Organophosphorus Chemistry (SPR Organophosphorus Chemistry (RSC)) (Vol 33)

Organophosphorus Chemistry Volume 33 A Specialist Periodical Report Organophosphorus Chemistry Volume 33 A Review of...

Author: D. W. Allen | J. C. Tebby

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Organophosphorus Chemistry Volume 33

A Specialist Periodical Report

Organophosphorus Chemistry Volume 33 A Review of the Literature Published between July 2000 and June 2001 Senior Reporter D.W. Allen, Sheffield Hallam University, Sheffield, UK J.C. Teb by, Staffordsh ire University, Stoke-on- Trent, UK Reporters N. Bricklebank, Sheffield Hallam University, Sheffield, UK C.D. Hall, King's College, London, UK B.J. Walker, The Queen's University of Belfast, UK D. Loakes, Laboratory for Molecular Biology, Cambridge M. Migaud, The Queen's University of Belfast, UK J.C. van de Grampel, University of Groningen, The Netherlands

RSeC advancing the chemical sciences

NEW FROM 2003 If you buy this title on standing order, you will be given FREE access to the chapters online. Please contact [email protected] with proof of purchase to arrange access to be set up. Thank you.

ISBN 0-85404-339-X ISSN 0306-0713 Copyright 0 The Royal Society of Chemistry 2003 All rights reserved Apart from any fair dealing for the purposes of research or private study, or criticism or review as permitted under the terms of the U K Copyright, Designs and Patents Act, 1988, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry, or in the case of reprographic reproduction only in accordance with the terms of the licences issued by the Copyright Licensing Agency in the U K , or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the U K . Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 OWF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Typeset by Vision Typesetting, Manchester, UK Printed by Athenaeum Press Ltd, Gateshead, Tyne and Wear, UK

Introduction to Volume 33

The flow of papers on the chemistry of organophosphorus compounds shows no sign of slackening off, and keeping pace with developments is a major task for our Reporters. We are pleased that Dr David Loakes, of the Laboratory for Molecular Biology, Cambridge, has joined our team, and, as we hoped, has provided a two-year survey of the literature on polynucleotide and nucleic acid chemistry, (July 1999-June 2001), thereby making up for the deficiencies of Volume 32 on these topics. A two-year coverage of progress in the chemistry of quinquevalent phosphorus acids is also presented. However, once again we are unable to provide specific coverage of ‘Physical Methods’ in this volume. The XVth International Conference on Phosphorus Chemistry was held in Japan in 2001, resulting in a very considerable volume of conference papers and posters which appeared in Phosphorus, Sulfur and Silicon, and Related Elements in the summer of 2002 (Vol 177, parts 6-7 (June) and 8-9, (August)). As in recent years, the synthesis of new chiral phosphines and related chiral tervalent phosphorus esters and amides continues to be a major preoccupation, being driven by the need for improved performance in metal-catalysed processes. It is very pleasing to note that two of the recipients of the 2001 Nobel Prize for Chemistry, William S. Knowles, and Ryoji Noyori, are honoured for their work in the synthesis and application in catalysis of chiral phosphine ligands. Interest in the structures of metallo-organophosphide systems, noted in the previous volume, has continued to develop. The chemistry of heteroaromatic ring systems, notably that of phospholes, and of low coordination number p,-bonded compounds, also remain active areas. The primary emphasis of most published work on the Wittig reaction, and its counterparts, continues to be applications in synthesis. A potentially useful advance in this area is the use of ionic liquids as a medium for Wittig reactions. Developments in the coordination chemistry of ylide derivatives, particularly iminophosphoranes, continue apace and show that these compounds afford a diverse range of metal complexes. In the mononucleotide area, the past year has been highlighted by the development of novel phosphate-protecting groups and their use in nucleotide and chiral nucleoside thiophosphate chemistry. Concise methodologies have been described for cost effective syntheses of oligonucleotide building blocks, and the collection of unnatural nucleotides reported to have been synthesised has been considerably expanded. The number of publications on oligonucleotides continues to increase, with many new applications. Advances in NMR techniques are enabling a growing V

vi

Introduction to Volume 33

number of oligonucleotide structures to be solved in solution. Also reported are developments in internucleotide linkages and sugar modifications, leading to a variety of new structures. Conjugation to oligonucleotides is also a rapidly developing field. Interest in DNA microarrays and the attachment of oligonucleotides to solid surfaces is developing, as is the generation of catalytically active DNA and RNA aptamers. Biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, continue to increase in importance and tetracoordinate phosphorus compounds continue to be a major source of transition state analogues for the generation of abzymes, etc. Since the reaction pathways for peptide bond hydrolysis and phosphate ester hydrolysis are quite different, i.e. tetrahedral and trigonal bipyramidal transition states, respectively, it has seemed unlikely that a single active site in an enzyme could catalyse both reactions. The number of reports of the synthesis of natural and unnatural sugar phosphates, particularly as probes for the investigation of enzyme mechanisms, continues to increase, as does activity in all aspects of inositols and related materials. Although applied in other areas, the use of monomethyl polyethylene glycol as the polymer support to allow either solid-phase or solution-phase chemistry to be carried out, depending on the solvent employed, is worth noting. The number and breadth of reports of synthetic studies relating to phosphatidylinositols and related structures has increased markedly. Numerous investigations of phosphate ester hydrolysis and exchange reactions continue to be reported. The importance of enantiomeric and asymmetric synthesis is illustrated in many reports and the synthesis, and use as chiral catalysts, of chiral phosphorus (V) amides features in many publications. Dynamic kinetic asymmetric transformation (DYKAT) of racemates has been applied to the asymmetric synthesis of D-myo-inositol 1,4,5-triphosphate. Interest in approaches to safer nerve gas hydrolysis continues and a new method of detection for fluorophosphorus nerve poisons has been reported. Phosphotriesterase (PTE) from Pseudomonas dirninuta catalyses the hydrolysis of organophosphorus pesticides and nerve gases with rate enhancements of up to 1012 and it has now been shown that the bridging ligand in the active site of Zn-substituted phosphotriesterase is hydroxide rather than water. The year has produced some consolidation in the field of hypervalent phosphorus chemistry in the form of two reviews, the first dealing with the reactions of trico-ordinate phosphorus compounds with fluorinated 1,3-diketones or trifluoroacctylphenols and the second covering chiral, P,N-bidentate ligands which afford catalysts on coordination with rhodium and palladium. A section in the second review deals with coordination of hydridophosphoranes with platinum or palladium (vide infru), a topic that was reviewed earlier. A review has also appeared on small ring compounds containing highly coordinated Group 14 elements (Si, Sn and Ge) and, by analogy with phosphorus chemistry, many of these compounds contain the Martin ligand, known to stabilize hypervalent systems. Several reviews have been published on polyphosphazenes. In addition to reports on new methods of synthesis and new polymers, some being very stable,

Introduction to Volume 33

vii

there has been a great deal of work reported on organometallic aspects. Ring opening polymerization of thf may or may not include phosphazene residues. High yields of graft polymers via radical polymerization have been obtained. Advances continue to be made on the Staudinger reaction, and other methods of synthesizing phosphazenes, including microwave methods and further applications of the P = N bond in organic synthesis, have been described. There is a new method for the generation of alkali metal phosphazides and an investigation of their catalytic use for the ring opening poymerisation of E-caprolactam. A molecular modelling approach for cyclophosphazenes has been described and ab initio calculations have indicated the lack of importance of d-orbitals. D.W.Allen and J.C.Tebby

Contents

Chapter 1 Phosphines and Phosphonium Salts By D. W. Allen

1 1

1 Phosphines 1.1 Preparation 1.2 Reactions of Phosphines

20

2 Phosphine Oxides and Related Chalcogenides 2.1 Preparation 2.2 Reactions 2.3 Structural and Physical Aspects 2.4 Phosphine Chalcogenides as Ligands

26 26 29 32 32

3 Phosphonium Salts 3.1 Preparation 3.2 Reactions

33 33 35

4 p,-Bonded Phosphorus Compounds

38

5 Phosphirenes, Phospholes and Phosphinines

43

References

47

Chapter 2 Pentacoordinated and Hexacoordinated Compounds By C. D. Hall

68

Summary

68

1 Introduction

68

2 Monocyclic Phosphoranes

68

3 Bicyclic, Tricyclic and Tetracyclic Phosphoranes

70

Organophosphorus Chemistry, Volume 33 0 The Royal Society of Chemistry, 2003

ix

Contents

X

References Chapter 3 Tervalent Phosphorus Acid Derivatives B y D. W.Allen

82 84

1 Introduction

84

2 Halogenophosphines

84

3 Tervalent Phosphorus Esters 3.1 Phosphinites 3.2 Phosphonites 3.3 Phosphites

86 86 87 88

4 Tervalent Phosphorus Amides 4.1 Aminophosphines 4.2 Phosphoramidites and Related Compounds

93 93 96

References

98

Chapter 4 Quinquevalent Phosphorus Acids B y B. J . Walker

103

1 Introduction

103

2 Phosphoric Acids and Their Derivatives 2.1 Synthesis of Phosphoric Acids and Their Derivatives 2.2 Reactions of Phosphoric Acids and Their Derivatives 2.3 Selected Biological Aspects

104 104 113 120

3 Phosphonic and Phosphinic Acids 3.1 Synthesis of Phosphonic and Phosphinic Acids and Their Derivatives 3.2 Reactions of Phosphonic and Phosphinic Acids and Their Derivatives 3.3 Selected Biological Aspects

122

4

151

Structure

References Chapter 5 Nucleic Acids and Nucleotides; Mononucleotides B y M . Migaud 1

Introduction

123 144 150

153 161

161

xi

Contents

2 Mononucleotides 2.1 Nucleoside Acyclic Phosphates 2.2 Nucleoside Cyclic Phosphates 2.3 Nucleoside Pyrophosphates

161 161 190 191

3 Nucleoside Polyphosphates 3.1 Nucleoside Pyrophosphates 3.2 Nucleoside Polyphosphates

196 196 198

References

200

Chapter 6 Nucleotides and Nucleic Acids; Oligo- and Polynucleotides By D.Loakes

204

1 Introduction 1.1 Oligonucleotide Synthesis 1.2 RNA Synthesis 1.3 The Synthesis of Modified Oligodeoxyribonucleotides and Modified Oligoribonucleotides

204 204 209

2 Aptamers

249

3 Oligonucleotide Conjugates

253

4 Nucleic Acid Structures

260

References

269

Chapter 7 Ylides and Related Species By N . Bricklebank

210

289

1 Introduction

289

2 Phosphonium Ylides 2.1 Mechanistic and Theoretical Studies of Phosphonium Ylides and the Wittig Reaction 2.2 Synthesis and Characterisation of Phosphonium Ylides 2.3 Reactions of Phosphonium Ylides 2.4 Synthesis and Reactions of Aza-Wittig Reagents 2.5 Ylides Coordinated to Metals

289

3 Wittig-Horner Reactions of Metallated Phosphine Oxide Anions

289 29 1 297 306 307 315

xii

Contents

4 Horner-Wadsworth-Emmons Reaction of Phosphonate Anions

316

References

318

Chapter 8 Phosphazenes B y J . C . van de Grampel

321

Introduction

321

Linear Phosphazenes

32 1

Cyclophosphazenes

336

Polyphosphazenes

347

Crystal Structures of Phosphazenes and Related Compounds

354

References

361

Abbreviations

BAD cDPG CE CK CPE CPmP

cv

DETPA DMAD DMF DMPC DRAMA DSC DTA ERMS ESI-MS EXAFS FAB FPmP HPLC LA-FTICR MALDI MCE MIKE PAH QDA PMEA SATE SIMS SSAT SSIMS TAD tBDMS TFA TGA TLC TOF XANES

Benzamide adenine dinucleotide Cyclodiphospho D-glycerate Capillary electrophoresis Creatine kinase Controlled potential electrolysis 1-(2-chloropheny1)-4-methoxylpiperidin-2-y1 Cyclic volt ammet ry Di(2-ethylhexy1)thiophosphoricacid Dimethylacetylene dicarboxylate Dimethylformamide Dimyristoylphosphatidylcholine Dipolar restoration at the magic angle Differential scanning calorimetry Differential thermal analysis Energy resolved mass spectrometry Electrospray ionization mass spectrometry Extended X-ray absorption fine structure Fast atom bombardment l-(2-fluorophenyl)-4-methoxylpiperidin-2-y1 High-performance liquid chromatography Laser ablation Fourier Transform ion cyclotron resonance Matrix assisted laser desorption ionization Micellar electrokinetic chromatography Mass-analysed ion kinetic energy Polycyclic aromatic hydrocarbons Hy droquinone-0,O’-diacetic acid 9-[2-(phosphonomethoxy)ethyl] adenine S-acyl-2-thioethyl Secondary ion mass spectrometry Spermidine/spermine-N 1-acetylt ransferase Static secondary ion mass spectrometry Thiazole-4-carboxamide adenine dinucleotide tert-Butyldimethylsilyl Trifluoroacetic acid Thermogravimetric analysis Thin-layer chromatography Time of flight X-Ray absorption near edge spectroscopy ...

Xlll

1 Phosphines and Phosphonium Salts By D. W. ALLEN

1

Phosphines

1.1 Preparation. - 1.1.1 From Halogenophosphines and Organometallic Reagents. Once again, the use of organolithium reagents has dominated the field in the past year, with relatively few examples of the use of Grignard reagents having been reported. Grignard routes have, however, found use in the preparation of a range of tertiary phosphines bearing a 2-thienyl group,' the phosphinopolythienyl system ( 1),2and the chiral diphosphine (2).3The reactions of Grignard reagents with benzyne have been used to prepare organometallic

%:to,* m1* G /

\ I

\ I (1)

/

Q

\

(3) X = OMe, NMe2, Me or P t R = But or Cy

(2)

reagents for the synthesis of a range of functionalised biphenylylphosphines, e.y., (3), some of which have subsequently been attached to polymeric s u p p ~ r t s . ~ ' ~ Both Grignard and organolithium reagents have been applied in the synthesis of some new unsymmetrical diphosphinoethane ligands (4),6 related diphosphinoethanes bearing fluorinated aryl substituents (5); the highly fluoroussilylated aryldiphosphines (Q8 and other arylphosphines, e.g., (7)9 bearing both linear and branched perfluoroalkyl tag^.^,'^ Grignard and organolithium routes were also involved in the synthesis of a range of phosphines bearing trialkoxysilyl-functionality, e.g., (8)" and (9),12both precursors for the synthesis of phosphino-functional sol-gel systems. Among other diphosphines prepared using organolithium reagents are the 9,lO-diphosphinoanthracene ( 10),13the atropisomeric diphosphine (11),14 and the related bis(aminoalkylary1phosphine) ( 12).15The diphosphine (13) has been obtained by regioselective metallation of diphenylacetylene using a combination of butyllithium and potassium t-butoxide (the LICKOR superbase system), followed by treatment with chlorodiphenylphosphine.16Direct metallation of a chiral oxathiane ring system is the Organophosphorus Chemistry, Volume 33 0The Royal Society of Chemistry, 2003 1

2

Organophosphorus Chemistry

Ph3-nP

0

CH2c(CFd2C3F7\ n

(7) n = 1-3

PPh2

I

q

p

P

P

h

2

Me -.P

CH2NMe2

h

CH2NMe2

key step in the synthesis of the phosphine (14) as a single diastereoisomer, isolated as a stable, crystalline borane a d d u ~ t .Nitrogen-directed '~ ortho-metallation of benzyldimethylamine is the key to the synthesis of the functionalised phosphine (15), the subsequent lithiation of which has also been studied.'* A similar directed 'ortho'-lithiation of a dimethylaminoalkyl- 1,2-dicarborane has afforded the related l-diphenylphosphino-2-dimethylaminomethyl-o-dicarborane." Directed metallation is also a key step in the synthesis of a series of phosphinoalkylimidazole systems, e.g. (16),20 the o-aminophenylphosphines (17),21the chiral amido systems (18)22and (19),23(the latter being capable of

1 :Phosphines and Phosphonium Salts

3

R’

Ph2P-(CH2)n

(16)

n = 0 or 1, R’ = But or H, R2 = Me or P i

(17) n=1-3

(18) R = Et or Pr‘

‘“K\

PR2

N,N

R2P\I.I But

(20) R = Pr’, BU’, c y or o-tolyl

C-PPh2 I

R

(21)

HPPh2

R

R

(22) R = H, Me, Ph or COPh

atropisomerism due to restricted rotation), and further examples in the diphosphinoazine series (20).24Treatment of C-lithiated phosphonium ylides with chlorodiphenylphosphine affords the phosphino-ylides (2 l),which, on treatment with carbonyl compounds, afford a route to vinylphosphines (22), with Z stereo~pecificity.2~ The reaction of fluorenyllithium with methylphosphonous dichloride has given the phosphine (23), said to be easily oxidised in air, and readily able to form salts from which a series of stable ylides has been characterised.26Direct lithiation of heterocyclic ring systems, followed by treatment with chlorophosphines, has been employed as the route to a series of heteroarylphosphines, including the new ionic phosphine ligand (24),27 the imidazolylphosphines (25),’* (26),29 and (27),30 the chiral system (28),31 and the phosphinopyridones (29).32Aryllithium reagents have also been applied in the Ar

(26) Ar = ptolyl

(27)

n = 1 or 2

4

Organophosphorus Chemistry OMe

p - + l r y OMe J 3

synthesis of the phosphino-crown ether (30),33and a range of optically-active C3-symmetric triarylphosphines, e.g., (3l).34Lithiated ferrocene systems have again been widely employed in the synthesis of a considerable number of new ferrocenylphosphines, many of which are chiral. An improved route to l-bromo1’-(dipheny1phosphino)ferrocene(32) has been developed, involving selective monolithiation of l,l’-dibrom~ferrocene.~~ Ortho-lithiation of chiral ferrocenyl systems has enabled the synthesis of the 0-methylephedrine derivative (33), which provides a route to other 1,2- disubstituted enantiopure and the diastereoisomeric oxazolinyl system (34).37Ortho-lithiation of ferrocenylmethylethers is the key step in the synthesis of a range of new chiral boraneprotected P,N-ferrocenyl ligands, e.g., (35).38Among other chiral monophosphinoferrocenes prepared are the C3-symmetric system (36),39and the [2]-ferrocenophanes (37), which on heating at 250 “C undergo ring-opening polymerisat i ~ n . ~ Generation ’ of ferrocenyllithium intermediates by treatment of arylsulfinylferrocenes with t-butyllithium (displacing the arylsulfinyl group) is a key step in the synthesis of a range of new enantiopure Cz- and C1-symmetric 2,2”-diphosphino-l,l”-biferrocenes (38);’ and a new class of 1,2-diphosphinoferrocenes possessing only planar chirality, e.g., (39).42-43 Routes to a series of cylindrically-chiral ferrocenyldiphosphines, e.g., (40), have also been des ~ r i b e d .The ~ ~ . reactions ~~ of (tri-t-butylplumby1)lithium with various chlorophosphines have given a range of (tri-t-butylplumbyl)phosphinesP6 Whereas the direct reaction of a-substituted alkenylzirconocene reagents with chlorophosphines does not lead to the related alkenylphosphines, two groups have now shown that if the reactions are carried out in the presence of copper(1) chloride the desired phosphines are obtained, initially as copper-complexes, from which they can be liberated by treatment with appropriate reagents. It is thought that alkenylcopper reagents are involved in these reactions, and, using this approach, new alkenylphosphines have been prepared, e.g., (41),47 and the diphosphines (42).48 1.I .2 Preparation of Phosphines from Metallated Phosphines. Metallophosphide reagents continue to find extensive use in the synthesis of new phosphines and, as

I : Phosphines and Phosphonium Salts

5

I

&:

Q?

I

Fe

Fe

Fe

(38) R' = R2 = Ph or 3,5-Me2C6H3

(37) R = Mes or Ph

(35)

PR'2

R' = d R

O

M

e

, R2 =

Me

4cF CF3

PPh2

I

&PPh2

I

Fe

I

Fe

q P P h 2 R (40) R = CHPh2, CHMe2, CHEt2, Pr or C(OMe)Me2

(39)

I

(41)

R (42) R = Me or Ph

usual, lithiophosphides continue to dominate the field. Treatment of dibenzylphenylphosphine with lithium in THF results in cleavage of a benzyl group from phosphorus, with the formation of lithium benzylphenylphosphide. This reagent has then been employed in the synthesis of the chiral phosphines (43)49and (44),50 both of which have been resolved via the use of chiral palladium complexes. The reactions of lithium diarylphosphides with halogenoalkane substrates have been used in the synthesis of the bidentate phosphino(hydroxy)camphane system (45):l the phosphinotetrathiafulvalenes (46),52the naphthalene system (47),53and a series of solid-phase supported p-aminoalkylphosphines (48), derived from the Merrifield resin.54Treatment of various iodoalkanes, bearing perfluoroalkyl chains, with lithium phosphide (LiPH2)provides a route to the primary phosphines (49), from which other trialkylphosphines, bearing fluorous substituents which are electronically insulated from phosphorus, can be prepared by addition of P-H bonds to appropriate a l k e n e ~A. ~lithiophosphide ~ reagent derived from an alkyl(acy1)phosphine has been treated with triisopropylgermyl chloride to give the germylphosphine (50) as the principal product.56Related reactions of

Organophosphorus Chemistry

6 Pr’ Ph-P

CH(OH)Ph Ph-P,

1

CH2Ph (43)

&OH (45)

CH2Ph (44)

(48) Ar = Ph or 0-tolyl

(46) R = Me or Ph2P(CH2)3-

\

/

P

R

(52) n = 1 or 2, R = Me or H

R

(53)

R

(54)

R

lithiophosphide reagents with various sulfur (VI) acid esters have also continued to be used in phosphine synthesis. The highly crowded silylphosphine (51) has been prepared from the reaction of dilithium tri-isopropylsilylphosphide with tri-isopropylsilyltriflate, and has an almost planar geometry at phosphorus, existing as a mixture of diastereoisomeric rotational isomers which do not interconvert up to 70 0C.57The dilithiophosphide reagent derived from l-adamantylphosphine has been used in the synthesis of 1-adamantyl-phosphetane and -phospholane systems (52), via reactions with a,w-ditosylate Related reactions of bis(di1ithiophosphide) reagents derived from bis(primary phosphines), with cyclic sulfate esters, have given chiral diphosphines in which each phosphorus is part of a 4- or 5-membered ring system, e.g., (53)59and (54).60 Among new mono-phosphines prepared by the reactions of lithium diphenylphosphide with tosylate, mesylate, or triflate esters are the chiral sulfonamidoalkylphosphine (55),61new chiral phosphinoalkyloxazolines, e.g., (56),62the new water-soluble phosphine (57),63and chiral phosphines prepared from (S)-valine, e.g., (58).64A similar approach has been used in the synthesis of the chiral diphosphines (59)65and (60),66and the cis,cis,cis-tetraphosphine (61).67The lithiophosphide-tosylate route has also been applied in the synthesis of the bis(ferroceny1phosphino)-DIOP analogue (62).68 Optically-active (2aminomethylferrocenyl)phosphines, in which phosphorus is the chiral centre, have been obtained by the reactions of lithium methyl(pheny1)phosphidewith an

1 :Phosphines and Phosphonium Salts

7

rpph2 N5 NHS02Me

P h q0

(55)

‘PPh2

(56)

H

(62) Fc = ferrocenyl

(61)

Q Ph2P Ph2P RPH OH (64) (63) R = Ph, Mes or 2,4,6-Pr‘3C6H2

Yh

BPh’ u ’ , p d O H (65)

4%

Me2P

OH (66)

enantiomeric planar-chiral palladium derivative of dimethylaminomethylferr ~ c e n eTwo . ~ ~ groups have reported lithiophosphide routes to phosphino-functionalised calixC41arene ~ y s t e m s . Ring-opening ~~,~~ of epoxides by lithiophosphide reagents is the key step in the synthesis of a range of P-H functional phosphino-alcohols, e.g., (63),’2the chiral diphosphine (64),73the chiral hydroxyalkylphosphine (65) (from which a series of chiral phosphino-phosphinito ligands has been deri~ed),’~ and the triphosphino-t-alcohol(66).Treatment of the latter with an excess of butyllithium has given various organolithium-lithium alkoxide complexes, one of which involved a triphosphinotrimethylenemethane diani~n.~’ The previously established nucleophilic ring-opening of the phosphaferrocenophane (67) with secondary butyllithium, giving the phosphide (68), has been used in the synthesis of copolymers derived from the latter and isoprene.76Homopolymers derived from the phosphaferrocenophane (67),by ring-opening photolysis in the presence of transition metal complexes, have also been de~cribed.’~ Treatment of the fluoroarylphosphonamide (69) with lithium phosphide (derived from the reaction of red phosphorus with lithium metal in a liquid ammonia-THF-t-butanol medium) gave the phosphinophosphonamide (70), hydrolysis of which has given the water-soluble phosphine (71).7*

