids with 1-methoxynaphthalene is delicately balanced because the aromatic ring of 1-methoxynaphthalene is electron-rich, but the drive to re-form the aromatic ring is not as great as it is for the methoxybenzenes. In this case the second factor dominates because the reaction of 4 with 1-methoxynaphthalene results in the formation of the rather unstable [3+4] annulation product 66 in 39% yield (Scheme 25). 37

~ +

N2 202Et ~CO2Et ==~ Rh2(OAc)4"' MeO OMe

CO2Et

4

Scheme 25.

66

CO2Et

Annulations of Vinylcarbenoids and Dienes

145

B. Furans

The reaction of vinylcarbenoids with furans can lead to two products, the [3+4] annulation product and a triene, in which the furan ring has been unraveled. The product ratio is sensitive to both the structure of the furan and the vinylcarbenoid. ~5'38'39In the reaction of 4 with furans, the ratio of [3+4] annulation product 67 to triene 68 varies greatly in changing from furan to 2-methylfuran to 2-methoxyfuran (Scheme 26). In the case of 2,5-dimethylfuran, the reaction with 4 results in clean formation of the [3+4] annulation product 69. The reaction of the vinyldiazomethane 15 with furan results in a product ratio similar to that obtained in the reaction of furan with 4. However, the siloxy-substituted vinyldiazoacetate 70 results in the clean formation of the [3+4] annulation product 71 in 90% yield, without any evidence for formation of the triene 72. CO2Et .

,C02Et + j ~ ; O 2 E t

co Et

ff

4

"

67

"co, Et

67, yield,%

68, yield,%

62

26 74 92

H Me OMe

8

0

Me

CO2Et

Me

CO2Et

Me

.CO2Et

70%yield

~ 69

C O N2.~O2RMeh2(OAc)4 ,~-.~?O2 MH_~,O ,...~__.~CO2Me 71 Diazo 15

70

72

R

71, yield,%

72, yield,%

H

51 90

15 0

OTBDMS

Scheme 26.

146

H U W M. L. DAVIES

73

74

The dramatic changes in product distribution observed with furans are consistent with a nonsynchronous cyclopropanation mechanism leading to two possible dipolar transition states 73 and 74. 40In the case of 2,5-disubstituted furans, initial bond formation is greatest at the ~-position leading to 73, which proceeds cleanly to the [3+4] annulation products. With furan and 2-substituted furans, however, initial bond formation is greatest at the or-position (structure 74). This circumstance leads either to [3+4] annulation products or to zwitterionic intermediates and the unraveling of the furan ring to trienes. As the furan becomes more electron-rich, the zwitterionic intermediates become favored, whereas a siloxy group on the vinylcarbenoid strongly enhances closure to the [3+4] annulation product. Padwa and co-workers have reported 41 that the rhodium(II) acetate catalyzed ring opening of the cyclopropene 75 results in the formation of the bicyclic system 78 of undefined stereochemistry in 52% yield (Scheme 27). It is considered that the reaction occurs by ring opening of 75 to the vinylcarbenoid 76. Cyclization of 76 produces the furan 77, which on reaction with a second equivalent of 76 forms the [3+4] annulation product 78. The oxabicyclo[3.2.1]octane system has been extensively used in organic synthesis as a key building block to various natural pro-

O% /I1 Rh2(OAc)4 LnRh~H Ph/~~C3H7 75

" O~ Ph 76 76

~~ C3H'

Ph "0" 77

C3H7,,,,,O~>~ ,~..~C3H7 Ph" '~COPh 78

Scheme 27.

C3H7

Annulations of Vinylcarbenoids and Dienes Me

147

MEe- ,C02Et

,C02Et

~O N2==~~Rh2(S-TBSP)4 =_~~. Me + ~ph 9--~% Y-~eld ~ ~h 14 860 79 ,CO2Me ,CO2Me Rh2(S'DOSP)4~O +N2=~OTBDMS 70 94%yield 80 46% ee

~OTBDMS

ee

Scheme 28.

ducts. 2a-c Consequently, the asymmetric synthesis of oxabicyclo[3.2.1 ]octanes is a useful synthetic process. This can be achieved either by using chiral catalysts (Scheme 28) or more generally by using a chiral auxiliary (Table 11).39 Chiral catalysis is very efficient for asymmetric induction of 2,5-disubstituted furans as can be seen in the formation of the oxabicycle 79, but triene formation becomes a major side reaction when furan and 2-substituted furans are the substrates. The only exception is the reaction with the siloxy-substituted vinyldiazomethane 70, which gives a high yield of [3+4] annulation product 80 in the reaction with furan, but the asymmetric induction is only moderate (46% ee). The chiral auxiliary approach is applicable to a range of furans (Table 11) leading to the oxabicycles in high yield (62-91%) and asymmetric induction (79-95% de). The oxabicycles are readily amenable for further conversion to a number of useful compounds that have been previously used for synthesis in racemic form. For example, 39the 5-methyl derivative 81, which is obtained in greater than 99% de after purification by column chromatography, is readily converted to the [3-ketoester 82 in 49% overall yield by catalytic hydrogenation with Wilkinson's catalyst, transesterification with sodium methoxide in methanol, and alkylation with methyl iodide (Scheme 29). Racemic 82 was used by Molander in a recent synthesis of 83, an advanced intermediate for natural product synthesis. 42

148

HUW M. L. DAVIES Table 11. Asymmetric Synthesis of

3-Si Ioxy-8-oxabi cyclo [ 3.2.1 ] octa-2,6-d iene-2-carboxy Iates CO2Xc CO2Xc O + R7

R6

OTBDMS

OTBDMS RT,- -,,~r~--,;,, i~6 R3

R3

Xc

R3

(S)-lactate (R)-pantolactone (S)-lactate (R)-pantolactone (S)-lactate (R)-pantolactone (S)-lactate (R)-pantolactone (S)-lactate (R)-pantolactone (S)-lactate (R)-pantolactone

H H Me Me H H Me Me H H Me H

R6

R7

H H H H H H H H Me H Me H Me H Me H COMe H COMe H COMe H Me COzMe

Yield (%)

de(%) (abs, stereochem.)

72 82 62 75 81 91 91 69 74 65 71 65

79 (IS) 94 (1R) 90 (IS) 95 (1R) 75 (IS) 83 (1R) 84 (1S) 94 (1R) 79 (IS) 94 (1R) 80 (IS) 82 (1R)

8-Oxabicyclo[3.2.1]oct-6-en-2-ones are also available from this chemistry, as illustrated in Scheme 30. 39 Treatment of 84 with sodium methoxide and then lithium hydroxide, followed by subjecting the resulting acid to the standard Curtius rearrangement conditions, resuits in the formation of 8-oxabicyclo[3.2.1]oct-6-en-2-one (85) in 52% yield. Racemic 85 has been used by Vogel in a stereoselective synthesis of the 13-C-hexopyranoside 86. 43 oH

(,~OH

. M~= 81

OTBDMS 2. NaOMe 3. NaH/Mel (49% overall)

O .~ M~

82

Scheme 29.

e /~.,OH

83~OTBDMS

149

Annulations of Vinylcarbenoids and Dienes Mo O

H

84

H

QAc O MeO2C~, / ~ O A c I Ref. 41 '"I I

CO2Me1. NaOMe 2. LiOH " 3. DPPA (52% overall) H 85

,. 0 _ ' ~ O A c

CH(OMe)2

86

Scheme 30.

C. Pyrroles A successful [3+4] annulation between vinylcarbenoids and pyrroles would be a very useful transformation because it would result in a direct access to the tropane skeleton. The direct reaction of the vinyldiazomethane 4 with pyrrole does not lead to the formation of [3+4] annulation products. Instead, the alkylation product 87 is formed in 71% yield (Scheme 31).44 This result parallels that observed with electron-rich benzene derivatives. To avoid the formation of alkylated products, the reaction was repeated with N-acylated pyrroles, such that the pyrrole ring would be less electron-rich and less prone to rearomatize. Rhodium(II) acetate catalyzed decomposition of the vinyldiazomethane 4 in the presence of N-carbomethoxy pyrrole results in the formation of the [3+4] annulation product (entry 1, Table 12), and this reaction is applicable to a range of vinylcarbenoid derivatives.44'45The tropanes are formed as the endo isomers, which is the expected stereochemistry for the tandem cyclopropanation/Cope rearrangement sequence. Further evidence in favor of a pyrrolocyclopropane intermediate was seen in the reaction of the bulky vinyldiazomethane 88 with N-acylated pyrrole (Scheme 32). 44 In this case, the bis-cyclopropanated derivative 90 is formed in 33% yield presumably, because

O H

/CO2Et +N2==~ Rh2(OAc)4 , 71% yield 4

C02Et

Scheme 31.