3

Organophosphorus Chemistry

8

aPRMe PHMe

(72) R = H o r Me

(73)

(74)

Applications of sodio- and potassio-phosphide reagents continue to appear, but in much lower numbers than those of the related lithio-systems. The reactions of sodiophosphide reagents derived from the diphosphines (72) with odichlorobenzene and o-chlorophenyldiphenylphosphinehave given the chiral phosphines (73)79and (74):' respectively. The latter was isolated as a single diastereoisomer. Treatment of red phosphorus (or phosphorus trichloride) with sodium in THF or DME in the presence of naphthalene or phenanthrene followed by an alkyl halide and two equivalents of t-butyl alcohol, provides a route to primary monoalkylphosphines in reasonable yield. Conversion into a related secondary phosphine is then possible under the same conditions.81Generation of disodium phenylphosphide from sodium metal and phenyldichlorophosphine has been used in a reaction with a 1,6-dibromohexa-2,4-diene to give a dihydro-1H-phosphepin oxide, but in low yield only.'* Generation of potassium phosphide from red or white phosphorus in the KOH-DMSO superbase system, followed by its reaction with 2-vinylpyridine, provides a route to the phosphine oxide (75) in good yield.83A series of terpene-derived chiral arylphosphines, e.g., (76) has been obtained by displacement of fluorine from fluoroarenes using potassium diphenylph~sphide.~~ Reactions of potassium diorganophosphide reagents with haloalkanes have been applied in the synthesis of chiral p-aminoalkylphosphines, e.g., (77), derived from e~hedrine,'~ phosphino derivatives (78) of serine;' and a series of diphenylphosphino-functionalised carbosilane d e n d r i r n e r ~Displacement .~~ of tosylate and related sulfonate anions by potassium diphenylphosphide has given an alternative route to the paminoalkylphosphine system (58), used subsequently in the synthesis of further examples of amidinoalkylphosphines, e.g., (79),88and also routes to chiral diphosphines, e.g., and (81).90Ring-opening of an oxetane precursor by potassium diphenylphosphide is a key step in an improved route to the chiral phosphine (82), a useful intermediate for the synthesis of a series of chiral, hybrid phosphine-phosphinite ligand systems.'l As has been the pattern in recent years, there has been considerable interest in the synthesis and characterisation of phosphide reagents derived from metals other than lithium, sodium, and potassium, and also in studies of the structure of metallophosphides in the solid state. A new route to P-chiral phosphine-boranes of high enantiopurity is afforded by treatment of the borane complexes of methyl(pheny1)phosphinewith a copper(1) reagent, giving the copper-phosphido intermediate (83), which, on subsequent treatment with an iodoarene in the presence of a palladium(0) catalyst, gives the related chiral t-phosphine-borane (84), with retention of configuration at phosph~rus.'~ Organophosphido systems

9

1:Phosphines and Phosphonium Salts

(75)

(77)

C02Me (78) R = Ph, @tolyl, 3,5-xylyl or cyclohexyl

k

/-N

PPh2

(79)n = 1 or 2 0 BH3

t

Ph"i'Cu Me

(83)

BH3

t

Ph"i'Ar Me (84)

@P-M+

Ph

Q-;cs+

CY,pA

..

2-.

(85)

N

0 (86) M = K orCs

(87)

involving zinc,93tin(II),94,95 zirc0nium,9~,"vanadium?* a l ~ m i n i u m ?lo'~ indium,Io2 and various lanthanide elements'03p105 have also been prepared and structurally characterised. Reviews have appeared of the structural diversity of alkali metal phosphides,106and of molecular clusters derived from dimetallated primary phosphines (and arsines).lo7Addition of monolithiocyclohexylphosphide to benzonitrile, followed by further treatment with butyllithium, yields a Lila-cage complex involving the delocalised anion (85).'08The structure of another unusual cage compound involving an amidophosphido dianion has also been reported."' A lithio(sily1phosphide)cluster system has been characterised,' lo and structurally associated calcium"' and magnesium'l2 phosphides have been obtained from tri-(t-buty1)silylphosphine. A series of stable heavier alkali metal phthaloylphosphides, e.g., (86), has been prepared,'I3 and a study of the coordination chemistry of the heteroarylphosphide (87) with amine donors has been reported.' l 4 Pyridine-adducts of sterically crowded lithium arylphosphides have also been ~haracterised.~'~ Whereas the sodium and potassium phosphides derived from bis(trifluoromethy1)phosphine are thermally unstable, the related tetraethylammonium- and 18-crown-6-complexed potassium-phosphides are both stable up to 140°C. Both of these compounds are useful sources of the bis(trifluoromethy1)phosphide anion for phosphine-synthesis via nucleophilic displacement of alkyl tosylates.' l 6 The related mercury(I1) bis(trifluor0methy1)phosphide has also been prepared.' l 7 Interest has also continued in the structural characterisation and synthetic application of phosphine systems which are metallated at atoms other than phosphorus. The lithio-arsenide (88) has been shown to undergo electrophilic ring-opening on treatment with alkyl halides, providing a simple route to the ~

10

Organophosphorus Chemistry

But

BuP ',

,p\

Bu'P; As-Li'

P'

But (88)

But.

P,

R' - j p u p i ; F 1 3 Me

'R

(89) R = Me, PhCH2 or ally1

(90) R' = Ad or But, R2 = But, Cy or Ph, R3 = Me, Cy or Ph

(91) R = Bu', Cy, Pr' or Ph

ful $malisedtriphosphines (89)."' Enantioselective metallation at methyl carbon of borane adducts of organodimethylphosphines in the presence of sparteine is the key step in routes to the chiral diphosphines (90)'19$'20 and (91).l2' A similar enantioselective deprotonation of aryldimethylphosphine-boranes,followed by treatment with 10,lO-dimethylanthrone, gave the hydroxyalkylphosphineborane (92), subsequently transformed into P-vinylphosphine-borane (93).12' Surprisingly, the reaction of o-lithiophenyldiphenylphosphinewith (-)-fenchone gave the stable phosphorane (94).122 The P-aminoalkylphosphine (95) has been obtained by treat ment of lithi ometh yldiphen ylpho sphine with benzylideneaniline. Acylation of (95) has given new P-amidoalkylphosphines, e.g., (96).123 Related lithiomethyldiorganophosphine reagents have been used in the synthesis of dendrimeric phosphines based on polyhedral, oligomeric, silsesquioxane cores.'24The reaction of an o-lithiocarboranylphosphine with dimethyltindihalides has given the related o-stannylcarboranylphosphines which show evidence of intramolecular tin-to-phosphorus c ~ o r d i n a t i o n .Metallation '~~ at the 5-position of the furan ring of the 2-furylphosphines (97)is the key step in the synthesis of related water-soluble phosphines, e.g., (98).'26A number of phosphines metallated at carbon have been structurally characterised, including the o-lithiobenzyldiorganophosphines (99),12' various phosphinomethanides,'z8~13* e.g., ( ( 101),130 and ( 102),131>'32 and also various metallated cyclopentadienylphosphines.' 3 3 ~341

APh

Ph2P

NHPh

1.1.3 Preparation of Phosphines by Addition of P-H to Unsaturated Compounds. Base-catalysed addition of diphenylphosphine to phosphazenes derived from diphenylvinylphosphine is the key step in a new route to monophosphazenes (103) of dipho~phinoethanes.'~~. Base-catalysed additions of primary or secondary phosphines to methyl 1-cyclohexenecarboxylateprovide a route to function-

1 :Phosphines and Phosphonium Salts

11

alised cyclohexylphosphines, e.g., (104).136 A general route to triazacyclononane systems, functionalised with pendant phosphine arms, e.g., the triphosphine (105), is afforded by free radical addition of diphenylphosphine to appropriate N-alkene precursors.13' The chiral bicyclic secondary phosphine (106) has been prepared as a mixture of stereoisomers by radical-promoted addition of phosAddition of borane-protected secondary phosphines phine (PH3) to 1im0nene.l~~ to imines has given a series of protected mono-N-substituted-a-aminophosphines, (107).139Interest has also been shown in addition reactions of primary and secondary phosphines coordinated to metals. Coordinated secondary phosphines have been shown to add to methyl acrylate, and acetylenic esters, to give complexes of ester-functionalised phosphines, e.g., (108)140and (l09).l4l Basecatalysed additions of chelating bis(primary phosphines) to vinyl- and allylphosphines, in the coordination sphere of a pentamethylcyclopentadienyl iron template, have given a series of nine- and ten-membered cyclic triphosphines, e.g., the triphosphacyclononane (110), many of which are capable of further elaboration.'42p144 Ph3-n-P-@$n

(98) X = C02Li, S02Li or P03Na2

(97)

rpR / Li

(99) R = Me or Ph

Me

Me

C- Li+ / \ Me2P SiMe3 (101)

(102) M = Na, Fib or Cs

PPh2

f

I

PPh2

Ph2P II

R" (103)

(104)R = H or Me

1.1.4 Preparation of Phosphines by Reduction. As usual, trichlorosilane remains the reagent of choice for the majority of reductions of phosphine oxides to the related phosphines. Trichlorosilane reduction is the final step of a multistage, large-scale route to phosphajulolidine (1 1 l).145 It has also been used widely in the synthesis of a range of carbofunctional phosphines, e.g., the previously unknown mercaptomethylphosphine (1 12),146 chiral p-aminoalkylphosphines (1 13),147 and a series of chiral phosphinoarylpyrrolidines e.g., (1 14).148Syntheses of various chiral binaphthyl monophosphines have also employed trichlorosilane reduction as the final step, e.g., for (1 15),'499'50 (1 16),lS1and the aminoarylphosphines

Organophosphorus Chemistry

12

QPH BH Ar ph;,

Me

A

NHR

F

H\ 0

,E- OMe

Ph2P!

Ph2P-C=CH.C02Me I

C02Me

I

H

Ar2P

R

(115) A r =

-Q

(117) R' = H or Me, R2 = H, Me, Et, PhCH2, COMe, COPh, C02Me or S02Me

R

R = CF3, Me or CI

(117).lj2This reagent has also been applied in the synthesis of a wide range of new diphosphines, many of which are chiral, including the 1,l'-binaphthyl system (118),lS3the bi-indole system (119),ls4the C2-symmetricdiphosphines ( the phosphonylated binaphthyl system (121),'56 the diphosphinobipyridyl (122),15' and the chiral rigid diphosphine ( 123).'j8In addition, trichlorosilane has been used in the synthesis of dendritic carbosilanes functionalised with diphenylphosphinocarboxylic acid ester end groups, e.g., ( 124).lS9Heating tertiary phosphinesulfides and -selenides with tris(trimethylsily1)silanein toluene in the presence of AIBN results in a radical-promoted reduction to the related phosphines, with retention of configuration at phosphorus.'60 A variety of silane reagents, e.g., phenylsilane, and also lithium aluminium hydride, have been used for the reduction of phosphinic acids to form secondary phosphines, subsequently protected as the related borane complexes.'61Lithium aluminium hydride has also been used to reduce sterically crowded aryldichloro-phosphines, -arsines,

1 : Phosphines and Phosphonium Salts

Ph2P

13

OR'

(1 18) R' = H, Me or CH2CH20(CH2CH20)2Me, R2 = H or C~CH2CH20CH20CH2CH20Me

(119) R = Me or CH20Me

and -stibines.162Treatment of chiral t-phosphine oxides with methyl triflate, followed by reduction of the intermediate methoxyphosphonium salt with lithium aluminium hydride, affords a route to the related chiral p h ~ s p h i n e s . A '~~ combination of lithium aluminium hydride with cerium(II1) chloride has been used in the synthesis of the chiral aminobiphenylylphosphines (125) from the related phosphine oxides.164The reagent HAlC12has been shown to reduce vinyland alkynyl-phosphonate esters to the related unsaturated primary phosp h i n e ~ . Perhaps '~~ the most interesting report in this section is the discovery by Keglevich's group that ring-strained cyclic phosphine oxides, usually five-membered ring systems, are reduced to the related phosphine-boranes on heating with the dimethyl sulfide-borane complex in chloroform. Among phosphine systems prepared by this route are (126) and (127).166The Schwarz reagent, [Cp2Zr(H)Cl],, has been used to reduce organodichlorophosphines to the related primary phosphines, and also organodicyanophosphines, R P(CN)2, to the cyanophosphines RP(H)CN.'67A new route for the reduction of phosphine oxides is to treat them with phosphorus oxychloride, followed by tris(diethy1amino)phosphine.Applied to triphenylphosphine oxide, this method gave a 61% yield of triphenylphosphine.16* 1.I .5 Miscellaneous Methods of Preparing Phosphines. Palladium-catalysed formation of phosphorus-carbon bonds continues to be developed as a useful route to organophosphines. The reactions of primary or secondary phosphines with aryl- or vinyl-halides in the presence of a palladium catalyst, usually palladium acetate or a zerovalent palladium-phosphine complex, have been used in the synthesis of steroidal phosphines, e.g., (128)p9the cationic diphosphine system

Organophosphorus C hernistry

14

(125) Ar = Ph, ptolyl, rn-tolyl, panisyl, pBu'C6H4 or 35-Me2C6H3

i-(NH2

(129) R =

4

!Me2

H O D P P h 2

q PPh,L

(130)

(131) R = Ph, CH2CH(Me)* or CH2CHMeCH2CMe3

(132)

(129),170the phenolic phosphine (130), (used subsequently in the synthesis of a water-soluble a,~-bis[4-(diphenylphosphino)phenoxy]poly(ethylene glycol),171 e.g., (13 l).'73Full details of the and various poly Cp-aryleneph~sphines],'~~~'~~ direct phosphination of aryl triflates using triphenylphosphine and other triarylphosphines in the presence of palladium acetate have now appeared,174and the procedure also applied to the synthesis of a series of functionalised arylphosphines, e.g., (132).'75In related work, it has been shown that the nickel(I1) complex (Ph3P)2NiC12 is an effective catalyst for the phosphination of aryl triflates using chlorodiphenylphosphine, and this route has been used for the synthesis of atropisomeric P,N-ligands, e.g., (133).'76A route to unsymmetrical, atropisomeric diphosphines, e.g., (134), is afforded by the sequential introduction of diarylphosphinyl groups into aryl triflates, promoted by palladium acetate, the final step being reduction of the phosphine oxide unit using trichl~rosilane.'~~ A simple, generic route to a range of arylphosphines bearing substituents which promote solubility in aqueous fluorous and supercritical carbon dioxide phases is afforded by the palladium-catalysed Heck olefination of haloarylphosphine oxides, followed by sequential reduction of both the alkenyl substituent and the phosphine oxide, to give the phosphines ( 135).17*An unprecedented palladium-

I : Phosphines and Phosphonium Salts

15 R I

(134)Ar = O- or ptOIyI

(135)n = 1 3 , X = c6F13, C~HCJ,

(136)R = Ph, ptOIyI,

C&7, CO~BU, Ph or pCIC6H4

pCICGH4 or panisyl

catalysed oxidative coupling reaction between diphenylvinylphosphine and imines provides a route to the phosphines (136).'79A rhodium-catalysed dehydrocoupling reaction of the diphenylphosphine-borane complex has given a series of new phosphinoborane rings, chains and macromolecules involving phosphorus-boron bonds.180 Triarylphosphines have been prepared by the crosscoupling of aryl halides and diorganochlorophosphines in the presence of electrogenerated nickel(0) complexes.'81 The phosphine [(E)-2-bromo-lphenylethenylldiphenylphosphine (137, X = Br), has been shown to undergo nickel(I1)-promoted cross-coupling with Grignard reagents to form the related vinylphosphines (137, X = alkyl or ,aryl).'**A route to the heterocyclic phosphines (138) is provided by the simultaneous reactions of the easily accessible heterocyclic system (139) with a mixture of alkylene diGrignard and monoGrignard-reagent~.'~~

X

APPh2 c b Ph

(137)

R PI

(138)R = alkyl or aryl, n = 1-3

Mey/J ,-7-)-JMe (139)

Vinylphosphine oxides have been shown to add primary amines to form P-aminoethylphosphine oxides, subsequently reduced to the related phosphines (140) using trichlorosilane. This addition route cannot be carried out using the vinylphosphines as precur~ors.'~~ In contrast, vinyldiphenylphosphine has been shown to undergo base-catalysed addition of ketones and nitriles, giving a simple route to a wide range of functionalised phosphines, e.g., (141) and (142).'85The chemistry of phosphacarborane systems continues to develop, the past year having seen reports of the preparation of the first 10-vertex phosphadicarbaboranes'86and the first parent representatives of the diphosphadicarbaborane series.187The formation of C-P bonds by the reaction of C-Si compounds with halogenophosphines has been utilised in the synthesis of the diphosphinomethane system ( 143).188 The styryl-functionalised diphosphine (144) has been prepared and copolymerised with a styrene-divinylbenzene system to give the related polymer-bound diphosphine, of interest for the preparation of a heterogeneous rhodium-based hydrogenation ~ata1yst.l'~The new polymer-bound triarylphosphine system (145) has been prepared and used in improved Staudinger/Aza-Wittig procedure^.'^^ The polymer-bound amino(ch1oro)diphosphine system (146) is easily accessible from the Merrifield resin by sequential treatment with t-butylamine and 1,2-bis(dichlorophos-

Organophosphorus Chemistry

16

phino)ethane, and offers a route to a wide range of new diphosphines, e.g., (147), final cleavage from the resin being achievable on treatment with phosphorus Interest has also continued in the trichloride or a range of nu~leophiles.'~' synthesis of dendrimer systems having phosphino-functionality at the surf a ~ e . ' ~The ~ ? first ' ~ ~asymmetric synthesis of P-stereogenic 2-hydroxyarylphosphines, e.g., (148) has been reported, the key step being an intramolecular ortho Friess-like rearrangement of a related borane-protected chiral o-haloaryl phosphinite ester, which proceeds with retention of configuration at p h o s p h o r ~ s . ' ~ ~ The chiral phosphinoborane complex (149)is converted into the chiral, boraneprotected secondary phosphine (150) on treatment with the lithium-naphthalene reagent. Subsequent lithiophosphide routes have given new chiral t-phosphines, e.g., (151).'95Treatment of ethynylphosphines, e.g., (152), with copper(I1) acetate in pyridine, has given a series of macrocyclic alkynylphosphines, (153), involving 1 5 , 20-, 2 5 , and 30-membered rings.'96The 3-membered ring system (154) is formed in the reaction of a tetramethylcumulene with in situ generated [PhP-W(C0)5].197Routes to new chiral phosphinoferrocenes, e.g., (155), have

e n N-P,

But'

CI CI'

<

(147) A r = 4

(146)

F F

-L

OH

(148)

PnPAr2

P-CI

(149)

(1 50)

(151)

been developed, involving the reactions of lithioferrocenes with borane-protected chiral p h o s p h i n i t e ~ . ' ~The ~ ~ 'new ~ ~ chiral dicyclopentadienylzirconium enolatodiphosphine (156) has been prepared by metallation of cx-diphenylphosphino-D-camphor, followed by treatment of the phosphinoenolate with dicyclopentadienylzirconium dichloride.*'' The reactions of azacrown-functionalised aryllithium reagents with dimethyl phenylphosphonite or triphenylphosphite have given the new phosphinoazacrown systems ( 157).201The previously

1 :Phosphines and Phosphonium Salts H

Ar-P

f #

H (152) Ar = 2,4,6-But&H2

17 P'

Ar

Ph

W(C0)s

(153) n = 1 - 4 o r 6

described phosphinophosphonous diamide (158) has been used as the key to a series of new chiral phosphinoarylphosphonites derived from chiral alcohols. Reduction to the primary phosphino-system (159) has also been achieved, enabling the synthesis of a wide range of new chiral o-diphenylphosphinoarylphospholanes via established lithiophosphide routes.202The primary phosphine (160, R = H) has been obtained by thermal disproportionation of endo-8-camphanylphosphinic acid, and converted into the related hydroxymethylphosphine (160, R = CH20H), by conventional treatment with f~rmaldehyde.~'~ Improved routes to the bicyclic systems (161) and (162), starting from tetrakis(hydroxymethy1)phosphonium chloride, have been reported.204The chiral bis(hydroxymethy1)phosphine (163) has also been prepared.205The reactions of hydroxymethylphosphines with primary amines have been used in the synthesis of new aminomethylphosphines, e.g., the macrocyclic system ( 164),206a series of pyridylaminomethylphosphines~07~208 e.g., (1 65),208 and dendrimers bearing aminomethylphosphine groups at the surface.209A series of chiral phosphinophosphito ligands, e.g., (166), has been obtained from the reaction of hydroxymethyldiphenylphosphine with chlorophosphite esters.210A very simple

Organophosphorus Chemistry

18

p h 2 +

OMe OMe

I

(167) R = H or Me

&

PPh2

@

(168)

/-

(169)

PBu'p

(170) n = O o r 1

route to the ferrocenylmethylphosphines (167) is afforded by treatment of the related dimethylaminomethyl derivatives with di-t-butylphosphine.2'1,212 A route to the silica-supported chiral diphosphinoferrocene (168) has been developed.213 Metallation of an imino(phosphino)ferrocene system, followed by treatment with dimethyl disulfide, is the key step in the synthesis of the chiral system (169),and related compounds.214Various routes to the cationic phosphinocobaltocenium system (170) have been explored.215The diphosphine (171) has been prepared by treatment of the related bis(bromomethy1)nitrobenzene with di-t-butylphosphine, followed by sodium acetate.216 A comprehensive review of the synthesis and general chemistry of silylphosphines has appeared.217Routes to diorgano(trichlorosily1)phosphines have been developed.218A route to perfluoroarylphosphines, e.g., (172), is afforded by the reactions of fluoroarenes with either dimethyl(trimethylsily1)- or dimethyl(trimethylstannyl)-phosphine~19 In a similar manner, primary, secondary, and tertiary phosphines, and their trimethylsilyl analogues, have been shown to react with pentafluoropyridine to give a range of tetrafluoropyridylphosphines.220The synthesis, coordination chemistry, and catalytic applications

1 :Phosphines and Phosphonium Salts

19

of a series of perfluoroalkyl-substituted phosphine ligands have also been reviewed.221 Interest has continued in the synthesis of water-soluble phosphines for use in catalysis under aqueous conditions. New water-soluble systems have been prepared, including N-(4-diphenylphosphino)phenylmethylgluconamide~22 various calixC41arenes bearing a tertiary phosphine group on one rim and a methoxyethylene glycol group on the other,223and the polyoxyethylene systems (173).224Elaboration of side-chains or functional groups present in phosphines has been widely exploited in the synthesis of new systems. Treatment of 2,6dimethylphenyldiphenylphosphinewith an osmium(1V) complex results in the The borane-protected diphosphine (175) formation of the diphosphine (174).225 has been obtained by a ruthenium-catalysed ring-closing olefin metathesis reaction on a borane-protected 1,2-bis(diallylphosphino)ethane~26 The chiral phosphinobinaphthyl esters (176) have been prepared by acylation of the related phosphinobinaphth01.2~~ A range of new chiral diphosphines (177), with tuneable bite-angles, is accessible by demethylation of the related dimethoxyphenyldiphosphine, followed by cyclic ether formation.228Elaboration of aldehyde - or carboxylic acid - groups of the simple ferrocenylphosphines (178) has given new chiral systems, e.g., ( 179)229 and (180).230 Related chemistry with o-diphenylphosphinobenzoic acid has given a range of new chiral amidophosphine e.g., (181),234and similar systems have been prepared by Trost's group from

(176) R = Pri2N or Bu'CH2

@

(179)

(177) n=1-6

(178) X = CHO or C02H

20

Organophosphorus Chemistry

diphenylphosphinonaphthalene carboxylic acid derivatives.235 Formation of amide links is also the key step in the attachment of p-diphenylphosphinobenzoic acid to a chiral polypeptide in the synthesis of a PEG-supported chiral diphosphine based on a diaminobinaphthyldiph~sphine?~~ in the attachment of an ortho-aminophenylphosphine to a calixarene system,238and in the synthesis of further examples of amides derived from P-aminoethylphosphines and diacid chlorides.239Schiffs base condensations of P-aminoalkylphosphines with heteroaryl aldehydes have given a range of new, hybrid donor ligands, e.g., (182).240Formation of imines from condensation reactions of o-diphenylphosphinobenzaldehyde continues to be exploited in the synthesis of new ligand systems, and a number of reports have appeared in the past year, including the synthesis of a series of diiminodiphosphine ligands derived from various chiral d i a m i n e ~ ?the ~ ~semicarbazone of the above ph~sphinoaldehyde:~~ a family of peptide-base iminophosphines, e.g., (183),243the hybrid diaminoiminophosphine (184)244and a related P-cyclodextrin-functionalised~ y s t e m . 2Condensation ~~ of o-diphenylphosphinobenzaldehydewith o-aminophenyldiphenylphosphinein benzene (but not in ethanol) gives the iminodiphosphine (185).246Each of the above imino-systems has the potential for reduction to the related aminoalkyl derivative, thereby providing an even greater variety of ligands. o-Diphenylphosphinobenzaldehyde has also been used in the synthesis of arylphosphines bearing chiral heterocyclic systems, e.g., (1 and (1 87),248the latter also able to be bound to a polystyrene support. A further example of a phosphino-azine ligand system (188) has been reported by Shaw's

1.2 Reactions of Phosphines. - 1.2.1 Nucleophilic Attack at Carbon. Interest has continued in developing the synthetic applications of the 1:l adducts of tertiary phosphines with dialkyl acetylenedicarboxylate esters. Protonation of the initial adduct from triphenylphosphine by phthalimide, followed by nucleophilic addition of the nitrogen of the resulting imido anion to the intermediate vinylphosphonium salt, has given the stabilised ylide system (189).250Similar reactions with isatin and 3-chlorotetrahydrofuran-2,4-dionehave given the yl-

1 : Phosphines and Phosphonium Salts

21

ides ( 190)251 and ( 191),252 respectively. The initial adducts of triphenylphosphine with alkyl propiolate esters also undergo similar reactions; in the case of the above furandione, the ylide (192) is formed via a [4 + 2) cycloaddition of the stabilised ylide with more of the propiolate ester, providing an example of the hitherto unknown furo[2,3-b]pyran The zwitterionic system (193, X = 0) has been obtained in 12% yield from the reaction of the tributylphosphine-dimethyl acetylenedicarboxylate adduct with carbonyl sulfide. The related thiocarbonyl derivative (193, X = S) was similarly obtained, but in only 3% yield, from the reaction of the initial adduct with carbon d i s ~ l f i d e Highly .~~~ functionalised unsaturated y-spirolactones have been obtained from the reaction of the triphenylphosphine-dimethyl acetylenedicarboxylate adduct with orthoand para-quinones, the phosphine being regenerated during this process.254 Metallated heterocyclic phosphonium systems, e.g., ( 194)2s5have been isolated from the reactions of allenylidene- and alkynylcarbene-metal complexes with p h o ~ p h i n e s ? ' Two ~ , ~ ~systems ~ have been devised for the scavenging of triphenylphosphine (and triphenylphosphine oxide) from reaction mixtures, which entail the use of either the Merrifield resin (converted into the iodobenzyl form)257 or a PEG-system (195) functionalised with chlorotriazine sites.2s8 0 PPh3

0

(189) R = alkyl

(190) R = alkyl

(192) R = Me or Et

I .2.2 Nucleophilic Attack at Halogen. A series of perfluorinated phosphoranes having two or three P(V) centres, e.g., (196), has been obtained by the solution phase direct fluorination of di- and tri-ph0sphines.2~~ Adducts of the heavier halogens with phosphines have continued to attract attention. A FT-microwave spectroscopic study of the PH3-Br2adduct has been reported.260The reactions of ferrocenyl(pheny1)phosphineswith iodine have been investigated using conductimetric titration techniques, together with 57Fe-Mossbauerspectroscopy, the products being iodophosphonium salts, the oxidation state of the iron in the ferrocenyl substituents being unchanged.261The adduct of an o-carboranyldialkylphosphine with iodine has been shown to have the familiar 'molecular spoke' structure, R3P- - I - - - I, the iodine-iodine bond length (3.021 A) being the shortest on record, attributable to the electron-withdrawing character of the o-carborany1 substituent.262Phosphine-positive halogen systems continue to find applica-

22

Organophosphorus Chemistry

(196) RF = CF3 or CF3CF2

(197) X = CI or Br

tions in synthesis. Following the discovery that the commercially available diphosphine ‘diphos’ (Ph2PCH2CH2PPh2)offers advantages over triphenylphosphine in Mitsunobu and Staudinger procedures, it has now been used in conjunction with carbon tetrahalides for the conversion of primary and secondary alcohols into the related haloalkanes, the advantage being that the diphosphine oxide precipitates out from the reaction mixture, thereby aiding w o r k - ~ pThe .~~~ triphenylphosphine-carbon tetrachloride system has now been applied in an improved method for the synthesis of ethynylferr~cene;~~ and for the halogenation of alcohols in the TADDOL series.265A triphenylphosphine-bromotrichloromethane-tetramethylguanidine system has been used to promote the direct polycondensation of carbon dioxide with various diols, giving polycarbonates.266Combination of N-chlorodiisopropylamine with triphenylphosphine gives a reagent system for the chlorination of hydroxyl groups in nucle~sides.~~’ A one-step synthesis of azetidin-2-ones is provided by the reactions of imines with carboxylic acids in the presence of the triphenylphosphine-trichloroacetonitrile-triethylamine system.’6s The triphenylphosphine-N-halosuccinimide system, leading to the phosphonium salt (197),has also been employed for the halogenation of and also in a new procedure for the preparation of para-substituted benzohydroxamic acids.270The stereochemistry of the bromination of various dialkyl-3-hydroxyoxepanes in the presence of several tertiary phosphine-bromine reagents has been in~estigated.~’~ Stereoselective reduction (debromination) of a-bromopenicillanates has been achieved by treatment with tributylphosphine in Combination of triphenylphosphine with 2,4,4,6-tetrabromo-2,5-cyclohexadienone gives a reagent system that has been used to convert aldehydes into the related geminal dibromides, and ketones into vinyl A kinetic study of the debromination of vicinal-dibromides in the presence of various trivalent phosphorus compounds has been reported, and mechanistic implications considered.274Terminal diols of cyclic and acyclic saccharides have been converted into related epoxy- and alkenyl-derivatives on treatment with triphenylphosphine, imidazole, and iodine.275 1.2.3 Nucleophilic Attack at Other Atoms. The reaction of tetra-t-butylcyclotetraphosphine with dry air gives rise to the corresponding monoxide. In contrast, oxidation with hydrogen peroxide gives a mixture of oxocyclotetraphosphines, which includes the monoxide, two isomeric dioxides, a trioxide, and the tetraoxide.276Transfer of oxygen from oxovanadium(V) and oxorhenium(V) complexes to phosphorus has been studied for triphenylph~sphine,?~~ and for the monoxidation of a,w-bis(diphenylphosphino)alkenes.z78The kinetics and mechanism of the autoxidation of phosphines, catalysed by imidorhenium(V) complexes, has also been inve~tigated.’~~ A review of oxygen-transfer reactions in-

1: Phosphines and Phosphonium Salts

23

cludes coverage of the intramolecular conversion of the o-phosphinonitrone (198) into the o-iminophosphine oxide ( 199).280Tertiary phosphine-borane adducts (i.e., R3P -+ BH3) have been used as pro-ligands for the synthesis of phosphine complexes of transition metals, the key point being the sacrificial oxidation of the borane unit by the metal ion in a higher oxidation state, resulting in a pure complex of the phosphine with a reduced metal ion. This avoids the wasteful oxidation of sacrificial phosphines in direct reactions with higher oxidation state metal salts.281New organoborane-phosphine complexes have been obtained by the insertion of carbenes into the B-H bonds of the related complexes of BH3and monoorganoboranes.282Intramolecular coordination from phosphorus to boron in the a-phosphinoalkylboranes (200) is clearly demonstrated by their products of pyrolysis under various conditions, giving the heterocyclic systems (201).283Phosphine adducts of various trivalent boron compounds have also been c h a r a c t e r i ~ e d . ~Treatment ~ ~ - ~ ~ ~ of the diphosphine (185) with an equimolar amount of sulfur results in the preferential formation of It is well known that trivalent phosphorus the diphosphine mono-sulfide (202).287 compounds can be used to desulfurise thiones, leading to the formation of carbon-carbon double bonds. A reaction intermediate has now been isolated on this pathway, treatment of the diphosphinothione complex (203) with tricyclohexylphosphine giving the dipolar system (204), clearly demonstrating nucleophilic attack at sulfur.28sCleavage of the sulfur-sulfur bond of disulfides by triphenylphosphine has been used for the synthesis of a range of oaminothiophenols, subsequently used in heterocyclic

(200)n = 3 or 4

(199)

(201)R = H or But

R2

(203) [Mn]

= Mn(C0)4+

Interest in the Staudinger reaction of phosphines with azides, and the Mitsunobu reaction involving nucleophilic attack by phosphorus at nitrogen in esters of diazodicarboxylic acids, has continued. Systems of the type (205) have been obtained from the reactions of secondary arylphosphines with a ~ i d e s . ~ ~ ' , ~ ~ ' Treatment of these with butyllithium results in deprotonation to form the diaminophosphonium diazaylides (206).291 Phosphazenes have been prepared from azido-q~inolines~~~ and -triazine~:~~ and also from dia~oket0ne.s~~~ and polycyanocyclopropanes?95The Staudinger reaction has been employed in the synthesis of phosphorus-containing d e n d r i m e r ~ ?and ~ ~ .in~ ~ new ~ approaches to amide298and ~ e p t i d synthesis. e ~ ~ ~ The reaction has also been used in a high-

Organophosphorus Chemistry

24 N-R Ar2P,

N-R 1,’ Ar2Pi,- Li’ N-R

/

NHR (205) Ar = Ph or 2-pyridy1, R = Me&

CN, COR or COAr

(206)

yielding one-pot solution-phase and polymer-supported synthesis of primaryStudies of the mechanand secondary-amines, via a tandem aza-Wittig ism of the Mitsunobu reaction using the chiral (S)-cyclohexylmethyl(l-naphthy1)phosphineindicate that routes via an intermediate phosphorane or a phosphonium salt in the second stage are in competition. Much depends on conditions, and the order of addition of reagents.301Interest is growing in the use of polymer-supported reagents in Mitsunobu procedures, particularly with respect to the ease of separation of products. The soluble polymeric phosphine (145) is highly effective in combination with diethyl azodicarboxylate in promoting the reactions of secondary alcohols with p-nitrobenzoic acid, which proceed with inversion of configuration at the alcohol carbon. This phosphine does not suffer disadvantages in the rate of the reaction compared to other polymersupported phosphines. The phosphine oxide side-product can be precipitated out from the reaction mixture simply by addition of methanoL302Stereochemical inversion of secondary alcohols has also been observed in Mitsunobu procedures involving other polymer-bound triarylph~sphines.~’~ A further development of this theme is the use of dinorbornenyl diazodicarboxylate in combination with diphenylphosphinopolystyrene.Not only is the polymeric phosphine oxide easily separated, but the hydrazine dicarboxylate side-product can also be converted into an easily separated polymeric system on treatment with a ruthenium carbene catalyst.304Conventional Mitsunobu procedures have been applied in a wide range of synthetic procedures including the formation of phenolic ethers305and ether linkages in dendrimer ~ynthesis,~’‘the N-alkylation of sulfonarnide~~” and hydr~xylamines,~’~ a new route to protected a-hydrazinoesters in high optical purity,’” the stereoselective synthesis of cis-4,5-disubstituted piperidin-2-ones;” a route to new asymmetric phosphonylated thia~olines,~~’ and in promoting skeletal rearrangements of an isocaryolane se~quiterpenoid.”~ A combination of tris-p-chlorophenylphosphine with diisopropyl azodicarboxylate promotes the selective formation of monophosphate esters from a polyhydric alcohol and dibutylpho~phite.’~’ Mitsunobu-like alternative systems involving cyanoalkylidenephosphoranes have found further application in the synthesis of thioe~ters’’~ and iri C-alkylation reactions.’15 I .2.4 Miscellaneous Reactions of Phosphines. The design of new phosphine ligands, and the application of phosphines in general as ligands in homogeneous catalysis, continues to be a major area of activity, and the past year has seen the appearance of a number of reviews, covering the ligating abilities of 1,l’bis(diphenylphosphino)ferrocene?l6 ‘wide-bite’ diphosphines,3” phosphinooxazoline ~ysterns,”~ and (2-f~ryl)phosphines.~’~ Theoretical considerations of the donor-acceptor properties of tervalent phosphorus compounds have continued to appear.320,32’ An X-ray study of the P,P-diphosphine (207, R = CH(SiMe3)*)in the solid state shows the longest P-P bond known for such

1: Phosphines and Phosphonium Salts

25

diphosphines, although in absolute terms the increase in length is not large compared to many others. However, in the vapour phase, (and also on melting or dissolution), this molecule dissociates readily to form the dialkylphosphino radical, R2P., the structure of which has been studied by electron-diffraction in the gas phase. As most diphosphines of type (207), even those with bulky substituents, retain the P-P bond under the above conditions unless activated by UV-irradiation, it has been suggested that the bis(trimethylsily1)methylgroups pack in a spring-like manner in the solid state, but when the constraints of the solid state are removed, the molecule is forced apart, effectively a molecular ‘Jack in the Ultraviolet irradiation of tetraphenyldiphosphine (207, R = Ph) has been used as an initiator for the free radical polymerisation of methyl metha~rylate.3~~ The diphenylphosphino radical has been trapped by a series of stable free Dye-sensitised photo-oxidation of tertiary phosphines, to give the radical cation, R3P+.,has received further attention, and the reactivity of these intermediates s t ~ d i e d .The ~ ~basicity ~ , ~ ~ of ~ the medium ring bicyclic phosphines (208H210) has received detailed study. Whereas the basicity of (208) is comparable to that of tri-(t-butyl)phosphine, as a result of the enlarged bond

n (207)

(208)

angles at phosphorus, the bicyclic systems (209) and (210) are significantly stronger bases. This has been attributed to the possible formation of ‘in-out’ cations, involving intramolecular P: + P+ coordination, as a result of pyramidal inversion at the unprotonated Schiemenz et al. have issued a note of caution concerning the uncritical use of 31PNMR data, and, to some extent, X-ray structural data, to support the suggested existence of hypervalent intramolecular N --* P coordination in (2-dimethylaminomethyl)phenylphosphines, e.g., (21l), and the 1,8-naphthalene system (212).In the latter, the geometry of the naphthalene ring system forces the 1,8- substituents together, and a short N-P distance is an inevitable consequence, with considerable distortion of the Clo ~ k e l e t o n .The ~ ~ ~electronic ’ ~ ~ ~ effects of the nido-o-carboranyl substituent have been studied in nido-~-carboranylmonophosphines~~~ Interest continues in the mechanism of the ring-chain rearrangement of phosphirane, and a recent theoretical study shows that phosphirane ring-opening induced by C-P cleavage is accompanied by hydrogen migration from carbon to phosphorus, yielding vinylphosphine. In contrast, a related ring-opening of silirane follows a different mechanism, involving a silylene intermediate.331The chiral diphosphine system (213) has been obtained via an asymmetric Diels-Alder addition between the furan system of 2-furyldiphenylphosphine and divinylphosphine in the presence of a chiral metal complex template.332Complexes of long-chain a-alkenylphosphines, e.g., (214),have been shown to undergo metal template-promoted cyclisation to form macrocyclic complexes, e.g., (215), in the presence of an olefinmetathesis Coordination of pentafluorophenylphosphines to a metal

Organophosphorus Chemistry

26

Bu' I

.p\ (Me@i)& -.Ga P-Bu' 'PI I

Ph2P

Bu'

H

(216)

(215)

has been shown to promote clean nucleophilic displacement of the para-fluorine atoms.334A new gallium-phosphorus heterocyclic system (216) has been isolated from the reaction of tri-(t-buty1)cyclotriphosphine with a polysilylated gallium(1) compound.335The P-complexed phosphinodithioformate (217) has been shown to undergo S-alkylation, giving new phosphine systems, e.g., (218) and (219).336 The sulfonation of triphenylphosphine using sulfur trioxide has been optimised giving the tris(su1fonated)phosphinein 90% The related trisodium salt has been shown to form inclusion complexes with f3-cyclode~trin.~~' Vinylfunctionalised triarylphosphines have been prepared and subjected to anionic block copolymerisation with styrene.339Similarly, the vinyl-functionalised triphosphine (220)has been copolymerised with styrene to give the first polymersupported tripodol triphosphine ligand.340It has been shown that x-delocalisation in the diazaphospholenes (221) not only weakens the P-H bond but also causes an umpolung of its pattern of reactivity, the hydrogen being hydridic, and phosphorus the positive centre. The P-H bond displays inverse regioselectivity in its addition to benzaldehyde, and on treatment with trityl tetrafluoroborate the phosphenium ion (222) is formed.341 R'

(218) R' = Me or NH2, R2 = H or Me

II

2

(221) R' = H or CI, R2 = But or Mes*

Phosphine Oxides and Related Chalcogenides

2.1 Preparation. - The diphosphines (223) can be oxidised to the related dioxides on treatment with oxygen or hydrogen peroxide. Treatment of the diphosphine (223, R = Ph) with an excess of sulfur in hot toluene affords the corresponding bis(su1fide). X-ray studies of representative dioxides and the above disulfide reveal considerable steric strain in the molecule, resulting in out of plane displacement of phosphorus atoms.342The reaction of (223, R = Ph) with an

27

1 : Phosphines and Phosphonium Salts PR2

PR2

I

Ph2P=Se PPh2

c!-JtJ

I

(223) R = Me, Et, P i , Cy, Bu' or Ph @P -P2i

(225)

S

II

Fe I

(224)

Ph2p_/Fph2

E

E = 0,S or Se

(227) n = O o r 1

(226)

excess of selenium affords only the monoselenide (224).NMR studies of the latter have revealed a possible through-space coupling between the trivalent phosphorus and the selenium A series of ferrocenyldiphosphine chalcogenides (225) has been prepared by conventional routes from the parent diphos~ h i n eThe .~~ disulfide ~ (226) has been obtained from the related tetraphosphine by treatment with sulfur in Borane adducts of chiral trivalent phosphorus compounds have been shown to undergo chemo-, regio-, and stereoselective conversion into the related phosphorus oxides and sulfides on treatment with either t-butyl hydroperoxide or This approach has also been used for the synthesis of chiral diphosphine dioxides, e.g., (227).347 A route to secondary phosphine oxides, R2P(H)=0, is offered by the reduction of phosphinyl chlorides, P,P-diphosphine dioxides, and phosphinic acid anhydrides, using alkali The synthesis of calixarenes bearing carbamoylmethylphosphine oxide groups on either upper or lower rim has been reviewed.349 Full details of the synthesis of chiral phosphine oxides (228) have appeared.350Treatment of aryl esters and amides of phosphinic- and thiophosphinic- acids, with lithium diisopropylamide at -78 "C, results in a molecular rearrangement to give chiral functionalised arylphosphine oxides and sulfides. Thus, e.g., the ester (229) gives the chiral system (230),and the thioamide (231) gives the phosphine sulfide (232). Me0

& \

d/'R

0

OMe

I

(228) R = Ph or Pr

Ph

@ / (229)

Ph

OH (230)

N-H

(231)

(232)

The reactions proceed with retention of configuration at p h o ~ p h o r u s .Various ~~' classical routes to alkylphosphine oxides have been applied in the synthesis of a range of potentially chelating and pincer-like ligands, e.g., (233),352,353 the binaphthy1 system (234),354 the hybrid phosphine oxide-N-oxide (235),355 and the chiral pyridine bis(phosphine oxide) (236).356 A route to diarylmethylphosphine oxides is afforded by the palladium-catalysed reaction of aryl bromides with tetrakis(hydroxymethy1)phosphonium chloride in the presence of a base.357The diastereoisomeric system (237) has been isolated from the reaction of a cyclic

Organophosphorus Chemistry

28 0

Ph

Ar2P Ph2P=O O=PPh2 (233)

0 (234) Ar = Ph or Me2NC6H4-p

0

0

.. I I" Bu'

0

(235)

0 (236)

0

R

(238) R' = Ph, R2 = But

(237)

(239) R3 = R4 = alkyl or aryl

phospholanium ylide with 8-phenylmenthyl e n o a t e ~ . ~In~ ' the presence of a lithiating agent, the allylic phosphine oxides (238) undergo Michael additions to ap-unsaturated esters, and related compounds, to form functionalised cyclopenThe Arbuzov reaction between N-(a-bromoaltylphosphine oxides, e.g., (239).359 ky1)phthalimides and ethyl diphenylphosphinite is the initial step of a route to the a-aminoalkyldiphenylphosphineoxides (240), from which a series of phosphonoalkyl derivatives of azacrown ethers, e.g., (24l), has been d e r i ~ e d . ~ ~ ' > ~ ~ ' Treatment of the phosphine oxide (242) with selenide anions results in the medium-ring heterocyclic systems (243). Subsequent reduction of (243, II = 2) and alkylation at selenium, using a variety of bridging groups, has given a range of macrocyclic systems, e.g., (244).362 A copper(1) triflate template cyclisation of 1,2-bis(phenylphosphino)ethanewith bis(haloalkanes), followed by removal of the copper and oxidation at phosphorus, has given the macrocyclic systems (245).363The new chelating diphosphine oxide ligand (246) has been obtained 0

0 II

H2N-(CH2),-PPh2

(240) n = 1-5

Ph

(243) n= 1 o r 2

(241) n = 1-5

29

I : Phosphines and Phosphonium Salts 0

0

II

II

ph2pMpph2 Na+ Ph2Pn

(245) R =

or

c

N\N/N

I1

Ar/

N

PPh2 II

E

(247)E = O o r S

F

OH

from the reaction of 1,2-bis(diphenylphosphinoyl)ethyne with sodium a ~ i d e . ~ ~ ~ Mono-imination, followed by oxidation at the second phosphorus, is the most practical route for the synthesis of the hybrid ligand systems (247),the first P-phosphinomethyl-hs-phosphazenes.365 These have been shown to suffer cleavage of the central P-C-P bridge on treatment with aqueous Various functionalised arylphosphine oxides, e.g., (248),367 (249),368 and (250),369 have been prepared, and used in the synthesis of polyarylene phosphine oxide systems involving imide or phenolic ether linkages. Treatment of a mixture of an alkyl halide and benzyl chloride with red phosphorus, in the presence of aqueous base and a phase-transfer catalyst, has given a mixture of all of the various possible alkyl/benzylphosphine oxides in a single Routes to new heteroarylphosphine oxides and sulfides have also been d e s ~ r i b e d . ~ ~ ' , ~ ~ ~ 2.2 Reactions. - Reviews have appeared covering the generation and uses in synthesis of a-phosphonovinyl carbanions, e.g., (25 1),373and also of hyA kinetic study of the drohalogenation reactions of allenylphosphine hydrolysis of styryldiphenylphosphine oxide under various pH conditions has A convenient method for the reduction of the double bond of been cyclic vinylphosphine oxides, using borane, has also been The azaphosphorinane oxides (252) have been obtained by the addition of primary amines to phenyldivinylphosphine A range of iminoalkylphosphine oxides (253) has been obtained from the Schiffs base reactions of aminomethyldimethylphosphine oxide with aromatic aldehydes.378The carbamoyl-functionalised systems (254) have been derived from the reactions of the isomeric aminophenoxymethyldimethylphosphine oxides with isocyanates and isothiocyanates, respectively.379The Williamson reaction of chloromethylphosphine oxides has received further study, using the frontal steric effect Tosylation of hydroxymethyldiphenylphosphine oxide, followed by treatment with potassium fluoride, provides a route to the fluoromethylphosphine oxide