.CO2Et "~ 87

Et

150

HUW M. L. DAVIES Table 12. Diastereoselective Synthesis of Tropanes

R1 NCO2R

?02R

N21

Rh2(OAc)4 N~,,R.

+

R3 Entry

1 2 3 4 5 6

R1

3

R2

R1

Me Et CH2CH2TMS Me Me Me

CO2Et CO2Et CO2Et CO2Et CO2Me CO2Et

Yield (%)

R3

CO~Et CO2Et CO2Et SO2Ph Ph CH=CHPh

62 54 71 61 53 18

the initially formed divinylcyclopropane 89 is too sterically constrained to undergo a Cope rearrangement, and instead, reacts further with a second equivalent of 88. In the case of vinyldiazomethanes with a single electron-withdrawing group, such as 9, the unsaturated tropane system 91 is not formed cleanly under the traditional reaction conditions of rhodium(II) acetate/dichloromethane (Scheme 33). 45 A major side product is the alkylation product 92, derived from reaction at the vinyl terminus of the vinylcarbenoid. 2~The side reaction, however, is readily eliminated by using rhodium(II) hexanoate/hexane, and under these conditions the tropane system 91 is formed in 75% isolated yield. Attempts to use chiral catalysts for the asymmetric synthesis of tropanes met with limited success, as illustrated in Scheme 34. 46 Rh2(S-TBSP)4 catalyzed decomposition of the vinyldiazomethane 9

C02Me /C02Et

--- MeO

"

C02Me 88

Et02C..,~'',,j'CO2Et

89

Scheme 32.

~N/OMe

Et02C C02Me 2 90

Annulations of Vinylcarbenoids and Dienes

151

CO2Me ,CO2Me CO2Me CH=CHCH2CO2Me / N \ # 2 % Rh2(O2CR)4 ~.. ,CO2Me~J.

i

+C N-O~

9

91

92

Reactionconditions

Ratio91:92

Rh2(OAc)4/CH2Cl2 Rh2(OHex)4/CH2Cl2 Rh2(OHex)4/hexane

55:45 15:85 >95:5

Scheme 33.

in the presence of N-BOC pyrrole results in the formation of two isomeric tropanes, 93 and 94, and two other azabicyclic products, 95 and 96, that are derived from zwitterionic intermediates. Furthermore, the major isomer of the tropane 93 is formed in only 46% ee. This mixture is formed because the prolinate ligands make the catalyst more electron-deficient than a standard rhodium carboxylate, and the 2-methylpyrrole is electron-rich. Consequently, the intermediacy of zwitterionic intermediates cannot be avoided in this case, even when hexane is used as solvent. An efficient method for the asymmetric synthesis of tropanes was developed by using chiral auxiliaries (Tables 13 and 14). 46 A wide range of tropanes were prepared in 30-85% yield and 25-79% de. Either enantiomeric series of tropanes can be prepared by using either (S)-lactate (Table 13) or (R)-pantolactone (Table 14) as the chiral

B,oc

CO2Me

Me,~+

BOC,,

B~

,.,.,,,^

Rh2(S-TBSP)4,~ ' - " . . ' 2 9

Me

93 (24%)

BOC~_ _.. + M e ~

%, _Et.CmM

. . . .+. ~ , " - ~,

94 (6%) C.O2Me +~ N Me "BOC

CO2Me 96 (21%) 95 (19%) Scheme 34.

152

HUW M. L. DAVIES

Table 13. Asymmetrical Synthesis of Tropanes Using (5)-Lactate As a

Chiral Auxiliary

x

o

~O"J"CO N2

Entry

R1

1 2 3 4 5 6 7 8 9 10 11 12 13

Me

2Et

R3 R2~N- BOC R1 BOC. Rh2(OOct)4 hexane

O Me

R 2 ~

x

R2

R3

X

Yield (%)

de (%)

H H Me H CH2OTBS H Ph H Ac H Me H H Me --(CH2)4H H Me H Ph H Ac H Me H

H H H H H Me H H H H H H Me

H H H H H H H H OTBS OTBS OTBS OTBS OTBS

82 54 62 64 30 33 19 48 85 55 74 58 30

66 59 70 53 67 25 52 55 66 58 52 79 52

auxiliary. This approach takes advantage of the fact that the interaction of the chiral auxiliary with the carbenoid (structure 97) enables transferring high asymmetric induction and also modulates the reactivity of the carbenoid (Scheme 35). 47

0

0

R'

8. 0 ~ 0 ~

R)~~

//#+ effectiveasymmetricinduction modifiedcarbenoidreactivity

and

Scheme 35.

products

153

Annulations of Vinylcarbenoids and Dienes

Table 14. Asymmetric Synthesis of Tropanes Using (R)-Pantolactone

As a Chiral Auxiliary R3

0

RI

N2"'~X

-

Rh2(OOct)4 hexane

B/3~O X,~0 0,, 0

Entry

R1

R2

R3

X

Yield (%)

de (%)

1

H

H

H

H

64

69

2

H

H

H

OTBS

66

68

3

Ph

H

H

OTBS

56

52

4

Ac

H

H

OTBS

69

78

H

OTBS

31

37

5

-(CH2)4-

The synthetic utility of this chemistry was highlighted by short syntheses of various biologically interesting tropanes (Scheme 36). Two natural products, ferruginine (98) and anhydroecgonine methyl ester (99), have been prepared by selectively hydrogenating the appropriate [3+4] annulation product followed by N-deprotection and N-methylation. 46'47A number of 413-aryl-313-propanoyl tropanes, such

Me ,

Me,

NO -

98

Me

~

~ ~

BOO

0

100

H,

/

0

0

'~OMe 99

101

Scheme 36.

154

HUW M. L. DAVIES

as 100, a selective dopamine re-uptake inhibitor, and 101, a selective serotonin re-uptake inhibitor, have been prepared by using this chemistry. 48

IV. INTRAMOLECULAR [3+4] REACTIONS OF VINYLCARBENOIDS WITH DIENES AND AROMATIC COMPOUNDS The formation of isomeric mixtures of cyclopropanes is not an issue in intramolecular reactions between vinylcarbenoids and dienes because the stereochemistry of cyclopropanation is controlled by diene geometry. 49In the case of 102 where the double bond nearest the ester tether is trans, cyclopropanation would generate cis-divinylcyclopropanes which would readily rearrange to cycloheptadienes (Table 15). The intramolecular cyclopropanation of trans-dienes by vinylcarbenoids is feasible even though the intermolecular cyclopropanation of a trans-alkene does not occur. Several examples of this type of intramolecular reaction are shown in Table 15.40In contrast, when the double bond nearest the tether is cis, as with 103, the trans-divinylcyclopropane 104 is formed in 94% yield (Scheme 37). 40 Other stereogenic centers may be used to control the stereochemistry of the seven-membered ring. 4~ Rhodium(II) acetate catalyzed decomposition of 105 results in the formation of the tricyclic systems Table 15. DiastereoselectiveSynthesis of

9-Oxabicyclo [5.3.0]decane Derivatives

0 0 N2

R

s 102

Entry

R5

t,.

07~o

Rh2(OAc)4 R

h

R6

RS'Rs Ph

R7

YieM (%)

1

Me

H

H

76

2

H

Me

H

53

3

H

H

H

68

4

H

H

Me

60

Annulations of Vinylcarbenoids and Dienes Me

~JO"~ ~0

103

155

"H

Ph

0

0

104

Scheme 37. 106, where the initial cyclopropanation occurred from the same face of the cycloalkene as the ester functionality (Scheme 38). In principle, with an appropriate diene component, a fourth stereocenter could also have been formed. The intramolecular [3+4] annulation can be carried out with high asymmetric induction and this was used to synthesize the epi tremulenolide A skeleton, as illustrated in Scheme 39. 50 Rh2(S-DOSP)4 catalyzed decomposition of 107, which contains a trans-alkene nearest the tether results in the formation of the [3+4] annulation product 108 with full relative stereochemical control but in only 35% ee. A much more effective procedure is to use 109, which contains a trans-alkene nearest the tether, as the substrate. Rh2(S-DOSP)4 catalyzed decomposition of 109 results in the formation of the transdivinylcyclopropane 110. On heating, 110 rearranges to the [3+4] annulation product 108, which is formed in 93% ee. The rearrangement presumably occurs through initial equilibration of 110 to the cis-divinylcyclopropane. However, as the equilibration occurs with epimerization of only two of the stereocenters in 110, the enantioselectivity of the cyclopropanation is maintained in the [3+4] annulation product 108. Alternative strategies have been developed for intramolecular reactions between vinylcarbenoids and dienes. In many instances, the ~(CH2)

ph/

r--(CH2)n

n

~_/ b

P.