Organophosphorus Chemistry

30 R

0

)-p

Y

II

X (251) X = OR, SR or alkyl,

Y = SR or alkyl

(252) R = alkyl

(256)

(253)

(257) R = Me, Et or Pr'

(255), which has then been applied as a reagent for the synthesis of 1-fluorovinyl system^.^^'.^^^ Cycloaddition reactions of unsaturated phosphine oxides continue to attract attention. A single stable isomer (256) of the Diels-Alder adduct of pentaphenylphosphole oxide with benzyne has been structurally characteri ~ e d Preparative-scale . ~ ~ ~ photolyses of related compounds, bearing bulky Psubstituents, in alcohol solvents, have given a series of aryl-H-phosphinates e.g., (257), and overall the results are consistent with a mechanism involving a pentacoordinate adduct involving the alcohol and the P=O bond, rather than a c ~ ~ h ~ - i n t e r m e d i aFurther t e . ~ ~ ~examples of cycloaddition reactions involving the P=O bond of both cyclic and acyclic phosphine oxides have been described by Keglevich's g r o ~ p . ~ ~ ~ , ~ ~ ~ Allenyldiphenylphosphine oxide undergoes cycloaddition with cyclic dienes to form adducts of the type (258).387The allenyldiynylphosphine oxides (259) have been shown to undergo a cobalt-mediated [2 + 2 + 21 cycloaddition, to give the phosphine oxides (260) in a completely regio-, chemo-, and diastereoselective manner.388The reactions of C-lithiated phosphine oxides continue to be exploited. Further Wittig-Horner chemistry has been reported by Warren's The P-hydroxyalkylphosphine oxides (26l), obtained by treatment of lithiated methyldiphenylphosphine oxide with aromatic aldehydes, have been oxidised to the related P-ketophosphine oxides (262). The latter are also accessible from the reactions of lithiomethyldiphenylphosphine oxide and carboxylic acid chlorides. Reduction of (262) using a chiral boraneoxazaborolidine system enabled the isolation of the alcohols (261) in chiral form.39oLithiation of the hydrazonylphosphine oxides (263), followed by alkylation with an ester of an a-haloalkanoic acid and base-promoted cyclisation, affords a route to phosphine oxides bearing heterocyclic substituents, e.g., (264).391A range of functionalised 1,2-alkadienylphosphine oxides has been obtained by treatment of lithiated allene-phosphine oxides with electrophilic

1 : Phosphines and Phosphonium Salts

31

reagents.392Interest in hydrogen-bonded adducts of phosphine oxides continues to grow. A range of novel H-bonded supramolecular systems has been characterised from the interaction of the chiral diphosphine dioxide (265) and tetrafluoroboric An adduct of 1,2-bis(diphenylphosphinoyl)ethaneand the bis(hydroperoxide) 'ketal' of acetone has been obtained from the direct oxidation of diphos with hydrogen peroxide in acetone, catalysed by diorganotin dihalides. Other phosphines and diphosphines failed to give such adducts under the same The extent to which aliphatic alcohols H-bond to trioctylphosphine oxide has been studied by a gas-chromatographic approach. Experimental data fit to a 1:l alcohol-phosphine oxide adduct, with assocation constants in the order primary alcohols > secondary alcohols > tertiary Hydrogenbonded adducts fully characterised by crystallographic studies include a 1:1 triphenylmethanol-triphenylphosphineoxide a hydrated adduct of triphenylphosphine oxide and p-chlorobenzoic and a molecular complex of triphenylphosphine oxide and nitric The chiral secondary phosphine oxide (266) has been resolved into its enantiomers using the hydrogen-bonded adduct formed with mandelic acid. Also noted was the conversion of the above secondary phosphine oxide into the related phosphinous chloride simply by heating it with carbon tetrachloride, rather than with the usual carbon tetrachloride-triethylamine system.399Secondary phosphine oxides have also been used as air-stable ligands which tautomerise during complex formation to give transition metal complexes of the related phosphinous acids, R2POH.400Diphenylphosphine oxide has been used as an alternative to tributyltin hydride to promote radical cyclisation reactions of 1,6-dienes, in the presence of carbon tetrachloride."" The acylphosphine oxides (267) and (268) have found use as photoinitiators for the radical polymerisation of acrylate monomers.4o2Chlorophosphonium salts have been obtained by treatment of phosphine oxides with phosphorus oxychloride in ben~ene.4'~ Combination of triphenylphosphine oxide and tosyl chloride in pyridine provides a new condensation reagent system, which has been applied in the polycondensation of aromatic dicarboxylic acids and d i p h e n o l ~ .Charge-transfer ~~ adducts of the disulfides of a,w-bis(phosphino)alkanes with iodine have been characterised in the solid state? Triarylphosphine selenides, including a polymer-bound system, have been used as selenium-transfer agents for the conversion of H-phosphonate diesters and phosphite triesters into the related phosphoroselenoate derivatives, of interest in nucleoside chemistry.N6

0

t

Ph2PCH2CH(OH)Ar

Ph2PCH2COAr

(261)

(262)

(265) Ad = 1-adamantyl

32

Organophosphorus Chemistry

2.3 Structural and Physical Aspects. - The stability of the various conformers of the phosphines oxides (269)-(271) has received theoretical ~ 0 n ~ i d e r a t i o nA. 4 ~ ~ new triclinic polymorph of triphenylphosphine sulfide has been structurally characterised, together with a related triclinic polymorph of triphenylphos~ h i n e . ~Two ' ~ reports of the solid state crystal structure of the phenolic phosphine oxide (272) have appeared.409,410 A crystallographic study has confirmed that the product of electrochemical oxidation of o-diphenylphosphinobenzenethiol is the disulfide-bridged bis(phosphine oxide) (273).411 Solid-state structural studies of the dioxides (274):12 the (R)-(+)-isomer of (275),413 1hexynyl(dipheny1)phosphine tribenzylphosphine and tris(tbuty1)phosphine se1enide,4l6have also been reported.

Me&OH

PPh2 Ph2P II

0

0 (273)

0

0

II

I1

Ph2P-(CH2),-PPh2 (274)

n = 2-8

(275)

2.4 Phosphine Chalcogenides as Ligands. - Adducts of tris(pentaf1uorophenyl)borane with a range of phosphine oxides and oxophosphorus(V) ester donors have been characterised, including a full structural study of the triphenylphosphine oxide a d d ~ c t . ~Phosphine " oxide complexes of lanthanide ions continue to attract attention, and complexes of simple t-phosphine oxides with lanthanum:'* lanthanide nifrate~,4'~ and scandium and yttrium4*0have been described. An erbium complex of the bis(phosphinoylmethy1)-functionalised macrocyclic ligand (276) has been ~haracterised.~~' The aminoalkylphosphine oxide ligands (277), (278), and triphenylphosphine oxide, have been shown to form complexes with the beryllium cation, Be2+,this work also providing the first X-ray crystal structural characterisation of a beryllium-phosphine oxide com~ l e xRhodium(1) . ~ ~ ~ complexes of the 2-pyridylphosphine oxides (279) have been characterised, and their behaviour as hydrogenation catalysts investigated.423 Interest in complexes of phosphine oxides with tin(1V) acceptors has also continued, with a spectroscopic study of complexes of substituted arylphosphine oxides with tin tetra~hloride,4*~ and the preparation of organotin halide complexes of bis(diphenylph~sphinoyl)alkanes!~~ Further studies of triphenylphosphine oxide complexes of diphenyltin dichloride and diphenylantimony trichloride have also been reported.426Complexation of triphenylphosphine oxide to the sodium ion, (already present in the form of a phthalocyaninate complex) has been described.427Polymeric chain-like complexes of copper(II), involving bridg-

33

1:Phosphines and Phosphonium Salts

(Ph2PCH2)3N 0

(Ph2PCH2CH&N 0

(277)

(278)

a

!

P

h3-"

(279) n = 2 o r 3

ing bis(diphenylphosphinoyl)ethane, have been fully characterised!28 Heterobimetallic complexes of the monoxide (280, X = 0)of diphos, involving palladium and a second metal, have been ~ r e p a r e d . 4Palladium ~~ complexes of the The related hybrid P,S-donor ligand (280,X = S) have also been ~haracterised.~~' phosphinoyldithioformate system (281)has attracted interest as a hybrid donor ligand. Complexes with organolead(1V) acceptors have been characterised, the preferred coordination mode being bidentate through oxygen and sulfur. The anionic ligands themselves have also been fully characterised in the form of tetraphenylphosphonium Interest continues in the coordination chemistry of phosphine chalcogenides based on the ferrocene nucleus. Complexes of the dioxide (282, X = 0)with ~ i l v e r ( I )and ~ ~ ~of, the diselenide (282, X = Se) with silver and gold;43 have been prepared. Further studies of the coordination chemistry of the hybrid donor system (283) have also been reported.434A sulfurbridged diplatinum complex of cyclopentadienyldiphenylphosphinesulfide has been chara~terised,"~~ and the crystal structure of a triphenylphosphine sulfide complex of niobium pentachloride Three types of cluster complexes have been prepared from the reactions of the tetraalkyldiphosphine disulfides (284) with dicobalt 0ctacarbony1.4~~ Cluster complexes have also been isolated from the reactions of triphenylphosphine selenide with osmium and a trinuclear ruthenium complex has been obtained from diphenyl(2-pyridy1)phosphine ~elenide.4~~ Gold(1) complexes of a range of trialkyl- and triaryl-phosphine selenides have been fully characterised by elemental analysis, infrared, and 31P NMR spectroscopy.40 x

S &b(Ph2

I

Fe X

@PPh2 I t

II

Ph2PCH2CH2PPh2 (280)

3

(281) R = Ph or PhCH2

X (282)

I

Fe

@PPh* (283)

(284) R = Me, Et, Pr or Bu

Phosphonium Salts

3.1 Preparation. - The tritylphosphonium salts (285) have been prepared by treatment of triarylphosphines with a trityl tetra(fluoroary1)borate reagent. An X-ray study of the salt from tris-(p-anisy1)phosphineshowed a very long phosphorus-trityl bond, ca. 1.93 A, attributable to steric repulsion, and also considerable distortion from the expected tetrahedral geometry at phosphorus.a' A

34

Organophosphorus Chemistry

Ar36-CPh3

L

CF? (285) Ar = Ph or panisyl Ph36 Br-

I

+

4-4--Y% (287)

+PPh3

Br-

PMe3 Br-

(288) n = 8, 10 or 14

simple route to alkyltriphenylphosphonium salts is afforded by the reactions of alcohols with a slight excess of triphenylphosphine in trifluoroacetic acid, under r e f l u ~ Conventional .~~~ quaternization reactions of tertiary phosphines with alkyl halides have given phosphonium salts bearing an L-(N-benzoylalanyl) the substituent (286),443water-soluble phosphonioalkylcarborane chiral binaphthyldiphosphonium salts (287),445a series of salts bearing wdienylalkyl groups, e.g., (288), which are capable of polymerisation to give amphiphiles having a defined nanostructure,446new phosphonioalkyl-functionalised silsesquioxanes,447and further examples of phosphonioalkyL'stoppered' rotaxane structure^."^^ A series of phosphonium aryloxides (289) has been prepared by the reactions of the ylide Ph3P=CHR with the appropriate phenol in dry toluene or THF. Solid-state structural studies using neutron diffraction reveal extensive aggregation, largely as a result of the existence of very short C-H 0 hydrogen The radical anion-containing phosphonium salt (290) has also been prepared and used in the synthesis of charge-transfer Routes to the salts (291) have been developed, involving a palladium-catalysed * *

Ph3kH2R1-0

R3

R2 (289) R1 = H or Me, R2 = Ph or Bu', R3 = H or Me

A

r

2

N

+>

Ph4P -0-N

NHS03-

(290)

GC = C G 6 P h j BF4-

(291) Ar = pMeOC6H4

C-C coupling reaction between an arylalkynylstannane with p-bromophenyltriphenylphosphonium br0rnide.4~~ A stereoselective synthesis of (E)- and (2)allylphosphonium salts is afforded by the palladium-catalysed addition of triphenylphosphine to allenes, in the presence of an acid, the stereochemical

I: Phosphines and Phosphonium Salts

35

course depending on ~onditions.4~~ The diphosphonio-bridged dimeric porphyrin systems (292) have been prepared by a direct one-pot electrochemical oxidation of zinc (meso-tetraphenylporphyrin) in the presence of various diphos~ h i n e s . 4The ~ ~ per-silylated and per-stannylated phosphonium salts (293) have been prepared and characteri~ed.4~~3~~~ A method for the synthesis of a new class of phosphonium betaines (294) has been and their reactivity exNew phosphonium betaines have also been obtained from the phosphonium salt (295).459As usual, a wide range of new phosphonium salts involving unusual anions has been described in the past year, including benzyltriphenylphosphonium glutaconaldehydep6' salts involving bimetallic ani0ns,461,462 polyhalide anions,463i464 complex thioantimonate anions,465,466 a hexaazidoarsenate and the salt Ph4P+Sg' , which contains the cyclic radical anion S6'-.468 New phosphonium-tetrachloroborate and -tetrachloroaluminate salts have also been structurally c h a r a c t e r i ~ e d , and 4 ~ ~a~new ~ ~ ~low-temperature phase-change characterised in tetraphenylphosphonium per~hlorate.4~~ Formation of phosphonium salts as side-products has been observed in a LC-MS study of the methoxycarbonylation of ethene catalysed by triphenylphosphine-palladium c0mplexes.4~~

CI ( Me3E)4P+X-

(293) E = Si or Sn, X = BPh4 or OTf

R'3;-S-&iR4R5 -CR2R3

(294) R1 = Ar, R2-R5 = alkyl

'PPh3 CI-

HO -0

(295)

3.2 Reactions. - Attempted deprotonation of the salt (296) with sodamide results in the formation of the chiral N-phosphino-substituted iminophosphorane (297), the structure of which has been confirmed by X-ray techniques.473 Alder's group has continued to explore the chemistry of bridgehead diphosphorus systems, and has discovered remarkable 'in-out' configurational inversion in the reactions of bridgehead diphosphonium propellane systems, e.g., (298),with nucleophiles, which result in cleavage of the P-P bond. These studies have revealed that the energy barrier to pyramidal inversion at phosphorus is much lower than normal in such systems, and also highlight the effects of ring-strain on the behaviour of these c o m p o ~ n d s . 4Various ~ ~ ~ ~ alkyl~ ~ and alkenyl-triphenylphosphonium salts have been shown to undergo cyclometallation on an aryl ring on heating with platinum(I1) chloride in 2-

36

Organophosphorus Chemistry

Br-

(296)

0

N'

(297)

(299)

(298)

methoxyethan01.4~~ Phosphonium salts of the type (299),having a bulky group at the ring carbon attached to phosphorus, have been shown to undergo hydrodephosphoniation on treatment with methanol in the presence of DBU, with cleavage of the P-C bond, and ring-opening, to give N-acyl-a-amino acid The reactions of aroyl- and acyl-phosphonium salts, prepared in situ by combination of tributylphosphine and the appropriate acid chloride, have attracted new interest. Treatment of substituted aroyltributylphosphonium salts with samarium diiodide provides a route to 4-aroylbenzaldehydes, although some substituents in the initial aroyl chloride promote the formation of adiket0nes.4~~ The reactions of Grignard reagents with bis-phosphonium or mono-phosphonium cations generated in situ from tributylphosphine and a,adiacyl chlorides or w-chloroacyl esters result in the formation of symmetrical diketones or keto-esters, re~pectively.4~~ In the presence of a base in acetonitrile, the o-nitrobenzylphosphonium salt (300) combines with aryl isocyanates to form 2-aryl-2H-indazoles (301).480Treatment of the aminophosphonium salt (302) \1 fPPh3 BrI

4,

(304) R = alkyl

(305)

Ph

Ph

(307)

with a base in the presence of a palladium-phosphine complex results in the formation of 1-aryl-1H-indazoles (303).48 * The (2alkoxycarbonyloxybenzy1)triphenylphosphonium bromides (304) have been shown to undergo base-induced rearrangement (via the oxoarylphosphonium salt (305)), with elimination of triphenylphosphine oxide, to form the alkyl (2-hydroxypheny1)acetates (306) under mild conditions!82 Treatment of the acylaminoalkylphosphonium salts (307) with enamines, or f3-dicarbonyl compounds, in the presence of a base, results in the formation of a-functionalised glycines, with loss of triphenylpho~phine.4~~ Further applications of vinylphosphonium salts in heterocyclic ~ynthesis,"~~ and in the synthesis of polymeric phosphonium s y ~ t e m s , 4have ~ ~ appeared. Prop-2-ynyltriphenylphosphonium bromide has been used as a coupling reagent in peptide Phosphonium tosylates have been investigated as solvents for the Diels-Alder reac-

37

1 :Phosphines and Phosphonium Salts

tion of isoprene with various dienophiles, and found to have favourable properAlkylphosphonium salts have also been found to catalyse dehydrohalogenative siliconsarbon coupling reactions between alkyl halides and trichlorosilane!88 The reactions of alkyl thiocyanates with phosphonium azides result in a quantitative yield of the related alkyl a ~ i d eCyanomethyltrialkyl.~~~ phosphonium iodides have proved to be efficient reagents for the intermolecular N-alkylation of amines with alcohols, both in solution, and also in the solid pha~e.4~' Triphenylphosphonium bromide has been used as a mild and quantifiable source of hydrogen bromide for the chemoselective ring-opening of epoxides to bromohydrins. A polymer-bound phosphine-hydrobromide salt behaves ~imilarly.4~~ A polymer-bound arylphosphonium perbromide salt has been used as a para-selective monobrominating agent for activated aromatic comp o u n d ~ ! ~Triphenylphosphonium ~ perchlorate has proved to be an effective catalyst for the imino Diels-Alder reaction of aldimines with cyclopentadiene or 3,4-dihydr0-2H-pyran:~~Incorporation of tetrabutylphosphonium chloride into a potassium peroxomonosulfate catalyst system has a positive effect on the rate of free-radical polymerisation of alkyl metha~rylates.4~~ Benzyltriphenylphosphonium peroxomonosulfate has found use for the bismuth-catalysed oxidative deprotection of trimethylsilyl- and tetrahydropyranyl-ethers:95 for the oxidation of urazoles to triazolinediones under solvent-free and for the oxidation of allylic and benzylic alcohols, this reaction also being catalysed by bismuth ~hloride.4~~ Among other phosphonium salts used in oxidation reactions are benzyltriphenylphosphonium b r ~ m a t e : benzyltriphenylphosphonium ~~ perbutyltriphenyl0xodisulfate,4~~benzyltriphenylphosphonium dichromate?@' phosphonium dichr~mate,"~and benzyltriphenylphosphonium chlorochromate.502Further papers have appeared on the uses of various phosphonium borohydrides as selective reducing agents.503505

(309)

(308)

n = 2-6 or 8-10

(310) E = P, As or Sb

The phosphonium cation (308)' normally unstable in aqueous solution, can be stabilised by incorporation as a guest in a tetrahedral cluster anion [Ga4L6]12-, (involving a multidentate phenolic amide ligand), with which it forms a selfassembled supramolecular a d d u ~ t . ~The ' ~ a-hydroxyalkylphosphonium salts (309) undergo a carbon-to-phosphorus oxygen transfer during mass spectral fragmentation under electron impact conditions, each compound forming a very characteristic (M - 1) ion derived from triphenylphosphine Interest has continued in structural studies on arylphosphonium salts which reveal 'multiple phenyl embrace' intermolecular interaction^^'^^ 509 and the search for such interactions has now been extended to related arylarsonium A structural comparison of the group 15 'onium salts (310)has revealed the extent to which a hypervalent nitrogen 'onium atom coordinative interaction occurs as the

-

38

Organophosphorus Chemistry

nature of the group 15 element is varied. In general, the strength of this interaction increases as the group is descended.511Donor-acceptor complexes between tetraphenylphosphonium halides and iodoform have been characterised, the interaction involving the halide Lyotropic liquid-crystalline phase behaviour has been studied in a series of long chain alkyltrimethylphosphonium A paper electrophoresis method has been developed for the separation and analysis of mixtures of alkyltriphenylphosphonium ions.514Capillary electrophoresis methods have been used to study the host-guest binding of tetraphenylphosphonium and tetraphenylborate ions to c y c l ~ d e x t r i n s . ~ ~ ~

4

p,-Bonded Phosphorus Compounds

The influence of the steric and electronic effects of protective groups on the stabilisation of a wide range of low coordination number organophosphorus compounds has been reviewed.516The dichlorodiphosphene (311)has been charTreatment of acterised as a complex with a tungsten pentacarbonyl the cationic system (312) with tetrakis(dimethy1amino)ethene results in the formation of the stable radical cation (313),which is stable for days at -30 0C.518 The familiar diphosphene (314) has been shown to undergo cleavage of the phosphorus-phosphorus double bond on treatment with tetrachloro-o-benzoquinone, with the formation of a spirophosphorane and a 1,3,2-dioxaphosp h ~ l a n e .A ~'~ structural study of the p,-bonded 'ylide' (315) reveals a short phosphorus-phosphorus bond (2.084 A), indicating some double bond character. This compound undergoes cleavage of the phosphorus-phosphorus bond on treatment with electrophiles. Thus, e.g., with iodomethane, the halogenophosphine (316)is formed.520The chemistry of group 15 p,-bonded systems involving inter-element bonds, e.g., P=As, P=Sb, has been reviewed.521Among new systems of this type reported in the past year are the phospha-arsene (317),522 and the first stable stibabismuthene (3 18).523 Mes*\+ CI -P=P-CI (311)

Ar

\

Ar

(315) Ar = mesityl

,P=P\ Me Mes* (312) Mes* = 2,4,6-But3C6H2

Mes*\+ P-P \ Me/ Mes* (313)

Mes*, P=P \ Mes* (314)

Ar

\

Ar

(316)

Mes*- P=As-Mes*

(317)

Ar -Sb=Bi-Ar CH(SiMe&

(318) Ar = QC(SiMed3 CH(SiMe,),

A detailed study of the vibrational spectra of phosphaalkenes has appeared, which includes studies of the influence of structural effects on the P-C bond.524

39

I: Phosphines and Phosphonium Salts

(320) R = H, Ph or C02Et

(321)

,A?

Af

I/ Mes*P// 'Mes* (323) Mes* = 2,4,6-But&H2

WR

\ ;A A? Mes* (325) R = Me or CH=CH2 (324) Ar' = Ph or 2,6-dichlorophenyl, Mes* = 2,4,6-But3C6H2 A? = pt-butylphenyl

The chemistry of phosphaalkene systems having inverse polarity, involving a partial negative charge at phosphorus, has been reviewed.525The reactive phosphaalkene (319) has been shown to react with diazo compounds, R(H)C-N2 to give the 1,2,3-diazaphospholes (320).526Among new phosphaalkene systems prepared are the phosphinoaryl system (321),527the diphosphapropene system (322),528the kinetically stabilised triphosphafulvene (323),529the bis(phosphaa1kene) (324) (and a related bi~(diphosphene)),5~'and the diphosphabutadiene system (325) from which a range of polymeric systems has also been Heating the known cyclic system (326) in toluene at 150 "C for 3 days results in elimination of an alkene to form the air-stable isophosphinoline system (327), a bright yellow solid, a31P = 197.4, which readily undergoes cycloaddition reactions at the P=C bond.532Further studies of the chemistry of phosphaalkenes bearing a complex metallo-substituent at phosphorus have been reported by Weber's A route to the phosphatrimethylenemethane system (328) (stabilised by coordination) has been developed,534and the (1,2,3-q)-trans-phosphabutadienyl system (329) has been similarly stabilised in a complex.535The reactivity of the phosphavinyl Grignard reagent (330) has been exploited for the synthesis of new phosphavinyl derivatives of aluminium, gallium and and tin,537e.g., (331). When treated with lead(I1) chloride, (330) is converted into Ph

OH

1

0

(326) R = C(Me)2Et, 1-methylcyclohexyl or 1-adamant9

Bu' P=C, P

P

- P (329)

h

CJ

MgCl (330)

cypYxYpcy

Bu' But (331) X = CyIn or Me2Sn

Organophosphorus Chemistry

40

the bicyclic system (332), the first endo:endo-2, 4-diphosphabicyclo[ l.l.O]butane.538The chemistry of allene and cumulene systems involving the group 15 elements in p,-bonded situations has been reviewed.s39The first diarsaallene (333) has been prepared.540The 1d,302-diphosphaallene system (334) has been prepared and characterised, and its reactivity explored.541A structural study of the new phosphazaallene (335) reveals shorter than 'normal' P=C bonds. The reactivity of this compound at both P=C and C=N bonds has also been investigat ed.s42

(332)

(333) Mes* = 2,4,6-But3C6H2

(335) Mes* = 2,4,6-BUt3C&, Ar = /l-CIC6Hd

(334)

The chemistry of phosphaalkynes continues to develop. Detailed vibrational spectroscopic studies of HCP and DCP have a p ~ e a r e d .Theoretical ~ ~ ~ , ~ ~ work ~ and mass spectroscopic studies of mixtures of C2 and Pz species have led to the conclusion that the diphosphabutadiyne, PCCP, does The reaction of appropriately substituted phosphaalkynes with phosphinocarbenes, which leads to the dipolar 02P, 04P-1,2-diphosphete system (336), has been explored by quantum chemical methods.s46Phosphaalkynes have been shown to undergo addition of Grignard reagents to give 2-phospha- 1-vinylmagnesium halides, similar to (330).547 The radical cation +CH2-O-CH2' has been found to transfer ionised methylene to 1-adamantylphosphaacetyleneto form the novel phosphorus-containing non-classical distonic ion (337).s48The first example of a catalytic dihydroamination of a phosphaalkyne has been reported. Treatment of t-butylphosphaacetylene with primary amines, in the presence of a trace of titanium tetrachloride, yields the diaminophosphines (338).549Phosphaalkynes have also been shown to react with annelated nucleophilic carbenes to give

CH~BU'

(336) R' = Me3Si, R2 = But, R3 = NPri2

(337)

R = 1-adamantyl

(338) R = Pr' or But

(339) R = CH2But

heterocyclic systems, e.g., the triphosphole (339).550The germadiphosphacyclobutene (340) has been isolated from the reaction of t-butylphosphaacetylene with a diar~lgermylene.'~~Cycloaddition of phosphaalkynes with iminovanadium(V) complexes results in the initial formation of the intermediate heterocyclic system (341), which undergoes further transformation in the presence of the phosphaalkyne to form the triphosphorin (342) and the azadiphosphole (343).5s2 Cyclooligomerisation of phosphaalkynes has been observed in the presence of a tungsten carbonyl complex, with the formation of various tungsten-

41

1 : Phosphines and Phosphonium Salts

stabilised heterocyclic systems.553A variety of new phosphorus-selenium cage systems (and the selenadiphosphole (344))has been isolated from the reactions of t- but ylphosp haacetylene with selenium.554 R2,

N-P

CI (341) R’ = e.g. But, R2 = 1-adarnantyl, CPh3, MeaSi, Pr‘ or Pr“

Me

Me

R2

R2

(342)

(343)

(344)

The first report of the gas-phase generation of the cis-isomer of the iminophosphene (345)(and the related iminoarsene) has appeared.555NMR and theoretical techniques have been used to study the E/Z-isomerism of the aminoiminophosphenes (346).556 The stabilisation of singlet nitrenes by N-iminophosphene substituents has been studied from a theoretical ~tandpoint.~”The phosphadiazonium cation (347) has been shown to form complexes involving the phosphorus atom as acceptor, on treatment with 2,2’-bip~ridyl.~~~

CI,

,SiMe2Bu‘ P=N

R2N-P=N-Mes”

(345)

(346) R = Me, Et or Pr’, Mes* = 2,4,6-Bd3C6H2

(347)

The chemistry of phosphenium cations continues to attract interest. It has previously been assumed that the P-halogenodiazaphospholenes (348) exist in equilibrium with the phosphenium salts (349).Structural and theoretical studies of a range of such compounds reveal that P-halogenodiazaphospholenes remain as essentially covalent compounds, unless in the presence of a halide ion acceptor.s59In a similar vein, treatment of the P-halogenodiazaphospholanes(350), derived from diamines of varying steric bulk, with silver triflate has given a series of sterically tunable phosphenium salts (351).560A theoretical study has shown that the phosphenium cation (352), which readily forms transition metal complexes, has strong n-acceptor properties. In such complexes, the main n-donors to the phosphorus centre are the metal orbitals, rather than the ring nitrogen Further examples of metal complexes of phosphenium ion ligands have been d e s ~ r i b e d . A ~ ~r ange ~ , ~ ~of~ cyclic triphosphenium salts (353) has been prepared.564Also reported is the first example of a 02h2-dioxaphospheniumsalt (354) which is stabilised by an intramolecular S + P+ bond.565 Interest in the chemistry of phosphinidenes, RP:, usually in the form of

42

(348)X = F, CI or Br

Organophosphorus Chemistry

(349)

(350)

(3511

(352)

tungsten pentacarbonyl complexes, continues to develop. Phosphinidene complexes generated from related azaphosphirene or 7-phosphanorbornadiene complexes have been trapped with 1-piperidinonitrile, and either dimethyl acetylenedicarboxylate or phosphaalkenes, to form new azaphosphole complexes, e.g., (355). These reactions involve the intermediacy of nitrilium ylide The phosphinidene complex [PhP=W(CO)5] has been complexes (356).566,567 shown to add to both carbon-carbon double bonds of 2,5-dimethylhexa-2,4diene to form the first bis(ph0sphiranes) (357) as a mixture of s t e r e ~ i s o m e r sA. ~ ~ ~ related cycloaddition to a silene (C=Si) has given the remarkably stable system (358).569Attempts to induce cycloaddition of 'PhP' to the C=C double bonds of phospholenes and phospholes, however, were unsuccessfu1.570Other phosphinidene-metal complexes have been p ~ e p a r e d , ~including ~ ' ? ~ ~ ~the first luminescent copper(1) phosphinidene complex.572Phosphinidene chemistry has also received some coverage in a review of low coordination N, P, S and Se-com-

-A/ Ph

W(C0)S

? #

. ,

D

i s

Ph

W(CO),

Very few papers have appeared which relate to the chemistry of tricoordinate 03h5-p,-bonded systems. The molecular structure of (359) has revealed a noticeable elongation of the F N bond (1.563 A) and a shortening of the P=C bond (1.617 A), attributed to the electron-withdrawing ability of s~bstituents.5~~ An interesting finding is that the phosphorus atom of (360) is sufficiently electrophilic to form a complex with 4-dimethylaminopyridine, which, in the presence of an excess of the donor, suffers displacement of the bromine with formation of the salt (361).575 The possible involvement of 03h5alkylideneoxophosphorane intermediates in the nucleophilic substitution reactions of benzyl- and diphenylmethyl-phosphonamidicchlorides with amines has received further study, competition between SN2P and elimination-addition mechanisms being identified.576

43

1 :Phosphines and Phosphonium Salts

NMes’ //

?\

Br -

NMes*

(359)

5

(361) D = M e , N c N

Phosphirenes, Phospholesand Phosphinines

Issues relating to the aromaticity of phosphirenium cations, phospholes, and phosphinines have been comprehensively reviewed.577A theoretical study of the phosphirene oxide system (362) (and its arsenic analogue) has concluded that these systems are stabilised by delocalisation, which is not the case, apparently, for the related a~irine-N-oxide.~’~ Poly(phosphirene) chain structures, e.g., (363), have been assembled in a stepwise route from the reactions of phospholes, diphenylacetylene and the phenylphosphinidene tungsten carbonyl complex.579 The chemistry of the azaphosphirene system has seen further development, in particular the mechanism of formation of 2H-azaphosphirene complexes (364)in the reactions of metal carbene complexes with p h o ~ p h a a l k e n e s Complexes .~~~~~~~ of type (364) have been shown to undergo unexpected dimerisation to form diazadihydrodiphosphinines (365), and other The complex (364, R = CH(SiMe3)2)undergoes a ferrocinium salt-induced ring-expansion in the presence of carbonyl compounds. Thus, e.g., with benzaldehyde, the 1,4,2oxazaphospholene complex (366)is formed.583 The complexes (364) also undergo bond- and regio-selective insertion of various nitriles into the P-N bond, to form the diazaphosphole complexes (367).584 The diphosphirenium salt (368) has been shown to undergo ring-cleavage on treatment with various nucleophiles, (and also with a cyclopentadienyl (dicarbonyl) ferrate complex) to form phosphaalkene systems, e.g., (369).585

Ph/

Ph (364)

(367) R’ = CH(SiMe&, R2 = -

N

3

(368) R = Pri2N

(365)

(369) X = R2P, R3Si or R3Sn

44

Organophosphorus Chemistry

The biphosphole (370) has been obtained in enantiomerically pure form by spontaneous resolution in the crystallisation of a racemic mixture, without the use of chiral auxiliaries.586A new approach to P-functionalised phospholes is afforded by metallation at a methyl group of l-phenyl-3,4-dimethylphosphole(in which both phosphorus and the diene unit are protected by coordination to an iron carbonyl acceptor), followed by treatment with electrophiles, to give C substituted products, e.g., (37 1). Copper(I1) oxidation of the intermediate lithiomethyl derivative leads to the formation of bridged systems, e.g., (372).587

)-3cH2siMe3 Ph

Ph

Ph

(3711

(370)

(372)

Phospholes (373), having a bulky aryl substituent at phosphorus, have been shown to undergo Friedel-Crafts acylation to form the 2-acylphospholes (374).'*' Such bulky arylphospholes have also been shown to undergo Diels-Alder reactions with N-phenylmaleimide to give cycloadducts with the bulky aryl substituent anti to the phosphanorbornene double bond.589The dienic reactivity of phospholes is enhanced by the presence of an electron-withdrawing group at phosphorus, providing an improved route to tervalent 7-phosphanorbornenes. Thus, e.g., the phospholes (375) readily add acrylonitrile to form the 7-phosphanorbornenes (376).590The addition of an acetylenic aldehyde acetal to simple

vMeMe4

Me

I

I

Ar R

Ar

X

(374)

(375)X = CN or Opt'

Me

(376)

(373)R +-=Ar R

R = P i or B U ~

P-phenyl phospholes also occurs readily, giving, (after acid deprotection), enantiopure l-phosphanorbornadiene-2-carboxaldehydes, e.g., (377).591 Related cycloaddition reactions involving chiral amino-alcohols have given new P-chiral P,N-ligands, e.g., (378).592 Further examples of cycloadditions between l-phenyl3,4-dimethylphosphole, coordinated to a chiral palladium or platinum complex, and functionalised vinylic systems have appeared, giving the thioamide system (379),593and various adducts of N,N-dimethylacetamide, 2-vinylpyridine, and diphenyl~inylphosphine.5~~ A related addition of phenyl(viny1)sulfonehas given the phenylsulfonyl-functionalised system (380), but, surprisingly, the addition easily reverses in New types of phosphole dimer have been obtained from the thermal dimerisation of 1-phenyl-3,4-dimethylphosphole in the coorReduction of a simple palladium(I1) dination sphere of ruthenium chelate of the pyridyl-phosphole (381) has given a novel, dinuclear complex

1 :Phosphines and Phosphonium Salts

45 [MI,

CHO p6

(377)

P

,Ph

Me2N AS

I

(378)

(379)

(383)

(384)

involving four palladium atoms, bridged by the p h o ~ p h o l eElaboration .~~~ of the dibenzophosphole system to give difunctional cyclopolymerisable intermediates, e.g., (382), is the key approach for the synthesis of cluster complexes of silver and gold.598Interest has continued in the chemistry of the bis(phosphonio)phospholide system (383). The best known compound (383, R = Ph) has been shown to be converted into the monophosphonium phospholide (384) on treatment with sodium b0rohydride.5~~ Also of interest has been the synthesis of further members of the series (383) in which one of the phosphonium sites contains an additional phosphine donor, e.g., (383, R = CH2CH2PPh2).600,601 The chiral system (385) undergoes the expected cleavage of the P-phenyl group on treatment with lithium metal in THF, to form the phospholide anion, from which a monophosphaferrocene and the diphosphole (386) have been prepared.602Phosphaferrocenes have also been prepared from the substituted phospholide anion (387),603and from a range of phospholide anions bearing carbofunctional groups, e.g., (388),6°4-607 from which a variety of new systems has been obtained, including

(386)R = (-) menthyl

(388)X = CHO, 'C02H or COCF3

(389)

46

Organophosphorus Chemistry

the new ferrocenophane (389).608 Further studies of the coordination chemistry of phosphaferrocenes (as P-donors) have been r e p ~ r t e d . ~Bridging ’ phospholyl complexes, and ever more complex triple-decker systems have also been described.610,61 A review of heterocyclopentadienide complexes of the group 13 metals contains much useful information on phospholide (and polyphospholide) complexes.612A structural study of a gallium(1) phospholide has been described.613The coordination chemistry of di- and tri-phospholide anions continues to d e v e l ~ p , ~and ~ ~ -the ~ Isolid ~ state structure of a potassiodiphosphastibolyl system described.619The chemistry of azaphosphole systems has also shown further d e ~ e l o p m e n t . 6 ~ ~ ~ ~ ~ ~ The coordination chemistry of phosphinines, including their polydentate and macrocyclic derivatives, has been reviewed.624Valence isomerism of phosphinines has continued to attract attention. The structures, energetics, and vibrational spectra of valence isomers of the parent system, phosphinine, (CH)5P, have been studied by theoretical te~hniques.6~~ Phosphatriafulvenes (390)readily react with kinetically-stabilised phosphaalkynes to give, initially, 1,3-diphosphinines, e.g., (391),which then undergo valence isomerism on heating in toluene

(390)

(391) R = e.g. But, Pen’ or 1-adamantyl

(393)

R

(394) R’ = SiMe3, R2 = H or Pr‘, R3 = H or Ph

\I

\I

Si-X-Si

(395) X = e.g. 0 or - 0

/

\

0--, R

= Ph

at 120 “C to form the Dewar-l,3-phosphinines (392) and (393).626 These reactions have also been reviewed.627 The established synthesis of phosphinine systems by the reaction of silyl-alkynes with diazaphosphinines has now been applied to the synthesis of new phosphinine-based tripodal ligands, e.g., (394)628and mixed phosphinine-(po1y)ether macrocycles (395).629A metal vapour synthesis of biphosphinines has provided an inseparable mixture of two isomers.63o The biphosphinine (396) has been reduced to the related radical monoanion, using potassium, and this has been characterised, as the lithium salt, by X-ray diffra~tion.~~’ Low oxidation state transition metal complexes of (396) and its dianion have been r e p ~ r t e d .Two ~ ~ ~groups , ~ ~ ~have reported studies of the reactivity of the triphosphinine (397). On treatment with a stable carbene, the 1,2,4-triphosphole system (398) is formed in a remarkable r i n g - c ~ n t r a c t i o nUnder . ~ ~ ~ base-catalysed conditions, alcohols have been shown to add to the P=C bonds of (397) to form the triphosphacyclohexane system (399),indicating that the extent of aromaticity of the triphosphinine system is

1 : Phosphines and Phosphonium Salts

47

+ NMe2 I ,NMe2

NCCH&H2CH2<\

-p ,

I NMe2 NMe2

(400)

Me2N Me2N--\P*

NMe2 P/-NMe2

bpJ I \

Me2N NMe2 (401)

Interest in h5-phosphinine systems has continued, the ‘aromatic’ or ‘ylidic’ state of these systems now having been evaluated using various magnetic property criteria. Much depends on the nature of the substituents at phosphorus, the more electron-withdrawing, the more aromatic is the molecule, but no evidence of d-orbital participation was A route to the h5-diphosphinine (400) has been Studies of the protonation of the h5-triphosphinine (401) have also appeared.638

References 1.

2. 3.

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518. S. Loss, A. Magistrato, L. Cataldo, S. Hoffmann, M. Geoffroy, U. Rothlisberger and H. Grutzmacher, Angew. Chem., Int. Ed., 2001,40,723. 519. M. Freytag, P. G. Jones, R. Schmutzler and M. Yoshifuji, Heteroat. Chem., 2001,12, 300. 520. S. Shah, G. P. A. Yap and J. D. Protasiewicz, J . Organornet. Chem., 2000,608, 12. 521. N. Tokitoh, J . Organomet. Chem., 2000,611,217. 522. M. Bouslikhane, H. Gornitzka, J. Escudie and H. Ranaivonjatovo, J . Organomet. Chem., 2001,619,275. 523. T. Sasamori, N. Takeda and N. Tokitoh, Chem. Commun., 2000,1353. 524. I. E. Boldeskul, F. Kh. Tukhvatullin and S. Sh. Ismailov, Ukr. Fiz. Zh., 2000, 45, 662; (Chem. Abstr., 133,222780). 525. L. Weber, Eur. J . Inorg. Chem., 2000,2425. 526. J. Grobe, A. Armbrecht, D. Le Van, B. Krebs, J. Kuchinke, M. Lage and E-U. Wurthwein, 2. Anorg. Allg. Chem., 2001,627, 1241. 527. D. J. Brauer, C. Liek and 0.Stelzer, J . Organomet. Chem., 2001,626,106. 528. S. Ito and M. Yoshifuji, Chem. Commun., 2001, 1208. 529. S. Ito, S. Sugiyama and M. Yoshifuji, Angew. Chem., Int. Ed., 2000,39,2781. 530. S. Shah, T. Concolino, A. L. Rheingold and J. D. Protasiewicz, Inorg. Chem., 2000, 39,3860. 531. N. Yamada, K. Toyota and M. Yoshifuji, Chem. Lett., 2001,248. 532. S. G. Ruf, J. Dietz and M. Regitz, Tetrahedron, 2000,56,6259. 533. L. Weber, S. Kleinebekel and T. Haase, 2. Anorg. Allg. Chem., 2000,626,1857. 534. N. H. T. Huy, A. Marinetti, L. Ricard and F. Mathey, Organometallics, 2001, 20, 593. 535. N. H. T. Huy, L. Ricard and F. Mathey, J . Organomet. Chem., 2001,617418,748. 536. C. Jones and A. F. Richards, J . Organornet. Chem., 2001,629,109. 537. C. Jones and A. F. Richards, J . Chem. SOC.,Dalton Trans., 2000,3233. 538. C. Jones, J. A. Platts and A. F. Richards, Chem. Commun., 2001,663. 539. J. Escudie, H. Ranaivonjatovo and L. Rigon, Chem. Rev., 2000,100,3639. 540. M. Bouslikhane, H. Gornitzka, J. Escudie, H. Ranaivonjatovo and H. Ramdane, J . Am. Chem. SOC.,2000,122,12880. 541. T. Kato, H. Gornitzka, A. Baceiredo and G. Bertrand, Angew. Chem., Int. Ed., 2000, 39,3319. 542. X-G. Zhou, L-B. Zhang, R-F. Cai, Q-J. Wu, L-H. Weng and Z-E. Huang, J . Organomet. Chem., 2000,604,260. 543. C. Beck, R. Schinke and J. Koput, J . Chem. Phys., 2000,112,8446. 544. J. Bredenbeck, C. Beck, R. Schinke, J. Koput, S. Stamatiadis, S. C. Farantos and M. Joyeux, 1. Chem. Phys., 2000,112,8855. 545. M. Bronstrup, J. Gottfriedsen. I. Kretzschmar, S. J. Blanksby, H. Schwarz and H. Schumann, Phys. Chem. Chem. Phys., 2000,2,2245. 546. G. Bertrand, W. Eisfeld, L. Nyulaszi, R. Reau, M. Regitz and D. Szieberth, J . Chem. SOC.,Perkin Trans. 2,2000,2324. 547. J. Renner, U. Bergstrasser, P. Binger and M. Regitz, Eur. J . Inorg. Chem., 2000, 2337. 548. F. C. Gozzo, L. A. B. Moraes, M. N. Eberlin and K. K. Laali, J . Am. Chem. Soc., 2000,122,7776. 549. F. G. N. Cloke, P. B. Hitchcock, J. F. Nixon and J. D. Wilson, Chem. Commun., 2000,2387. 550. F. E. Hahn, L. Wittenbecher, D. Le Van, R. Frohlich and R. Wibbeling, Angew. Chem., Int. Ed., 2000,39,2307.

1 : Phosphines and Phosphonium Salts

65

551. F. Meiners, W. Saak and M. Weidenbruch, Chem. Commun., 2000,215. 552. F. Tabellion, C. Peters, U. Fischbeck, M. Regitz and F. Preuss, Chem. Eur. J., 2000, 6,4558. 553. P. Kramkowski and M. Scheer, Eur. J . Inorg. Chem., 2000,1869. 554. P. B. Hitchcock, J. F. Nixon and N. Sakarya, Chem. Commun., 2000,1745. 555. K. Miqueu, J-M. Sotiropoulos, G. Pfister-Guillouzo and V. D. Romanenko, New J . Chem., 2001,25,930. 556. D. Gudat, W. Hofiauer, A. B. Rozhenko, W. W. Schoeller and M. I. Povolotskii, Magn. Reson. Chem., 2000,38,861. 557. W. W. Schoeller and A. B. Rozhenko, Eur. J . Inorg. Chem., 2001,845. 558. N. Burford, T. S. Cameron, K. N. Robertson, A. D. Phillips and H. A. Jenkins, Chem. Commun., 2000,2087. 559. D. Gudat, A. Haghverdi, H. Hupfer and M. Nieger, Chem. Eur. J., 2000,6,3414. 560. M. B. Abrams, B. L. Scott and R. T. Baker, Organometallics, 2000,19,4944. 561. K. Takano, H. Tsumura, H. Nakazawa, M. Kurakata and T. Hirano, Organometallics, 2000,19, 3323. 562. D. Gudat, A. Haghverdi and M. Nieger, J . Organomet. Chem., 2001,617418,383. 563. H. Nakazawa, M. Kishishita, T. Ishiyama, T. Mizuta and K. Miyoshi, J . Organomet. Chem., 2001,617418,453. 564. J. A. Boon, H. L. Byers, K. B. Dillon, A. E. Goeta and D. A. Longbottom, Heteroat. Chem., 2000,11,226. 565. S . E. Solovieva, M. Gruner, I. S. Antipin, W. D. Habicher and A. I. Konovalov, Org. Lett., 2001,3, 1299. 566. R. Streubel, U. Schiemann, P. G. Jones, N. H. T. Huy and F. Mathey, Angew. Chem., Int. Ed., 2000,39, 3686. 567. F. G. N. Cloke, P. B. Hitchcock, J. F. Nixon, U. Schiemann, R. Streubel and D. J. Wilson, Chem. Commun., 2000,1659. 568. M. J. M Vlaar, A. W. Ehlers, F. J. J. de Kanter, M. Schakel, A. L. Spek and K. Lammertsma, Angew. Chem., Int. Ed., 2000,39,2943. 569. M. J. M. Vlaar, A. W. Ehlers, F. J. J. de Kanter, M. Schakel, A. L. Spek, M. Lutz, N. Sigal, Y. Apeloig and K. Lammertsma, Angew. Chem., Int. Ed., 2000,39,4127. 570. M. J. M. Vlaar, F. J. J. de Kanter, M. Schakel, M. Lutz, A. L. Spek and K. Lammertsma, J . Organomet. Chem., 2001,617418,311. 571. B. T. Sterenberg and A. J. Carty, J . Organornet. Chem., 2001,617418,696. 572. V. W-W. Yam, E. C-C. Cheng and N. Zhu, Chem. Commun., 2001,1028. 573. N. Inamoto, Heteroat. Chem., 2001,12, 183. 574. E. B. Rusanov, A. N. Chernega and M. I. Povolotskii, J . Chem. Crystallogr., 1999, 29, 1277. 575. M. Blattner, M. Nieger, A. Ruban, W. W. Schoeller and E. Niecke, Angew. Chem., Int. Ed., 2000,39,2768. 576. M. J. P. Harger, J . Chem. Soc., Perkin Trans. 2,2001,41. 577. L. Nyulaszi, Chem. Rev., 2001,101, 1229. 578. J. J. Molina, R. El-Bergmi, J. A. Dobado and D. Portal, J . Org. Chem., 2000, 65, 8574. 579. N. H. T. Huy, L. Ricard and F. Mathey, Angew. Chem., Int. Ed., 2001,40,1253. 580. R. Streubel, M. Hobbold and S. Priemer, J . Organomet. Chem., 2000,613, 56. 581. R. Streubel, S. Priemer, J. Jeske and P. G. Jones, J . Organomet. Chern., 2001, 617418,423. 582. R. Streubel, H. Wilkens, F. Ruthe and P. G. Jones, Chem. Commun., 2000,2453. 583. R. Streubel, C. Neumann and P. G. Jones, J . Chem. SOC.,Dalton Trans., 2000,2495.