105 a" n - l " b "

n-2

Scheme

38.

o 106

156

HUW M. L. DAVIES

Me

Me

O~ JOJ,~ 2~ Rh2(S.DOSP)4~ N hexane,-78gC _~

H

100H [ 93*/*eel ~~110H 140 gC

/~=N2~ Rh2(S'DOSP)4 .exane,- oC

108

Scheme 39.

reaction of metal-stabilized carbenoids with alkynes lead to vinylcarbenoids that are then trapped by an appropriately positioned diene to generate cycloheptadienes. Padwa and co-workers 51 reported that rhodium(II) mandelate catalyzed decomposition of 111 generates the tetracyclic systems 113 of undefined stereochemistry (50-58% yield), presumably via the intermediacy of the vinylcarbenoids 112 (Scheme 40). Harvey and co-workers 52 reported a similar approach which begins with the molybdenum carbene complex 114 and the dienyne 115, leading to the molybdenum vinylcarbene complex 116, which then cyclizes to a 4.8:1 mixture of the hydroazulenes 117 in 87% yield. The intramolecular version of the reaction of vinylcarbenoids with a benzene ring is interesting because several isomeric structures can be formed, and the isolated product is very dependent on the reaction conditions. 37 Rhodium(II) octanoate catalyzed decomposition of 118 at 0 ~ results in forming the norcaradiene 119 in 48% yield (Scheme 41). On standing in solution, 119 slowly undergoes a Cope rearrangement to 120. When the rhodium catalyzed reaction is carried out at 40 ~ the [3+4] annulation product 120 is isolated directly in 72% yield. In solution, 120 is also of limited stability, and over several days at room temperature rearranges to the formal [3+2] annulation product

Annulations of Vinylcarbenoids and Dienes

157 R

R

O

Rh(ll) ~

O

O 111

112

Mo(CO)s EtO2C'--J---~L~ Bu,~OM e

R=H, Me 113

Et02C~ > (CO)5Mo~

H Et02C'.'.~

Scheme 40.

121. Indeed, when the rhodium catalyzed reaction is carried out at 80 ~ 121 becomes the major product (17% isolated yield). An alternative approach for intramolecular reactions between vinylcarbenoids and benzenes was reported by Kohmoto and co-workers starting with the (5H)-pyrazole 122 (Scheme 42). 53 Photolysis of 122 followed by thermolysis at 110 ~ results in the formation of the norcaradiene 123 as a mixture of stereoisomers. The norcaradiene 123

M e O ~ o I , J MeO~ N,~ 0

~J ~.,-._-.---0 -R,~(oo~), ;.,~o..f~..~o O'C MeO"~"~"" ~

IIRh2(OOct)4 8ogc

~

25 gC

?..Fo

MeO" '~ "- ",,, H Ph

~"

MeO Ph 120

121

Scheme 41.

158

H UW M. L. DAVI ES Me

1.hv

9 - v

.:" .,k==__0220 gC

~._.~Me(52%yield) Me Me 122 123 M~,kO Me'/~~ ",

0 +

~ k/leMe 124

Me 125

Scheme 42.

is less prone to rearrangement than 119 presumably because it is more sterically crowded. When heated to 220 ~ 123 rearranges to a mixture of [3+2] annulation 124 and [3+4] annulation product 123. The product ratio is independent of which diastereomer of 123 is used, and this result indicates that both reactions proceed through a common diradical intermediate. The outcome of the intramolecular reaction between vinylcarbenoids and furans depends on the structure of the vinylcarbenoid and the position of the tether. In the case of the 2-substituted furan 126, the triene 127 is formed exclusively (Scheme 43). 42 Presumably, the additional strain in the intramolecular version favors unraveling of the furan ring to the triene rather than forming the [3+4] annulation product. In contrast, reaction of the 3-substituted furans 128 results in the synthesis of novel tricyclic products 129 that contain two formally anti-Bredt double bonds. 54 The structure of the vinylcarbenoid has a major influence on the outcome of intramolecular reactions involving pyrroles. 55 In particular, the presence of a siloxy group on the central carbon favors [3+4] annulation over the formation of side products derived from zwitterionic intermediates. This effect is illustrated in the reaction of the 2-substituted pyrroles 130 and 132. Decomposition of the siloxy derivative results in the formation of the [3+4] annulation product 131, whereas the unsubstituted vinyldiazomethane results in the formation

Annulations of Vinylcarbenoids and Dienes 0

r

~

O

12

159

Ph

Ph

Rh2(OAc)4 0H2012

~ O H

126

127

0

' Hexanes R1/L,,~~/r OTBS O

1/O

OTBS

O

128

a

b c d

129

R1

R2

R3

H

H

H

H CH2OBn H

Me H H

yield,% 83

H H Et

29 66 48

Scheme 43.

of the fused azetidiene 133. The formation of 133 is believed to occur by unraveling of the pyrrole to a trieneimine analogously to furan followed by consecutive 8n and 6re electrocyclizations. A similar effect of the siloxy group was seen in the reaction for the 3-substituted pyrroles. 55 Reaction of the siloxy-substituted vinyldiazomethane 134 results in the formation the tricyclic product 135, whereas reaction of the vinyldiazomethane 136 results in the forma-

Boc

Boc

N 2 = = ~ OTBDMs 63o/0

\OTBDMS

~0

130

131

Boc o

,9% Bo -N'J

132

133

Scheme 44.

HUW M. L. DAVIES

160

0

Boc

0

-~~"~OTBDMS

Rh2(OOct)4 53%

134

"/~~OTBDMS 135

i ~ ~ ==~0 Rh2(OOct)4 Boc / / 77%

0 137

136

Scheme 45.

tion of the trienimine 137 (Scheme 45). In this case, the trieneimine is geometrically constrained, so that the further electrocyclizations cannot occur. In summary, the [3+4] annulation of rhodium stabilized vinylcarbenoids with dienes is a general method for stereoselectively synthesizing highly functionalized seven-membered tings. The success of this chemistry results from the highly stereoselective nature of vinylcarbenoid cyclopropanations which strongly favor the formation of cis-divinylcyclopropane intermediates. A further advantage of this strategy is that two complementary methods have been developed for achieving asymmetric induction in these transformations.

ACKNOWLEDGMENTS The author thanks the members of his group, both past and present, who have contributed to much of the work described in this report. These studies were generously supported by the National Science Foundation (CHE 9024248, CHE 9421649, and CHE 9726124) and by PHS grants DA-06301 and DA-06634.

REFERENCES 1. For general reviews, see (a) Heathcock, C. H.; Grahm, S. L.; Pirrung, M. C.; Plavac, E; White, C. T. In The Total Synthesis of Natural Products; Simon, J., Ed.; Wiley: New York, 1983; Vol. 5, pp. 333-384. (b) Rigby, J. H. In Studies in Natural Products Chemistry; Rahman, A., Ed.; Elsevier: New York, 1988, Vol. 1, pp. 545-576. (c) Vandewalle, M.; De Clercq, P. Tetrahedron 1985, 41, 1767.