66

Organophosphorus Chemistry

584. R. Streubel, H. Wilkens and P. G. Jones, Chem. Eur. J., 2000,6,3997. 585. T. Kato, 0. Polishchuk, H. Gornitzka, A. Baceiredo and G. Bertrand, J . Organomet. Chem., 2000,613,33. 586. 0.Tissot, M. Gouygou, F. Dallemer, J-C. Daran and G. G. A. Balavoine, Angew. Chem., Int. Ed., 2001,40, 1076. 587. B. Deschamps, F-X. Buzin, A. Avarvari, F. Nief and F. Mathey, J . Organomet. Chem., 2001,624,105. 588. G. Keglevich, T. Chuluunbaatar, B. Dajka, A. Dobo, A. Szollosy and L. Toke, J . Chem. Soc., Perkin Trans. I , 2000,2895. 589. G. Keglevich. M. Trecska, B. Dajka, B. Pete, A. Dobo and L. Toke, Heteroat. Chem., 2000,11,271. 590. E. Mattmann, D. Simonutti, L. Ricard, F. Mercier and F. Mathey, J . Org. Chem., 2001,66,755. 591. S. Lelievre, F. Mercier, L. Ricard and F. Mathey, Tetrahedron: Asymmetry, 2000,11, 4601. 592. S. R. Gilbertson, D. G. Genov and A. L. Rheingold, Org. Lett., 2000,2,2885. 593. P-H. Leung, Y. Qin, G. He, K. F. Mok and J. J. Vittal, J . Chem. Soc., Dalton Trans., 2001,309. 594. K. D. Redwine, W. L. Wilson, D. G. Moses, V. J. Catalan0 and J. H. Nelson, Inorg. Chem., 2000,39,3392. 595. P-H. Leung, H. Lang, X. Zhang, S. Selvaratnam and J. J. Vittal, Tetrahedron: Asymmetry, 2000,11,2661. 596. K. D. Redwine and J. H. Nelson, Organometallics, 2000,19, 3054. 597. M. Sauthier, B. Le Guennic, V. Deborde, L. Toupet and J-F. Halet, Angew. Chem., Int. Ed., 2001,40, 228. 598. B. K. Teo and H. Zhang, Inorg. Chim. Acta, 2001,317,l. 599. D. Gudat, S. Hap, L. Szarvas and M. Nieger, Chem. Commun., 2000,1637. 600. D. Gudat, S. Hap, V. Bajorat and M. Nieger, 2.Anorg. Allg. Chem., 2001,627,1119. 601. S. Hap, M. Nieger, D. Gudat, M. Betke-Hornfeck and D. Schramm, Organometallics, 2001,20,2679. 602. M. Orgasawara, K. Yoshida and T. Hayashi, Organometallics, 2001,20, 1014. 603. X. Sava, L. Ricard, F. Mathey and P. Le Floch, Organometallics, 2000,19,4899. 604. A. Klys, J. Zakrzewski, K. Nakatani and J. A. Delaire, Inorg. Chem. Commun., 2001, 4,205. 605. A. Klys, J. Zakrzewski, A. Rybarczyk-Pirek and T. A. Olszak, Tetrahedron: Asymmetry, 2001, 12, 533. 606. A. Klys, R. B. Nazarski and J. Zakrzewski, J . Organornet. Chem., 2001,627,135. 607. R. Shintani, M. M-C. Lo and G. C. Fu, Org. Lett., 2000,2,3695. 608. E. Deschamps, L. Ricard and F. Mathey, Organometallics, 2001,20, 1499. 609. A. J. Toner, B. Donnadieu, S. Sabo-Etienne, B. Chaudret, X. Sava, F. Mathey and P. Le Floch, Inorg. Chem., 2001,40,3034. 610. G. E. Herberich and B. Ganter, Inorg. Chem. Commun., 2001,4,100. 61 1. A. R. Kudinov, D. A. Loginov, S. N. Ashikhmin, A. A. Fil'chikov, L. S. Shul'pina and P. V. Petrovskii, Russ. Chem. Bull., 2000,49, 1637. 612. F. Nief, Eur. J . Inorg. Chew., 2001,891. 613. J. Chojnacki, E. Baum, I. Krossing, D. Carmichael, F. Mathey and H. Schnockel, 2. Anorg. Allg. Chem., 2001,627, 1209. 614. M. D. Francis, P. B. Hitchcock and J. F. Nixon, Chem. Commun., 2000,2027. 615. F. G. N. Cloke, J. C. Green, J. R. Hanks, J. F. Nixon and J. L. Suter, J . Chem. Soc., Dalton Trans., 2000,3534.

1 : Phosphines and Phosphonium Salts

67

616. R. Bartsch, F. G. N. Cloke, J. C. Green, R. M. Matos, J. F. Nixon, R. J. Suffolk, J. L. Suter and D. J. Wilson, J . Chem. Soc., Dalton Trans., 2001, 1013. 617. F. W. Heinemann, H. Pritzkow, M. Zeller and U. Zenneck, Organometallics, 2000, 19,4283. 618. F. W. Heinemann, H. Pritzkow, M. Zeller and U. Zenneck, Organometallics, 2001, 20,2905. 619. C. Jones and R. C. Thomas, J . Organomet. Chem., 2001,622,61. 620. J. Kerth and G. Maas, Eur. J . Org. Chem., 2001,1581. 621. V. V. Yanilkin, B. I. Buzykin, R. M. Eliseenkova, N. I. Maksimyuk and N. V. Nastapova, Russ. Chem. Bull., 1999,48,2065. 622. V. F. Mironov, N. G. Khusainova, G. R. Reshetkova, T. A. Zyablikova and R. A. Cherkasov, Russ. J . Gen. Chem., 2000,70,984. 623. V. V. Zverev, N. G. Khusainova, G. R. Reshetkova and R. A. Cherkasov, Russ. J . Gen. Chem., 2000,70,399. 624. N. Mezailles, F. Mathey and P. Le Floch, Progr. Inorg. Chem., 2001,49,455. 625. U. D. Priyakumar, T. C . Dinadayalane and G. N. Sastry, Chem. Phys. Lett., 2001, 336,343. 626. M. A. Hofmann, H. Heydt and M. Regitz, Synthesis, 2001,463. 627. M. A. Hofmann, U. Bergstrasser and M. Regitz, Pure. Appl. Chem., 2000,72, 1769. 628. U. Rhorig, N. Mezailles, N. Maigrot, L. Ricard, F. Mathey and P. Le Floch, Eur. J . Inorg. Chem., 2000,2565. 629. N. Mezailles, N. Maigrot, S. Hamon, L. Ricard, F. Mathey and P. Le Floch, J . Org. Chem., 2001,66,1054. 630. D. Charmichael, F. G. N. Cloke, A. R. Dias, A. M. Galvao and J. L. F. Da Silva, Appl. Organomet Chem., 2000,14,561. 631. S . Choua, H. Sidorenkova, T. Berclaz, M. Geoffroy, P. Rosa, N. Mezailles, L. Ricard, F. Mathey and P. Le Floch, J . Am. Chem. Soc., 2000,122,12227. 632. P. Rosa, L. Ricard, F. Mathey and P. Le Floch, Organornetallics, 2000,19,5247. 633. N. Mezailles, P. Rosa, L. Ricard, F. Mathey and P. Le Floch, Organometallics, 2000, 19,2941. 634. S . B. Clendenning, P. B. Hitchcock, J. F. Nixon and L. Nyulaszi, Chem. Commun., 2000,1305. 635. M. Krein, U. Bergstrasser, C . Peters. S. G. Ruf and M. Regitz, Chem. Comrnun., 2000,2015. 636. Z. X. Wang and P. von R. Schleyer, Helu. Chim. Acta, 2001,84, 1578. 637. G. Heckmann, S. Plank, B. Neumuller and E. Fluck, 2. Anorg. Allg. Chem., 2000, 626,1739. 638. G. Heckmann, E. Gorbunowa-Jonas, S. Plank, R. Janoschek, M. Westerhausen and E. Fluck, 2. Anorg. Allg. Chem., 2000,626,1974.

2 Pentacoordinated and Hexacoordinated Compounds BY C.D. HALL

Summary The year has seen a considerable extension of the principles of hypervalent phosphorus chemistry into the fields of other elements notably Si, Sn, Ge and Sb and in this context the well-known Martin ligand has proved to be especially valuable. Particularly interesting contributions have been provided by Ju et a l l 2 on the relative rates of reaction of pentoses and hexoses with pentacoordinate phosphorus, by Bentrude et al.” on the mechanism of the reaction of hydridophosphoranes with dimethyl disulfide and by Kawashima et al.25on the isolation of two carbaphosphatranes containing covalent P-C bonds. Holmes et report on the fluxional properties of propeller shaped phosphoranes and Buono et al.” have also demonstrated the utility of hydridophosphoranes in some highly diastereoselective reactions with isocyanates. In summary, although the number of reports was small, the year was noteworthy for some very sophisticated contributions to the field. 1

Introduction

The year has produced some consolidation in the field of hypervalent phosphorus chemistry in the form of two reviews, the first dealing with the reactions of tricoordinate phosphorus compounds with fluorinated 1,3-diketones or trifluoroacetylphenols’ and the second covering chiral, P,N-bidentate ligands which afford catalysts on coordination with rhodium and palladium.2 A section in the second review deals with coordination of hydridophosphoranes with Pt or Pd (vide infra), a topic that was reviewed earlier.3A review has also appeared on small ring compounds containing highly coordinated Group 14 elements (Si, Sn and Ge) and by analogy with phosphorus chemistry many of these compounds contain the Martin ligand, known to stabilize hypervalent system^.^

2

Monocyclic Phosphoranes

Trichloro-(o-pheny1enedioxy)phosphorane(1) reacts with (2a+) to give chloroOrganophosphorus Chemistry, Volume 33 0 The Royal Society of Chemistry, 2003 68

2: Pentacoordinated and Hexacoordinated Compounds

69

phosphate (3) and the chlorophosphonates (4a-e) by selective replacement of one alkoxy group without attacking the cumulene m ~ i e t y . ~

(2) a, R = MeO, R' = H b, R = EtO, R' = H c, R = Pro, R'= H d, R = MeO, R'= Me e, R = EtO, R' = Me

High resolution mass spectrometry and multinuclear NMR/IR spectroscopy have been used to show that the products of the reaction of 2,2,2-trichloro-5halobenzo[d]-1,3,2 h5-dioxaphospholes with phenyl- and p-bromophenylacetylenes are trihalogenated six-membered heterocycles. For example the 5-chloro analogue ( 5 ) reacts with phenylacetylene (6) to give (7) and the incorporation of two chlorine atoms in positions 6 and 7 of the product was proved by X-ray crystallography of the hydrolysis product (Q6

A series of hexachlorodiazaphosphetidines(9a-h) have been synthesized by a modified Kirsanov reaction and their structures determined by X-ray crystallography. Steric hindrance was observed with R = cyclohexyl(9d) but was absent in the analogous hexafluorodiazaphosphetidine, thus demonstrating that the size of the halogen atom was cruciaL7This was evident from P-N-C bond angles of 137.43"and 123.43" in (9d) us. 131.32" and 128.96" in the fluoro analogue and by and the fourangles between the plane of the cyclohexyl ring (C2,C3,C5,C6) membered diazaphosphetidine ring of 89.5" in (9d) us. 59.8" in the fluoro analogue.

2PCI5 + 2RNH2 I

R (9) a, R = Me b, R = Et C, R = A ' '

-4HCI

N C13P< ;PCl3 N I

R (9) d, R = C Y C I O C ~ H ~ ~

e,R=/Y f, R = PhCH2 g, R = P h h, R=$ Me

In a paper dealing with the reactions of methylenediphosphines with hexafluoroacetone (HFA) and hexafluorothioacetone (HFTA) dimer, Raschenthaler

70

Organophosphorus Chemistry

et al. showed that carbodiphosphorane (10) reacted with a second mole of HFA to give the cyclic phosphorane (11) a stable intermediate of the Wittig reaction.' The addition of HFTA to the thio analogue (12), however, gave the unexpected isomerization product (13) rather than the phosphorane (14). The molecular structures of (11) and (13) were confirmed by X-ray crystallography.

3

Bicyclic, Tricyclic and Tetracyclic Phosphoranes

The crystal structure of the ozonide (15) reveals a symmetric, almost planar PO3 ring with two crystallographically asymmetric molecules in the unit cell.9 The reaction of (E)-bis-(2,4,6-tri-t-butylphenyl)diphosphane (16) with a four equivalent excess of tetrachloro-o-benzoquinone (17) gave (19). Evidence was presented to suggest that the reaction occurred via (18) with cleavage of the P-P bond and indeed, with two equivalents of (17) a low yield of (18)was isolated. The structures of the products were determined by X-ray crystallography and it was also suggested that the formation of (18) involved an electron transfer mechanism (Route A or Route B, Scheme 1) via a phosphinium radical cation and the radical anion of (17)." The reaction of 1,2-O-isopropy~idene-a-~-g~ucofuranose phosphite (20) with (17) or hexafluorobiacetyl(22) gave (21) and (23) respectively in almost quantitative yield and the products were characterized by elemental analysis and multinuclear (I3C,19F,31P)NMR.ll Ju et al. investigated the reaction of (24) with D-glucose (25), D-mannose and D-ribose in pyridine and followed the reactions by 31PNMR. It was found that D-ribose reacted about six times faster than either D-glucose and D-mannose and that both the intermediates and final products of the hexose and pentose reactions were different. In the case of D-glucose, for example, a mixture of three pentacoordinate intermediates (26-28) was detected by 31PNMR and the final product was alleged to be (29). With D-ribose (30), however, in addition to a mixture of pentacoordinate intermediates a 31PNMR signal was detected at -91 ppm and assigned to a hexacoordinate intermediate (31). The final product of this reaction was thought to be a pyrophosphate (32) with 31PNMR signals at 0

2: Pentacoordinated and Hexacoordinated Compounds

+.

Mes*

71

Mes*

,P=P’

CI

Mes* -0

-0

0 +I

Mes*

-

,P-P’

CI

Mes*

CI

Mes*

Mes*

Scheme 1

CI

CI

Organophosphorus Chemistry

72

CI cl@ CI CI

0

CI

(20)

.

'

Ph -0

OMe (29)

pyridinelRT

0 H

O

2 ,OH

0

II

II

Ribosyl-0 - P -0 -P -OH I

OH HO'

'OH

OH

(32)

(30)

and -9.1 ppm and it was suggested that the different behaviour observed for hexoses us. pentoses may be of some significance in bio-organic mechanisms.12 The reaction of phosphite (33) with diethyl benzylidenemalonate (34) gave a mixture of two products (36 and 37) presumably via (35) formed by nucleophilic addition to the activated dicarbonyl compound. Heating the reaction mixture for a short time led to the disappearance of (36) and the formation of the phosphonate (37) in a diastereomeric ratio of 3: l . 1 3

73

2: Pentacoordinated and Hexacoordinated Compounds

0 (33)

v\

R = H Or CH&I

R O

R O

I

* HPOH II

v\

I

HO

HP=O

0

OH w

I

O*OH R

(38a,b)

R

rh

0, o , H-P 0’ ‘ 0

A detailed 31PNMR study of the mechanism of ribozymomimetic phosphonylation with phosphorus acid and two oxiranes revealed consecutive formation of P-hydroxy-H-phosphonate monoesters (38a,b), di-(P-hydroxyalky1)H-phosphonates (39a,b), alkylene-H-phosphonates (40a,b), P-hydroxyalkylalkylene phosphites (41a,b) and the corresponding stereoelectronically-stabilized H-tetraoxaspirophosphoranes (42a,b). The equilbrium between (41a,b) and (42a,b) shifts towards (41a,b) at higher temperat~re.’~ An interesting paper has appeared on the effects of structure on free radical reactions of hydridophosphoranes with dimethyl disulfide.” In general, these reactions may be summarized by the equations shown in Scheme 2, describing a free radical chain process.

Z4PH + RS’ Z4P. + R2S2

-

-

&P* + RSH

(2)

Z4PSR + RS.

(3)

Z4PH + R2S2 Z4PSR + RSH Scheme 2

74

Organophosphorus Chemistry

On the basis of structural variations in the hydridophosphorane it was previously suggested16that the final step in this sequence was consistent with 'reversible formation of a sulfuranyl radical intermediate (43) followed by rate-determining sulfur-sulfur cleavage or a concerted process with a T.S. having a relatively high degree of phosphorus-sulfur bond formation'. In the present paper the UV-initiated reactions of a series of nine hydrophosphoranes (44-52) with dimethyl disulfide were followed by 31PNMR. Only (44), (45) and the previously investigated (47) gave high (virtually quantitative) yields of the corresponding methylthiophosphoranes (53, 54 and 55). The lack of

?S'SR

Z4P. + R2S2

n

0,

/o

P i g

u (44) Z = H (53) Z = S M e

TBP (RP) RNCO

(45) Z = H (54) Z = SMe

(46) Z = H

(60a-e) R' =

(48) Z = H

R'NCO (56) R'= Ph

b, R = Et, C, R = Pr' d, R = Ph e, R = Bz

(59a-e) R'= Ph

(47) Z = H (55) Z = S M e

(57) R' =

Ph

f- H Me

Ph

--f - H Me

2: Pentacoordinated and Hexacoordinated Compounds

75

reactivity in the remaining six compounds was ascribed in one case (46) to apical hydrogen and in the remainder to either electronic and/or steric destabilization of the intermediate sulfuranyl radical or the T.S. for concerted attack at sulfur. Phenyl isocyanate (56) and (R)-phenylethyl isocyanate (57) react with tricyclic hydridophosphoranes (58a-e) to form chiral bicyclic oxazaphospholidines (59a-e) and (60 a+) re~pective1y.l~ With R = H, (59a) and (60a) were formed in quantitative yield with a diastereomeric ratio, 60a-Rp:60a-Spof 1:1 showing that no dynamic, chiral discrimination occurred during the attack of (57) on the enantiomeric forms of (58a). In the case of the chiral triquinphosphoranes ( 5 8 k ) , however, 13Cand 31PNMR showed that the condensation of (56) and (57) occurred with complete diastereoselective opening of the diazaphospholidine ring to yield a single diastereomer in each case. Compound (60e) was reacted with BH3.SMe2and the structure of the resultant borane complex (61e) was determined by single crystal X-ray diffraction. A mechanism for the reaction of (58a-e) with isocyanates was proposed involving preferential attack at the least hindered axial nitrogen of the Sp phosphorane diastereomer (Scheme 3).

Scheme 3

Complexation of four hydridophosphoranes (62-65) with various transition metal complexes including [Rh(C0)2C1]2with (62, 63 and 65), [MC12(COD)] where M = Pd or Pt with (64) and [PdCl,(COD)] with (65) has been studied and the products characterized by multinuclear ('H, 2H,13Cand 31P)NMR, IR spectroscopy, laser-desorption mass spectrometry and X-ray photoelectron spectroscopy.'* A possible mechanism for hydridophosphorane complexation was proposed and a correlation between Lewis basicity and coordination activity for ligands (62-64) was reported. Phosphorane (65) was found to coordinate through two structural isomers (66a and 66b) of its open chain (PIII) form. The crystal structures of two tetraoxaspirophosphoranes (67 and 68) have been reported and in both cases the geometry around the pentacoordinate phosphorus was found to be intermediate between sqp and tbp with a maximum distortion towards sqp of 19.5% in one molecule of (67).19 A series of 1,3,2 h5-oxazaphosphetidines (7la-c) bearing the Martin ligand were synthesized by the reaction of (69) with (70a-c) in THF and the products

76

Organophosphorus Chemistry

F3$

F35

,CF3

,CF3

R’R~C=O

(69)

(70) a, R1 = Ph, R2 = H b, R’ = Ph, R2 = CF3 C, R’ = R2 = CF3

(71a-c)

cc: F3c

140 OC/C708

(71c)

sealed tube

*

(F3C)2C=NPh + (72)

CF3

I

Tip/ ‘ 0

(73)

were characterized by multinuclear (‘H,19F,’’P)NMR and X-ray crystallography. Thermolysis of (71c) at 140 “C(sealed tube) in C7Dsgave the corresponding imine (72) and cyclic phosphinate (73), illustrating that (71c) is an intermediate in the aza-Wittig reaction.20 Reaction of the iminophosphorane (74) with dimethyl acetylenedicarboxylate (DMAD) gave (76) via the undetected (2 + 2) cycloaddition product (75). Hydrolysis of (76) gave (79) presumably via (77) and (78) and the final product was characterized by elemental analysis, multinuclear NMR and X-ray crystallography.” Chloromethylphosphonic dichloride (80) reacts with o-aminophenol (8 1) to form a 1:1 mixture of (83) and the spirophosphorane (86) presumably via intermediates (82), (84) and (85). Phosphoramidite (87) allegedly as its phosphonimidate tautomer (88) also phosphorylates o-aminophenol to form the

77

2: Pentacoordinated and Hexacoordinated Compounds

spirophosphorane (90) via the addition product (S9).22Both phosphoranes were characterized by elemental analysis, 3’P NMR and single-crystal X-ray diffraction. Although the structure of (86) has been reported earlier,23the present work affords a more complete set of experimental data which in turn allows a more accurate determination of the geometric parameters.

(74)

I

DMAD/C&

t H2O

(76)

The reaction of amine (91) with methyltriphenoxyphosphonium iodide (92) or (92) + 12,gave the two phosphoranes (93) and (94) respectively. X-ray crystallography revealed weak P-N interactions in both molecules, the first examples of phosphatranes containing all six-membered rings.24Variable temperature NMR of (93) indicated fluxional behaviour whereby enantiomeric forms of the phosphonium salt (chiral by virtue of clockwise and anticlockwise orientations of the propeller-shaped molecule when viewed along the C-P-N axis) interconverted rapidly at room temperature. The free energy of activation for the enantiomeric interconversion was reported to be 11.2 kcal mol-’compared to the isoelectronic silatrane (95) at 10.3 kcal mol ’.

Organophosphorus Chemistry

78

+ X-

H

0

Me0

(96) A r = Bu'

(99) ?j3'P =21

2: Pentacoordinated and Hexacoordinated Compounds

79

Two carbaphosphatranes (98) and (99), the first examples of main group atranes containing a P-C covalent bond, have been prepared by reaction of the phosphinate (96) with trimethylsilyl iodide (97) either at room temperature (for 98) or in a sealed tube at 80 "C for (99).25By contrast with its aza analogue (100) carbaphosphatrane (98) was stable and its structure was determined by X-ray crystallography. The apical bond lengths are 1.921 (2) and 1.38(2)A for the P-C and P-H bonds respectively and the sum of the angles between the equatorial bonds is 359.7", consistent with a near perfect tbp structure with the oxygen atoms located in equatorial positions, thus providing a rare example of an 'anti-apicophilic' arrangement. Carbaphosphatrane (98) was also reacted with either oxygen or sulfur in the presence of base (e.g. DBU or Et3N) to form the

H

Bu' B

V

(105) a, R = Me b, R = Pr' c, R = Piv d, R = Bu'

0

(106) a, Ar = pCNCeH4 b, Ar = pCIC6H4 c, Ar = rn-BrC6H4

e, Ar = l-naphthyl f, Ar = 2-naphthyl g, Ar = 9-phenanthryl

h, Ar=

@

i. Ar = Ph

\ /

(105a)

(107a-i)

80

Organophosphorus Chemistry

corresponding phosphonate (103) or thiophosphonate (104) presumably via the deprotonated form (102) of the phosphonite tautomer (101). 31PNMR has been used to determine the pK, values of series of proazaphosphatranes (105a-d) and values of 32.90 (105a), 33.63 (105b), 32.84 (105c) and 33.53 (105d) were reported in comparison with a value of 32.82 for (105a) determined by UV-VIS titration.26 Proazaphosphatrane (105a) has been shown to deoxygenate a series of aryl aldehydes (106a-i) to form the corresponding diary1 epoxides (107a-i) in high yields and with translcis ratios as high as 99 : l.27The high diastereoselectivity was attributed to the rigidity of the pentacoordinate 1 :2 adduct (Scheme 4) with the cis arrangement of the aryl groups offering less steric hindrance within the pentacoordinate intermediate. Ar

I Me ArCHO

-ArCHO

(106a-i)

0-

O ,

L

0 Ar

N

P+--- /Me hN>Me >

ArPr 0

(trace) Scheme 4

Three new proazaphosphatrane bases (108ab) and (109) have been prepared and a pK, value of 34.49 reported for (109). A comparison of the catalytic properties of three bases (108c-e) was also made in the synthesis of P-hydroxynitriles, P-nitroalkanols, a,P-unsaturated esters and for the Michael addition of alkyl alcohol to a$-unsaturated ketones.28

(108) a, R = Me3CCH2 b, R = MepCHCHp C, R = Pr'

d, R = Piv e, R = BU'

81

2: Pentacoordinated and Hexacoordinated Compounds

Although outside the realm of hypervalent phosphorus chemistry, evidence has been presented for pseudorotation at the central antimony atom in pentacoordinate antimony compounds.29Thus stiborane (110) was reacted with triphenylphosphine under irradiation with a tungsten lamp to give a mixture of four diastereomers (11la-d) that were separated by TLC and their stereochemistry determined by X-ray crystallography. Thermal equilibration of each diastereomer by heating in o-dichlorobenzene was monitored by 19FNMR and showed that isomerization occurred through pseudorotation at the central Sb atom (Scheme 5). Small amounts of decomposition products and unexpected stereoisomers (e.g. 11l b and 11l c from 11l d or 11l a and 11Id from 11lc) were ascribed to random recombination of the diradicals formed from cleavage of the Sb-Fe bond.