Annulations of Vinylcarbenoids and Dienes

161

2. For general reviews on [3+4] annulations using allyl cations, see (a) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1984, 23, 1. (b) Noyori, R. Acc. Chem. Res. 1979, 12, 61. (c) Mann, J. Tetrahedron 1986, 42, 4611. (d) Hosomi, A.; Tominaga, Y. Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991, Vol. 5, pp. 593-616. (e) Harmata, M. Tetrahedron 1997, 53, 6235. 3. (a) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6695. (b) Boger, D. L.; Brotherton, C. E. J. Am. Chem. Soc. 1986, 108, 6713. (c) Hamer, N. K. J. Chem. Soc., Chem. Commun. 1990, 102. 4. (a) Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. (b) Wender, P. A.; Mascarefias, J. L. Tetrahedron Letr 1992, 33, 2115. (c) Bromidge, S. M.; Archer, D. A.; Sammes, P. G. J. Chem. Soc., Perkin Trans. 1 1990, 353. (d) Dennis, N.; Katritzky, A. R.; Parton, S. K.; Nomura, Y.; Takahashi, Y.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 1976, 2289. (e) Tamura, Y.; Saito, T.; Kiyokawa, H.; Chen, L.; Ishibashi, H. Tetrahedron Letr 1977, 4075. (f) Mak, C.; Buchi, G. J. Org. Chem. 1981, 46, 1. (g) Engler, T. A.; Letavic, M. A.; Reddy, J. P. J. Am. Chem. Soc. 1991, 113, 5068. (h) Mortlock, S. V.; Seckington, J. K.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1988, 2305. (i) Lee, T. V.; Boucher, R. J.; Rockell, C. J. M. Tetrahedron Letr 1988, 29, 689. (j) Wender. P. A.; Siggel, L.; Nuss, J. M. Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991, Vol. 5, pp. 645-674. (k) Rumbo, A.; Mourino, A.; Castedo, L.; Mascarenas, J. L. J. Org. Chem. 1996, 61, 6114. (l) Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1996, 61, 9135. 5. For other examples of annulation methods for the construction of seven-membered rings, see (a) Trost, B. M.; MacPherson, D. T. J. Am. Chem. Soc. 1987, 109, 3483. (b) Molander, G. A.; Shubert, D. C. J. Am. Chem. Soc. 1987, 109, 6877. (c) Molander, G. A.; Cameron, K. O. J. Org. Chem. 1991, 56, 2617. (d) Hemdon, J. W.; Chatterjee, G.; Patel, M. D.; Matasi, J. J.; Tumer, S. U.; Harp, J. J.; Reid, M. D. J. Am. Chem. Soc. 1991, 113, 7808. (e) Wender, E A,; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720. 6. For a review on our earlier studies on vinylcarbenoid cyclopropanations, see Davies, H. M. L. Tetrahedron 1993, 49, 5203. 7. (a) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165. (b) Rhoads, S. J.; Raulinus, N. R. Org. React. 1975, 21, 1. (c) Hudlicky, T.: Fan, R.; Reed, J. W.; Gadamasetti, K. G. Org. React. 1992, 41, 1. (d) Piers, E. Comprehensive Organic Synthesis; Trost, B. M. Ed.; Pergamon: Oxford, 1991, Vol. 5, pp. 971-998. 8. (a) Piers, E.; Nagakura, I. Tetrahedron Lett. 1976, 3237. (b) Piers, E.; Morton, H. E.; Nagakura, I.; Thies, R. W. Can. J. Chem. 1983, 61, 1226. (c) Piers, E.; Burmeister, M. S.; Reissig, H.-U. Can. J. Chem. 1986, 64, 180. (d) Marino, J. E; Kaneko, T. J. Org. Chem. 1974, 39, 3175. (e) Marino, J. P.; Browne, L. J. Tetrahedron Letr 1976, 3245. (f) Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 111, 6691. (g) Hudlicky, T.; Fleming, A.; Heard, N. J. Org.

162

HUW M. L. DAVIES

Chem. 1990, 55, 2570. (h) Wender, P. A.; Eissenstat, M. A.; Filosa, M. P. J. Am. Chem. Soc. 1979,101, 2196. (i) Wender, P. A.; Filosa, M. P. J. Org. Chem. 1976, 41, 3490. (j) Nakamura, E.; Isaka, M.; Matsuzawa, S. J. Am. Chem. Soc. 1988, 110, 1297. (k) Kohmoto, S.; Nakayama, N.; Takami, J.; Kishikawa, K.; Yamamoto, M.; Yamada, K. Tetrahedron Lett. 1996, 37, 7761. (1) Lee, J. H.; Kim, H. J.; Cha, J. K. J. Am. Chem. Soc. 1995, 117, 9919. (m) Takeda, K.; Takeda, M.; Nakajima, A.; Yoshii, E. J. Am. Chem. Soc. 1995, 117, 6400. (n) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. 9. Franck-Neumann, M.; Dietrich-Buchecker, C. Tetrahedron 1978, 34, 2797.

10. For general reviews on applications of rhodium(II)-stabilized carbenoids, see (a) Maas, G. Top. Curr. Chem. 1988,137, 75. (b) Doyle, M. P. Chem. Rev. 1986, 86, 919. (c) Demonceau, A.; Noels, A. E; Hubert, A. J. Aspects Homogeneous Catalysis 1988, 6, 199. (d) Davies, H. M. L. Comprehens&e Organic Synthesis; Trost, B. M. Ed.; Pergamon: Oxford, 1991, Vol. 4, pp. 1031-1068. (e) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765. (f) Padwa, A.; Hornbuckle, S. E Chem. Rev. 1991, 91,263. (g) Padwa, A.; Krumpe, K. E. Tetrahedron 1991, 47, 5385. 11. (a) Mueller, L. G.; Lawton, R. G. J. Org. Chem. 1979, 44, 4741. (b) Salomon, R. G.; Salomon, M. E; Heyne, T. R. J. Org. Chem. 1975, 40, 756. (c) Salomon, R. G.; Salomon, M. E; Kachinski, J. L. C. J. Am. Chem. Soc. 1977, 99, 1043. (d) Mandai, T.; Hara, K.; Kawada, M.; Nokami, J. Tetrahedron Lett. 1983, 24, 1517. (e) Corey, E. J.; Achiwa, K. Tetrahedron Len. 1969, 3257. (f) Corey, E. J.; Achiwa, K. Tetrahedron Lett. 1970, 2245. (g) Coates, R. M.; Freidinger, R. M. J. Chem. Soc., Chem. Commun. 1969, 871. 12. Gant, T. G.; Noe, M. C.; Corey, E. J. Tetrahedron Lett. 1995, 36, 8745. 13. (a) Brewbaker, J. L.; Hart, H. J. Am. Chem. Soc. 1969, 91, 711. (b) Pincock, J. A.; Murray, K. P. Can. J. Chem. 1979, 57, 1403. (c) Theis, W.; Regitz, M. Tetrahedron 1985, 41, 2625. (d) Robertson, I. R.; Sharp, J. T. Tetrahedron 1984, 40, 3095. 14. Pincock, J. A.; Murray, K. P. Can. J. Chem. 1979, 57, 1403. 15. Davies, H. M. L.; Clark, D. M.; Smith, T. K. Tetrahedron Len. 1985, 26, 5659. 16. For the synthesis of the vinylcarbenoid precursor, see Baum, J. S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth. Commun. 1987, 17, 1709. 17. Davies, H. M. L.; Smith, H. D.; Korkor, O. Tetrahedron Lett. 1987, 28, 1853. 18. Davies, H. M. L.; Saikali, E.; Clark, T. J.; Chee, E. H. Tetrahedron Lett. 1990, 31, 6299. 19. Davies, H. M. L.; Clark, T. J.; Smith, H. D. J. Org. Chem. 1991, 56, 3817. 20. For the synthesis of the vinylcarbenoid precursor, see Davies, H. M. L.; Hougland, P. W.; Cantrell, W. R., Jr. Synth. Commun. 1992, 22, 971. 21. Davies, H. M. L.; Hu, B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem. 1994, 59, 4535. 22. Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron Lett. 1989, 30, 5057

Annulations of Vinylcarbenoids and Dienes

163

23. (a) Davies, H. M. L.; Cantrell, W. R., Jr. Tetrahedron Lett. 1991, 32, 6509. (b) Davies, H. M. L.; Huby, N. J. S.; Cantrell, W. R., Jr.; Olive, J. L. J. Am. Chem. Soc. 1993, 115, 9468. 24. (a) Davies, H. M. L.; Hutcheson, D. K. Tetrahedron Len. 1993, 34, 7243. (b) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897. 25. For examples on the use of rhodium prolinates in other carbenoid transformations, see Roos, G. H. P.; McKervey, M. A. Synth. Comm. 1992, 22, 1751. (b) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H. P. J. Chem. Soc., Chem. Commun. 1990, 361. (c) Collins, J. C.; Dilworth, B. M.; Garvey, N. T.; Kennedy, M.; McKervey, M. A.; O'Sullivan, M. B. J. Chem. Soc., Chem Commun. 1990, 362. (d) McKervey, M. A.; Ye, T. J. Chem. Soc., Chert, Commun. 1992, 823. (e) Ye, T.; Garcfa, C. E; McKervey, M. A. J. Chem. Soc., Perkin Trans. 1 1995, 1373. (f) Garcfa, C. E; McKervey, M. A.; Ye, T. Chem. Commun. 1996, 1465. 26. Davies, H. M. L.; Peng, Z. Q.; Houser, J. H. Tetrahedron Lett. 1994, 35, 8939. 27. Davies, H. M. L.; Stafford, D.; Houser, J. H.; Doan, B. D. J. Am. Chem. Soc. 1998, 120, 3326. 28. Davies, H. M. L.; Hu, B. Heterocycles 1993, 35, 385. 29. Davies, H. M. L.; Doan, B. D. J. Org. Chem. 1998, 63, 657. 30. Cantrell, W. R., Jr.; Davies, H. M. L. J. Org. Chem. 1991, 56, 5696. 31. Schneider, M. P.; Rau, A. J. Am. Chem. Soc. 1979, 101, 4426. 32. de Meijere, A.; Schulz, T.-J.; Kostikov, R. R.; Graupner, E; Murr, T.; Bielfeldt, T. Synthesis 1991, 547. 33. Wulff, W. D.; Yang, D. C.; Murray, C. K. J. Am. Chem. Soc. 1988, 110, 2653. 34. Barluenga, J.; Aznar, E; Martin, A.; Vazquez, J. T. J. Am. Chem. Soc. 1995,117, 9419. 35. Davies, H. M. L.; Clark, T. J.; Kimmer, G. E J. Org. Chem. 1991, 56, 6440. 36. Davies, H. M. L.; Clark, T. J. Tetrahedron 1994, 50, 9883. 37. Davies, H. M. L.; Smith, H. D.; Hu, B.; Klenzak, S. M.; Hegner, E J. J. Org. Chem. 1992, 57, 6900. 38. Davies H. M. L.; Clark, D. M.; Alligood, D. B.; Eiband, G. R. Tetrahedron 1987, 43, 4265. 39. Davies, H. M. L.; Ahmed, G.; Churchill, M. R. J. Am. Chem. Soc. 1996, 118, 10774. 40. Davies, H. M. L.; McAfee, M. J.; Oldenburg, C. E. M. J. Org. Chem. 1989, 54, 930. 41. Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1991, 56, 6971. 42. Molander, G. A.; Swallow, S. J. Org. Chem. 1994, 59, 7148. 43. Fattori, D.; Vogel, P. Tetrahedron Lett. 1993, 34, 1017. 44. Davies, H. M. L.; Young, W. B.; Smith, H. D. Tetrahedron Lett. 1989, 30, 4653. 45. Davies, H. M. L.; Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696. 46. Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.; Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095.

164

H U W M. L. DAVIES

47. Davies, H. M. L.; Matasi, J. J.; Thomley, C. Tetrahedron Lett. 1995, 36, 7205. 48. (a) Davies, H. M. L.; Saikali, E.; Huby, N. J. S.; Gilliatt, V. J.; Matasi, J. J.; Sexton, T.; Childers, S. R. J. Med. Chem. 1994, 37, 1262. (b) Davies, H. M. L.; Kuhn, L. A.; Thomley, C.; Matasi, J. J.; Sexton, T.; Childers, S. R.J. Med. Chem. 1996, 39, 2554. 49. For leading references on intramolecular cyclopropanations of dienes, see Hudlicky, T.; Natchuz, M. G.; Zingde, G. S. J. Org. Chem. 1987, 52, 4644 and references cited therein. 50. Davies, H. M. L.; Doan, B. D. Tetrahedron Lett. 1996, 37, 3967. 51. Padwa, A.; Krumpe, K. E.; Gareau, Y.; Chiacchio, U. J. Org. Chem. 1991, 56, 2523. 52. Harvey, D. E; Lund, K. P. J. Am. Chem. Soc. 1991, 113, 5066. 53. Kohmoto, S.; Nakayama, N.; Takami, J.; Kishikawa, K.; Yamamoto, M.; Yamada, K. Tetrahedron Lett. 1996, 37, 7761. 54. Davies, H. M. L.; Calvo, R.; Ahmed, G. Tetrahedron Lett. 1997, 38, 1737. 55. Davies, H. M. L.; Matasi, J. J.; Ahmed, G. J. Org. Chem. 1996, 61, 2305.

INDEX

1-Acetoxy- 1,3-butadiene, reaction with vinylcarbenoids, 134-135 Acrolein, 8 Acrylonitrile, 91 N-Acryloyloxazolidinones, as dienophiles in 2-pyrone [4+2] cycloadditions, 79-80 Aldol condensation, 7 Alkaloid synthesis, 28 Alkenes, strained, 93 4-Alkoxy-2-pyridones, 90-91 Alkynes, cobalt complexes of, 8 Allenes, cycloaddition reactions of, 3639 Allenes, reaction with dienes, metalcatalyzed, 26-27 Alloyohimbane, 29 Allyl cations, 120 Allyl magnesium bromide, 107 Ambrosin, 6 Amides, hydrolytic and reductive ring opening of, 112-115 Anhydroecgonine, methyl ester, 153 Annulation, [3+2], 140, 158 Annulation, [3+2], formal, 156 Annulations, [3+4], intermolecular, of vinylcarbenoids with dienes, 122143 Annulations, [3+4], of vinylcarbenoids and dienes, 119-164

Annulations, [4+3], 120 Annulations, [5+2], 120 Anthracene, photoreaction with 1,3 dienes, 93 Anti-Bredt double bond, 158 Arynes, 50 Asteriscanolide, 24, 25 Asymmetric cycloaddition, of 2-pyrones, 69 Asymmtric induction, in vinyl carbenoid cyclopropanations, 142143 Axetidine, fused, 159 Barbatusol, 7 Benzene, photoreaction with 1,3 dienes, 93 Benzenes, reactions with vinylcarbenoids, 143-144 Benzophenanthridine alkaloids, 50 Benzophenone, sensitization by, 89, 98 Benzotriazole, 12 Benzyl vinyl ether, 74 Benzyne, 50 Benzyne, 3,4-(methylenedioxy), 50 Benz[f]indole, 50 Bicycloadducts, isolable, from 2-pyrone [4+2] cycloadditions, 56-80 Bicyclo[2.2.2] system, 143-144 Bicyclo[2.2.2]octenes, 54, 57

165

166

Bicyclo[ 3.2.0] heptanes, fragmentations of, 15-16 Bicyclo[3.2.1]octadienes, 125, 128 Bicyclo[3.2.2]nonane, 12 Bicyclo[4.1.0]heptanes, fragmentations of, 16-17 Bicyclo[4.4.1 ]ring system, 8 Bicyclo[5.3.0]decane, 10 Binaphthol Lewis acids, 76-78 Biotechnology, applications of synthesis to, 3 Bisaminal, 112 Boat conformation, 101 N-BOC pyrrole, reactions with vinylcarbenoids, 151 Bond lengths, in 2-pyridone dimers, 97 5-Bromo-2-pyrone, reaction with chiral acrylates, 70 5-Bromo-2-pyrone, [4+2] cycloaddtion reactions of, 67-68 3-Bromo-2-pyrones, [4+2] cycloaddtion reactions of, 66-67 Bronsted base, catalysis by, in 2-pyrones [4+2] cycloadditions, 78-79 s-BuLi, 6 t-BuLi, 7 n-Butyl-2-pyridone, 112 Butyl vinyl ether, reactions with 2-pyrones, 73, 74 (R)-t-Butylbenzyl vinyl ether, 70 1-(tert-Butyldimethylsilyloxy)-1,3-butadiene, 135-136 Cage compound, 55 Carbazoles, 50 Carbazoles, [a]-annelated, 51 Carbazoles, [b]-annelated, 50 Carbazoles, [c]-annelated, 51 Carbenes, metal, 10 Carbenoids, 10 Carbenoids, metal-stabilized, reaction with alkynes, 156-157 3-Carbomethoxy-2-pyrone, 54