F3C CF3 (1 10)

( l l l a ) 15%

Me ,CF3

( l l l b ) 12%

F3C Me

\,

\./

( l l l c ) 20%

( l l l d ) 10%

[wsbl

F3C CF3

( l l l d ) (C, Sb, Fe) = (R, R, S)(S,S, R)

Me CF3 \ .’

[b+

( l l l a ) (C, Sb, Fe) = (R, S, S)(S,R, R)

-Th3 ,

[Wsbl

-co

L

-

/.\

F3C CF3 ( 1 1 l c ) (C, Sb, Fe) = (R, S, R)(S, R, S)

F3C CF3

l l l b ) (C, Sb, Fe) = (R, R, R)(S, S, S) Scheme 5

82

Organophosphorus Chemistry

Finally, although no specific examples of hexacoordinate phosphorus chemistry emerged during the year, Akiba et aL3'reported the synthesis and X-ray crystallographic structures of two hexacoordinate antimony compounds (114) and (115)without halogen ligands. Compound (114)was prepared by reaction of the pentacoordinate chlorostiborane (112) with (113) followed by countercation exchange with tetraethylammonium bromide. The crystal data showed clearly that (114)was octahedral and in the mer (rather thanfac) configuration. Reaction of (114) with triethyloxonium tetrafluoroborate resulted in alkylation of the oxygen atom anti to carbon to form (115) whose structure was intermediate between penta- and hexacoordinate but closer to the latter.

7

0 F3C CF3

References 1.

2. 3.

4. 5.

6.

7. 8. 9. 10.

11.

R.-M. Schoth, D. Sevenard, K. Pashkevich and G.-V. Roschenthaler, Coord. Chem. Rev., 2000,210, 101. K.N. Gavrilov and A.I. Polosukhin, Russ. Chem. Rev., 2000,69(8), 661. K.N. Gavrilov and I.S. Mikhel', Russ. Chem. Rev., 1996,65,225. T. Kawashima, J . Organomet. Chem., 2000,611,256. N.G. Khusainova, G.R. Garipova, T.A. Zyablikova, R.A. Cherkasov and A.N. Pudovik, Russ. J . Gen. Chem., 2001,71(3), 339. V.F. Mironov, I.A. Litvinov, A.A. Shtyrlina, A.T. Gubaidullin, R.R. Petrov, A.I. Konovalov, N.M. Azancheev and R.Z. Musin, Russ. J . Gen. Chem., 2000, 70(7). 1046. A. Thonnessen, T. Siedentop, P.G. Jones and R. Schmutzler, 2.Anorg. Allg. Chem., 2001,627,73 1. I.V. Shevchenko, R.N. Mikolenko, E. Lork and G.-V. Roschenthaler, Eur. J . Inorg. Chem., 2001,2377. A. Dimitrov and K. Seppelt, Eur. J . Inorg. Chem., 2001,1929. M. Freytag, P.G. Jones, R. Schmutzler and M. Yoshifuji, Heteroat. Chem., 2001, 12(4),300. V.A. Sychev, M.P. Koroteev, Z.M. Dzgoeva and E.E. Nifant'ev, Russ. J . Gen. Chem., 2001,71(2), 188.

2: Pentacoordinated and Hexacoordinated Compounds

12. 13. 14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

83

Y. Ju, J.-J. Hu and Yu-F. Zhao, Phosphorus, Sulfur and Silicon, 2000,167,93. L.M. Burnaeva, V. Mironov, S.V. Romanov, G.A. Ivkova, I.L. Shulaeva and I.V. Konovalova, Russ. J . Gen. Chem., 2001,71(3),488. S.B. Tzokov, B. Svetomir, N.G. Vassilev, R.T. Momtcheva, J. Kuneti and D.D. Petrov, Phosphorus, Sulfur and Silicon, 2000, 166, 187. M. Garrossian, W.G. Bentrude and G.-V. Roschenthaler, J . Org. Chem., 2001,66, 6181. W.G. Bentrude, T. Kawashima, B.A. Keys, W.H. Garroussian and D.A. Wedegaertner, J . Am. Chem. SOC., 1987,109,1227. C . Marchi, G. Delapierre, F. Fotiadu and G. Buono, Chem. Commun., 2000,2227. K.N. Gavrilov, A.V. Korostylev, A.I. Polosukhin, O.G. Bondarev, A.Yu. Kovalevsky and V.A. Davankov, J . Organomet. Chem., 2000,613,148. A. Neuman, Y. Leroux, D. El Manouni and T. Prange, Z . Kristallogr., New Crystal Struct., 2000,215, 539. N. Kano, J.-H. Xing, S. Kawa and T. Kawashima, Tetrahedron Lett., 2000,41,5237. N. Kano, J.-H. Xing, A. Kikuchi and T. Kawashima, Heteroatom. Chem., 2001, 12(4),282. S.A. Terent’eva, M.A. Pudovik, A.T. Gubaidullin, I.A. Litvinov and A.N. Pudovik, Russ. J . Gen. Chem., 2001,71(3), 330. A.N. Chekhlov, A.N. Bovin and E.N. Tsvetkov, Izu. Akad. Nauk. SSSR, Ser. Khim, 1991 (7), 1523. A. Chandrasekaran, R.O. Day and R.R. Holmes, Inorg. Chem., 2000,39,5683. J. Kobayashi, K. Goto and T. Kawashima, J . Am. Chem. Soc., 2001,123,3387. P.B. Kisanga and J.G. Verkade, J . Org. Chem., 2000,65,5431. X. Liu and J.G. Verkade, J . Org. Chem., 2000,65,4560. P.B. Kisanga and J.G. Verkade, Tetrahedron, 2001,57,467. K. Toyota, Y. Wakisaka, Y. Yamamoto and Kin-ya Akiba, Organometallics, 2000, 19,5122. Y. Wakisaka, Y. Yamamoto and Kin-ya Akiba, Heteroat. Chem., 2001,12(1), 33.

4 Quinquevalent Phosphorus Acids BY B. J. WALKER

1

Introduction

The current review, although hopefully balanced, is again selective. The main areas of activity are similar to last year. For example, biological aspects of quinquevalent phosphorus acid chemistry, quite separate from nucleotide chemistry, continue to increase in importance and tetracoordinate phosphorus compounds continue to be a major source of transition state analogues for the generation of abzymes, etc. Since the reaction pathways for peptide bond hydrolysis and phosphate ester hydrolysis are quite different, i.e. tetrahedral and trigonal bipyramidal T.S’s, respectively, it has seemed unlikely that a single active site in an enzyme could catalyse both reactions. Just such an example, a zinc aminopeptidase from Streptomyces griseus, has now been reported. The numbers of reports of syntheses of natural and unnatural sugar phosphates, particularly as probes for the investigation of enzyme mechanisms, continue to increase, as does activity in all aspects of inositols and related materials. Although applied in other areas, the use of monomethyl polyethylene glycol as the polymer support to allow either solid-phase or solution-phase chemistry to be carried out, depending on the solvent employed, is worth noting. The number and breadth of reports of synthetic studies relating to phosphatidylinositols and related structures has increased markedly. One report demonstrates that such compounds with fatty acid side chains as small as Cg show reactivity comparable to that of the natural substrate towards phosphatidylinositol3-kinase. Numerous investigations of phosphate ester hydrolysis and exchange reactions continue to be reported. The recently proposed alternative mechanism for phosphate monoester dianion hydrolysis, involving initial proton transfer from the nucleophile, has been dismissed as unlikely in a new report. The importance of enantiometric and asymmetric synthesis is illustrated in many reports and the synthesis, and use as chiral catalysts, of chiral phosphorus(V) amides features in many publications. Dynamic kinetic asymmetric transformation (DYKAT) of racemates has been applied to the asymmetric synthesis of D-myo-inositol 1,4,5triphosphate. One of few reports of the synthesis of a single enantiomer of an a-fluoroalkylphosphonate has appeared and the first catalytic asymmetric synthesis of (S)-a-hydroxy-H-phosphinates and (S,S)-a,a’-dihydroxyphosphinates has been achieved by the reaction of methyl phosphinate with aldehydes in the Organophosphorus Chemistry, Volume 33

0The Royal Society of Chemistry, 2003 103

Organophosphorus Chemistry

104

presence of a BINOL comex. Interest in approaches to easier/safer nerve gas hydrolysis continues. A new method of detection for fluorophosphorus nerve poisons has been reported. Phosphotriesterase (PTE) from Pseudomonas diminuta catalyses the hydrolysis of organophosphorus pesticides and nerve gases with rate enhancements of up to lo'* and it has now been shown that the bridging ligand in the active site of Zn-substituted phosphotriesterase is hydroxide rather than water.

2

Phosphoric Acids and Their Derivatives

2.1 Synthesis of Phosphoric Acids and Their Derivatives. - A series of monoalkyl and dialkyl phosphorus acid chiral esters have been synthesised for use as carriers for the transport of aromatic amino acids through supported liquid membranes.' The compounds acted as effective carriers but enantio-separation was at best moderate. A range of phosphono- and phosphoro-fluoridates have been prepared by treatment of the corresponding thio- or seleno- phosphorus acids with aqueous silver fluoride at room temperature (Scheme 1).2 In some cases oxidation rather than fluorination occurred. Stereospecificallydeuteriumlabelled allylic isoprenoid diphosphates, e.g. (l),have been synthesised from the corresponding deuterium-labelled aldehyde by asymmetric reduction, phosphorylation and SN2displacement with pyrophosphate (Scheme 2).3

X = 0 , S , Se Y = SR, SScheme 1

Scheme 2

The number of reports of the syntheses of natural and unnatural sugar phosphates, particularly as probes for the investigation of enzyme mechanisms, continues to increase. A new, efficient procedure for the phosphorylation of sugar hydroxy functions involves reaction with triimidazolylphosphine to give the hydrogen phosphonate (2), followed by conversion into the fluoren-9-ylmethyl phosphate diester (3) and hydrolysis to give the phosphate monoester (4) in excellent overall yield (Scheme 3).4 Similar hydrogen phosphonate intermediates, e.g. (5),are involved in a new synthesis of keto-glycosyl phosphates, e.g. (6).5 In this case a combination of ruthenium oxide, sodium periodate and benzyltriethylammonium chloride are used to simultaneously oxidise the phosphonate and alcohol functions. In a different approach, homologous C-glycosyl-phosphate (9) and -phosphonate (10) analogues of N-acetyl-a-D-glycosamine l-phos-

4: Quinquevalent Phosphorus Acids

105

-& 0

I I 0-

i, ii

Reagents: i,

iii, iv

?>):,

MeCN; ii, Et3iHHC03-; iii,

py, Me3CCOCI; iv, 12, py, H20; CHZOH

v, py, CH2CI; vi, H20

Scheme 3

HO*

RuO,, NaI04 +

BnO

&

Ho+ HO

AcO

AcHN

NHAc (7)

:

(8)

x =OP(OH),

(9)

x = CH2CH,0P(OH),

(10)

x = CH2CH2P(OH)2

: :

phate (8) have been synthesised from the protected (acetamido-deoxy-a-Dglycopyranoy1)-prop-1-ene (7).64-Deoxy-~-fructose6-phosphate (12) has been prepared by a combination of enzymic and chemical steps from (3S)-l,l-diethoxy-3,4-epoxybutane (1l), itself obtained by epoxide hydrolase-catalysed resolution.' Reports of the synthesis of various open-chained sugar and related phosphates have also appeared. [5,5-2Hz]-1-Deoxy-~-xylulose-5-phosphate (14), an intermediate in the methylerythritol pathway of isopentenyl diphosphate biosynthesis, has been obtained from the deuterated alcohol (13)by chlorophosphate-based phosphorylation and deprotection (Scheme 4)' 2-C-Methyl-~erythritol 4-phosphate (15) is an early intermediate in the biosynthesis of bacteria, algae, and plant chloroplasts and a number of syntheses of the single enantiomer have been reported, for example, in seven steps from propane-1,2diol.' Two other approaches, one in nine steps from commercially available 0

2-02po II

CH20H

OH (12)

106

Organophosphorus Chemistry Me

Lk - ';TH I

c=o

CD20H

OH

i-iii

0

Me

II

0

CD20P(OH)2

Reagents: i, ~ o : P ? ~ ii, l ;Br2. H20; iii, H30+ 0

Scheme 4

1,2-O-protecte~-a-~-xylofuranose~~ and the other in thirteen steps from 1,2:5,6di-O-isopropylidene-D-mannitol,' have been designed to allow the introduction of different isotopes of hydrogen and carbon at various sites. Chemical-enzymic methods have been used to synthesise phosphorylated cyclic amines and imines, e.g. (16) and (17).12Compound (17) exists as an equillibrium mixture of pyranose and iminofuranose forms, with the latter predominating. Dihydroxyacetone monophosphate (DHAP) (18) acts as a substrate for a number of enzymes and as such is a useful synthetic intermediate. Unfortunately, DHAP is unstable and so a precursor is generally used in its place. A new route to a commonly used precursor (19) of DHAP has now been reported (Scheme 5).13 Although the M e 0 OMe

A L

OH

OH

M e 0 OMe

ii

o\p'o

d'\OPh Reagents: i, PhOP(O)CI2,py; ii, Ba(OH)2, 96 "C Scheme 5

Mexe 0 ,

OH p022-

d'

(19)

0 ,

OH p022-

d'

(18)

overall yield of (19) is poor, the method has the advantages of being inexpensive and potentially scalable. An efficient synthesis of (-)-shikimate (20) and (-)quinate (21) 3-phosphates, from shikimic and quinic acids, respectively, has been reported.I4 A key step in the method for both syntheses is the use of the 2,2,3,3-tetramethoxybutanegroup for selective protection of the trans-diol function. Further work on various saccharide phosphates associated with the Leish-

107

4: Quinquevalent Phosphorus Acids 0

0

mania protozoan parasites has been reported, including the synthesis of inositol phosphoglycan fragments by a convergent method using established methods" and the preparation of three structural analogues, (22), (23), and (24), of the minimum exogeneous acceptor substrate structure required by the a-D-mannopyranosyl phosphate-transferase of the parasite? Two acyclic mimics, (25) and (26), of dec-9-enyl P-D-galactopyranosyl-(1 + 4)-a-~-mannopyranosyl phosphate have been ~ynthesised.'~ Work aimed at the ultimate synthesis of Leishmania lipo- and proteo-phosphoglycans continues. Reports include the synthesis of a number of mono- and tri-phosphate fragments using coupling of di- and tri-saccharide hydrogen phosphonates to construct the phosphate diester bridged8 and a polymer-supported synthesis of phosphorylated tetra- and hexasaccharide fragments of the lipopho~phoglycan.'~ In the latter report the use of monomethyl polyethylene glycol as the polymer support allows either solidphase or solution-phase chemistry to be carried out, depending on the solvent employed.

OH

H @ o;b

x,\ P'O(cH*)!3Me 7

OH

arm

?, ,o-

HO OH OH (22) x = s, Y = 0(23) X=BH3, Y=O(24)X = 0, Y = Me

HOW'

P\O(CH2)8CH=CH2

(25)

Lo:<, 0 0-

ti0-O

Et$H

(26)

Et3iH

O(CHd9Me

The preparation of inositol and structurally related phosphates continues to be actively explored. Examples include the first total synthesis of the inositol tetraphosphate enantiomeric pair, Ins(1,2,3,4)P4 (27) and Ins(1,2,3,6)P4(28).20 Compounds (27) and (28) were dephosphorylated by a number of different enzymes and thus provide routes to specific inositol triphosphates. A number of myo-inositol 1,4,5-triphosphates, e.g. (29)-(32), modified at the 6-position have been prepared.21 All such derivatives investigated showed poor affinity for Ins(1,4,5)P3receptors. A new and comparatively convenient synthesis of 1 - ~ - 6 - 0 (2-am~no-2-deoxy-a-~-g~ycopyranosy~)-chiro-~nos~to~ 1-phosphate (33) and the corresponding 1,2-cyclic phosphate (34) has been reported.22The first examples of poly(ethy1ene glycol)-linked dimers (35) of D-myo-inositol 1,4,5-triphosphate have been prepared as probes for multi-subunit binding proteins for

108

Organophosphorus Chemistry

2-03POQ1Qj20 ~ 0 ~ ~ -

2 - 0 3 1 10~ ~ o P0o ~3 2~ - -

2-~3 PO'

HoQTHz

' 0 ~ 0 ~ ~ H ~- O ~ P O ' OH (27)

OH (28)

(29) (30) (31) (32)

OP03H2 R' = R2 = H R' = H, R2 = F R1 = H, R2 = NH2 R1 =OH, R 2 = H

I OR' OR2

OH

I

H O

/

2-o

'

V

N

~

o

~

O

~

o

H~

O

A

N

~

o

O 0 ~ 0 ~ ~ -

G3PO OH

(35) n = 4 , n=30, n = 7 5 , n=180,

Ins( 1,4,5)P3.23 A number of phosphates, e.g. (37),which act as inositol monophosphatase inhibitors have been synthesised from the 1,6-epoxy-4-benzyloxycyclohexan-2-01 (36).24Conduritol derivatives (39) are useful synthetic building blocks. However, the enantioselective palladium-catalysed ally1 alkylation and similar reactions of (38) are complex due to C2 symmetry. It has now been reported that dynamic kinetic asymmetric transformation (DYKAT) of racemic (38) using palladium chemistry can give high e.e. values.25For example, the derivative (38)(R = C02CH2CCl3)reacts with dibenzylamine in the presence of a Pd catalyst and the chiral diphosphine (40)to give the mono-substituted product (39) in 89% yield and with 95% e.e. The yield of >50% shows that DYKAT is operating and the method has been applied to the synthesis of D-myo-inositol 1,4,5-triphosphate. OR

OP03H2

H O G o

H O 0 , O P r

N(CH2W2

+ (PhCH&NH

&R

OBn (36)

I

OH (37)

Q""

7.5% (R,R)-(40)

OR I

5% dba3Pdp.CHC13

I

OR I

OR (38)

OR (39) R = C02CH2CC13

PPh2

Ph2P (40)

4: Quinquevalent Phosphorus Acids

109

The number and breadth of reports of synthetic studies relating to phosphatidylinositols and related structures has increased markedly as the following selection demonstrates. A series of unnatural phosphatidylinositols (41) with C2 to c18 fatty acids replacing the natural C20fatty acid at the sn-2 position have been prepared and subjected to phosphorylation conditions with phosphatidylinositol 3 - k i n a ~ e .The ~ ~ results show that phosphorylation can be achieved in molecules carrying small fatty acid side chains; c g shows reactivity comparable to that of the natural substrate. 1-D-1-(sn-3-Phosphatidyl)-myoinositol(42) has been prepared in excellent yield by the direct phosphatidylation of 1-~-2,3,4,5,6-penta-O-benzyl-myo-inositol with sn-3-phosphatidic acid and subsequent deprotection (Scheme 6).27The method has the advantage of producing products of unequivocal structure and stereochemical purity and being Rco2~oCoc17H35

HO$$-."=O

0 I

OH

H( OH (41) R=C2-C18

R'C02 R2C02

Brio OH

R'co2j i, ii

OBn BnO+oBn

+

OBn

R2C02

II OP(OH)2

(42)OH

Reagents: i, TPSCI, py; ii, H2lPd-C

TPSCl =@-

S02CI

Scheme 6

adaptable to large scale production. The synthesis of a number of 6-deoxy phosphatidylinositol analogues and phosphonate isosteres from the protected cyclohexanone polyol (43) has been reported.28Reports of synthetic studies of phosphatidylinositol phosphates include a highly efficient, total synthesis of L-a-phosphatidyl-D-myo-inositol 3-phosphate (44), 5-phosphate (49, and 3,5bisphosphate [PI(3,5)P2] (46).29Two other diphosphates, PI(4,5)P2 (47) and PI(3,4)P2(48), and a triphosphate, PI(3,4,5)P3(49), have been prepared from the readily available ~-(-)-quebrachitol.~'The low cost of the starting material, the minimum amount of chromatography required and the inexpensive protecting groups used suggest that this a highly competitive approach. The synthesis of the bioactive phosphatidylinositide diphosphate ( 5 1)in ten steps from deoxyinosose

Organophosphorus Chemistry

110

0-P-0 I

OBn

OH OH (44) R’ = H, R2 = P(O)(OH)2 (45) R’ = P(O)(OH)2, R2 = H (46) R’ = R2 = P(O)(OH)*

(43)

(50) uses phosphoramidite chemistry to introduce all three phosphate groups.31 Other reports of triphosphate syntheses include those of various PI(3,4,5)P3’s (52).32Finally, the preparation of a number of glycosyl phosphatidylinositol anchors (53) incorporating either fluorescent- or radio-labels is worth

R2&0, R ~ O

R’O OH O C O 1 H 3 5 C ,1A ,P ,O ,,

(?C0C15H31

// \ HO 0 OH (47) R’ = R2 = PO3H2, R3 = H (48) R’ = H, R2 = R3 = PO3H2 (49) R’ = R2 = R3 = PO3H2

0 OTBS OBOM ( H 00 ) $ 0O$(OH)p 0 0 H

~

::

JOR’

2 - 0 3 p 0 OH ~ 0 - ~ - {

OR2 I

0 (50) TBS = Bu‘Me2Si BOM = PhCH20CH2 MPM = 4-MeOC6H4CH2

2-~P 3 0’

‘0-P-0

HO’ OH

’OH

OCOR’

0 ~ 0 ~ ~ -OCOR2

OH

HO

t

0 -CO(CH2),Me 0 -CO(CH2),Me

The synthesis of phospholipids and analogues, mainly by well-established methods, continues to be actively pursued. A new, stereospecific route to functionalised ether phospholipids, e.g. (54) and (55), as analogues of l-O-alkyl-2acetyl-sn-glycero-3-phosphocholine(PAF) and modulation phospholipids, has been reported.34The route uses (Qglycidyl tosylate (56) as the chiral precursor

111

4: Quinquevalent Phosphorus Acids CH20(CH2),CO2HO+H

oI I

/NH3

0

CH2-O-P-O-CH-CH I I \ OH R' R2 (54) R' = Me, R2 = CO; (55) R' = CH2C02-, R2 = H

OTs (56)

and a key step is BF3-catalysed ring-opening alkylation of (56) to generate functionalised sn-1-alkyl intermediates. Another approach uses L-glyceric acid as the chiral starting material and this method has been applied to the preparation of a wide range of phospholipid-like The synthesis of a bifunctionalised phospholipid containing biotin and nitriloacetic acid functions in the head group, and capable of binding streptavidin or poly-histidine-tagged proteins, has been published.36Phosphoramidite chemistry has been used to prepare phospholipid analogues possessing biocompatible properties and the monomer (57) used in the preparation of biocompatible polymers (Scheme 7).37A new