INDEX

Carbon 13 data, of 3-substituted pyrones, correlation with reactivity, 59 Carbon-carbon bond formation, Lewis acid-mediated, 7 3-Carbonyl-2-pyrones, [4+2] cycloaddition reactions of, 59-62 N-Caromethoxypyrrole, reactions with vinylcarbenoids, 149 Cascade reaction, 6-7, 9 Cation-initiated reaction, 7-8 Cationic intermediate, 7 Ceroplastols, 108 Chelates, 73 Chiral auxiliaries, in 2-pyrone [4+2] cycloadditions, 49 Chiral auxiliaries, in enantioselective cyclopropanation, 121 Chiral auxiliary, 147 Chiral catalysts, in enantioselective cyclopropanation, 121,147 Chirality transfer, in allene cycloadditions, 38 6-Chloro-2-pyridone, 90 3-Chlorocarbonyl-2-pyrone, 59 Chloroimine, 90 Chromium carbene complex, 14 Chromium tricarbonyl triene complexes, 21 Chromium vinylcarbenes, 137-138 Cinchona alkaloids, as catalysts in 2pyrone cycloadditions, 79 Cinchonidine, 80 Cinchonine, 80 Citric acid, 138 Claisen rearrangement, 15 Co(acac)2, 22 Combinatorial synthesis, 3 Confertin, 14 Cope rearrangement, 11, 95-96, 99, 103,110, 120-121,123-124, 130, 134, 149-150, 156 Copper, 18 Coronand, subunit of, 54-55

Index Coumarins, 50-51 Cuprates, 14 Curtius rearrangement, 148 Cyclization, palladium-catalyzed, 11 Cyclization, transannular, radical-mediated, 11 Cycloaddition, metal-mediated, 22 Cycloaddition [4+2], 123 Cycloaddition, [5+2], intramolecular, of yne-vinylcyclopropanes, 30-32 Cycloaddition, [5+2], of yne-vinylcyclopropanes, mechanism, 30 Cycloadditions, intramolecular, of 2pyridones, 98-104 Cycloadditions, transition metal-catalyzed, 23-29 Cycloadditions, [3+2+2], 23 Cycloadditions, [3+2], 19, 21-22 Cycloadditions, [4+2], 26-9, 48 Cycloadditions, [4+2], of 2-pyrones, facial selectivity of, 73 Cycloadditions, [4+2], of 2-pyrones, intramolecular, stereocontrol in, 74 Cycloadditions, [4+2], of 2-pyrones with alkenes, 52-80 Cycloadditions, [4+2], of 2-pyrones with alkynes, 50-52 Cycloadditions, [4+3], 18-9, 22 Cycloadditions, [4+4], 23-26 Cycloadditions, [5+2], 19, 29-40 Cycloadditions, [5+2], intramolecular, of allenevinylcyclopropanes, 36-39 Cycloadditions, [5+2], intramolecular, of ene-vinylcyclopropanes, 32-36 Cycloadditions, [5+2], intramolecular, of ene-vinylcyclopropanes, mechanism, 33 Cycloadditions, [6+4], 21 Cyclobutanone, ring expansion of, 13 Cyclobutenone, ring expansion of, 13 Cyclodecyne, 10 Cycloheptadienone, 13 Cyclohexadienes, 52

167

Cyclohexadienes, dehydrogenation of, 52 Cyclopentadiene, 122-128 Cyclopropanation, 121 Cyclopropanation, asymmetric, 127 Cyclopropanations, by vinylcarbenoids, diastereoselectivity of, 126 Cyclopropanations, by vinylcarbenoids, mechanistic analysis of, 142-143 Cyclopropanations, by vinylcarbenoids, stereoselectivity of, 120 Cyclopropanations, intermolecular, 122 Cyclopropanations, intramolecular, of trans-dienes, 154 Cyclopropanations, vinylcarbenoid, stereoselectivity of, 142 Cyclopropene, 146 Cyclopropenone ketals, [4+2] cycloaddition with 2-pyrone, 53 Cycloreversion, 53 Damsin, 6 Damsinic acid, 14 Danishesky's diene, 137 DDQ, 138, 141 Dehydration, 7 Dewar pyridone, 87-90, 92 Di-t-butyl carbonate, 113-115 Dictamol, total synthesis of, 39-40 3,4-Didehydropyridine, 50 Dieckmann reaction, retro, 7 Diels-Alder cycloaddition, 2, 17, 26 Diels-Alder cycloadditions, double, 54-55 Diels-Alder cycloadditions, of 2-pyrones, 47-83 Diels-Alder reaction, retro, 63 Diels-Alder reactions, 51-52 Diels-Alder reactions, high pressure, 53 Dienes, heteroatom-substitutes, reactions with vinylcarbenoids, 133142

INDEX

168

1,3-Dienes, photocycloaddition of, 93 Diethylaluminum chloride, 8 Dihydrobenzenes, 54 Dihydrofuran, reactions with 2-pyrones, 73 1c~,25-Dihydroxyvitamin D3, synthesis of precursor to, 69 Diiron nonacarbonyl, 18 Diisopropoxytitanium dichloride, 74 1,2-Dimethoxybenzene, reactions with vinylcarbenoids, 143 Dimethylaluminum chloride, 70 Dimethyldioxirane, 110 2,5-Dimethylfuran, reactions with vinylcarbenoids, 145 Dioxirane, 10 Diphenylmethyl vinyl ether, 74 Dissolving metal reductions, 111 Divinylcyclopropanes, 124 Divinylcyclopropanes, cis, 120-121, 123, 151 Divinylcyclopropanes, trans, 154-155 Divinylcyclopropane rearrangement, 13 Divinylcyclopropane, sterically hindered, 150 Diyls, 9 Dopamine, re-uptake inhibitor of, 154 Eight-membered ring synthesis, 23 Electrocyclic rearrangement, 53, 90 Electrocyclizations, 159 Ellipticine, 50 Enamines, cycloaddition of, 13 Enol ether, hydrolysis of, 114 Enolates, protonation of, 112 Epi-tremulenolide A, skeleton of, 155 (+)- 10-Epijuneol, 54 Epimerization, 155 Epoxides, anionic opening of, 6 Ethyl cyanoformate, cycloaddition with 2-pyrone, 52 Ethyl diazoacetate, 126 Eu(fod)3, 72 (+)-Eu(hcf)3, 72

Extinction coefficient, 92 Ferruginine, 153 Fluorenyl vinyl ether, 74 Fluorescent lifetime, of a pyridone, 89 2-Fluoroalkylvitamin D analogs, 74 Fragmentation, 5 Fullerene, [4+2] cycloaddition reaction with 2-pyrone, 59 Furans, reactions with vinylcarbenoids, 145-148 Fusicoccin A, 108-111 Fusicoccins, 108 Gibberilic acid, 58 Grubbs' catalyst, 10 2(E),4(Z)-Hexadiene, regiocontrol in reaction with vinylcarbenoids, 131 ~-C-Hexapyranoside, 148-149 High pressure, in 2-pyrone [4+2] cycloadditions, 56-57 Homopyrrole, 20 Hydroazulene skeleton, 133-134 Hydrochloric acid, 114 Hydrogen bonding, intramolecular, 100, 109 3-Hydroxy-2-pyrone, 79 o~-Hydroxy esters, as chiral auxiliaries, 126-127 Ingenol, 8, 15, 21 Iodomethane, 111 Irida-2(7),5-diene, 63 Iridium complex, 23 Isoellipticine, 50 80t-Isoestradiol, 17[3-acetate, 3-methyl ether, 28 Isomerization, of vinylcyclopropanes, 130 Isoquinolines, 52 Ketene, 90 ~-Ketoester, 147-148

Index 13-Lactams, 90, 104 (S)-Lactate, 141 Lactate ester, 71 Lactone, nucleophilic ring opening of, 49 LDA, 6 Lewis acids, homochiral, in 2-pyrone [4+2] cycloadditions, 49 Lithium aluminum hydride, 111 Lithium borohydride, 111, 114-115 Lithium hydroxide, 148 Lithium, in ammonia, 112-113 Lycorine alkaloids, 51 Macrocyclization, 9 Macroexpansions, 12 Manganese triacetate, 9 Materials Science, applications of synthesis to, 3 Medicine, applications of synthesis to, 3 Mercury lamp, high pressure, 90 Mercury lamp, medium pressure, 92 Mesylation, 111 MetaUocyclohexene, 29 Metallocyclooctadiene, 29 Metallocyclopentene, 29 Metathesis, 10 Methanesulfonic acid, 8 1-Methoxy- 1-trimethylsilyloxy- 1,3-butadiene, 138-139 4-Methoxy-2-pyridone, 92, 112 1-Methoxybenzene, reactions with vinylcarbenoids, 143 3-Methoxycarbonyl-2-pyrone, 77, 78 5-Methoxycarbonyl-2-pyrone, 55 3-Methoxycarbonyl-2-pyrone, reactions with vinyl ethers in the presence of TADDOL Lewis acids, 75 3-Methoxycarbonyl-2-pyrone, [4+2] cycloadditions with vinyl ethers, 60 5-Methoxycarbonyl-2-pyrone, [4+2] cycloaddtion reactions of, 62-63

169

2-Methoxyfuran, reactions with vinylcarbenoids, 145 1-Methoxynaphthalene, reactions with vinylcarbenoids, 144 3-Methoxytropones, 139-141 4-Methyl- 1,3-pentadiene, reaction with vinyl carbenoids, 128-130 1-Methyl-2-pyridone, 93 1-Methyl-2-pyridone, photodimerization product of, 87-88 Methyl acrylate, 58 Methyl coumalate, 55 Methyl iodide, 147 (-)-Methyl triacetyl-4-epishikimate, synthesis of, 69 Methyl vinyl ether, 91 2-Methylfuran, reactions with vinylcarbenoids, 145 Methyllithium, 139-140 N-Methylmaleimide, 79 Methylrhenium trioxide, 10 Methyltrifluoromethyl dioxirane, 10 Micelles, photodimerization of 2-pyridones in, 96 Michael addition, 7 Moisture content, of molecular sieves, effect on stereocontrol in 2-pyrone cycloadditions, 76 Molecular sieves, 74, 75 Molybdenum carbene complex, 14 Molybdenum carbene complex, 156157 Montmorillonite clays, as catalysts for 2-pyrone cycloadditions, 60-61 Nanotechnology, applications of synthesis to, 3 Naphthalyne, 50 1-Naphthylmethyl vinyl ether, 74 Natural products, 11 Nezukone, 139 Ni(COD)2, 23, 25-28 Nitrile, 90 Norbornadienes, 22

170

Norcaradiene, 157 Ophiobolin ring system, 24 Ophiobolins, 108 Osmium tetroxide, 106-107 8-Oxabicyclo [3.2.1 ]octa- 2,6-dienes, 148 8-Oxabicyclo [3.2.1 ]oct-6-en-2-ones, 148-149 Oxabicyclo[3.2.1 ]octane system, 146147 Oxaziridine, photorearrangement of, 12 18-Oxo-3-virgene, 16 Oxyallyl cations, 18 P(O-i-C3HF6)3, 28 Paclitaxel, 105-108 Palladium acetate, 11, 19, 22 Pantolactone, 74 (R)-Pantolactone, as chiral auxiliary, 126-127, 135, 142, 151 Perhydroazulenes, 16 Phorbol, 19 Phospahalkynes, cycloaddition with 2pyrone, 52 Photochemistry, of 2-pyridones, 87-98 Photocycloaddition, [2+2], 16 Photocycloaddition, [4+4], of 2-pyridones, 85-118 Photocycloadditions, benzophenonesensitized, 89, 98 Photodimerization, 90 Photodimerization, of 2-pyridones in the solid state, 96 Photoisomerization, 90 Photoisomerization, of 2-pyridones in the solid state, 96 Photolysis, 12 Photoproducts, of 2-pyridones, synthetic transformations of, 111-115 Photosensitizer, 89 Piperylenes, 133 Platinum oxide, 114 (-)-Podophyllotoxin, total synthesis of, 70

INDEX

Polymers, from 2-pyrone [4+2] cycloadditions, 54-55 Potassium carbonate, 133 Pr(fod)3, 72 (-)-Pr(hfc)3, 71-72 (S)-Prolinate, 143 Psilostachyin, 6 (5H)-Pyrazole, photolysis of, 157 (3H)-Pyrazoles, photolysis of, 121 Pyrex, 92 2-Pyridones, head-to-head tethered, intramolecular cycloadditions of, 102-104 2-Pyridones, head-to-tail tethered, intramolecular cycloadditions of, 98102 2-Pyridones, N,N'-tethered, intramolecular cycloadditions of, 98 Pyridones, self-assembly of, 110 2-Pyridones, tail-to-tail tethered, intramolecular cycloadditions of, 102104 Pyrido[3,4-b]indoles, 52 2-Pyrone-2-carboxylate, 74 2-Pyrone, [4+2] cycloaddition reactions of, 57-59 2-Pyrones, 48 Pyrones, 22 Pyrroles, 8 Pyrroles, N-acylated, 149 Pyrroles, 2-substituted, intramolecular reactions with vinylcarbenoids, 158 Pyrroles, intramolecular reactions with vinylcarbenoids, 159 Pyrroles, reactions with vinylcarbenoids, 149-154 P[OCH(CF3)(o-CH3OPh)]3, 27 Quatemization, of amines, 111 Radical intermediates, 13 Radicals, 12 Raney nickel, 114

Index Rearrangement, 1,5-homodienyl, 130 Reductive elimination, 29 Regioselectivity, of 2-pyridones photocycloadditions, 94-96 Regioselectivity, of cycloheptadiene formation, 130-131 [Rh(CH2=CH2)C1]2, 27 Rh(COD)C12, 27 Rh2(S-DOSP)4, 127-129, 132-133, 147, 155-156 Rh2(S-TBSP)4, 127, 136, 147, 150-151 Rhodium (II) acetate, 122-123, 128131,135-140, 145, 150-151, 154, 159 Rhodium (II) carboxylates, 124, 126 Rhodium (II) hexanoate, 135-136, 150-151 Rhodium (II) mandelate, 135-136, 156 Rhodium (II) octanoate, 132, 152, 156157, 159 Rhodium (II) pivalate, 124-125, 135, 139-140 Rhodium (II) prolinates, as chiral catalysts for asymmetric cyclopropanations, 127 Rhodium (II) trifluoroacetate, 124, 143 Ricinine, 90 Ring expansions, four atom, 13-15 Ring expansions, one atom, 12 Ring expansions, three atom, 13 Ring expansions, two atom, 12-13 Ring synthesis, strategies for, 3-4 Rings, seven-membered, from acyclic precursors, 5-11 Rings, seven-membered, synthesis of, 1-45 Salsolene oxide, 24, 25 Samarium iodide, 10 Saponification, 7 Serotonin, re-uptake inhibitor of, 154 Seven-membered rings, 120 Seven-membered rings, enthalpic and entropic barriers to formation of, 6

171

Seven-membered rings, heterocyclic, 6 Seven-membered rings, synthesis of, by ring contraction, 15 Seven-membered rings, synthesis of, cycloaddition strategies, 17-23 Seven-membered rings, synthesis of, electrophilic approaches, 7-8 Seven-membered rings, synthesis of, from larger and smaller rings, 11-5 Seven-membered rings, synthesis of, metal carbene approaches, 10 Seven-membered rings, synthesis of, nucleophilic approaches, 6-7 Seven-membered rings, synthesis of, radical approaches, 9-10 Seven-membered rings, synthesis of, transition metal approaches, 10-1 Seven-membered rings, synthesis of, via fragmentation, 15-17 (+)-Shizuka-acoradienol, 63 Silica, as a catalyst for 2-pyrone cycloadditions, 60-61 Silicon tethers, 74 Silver triflate, 27, 31-32, 34-38 Singlet quenchers, effect on 2-pyridone photochemistry, 87-88 Sirenin, 121 Sodium borohydride, 114-115 Sodium hydride, 111 Sodium iodide, 18 Sodium methoxide, 147-148 Solvent, effect of, on [4+2] cycloadditions fo 2-pyrones, 78 Stereochemistry, bridgehead, in-out, 8 Stereochemistry, control of in 2-pyrone [4+2] cycloadditions, 69-80 Stereochemistry, relative, control of in 2-pyrone [4+2] cycloadditions, 56-68 Stereoselectivity, of 2-pyridones photocycloadditions, 94-96 Steric effects, in Cope rearrangement, 134 Steroid synthesis, 28

172

Styrene, 126 3-Sulfenyl-2-pyrones, [4+2] cycloaddtion reactions of, 65 3-Sulfinyl-2-pyrones, [4+2] cycloaddtion reactions of, 64-65 3-Sulfonyl-2-pyrones, [4+2] cycloaddtion reactions of, 63-64 Sulfoxide, 12 TADDOL Lewis Acids, 75-76 Taxane ring system, 24 Taxol, 105-108 Taxol, analogs of, 9 Taxol, C-ring fragment of, 70 {~-Terpinene, 54 Tetracyanoethylene, 21 Thermal cleavage, of 2-pyridone cycloadducts, 95 Thorpe-Ingold effect, 31 Titanium tetrachloride, 7, 18, 23 p-Toluenesulfonyl cyanide, cycloaddition with 2-pyrone, 52 Transannulation, 9 Tremulenediol A, 14 (+)-Tremulenolide A, 132 Tremulenolide A, 14 Tri-o-biphenylphosphite, 27 Triazole, 93 Tributyltin hydride, 9, 10, 16 Trienes, as side products in vinylcarbenoids reactions with furans, 145-146 Trienimine, 160 1,2,3-Trimethoxybenzene, reactions with vinylcarbenoids, 143-144 Trimethylenemethane, 19 1-Trimethylsilyloxy-1,3-butadiene, 136 Triplet quenchers, effect on 2-pyridone photochemistry, 87-88 Tris(tripenylphosphine)rhodium chloride, 13, 30, 32, 34-40 Tropanes, 138, 149-151 Tropanes, 4b-aryl-3b-propanoyl, 153 Tropoloisoquinolines, 53

INDEX

Tropolone, methyl, 149-151 Tropolones, 53 Tropones, 53 Tungsten carbene complex, 14-15 Vinyl carbenes, 121 Vinyl ethers, [4+2] cycloadditions with 3-substituted 2-pyrones, 59-62 Vinyl thioethers, 77 Vinyl thioethers, reaction with 3-sulfonyl-2-pyrones, 64-65 Vinyl thioethers, reactions with 2-pyrones, 73 Vinylcarbene, nucleophilic, 120 Vinylcarbenoids, intermolecular reactions with aromatic systems, 143154 Vinylcarbenoids, intramolecular [3+4] reactions with dienes and aromatic compounds, 154-160 Vinylcyclopropanes, 20 Vinyldiazomethane, 122, 126 Vinyldiazomethanes, chlorinated, reactions with oxygenated dienes, 136-137 Vitamin D analogs, 60, 66-67 Vitamin D3, synthesis of A-ring, 77 Wilkinson's catalyst, 132-133,147-148 Xanthone, 89 Yb(OTf)3, 74 Yne-vinylcyclopropane, 29, 30-32 Yohimbane, 28 Zinc, 111 Zinc bromide, 61, 74 Zinc salts, as catalysts for 2-pyrone cycloadditions, 60-61 Zizaene, 58 Zwitterionic intermediates, in annulations of vinylcarbenoids, 125, 140-141,144, 151

Advances in Cycloaddition Edited by Michael Harmata, Department of Chemistry, University of Missouri, Columbia

REVIEW: 'q'his volume is highly recommended to all those who want to stay abreast of developments in the mechanisms and synthetic applications of 1,3dipolar cycloaddition reactions. The writers have realized a good balance between the summary of achievements and the reporting of gaps in understanding or remaining synthetic challenges. The articles are well written, they are amply illustrated with equations or schemes" - - Journal of the American Chemical Society Volume 1, 1988, 208 pp. ISBN 0-89232-861-4

$109.50/s

CONTENTS: Introduction to the Series: An Editor's Foreword, Albert Padwa. Preface, Dennis P. Curran. Steric Course and Mechanism of 1,3-Dipolar Cycloadditions, Rolf Huisgen. NonstabUized Azomethine Ylides, Edwin Vedejs. Molecular Rearrangements Occurring from Products of lntramolecular 1,3 Dipolar Cycloadditions: Synthetic and Mechanistic Aspects, Arthur G. Schultz. Dipolar Cycloadditions of Nitrones with Vinyl Ethers and Silane Derivatives, Philip DeShong, Stephen W. Lander, Jr., Joseph M. Leginus and C. Michael Dickson. The Cycloaddition Approach to b-Hydroxy Carbonyls: An Emerging Alternative to the Aldol Strategy, Dennis P. Curran. Index. Volume 2, 1990, 220 pp. ISBN 0-89232-951-3

$109.50/s

CONTENTS: Introduction to the Series: An Editor's Foreword, Albert Padwa. Preface, Dennis P. Curran. Intramolecular 1,3-Dipolar Cycloaddition Chemistry, Albert Padwa and Allen M. Schoffstall. Stereochemical and Synthetic Studies of the Intramolecular Diels-Alder Reaction, William R. Roush. Thermal Reaction of Cyclopropenone Ketals, Key Mechanistic Features, Scope and Application of the Cycloaddition Reactions of Cyclopropenone Ketals and p - Delocalized Singlet Vinyl Carbenes; Three Carbon I,I-/1,3-Dipoles, Dale L. Boger and Christine E. Brotherton-Pleiss. Index. Volume 3, 1993, 210 pp. ISBN 1-55938-319-4

$109.50/s

REVIEW: "This series continues to play a valuable role in keeping the specialist and nonspecialist informed of this important field of chemistry.

Journal of American Chemical Society. CONTENTS: Facial Diastereoselection in Diels-Alder Cycloadditions and Re-

lated Reactions: Understanding Planar Interactions and Establishing Synthetic Potential, A. G. Fallis and Yee-Fung Lu. Substituent and Structural Effects in the Ozonolysis of Cyclic Vinylogous Esters, W. H. Bunnelle. N-Metalated Azomethine Ylides, S. Kanemasa and Otohiko Tsuge. Azomethine Ylide Cycloadditions via 1,2- Prototropy and Metallo-Dipole Formation from Imines, R. Grigg and V. Sridharan. Index. Volume 4, 1997, 210 pp. ISBN 1-55938-695-9

$109.50/s

REVIEW: "This volume underscores the unique character of the topics of cycloaddition chemistry and should be a valuable source of information for the specialist and nonspecialist alike."

Journal of American Chemical Society CONTENTS: Preface, Mark Lautens. Photocyclization and Photocycloaddition

Reactions of 4- and 2-Pyrones, Frederick G. West. Intramolecular [4+3] Cycloaddition Reactions, Michael Harmata. Lewis Acid Catalyzed [2+2] Cycloaddition Reactions of Vinyl Sulfides and Their Analogues: Catalytic Asymmetric [2+2] Cycloaddition Reactions, Koichi Narasaka and Yujiro HayashL Vinylboranes as Diels-Alder Dienophiles, Daniel A. Singleton. Preparation and ExoSelective [4+2] Cycloaddition Reactions of Cobaloxime-Substituted 1,3Dienes, Mark E. Welker, Marcus W. Wright, Heather L. Stokes, B. Matthew Richardson, Torrey A Adams, Terrence L. Smalley, Stacia P. Vaughn, Ginger J. Lohr, Louise Liable-Sands, and Arnold L. Rheingold. Index.

i~``:~:~`!~i~`~:~i~`*`~i~i~:~:i:i~i~:~:~i~:i~:i:`~.*i~i:~i:i~%:i~!~;!:~:~!~i:i:~`~i~:!~i~:~:~:~~:~:~:~:~:~~:~i:~i~:~ ~i~!! ~ii~!iii~iii~i!~i!i~i~iiii~ii~i~!~ii~ii~i~i!~i~i~i~i~ ~i~i~~?~?~!~!~i~i~!~!~i~!~!~i~!~iiii~

" ~ ~,~.~

~ ~ %:~:.~.~i.~

~i~?~!~i~!~!!'i~i~i~i~!~i~!iiii!~-ii~"~i~i~!~i~!~i,~!~:!~!~i~-~! ~ii~!~?ii~!i~.'ii ~?'i ~~"~ ~~ i i ~ i ~ . ~ i ~ i ~ i ~ , ! i ! ~ ! ~ i ~ ! ~ ! ~ i ~ i ~

~ii i i ~~ii i i i i i i!ii ii i i!iliili ili i i ~i!iiilili il i i ~i ili ii~i i i i i i i i i i i i i ~i i i i i i i i i i ~~i~i i~i