I 0

CI

ii, iii

(57)

ii, ~e,A-o-; iii, Me3N H

Scheme 7

synthetic approach to produce phosphorylcholine groups covalently bound to silica oxide surfaces (58) has been reported.38 These monolayers inhibit the deposition of enzymes and proteins and so improve biocompatibility. The phosphonooxymethyl group has been investigated as a novel functionality to provide water-soluble prodrugs (60) of drugs containing tertiary amine functional Compounds (60) were synthesised by reaction of the tertiary amine with di-t-butyl chloromethyl phosphate (59) followed by deprotection. Prodrugs of a number drugs were prepared and in one case, cinnarizine, the prodrug was

112

Organophosphorus Chemistry

shown to be completely converted into the free drug in vivo. A fluorescencelabelled phosphonooxyethyl analogue (61) of lipid A has been synthesised and shows cytokine-inducing activity similar to the natural lipopolysaccharide!’ Increasingly complex phosphorus-containing dendrimers have been prepared. For example, the addition of three types of tetraazamacrocyles, e.g. (62), to the surface of dendrimers carrying P(S)Cl2 end groups4’ and the synthesis of new dendritic polythionophosphates, e.g. (63), have been reported.42

0

DABCO, PhMe

R,’

,S02NH2

X (64)

R’X = n-Oct-0, R4

DIAD, THF

X (65)

co@

A

* R,’

,so~N=P(oR~)~

* R,’

,:,

X I1 N’ O H

0 !(OR2

(66)

NH

0 I1

1-111

(R0)2PH

0

R’

II

H Reagents:

R’ 1 H i, CCI4, CH2CI2,H&-C,*’ ; COZEt

(67)

ii, NaOH, H20; iii, HCI, H20 Scheme 8

N-Phosphoryl sulfamates (66) can be considered bioisosteres of pyrophosphate. Compounds (66) have now been prepared by the reaction of sulfamates (64) with trialkyl phosphites to give (65) which readily isomerise under basic c0nditions.4~A variety of N-phosphoamino acids (67) carrying long-chain alkyl groups on phosphorus have been prepared from the corresponding dialkyl phosphite and amino acids (Scheme 8).44A modified approach to the solid-phase

113

4: Quinquevalent Phosphorus Acids

synthesis of phosphopeptides has been reported in which the asymmetrically protected phosphoramidite (68) is used as the phosphorylation ~eagent.4~ The method offers a number of advantages over those previously used. Se-Alkenyl 0,O-dialkyl phosphoroselenoates (69) have been synthesised in good yields from potassium 0,O-dialkyl phosphoroselenoates!6 The first chiral phosphorus-containing porphyrins (70) having molecular symmetry have been prepared, resolved by chiral HPLC and their conformation in solution in~estigated.4~ ,OCH2CH2CN

Me

P'\

Pri2N-

OBu'

(68) 0 II

"'F SeP(oR)2

H

H

(69)

'e

(70)

Et

2.2 Reactions of Phosphoric Acids and Their Derivatives. - Phosphorus(V) halides are commonly used reagents and a few new reports of their reactions are worth noting. Phosphorodiamidic chlorides are known to activate carboxylic acid groups, for example, towards ester formation. The chloride (71) has now been used as the coupling reagent with 2-naphthol and chiral carboxylic acids in a one-pot procedure to prepare chiral2-naphthyl carboxylates, the CD spectra of which provide a method of assigning the stereochemistry of the original chiral carboxylic acid:* Several mechanisms have been proposed for the formation of diphosphates (74) from the reaction of the chlorophosphate (73) with the corresponding ester (72) or acid. Similar biphosphates (76), and intermediates, are formed as byproducts in the reactions of chiral chlorophosphate (75) with alcohols and amines. NMR studies of these reactions has now led to a new insight into the stereochemistry and mechanism of formation of biphosphates in all these reactions.49A new method of detection for fluorophosphorus nerve poisons has been rep~rted.~' Porous silicon films incorporating a catalyst for P-F hydrolysis are exposed to the nerve poisons and reflectivity spectra recorded. The method estimates the amount of HF produced through changes in the silicon surface caused by its reaction with HF (Scheme 9). The reaction of phosphorochloridates, e.g. (77), with DBU has been investigated using 31PNMR as the main probe.51The initially formed product (78) undergoes P-N to P-C rearrangement to give (79). The kinetics and mechanism of the reaction of aryl phenyl chlorophosphates (80) with pyridines have been investigated and the differences from similar, but slower, reactions with anilines are Numerous investigations of phosphate ester hydrolysis and exchange reactions continue to be reported. The recently proposed alternative mechanism (Scheme 10) for phosphate monoester dianion hydrolysis, involving initial proton transfer from the nucleophile, has been the subject of a detailed investigat i ~ n On . ~ the ~ basis of their results the authors conclude that the alternative mechanism is unlikely. Hydrolysis of D-1-S,-myo-inositol [170]-thiophosphate (81), catalysed by myo-inositol monophosphatase, takes place with inversion of

114

Organophosphorus Chemistry

n

f

n

"-r"Ko

OK

(71)

K+K

(75)

+

Rl-7,

?

H20

F Catalyst

R2

0 H20 + -0-P-OR I

0-

0

SiOz

II

OH + HF

0 II

HO- + -0-P-OR I

OH

SiF4

R2 Scheme 9

0

0 RO- + HO-P-0I

Scheme 10

OH

II

A

ROH + -0-P-0OH

configuration at p h o s p h ~ r u s This . ~ ~ result indicates that the phosphate transfer reaction takes place by an in-line mechanism analogous to the classic SN2. 4-Nitro-1,S-naphthyl phosphate (82) is lo2 to lo3 times more reactive to basic and metal cation-mediated hydrolysis than the acyclic analogue (83).55The authors suggest a number of factors that may contribute to this substantial rate difference.Various studies of metal ion- and metal complex-catalysed hydrolyses of phosphate esters have appeared. Significant rate enhancements of 4-nitrophenyl phosphate hydrolysis have been reported when the reaction is carried out in the presence of Cu(I1)-metallated polymers derived form 9-all~ladenine.~~

4: Quinquevalent Phosphorus Acids

115

Reports which have clear applications in DNA hydrolysis include one of a dinuclear lanthanum(II1) complex that catalyses phosphate diester hydrolysis to give unprecidented rates of and one describing the preparation of two new dinuclear bisimidazolyl-Cu(I1) calixarenes and an investigation of these complexes as metalloenzyme models for phosphate diester cleavage.58The importance of tuning microenvironments when designing synthetic nucleases is illustrated by a report that intramolecular trans-esterification of 2-hydroxypropyl-4-nitrophenyl phosphate (84) is up to 5000 times faster in organic solvents than in water.59 A detailed 31PNMR study has been reported of the hydrolysis, in aqueous solution at specific pH values, of the alkylating anti-tumour agent ifosfamide (85), and its metabolites (86), (87), and (88).60The first step in each case is ring-opening by hydrolysis of the endo-cyclic P-N bond. In kinetic studies aimed at modelling enzyme-mediated formation of high-energy phosphates, the

(84)

acetylation of n-decyl phosphate quaternary ammonium salt (89) by 2,4-dinitrophenyl acetate to give (90) has been in~estigated.~' The reaction takes place in acetonitrile but is strongly inhibited by water. When concentrations of water exceed 20 vol.% in acetonitrile, (90) cannot be detected and the results indicate that this is due to the rapid competing hydrolysis of 2,4-dinitrophenyl\acetate. It is reported that trimethylamine reacts with 2-alkoxy-2-0x0- 1,3,2-dioxaphospholane (91) by attack at the methyl ester group to give the salt (92) rather than by ring-opening to give the betaine (93).62It is worth noting that this reaction also takes place with tetramethylethylene diamine, a reagent which is often used as a base in the preparation of (91). The alkylation of phosphate diesters can be achieved by reaction with quinone methides. However, the fact that diester and triester products are in equillibrium in these reactions restricts their use. It is now reported that the triester catechol adducts (94) can be stabilised by using quinone methides carrying a side-chain that allows trapping by in situ lactonisation

116

Organophosphorus Chemistry

fi?

Dec-0-7-0-

BnhMe3 + M e ! - O b N O *

DecOPOCMe + I

OH (89)

OH

Scheme 11 0

hv

Ph 0 -

Sensitizer

0 II HOP(OEt)2

Scheme 12

(Scheme 1l).63 The phenacyl group provides a new, photo-releasable protecting group for phosphates (Scheme 12).64 Reports of the interaction of phosphate esters with cyclodextrins have appeared. The binding of phosphate monoester dianions and diester monoanions to aminocyclodextrins (ACDs) has been studied and compared to the binding of neutral guest molecules to ACDs and to the binding of both types of guest to cycl~dextrins.~~ The effect of buffers on the binding of positively charged cyclodextrins to three phosphate aryl monoesters (95) has been in~estigated.~~ Negatively charged buffers compete with the esters for binding much more strongly than positively charged buffers. Phosphate esters have been used as leaving groups in a variety of synthetic methods. For example, enol phosphate esters have been used as substrates in reactions with lithium butyltelluride to give vinylic tellurides (96) and in Suzukitype reaction^.^' Examples of the latter include the synthesis of a variety of novel substituted nitrogen-containing heterocycles (97) from aryl- or heteroarylboronic acids6*and the use of phosphate (98) in a Suzuki cross-coupling reaction with the alkylborane (99) as the key step in a synthesis of an HIJK ring-model of c i g ~ a t o x i nA . ~ ~modified approach to glycoside synthesis using protected Dmannopyranosyl phosphate triesters (100)in the presence of TMSOTf has been reported.'' A variety of different 0-nucleophiles were used and yields were generally good to excellent. The stereochemistry of the glycoside link formed was influenced by the quantity of TMSOTf used in the reactions. Glucose 6-phos-

4: Quinquevalent Phosphorus Acids

117

phate concentrations in the micromolar range have been determined using a trisboronic acid receptor and a fluorescein indi~ator.~'

R

co;

(95) R = N02, CH,-(+

, CHz-(c02Me NH3

0 II

R'C=CHCR2

+ LiTeBu

NHAc

-

t

R'C=CHCR2 I

TeBu

(96) Pd(Ph,P)4 ArB(OH),

Ar Boc (97) Y = CH, N, Z = O , S

Boc

1

Pd(PPh,),,

DMF, NaHC03, H20

BnO yB *n

x

9 o'p'o

(100) X = H , Y

I?

9

I?

o,p,

= u ; X = u o . Y=H

The phosphate to phosphonate rearrangement in mixed esters (101),initiated by metallation with sBuLi/TMEDA at low temperature, has been studied using reaction product analysis, deuterium-labelled reactants and NMR.72The regioselectivity of deprotonation and hence the product distribution is strongly dependent on the nature of the ester alkyl groups. The influence of a range of parameters on the P-0 to P-C rearrangement of (102)to give the chiral o-hydroxyaryl diazaphosphonamaides (103)has been studied (Scheme 13).73The l-oxo-2,5,8-triaza-lh5-phosphabicyclo[3.3.O]octane(104)(R = Ph) is known to

118

Organophosphorus Chemistry 0 II . RCH20P(OPr')2 (101)

s-BuLi

0 OH \I I

* (Pri0)2PCHR +

TMEDA, EtZO,-78 "C

Ph (102) Reagents: i, 2 x LDA, THF, -78 "C; ii, NH4CI

0 Me 1 P-C-Me RCH2d 'OH Pr'0,II

Ph (103)

Scheme 13

undergo acid-induced ring-opening with alcohols to give (105) (R = Ph) which spontaneously rearranges to the isomeric diazaphospholine derivative (106) (R = Ph). A series of new analogues of (104) have now been prepared and their acidand base-induced ring-opening, and the factors affecting the rearrangement of the resulting %membered cyclic diamide product (105), i n ~ e s t i g a t e d . ~ ~ Experimental and theoretical studies of reactions of P-phosphatoxyalkyl radicals have been r e p ~ r t e d . ~Radical ' , ~ ~ (108),generated by photolysis of the corresponding PTOC ester (107), forms the radical (109) by 1,2-migration of phosphate and (1 10)by e l i m i n a t i ~ nThe . ~ ~radical (112),when generated by photolysis of (111) in the presence of ally1 alcohol and t-butyl mercaptan, forms tetrahydrofurans (114) in good yield and with high trans-~electivity.~~ These studies provide evidence that the reactions take place via dissociation of the radical (112) to give radical cation (113) as an intermediate (Scheme 14).In kinetic studies of a similar radical (116),generated from (1 15)by laser flash photolysis, triaryl amines were used as reporter molecules and the rate of formation of the amine radical cation (117) was monitored (Scheme 15).77The method has application in studies of the formation and reactions of nucleotide C4' radicals, the formation of which has been implicated in the mode of action of antitumour antibiotics. Thiyl radicals cause cis to trans isomerisation of phospholipids containing cis-fatty acids via reversible addition to the double bond.78This isomerisation leads to

4: Quinquevalent Phosphorus Acids

119

changes in barrier properties and functions of biological membranes. The photodissociation of benzoin diethyl phosphate (118)has been studied by nanosecond and picosecond laser flash phot~lysis.'~ The lowest triplet state of (118) was identified as the reactive excited state and two different decomposition pathways, involving, respectively, release of diethyl phosphoric acid and the corresponding anion, have been identified. Tetrakis( l,l'-binaphthyl-2,2'-diylphosphate) complexes (119) are reported to be much more effective catalysts than the more commonly used carboxylate complexes for enantioselective intramolecular, tandem, carbonyl ylide formation/cycloaddition of a-diazo-P-keto esters.'' The ring-opening reactions of epoxides with diphenyl phosphorazidate (120) have been investigated.*lA wide range of epoxide substrates have been studied and the products, (121) or (122), depend on the substrate structure. The microbial hydroxylation of novel phos-

120

Organophosphorus Chemistry

phorus-containing azabicycloalkanes (123), (124), and (125) using Beauveria bassiana have been studied.**Compounds (123) and (124) undergo monohydroxylation to give (126) and (127), respectively, while (125) gives both monohydroxylation to give (128) and dihydroxylation to give (129). The use of 31Pand 'H NMR titration experiments to study the protonation of the individual phosphate groups in myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)(130), Ins( 1,4,6)P3(131), and 3-deoxy-Ins(1,4,5)P3(132) and its C-4 epimer, has been reported.s3 0

(123) R = OEt (124) R = P h (125) R = OPh

7

r:

0

I I ,O-Ph

N/P(oPh)2

OH

2.3 Selected Biological Aspects. - Since the reaction pathways for peptide bond hydrolysis and phosphate ester hydrolysis are quite different, i.e. tetrahedral and trigonal bipyramidal T.S's, respectively, it has seemed unlikely that a single active site in an enzyme could catalyse both reactions. Just such an example, a zinc aminopeptidase from Streptomyces griseus, has now been reported.84 A rate enhancement of 10'' for phospho diester hydrolysis was observed. Phosphotriesterase (PTE) from Pseudomonas diminuta catalyses the hydrolysis of organophosphorus pesticides and nerve gases with rate enhancements of up to 10" and so a more de:ded understanding of these enzymes is important. Followir.g the inability of an X-ray crystal structure to distinguish between the two possjbilities, molecular dynamics and quantum mechanical calculations now indicate that the bridging ligand in the active site of Zn-substituted phosphotriesterase is hydroxide rather than water.85The role of ferric ion in purple acid phosphatases has been investigated by replacing the ferric ion in the dinuclear Fe3+-M2+centre in their active site by A13+,Ga3+,and In3f.86The fact that the example containing A13+in the active site has very similar properties to the natural Fe3+-containingphosphatase is in conflict with current thinking that A13+ in active sites of dinuclear enzymes makes them ineffective. The spectroscopic characterisation of a ternary phosphatase-substrate-fluoride complex in

4: Quinquevalent Phosphorus Acids

121

a purple acid phosphatase and a discussion of the implication of these results on the mechanism of dinuclear hydrolyses in general, have been rep~rted.~’ There have been a number of investigations of mechanism of phosphoryl transfer by phophatase enzymes. One study involves the reaction catalysed by the Mn2+ form of both native and a mutant bacteriophage h-phosphatase using p-nitrophenyl phosphate as The results indicate that P-0 bond cleavage is rate limiting, the first example of this for a metallophosphatase. The effect of the conserved arginine on the transition state for phosphoryl transfer in the protein-tyrosine phosphatase from Yersinia has been investigated by studying mutants where arginine is replaced by lysine or a l a r ~ i n eAlthough .~~ the mutants are less effective catalysts, the results indicate that while the arginine residue stabilises the T.S., it does not alter its structure from that in the uncatalysed reaction. A common mechanism for bacterial resistance to aminoglycoside antibiotics (133) is irreversible phosphorylation of the 3‘-OH group by aminoglycoside-3’-phosphotransferases[APH( ~ ‘ ) s ] . ~ OIt is now reported that replacement of the 3’-hydroxyl by a ketone group to give (135) leads to reversible phosphorylation of the corresponding hydrate (134) formed in situ from (135), continually regenerating the antibiotic and hence overcoming bacterial resistance by this mechanism. Rotational-echo double resonance (REDOR) solidstate NMR experiments allow interatomic distances to be measured in some cases. This technique has now been applied to achieve the first direct identification of active site residues of the enzyme 3-deoxy-~-manno-2-octu~osonate-8phosphate synthase (KD08PS).91KD08PS catalyses a reaction that is crucial in the assembly of lipopolysaccharides by Gram-negative bacteria. HO

Amino, Amino glyco 0’ glyco (133)

-H

HO

P

O

S

Amino, Amino glyco 0’ glyco

I

(135)

O=P-OH I

OH

(134)

Calculations suggest that phosphorodithioates may be better Transition State analogues for enzymic acyl transfer reactions than the corresponding oxygen compounds. Such an analogue, (136), has been synthesised and used as a hapten to generate monoclonal a n t i b ~ d i e sThe . ~ ~ results support the predictions in that the most efficient catalyst produced in this study is one of the most active carbonate-hydrolysing antibodies yet reported. Although metal-binding proteins are commonly found in nature, metal ions alone are thought to be incapable of eliciting a specific antibody response. A new study using the bound phosphorodithioate chelate (137) to coordinate a range of metal ions for exposure to a single chain antibody library has identified antibodies that bind unique

122

Organophosphorus Chemistry

metal ions with excellent affinity.93The results have wide application; for example, the use of such antibodies in uiuo as carriers of radionuclides. The farnesyl pyrophosphate analogue (138), where the terminal isoprene unit has been replaced by an aniline function, has been s~nthesised.~~ Compound (138)is a substrate for protein farnesyltransferase and this, together with the fact that (138) is the first such compound that is not also an inhibitor of squalene synthase, offers a useful probe for studies of protein farnesylation; a process that is involved in malignant tumour transformation. The biosynthetic origin of the p-lactam carbons in calvulanic acid (140)has been determined.95The first gene in the clavulanic acid gene cluster in Streptomyces clavuligerus encodes a thiamine pyrophosphate-dependent enzyme that carries out a previously unknown condensation of L-arginine with ~-glyceraldehyde-3-phosphate to give (139). The methylerythritol phosphate pathway used by the bacterium Zymomonas mobilis has been studied in vivo using deuterium-labelled NADP2H.96Further investigations of the mechanism of formation of pyridoxol phosphate (141) in the biosynthesis of vitamin B6 have been r e p ~ r t e d . ~A~ .key ~ ' experiment is the use of [3,4-"02] 1-deoxy-D-xylulose 5-phosphate (143), prepared enzymatically from unlabelled dihydroxyacetone phosphate ( 142).97It is also reported that an E. coli protein, PdxJ, catalyses the condensation of 1-deoxy-D-xylulose 5-phosphate and 3-phosphonohydroxy-1-aminoacetone(144) to give pyridoxol 5'-phos-

hate.^^ The glycoside phosphoramidate (145) has potential as a pro-drug for use in conjunction with gene-directed therapy since (145) is readily transformed into the phosphorus mustard agent (146) when incubated with E . coli P-galact0sidase.9~ 3

Phosphonic and Phosphinic Acids

The synthesis of phosphonates by nucleophilic substitution at phosphorus by carbon nucleophileslOO and methods of synthesis of natural products containing a

4: Quinquevalent Phosphorus Acids

123 H

HO H

H02C

o-Po,~-

H

H

o' P-o: 0 v O P 0 3 2 -

Ho+OH

0

OH OH HOk & & O O C H 2 OH

PdxJ

II H

0-P(NCH&H2CI)*

f

HOP(NHCH2CH2C1)2 (145)

(146)

C-P bond"' have been the subjects of reviews. In the latter publication the synthesis, including enantioselective synthesis, of 2-aminophosphonic acid derivatives, phospholipids, aminomethylphosphonic acid, fosfomycin, phosphonopyruvic acid, and a variety of other, often complex, structures is described. 3.1 Synthesis of Phosphonic and Phosphinic Acids and Their Derivatives. - 3.2 .I Alkyl, Cycloalkyl, Aralkyl and Related Acids. In view of the importance and wide spread use of alkylphosphonates, new synthetic approaches are always welcome. The metal complex-catalysed addition of hydrogen phosphonates to activated alkenes to give alkylphosphonates has been achieved for the first time.''* A number of palladium catalysts have been successfully used (Scheme 16). However, while reactions with the five-membered cyclic phosphonate (147) gave excellent yields, reactions with acyclic or six-membered cyclic phosphonates were much less effective. The Arbusov reaction of secondary alkyl halides is not an effective route to secondary-alkylphosphonates or phosphinates (148). The latter compounds have now been prepared by a sequence of reactions from the corresponding ketone (Scheme 17).lo3The addition of organocerium reagents to phosphinoyl chlorides or chlorophosphates at -20°C provides a new route to phosphine oxides or phosphonates, respectively, in moderate to good yields

124

Organophosphorus Chemistry

'

(147)

Scheme 16

0 R: II ,C=O + MeP-H I

R2

i-iv

OEt

R' 0 &!-Me R2

OEt (148) Reagents: i, HNSiMe3; ii, Et3N,3HF; iii, CICO.CO2Me; iv, Bu3SnH, AIBN

Scheme 17

0 It

R'2PCI + R2CeCI2

-20 "C

0 II

RI2PR2

THF

R' = Ph, OEt, R2 = alkyl, alkenyl, aryl Scheme 18

(Scheme 18).'04Phosphonic acid derivatives, e.g. (149), of prostaglandins Fluand FZahave been prepared by Arbusov reactions of the corresponding prostaglandin terminal iodides.lo5The familiar difficulty of removing both phosphorus ester groups was encountered. A wide range of phosphonates carrying cyclopropane groups has been prepared (see also Section 3.1.6). Electrosynthetic routes to 2-substituted 1,l-cyclopropanediylbisphosphonates (150) (Scheme 19),Io6a-aryl P-substituted cyclopropylphosphonates - (Scheme 2O),lo7and the first example of a-fluorinated cyclopropylphosphonates (152) (Scheme 2 1)'08 have been reported. The reactions 0

H?

I

HO

OH (149)

0 0 II

0 [(Et0),~]2CC12 +

=(

R'

2e-, MeCN

R2

Et,NBr, C-Cathode

t

Scheme 19

II

x<;;

(Et0)2P

'(OEt)2

(150)

of 1-seleno-2-silylethenewith trimethyl 2-phosphonoacrylate and with the 2,2dicyanoethene-1,l-dicarboxylate(157) in the presence of SnClj to give the cyclopropanes (155) and (156),and the cyclobutanes (158) and (159), respectively, have been studied using deuterio-labelled (153) and (154) (Scheme 22).'09 The results confirm that 1,2-silicon migration occurs for [2 + 11-cycloaddition but not for [2 + 21-cycloaddition. A variety of fullerene derivatives, e.g. (160), bearing phosphonate, phosphonic acid, phosphine oxide, and phosphite groups have been synthesised"' and the tetraethyl methano[60]fullerenediphosphonate (161) has

125

4: Quinquevalent Phosphorus Acids

(1511

Scheme 20

0 0

e-, Mg'

(Pr'O),$CFBr2

+

V

(152) '

Scheme 21 0

KSePh "2% ,C02Me Me3SiK

Y

(155) X = H , Y = D (156) X = D , Y = H

w

NC(,57)C02Me

(153) X = D , Y = H (154) X = H , Y = D

NC C02Me NC w C 0 2 M e x - ] 4 Y MeaSi SePh (158) X = H, Y = D (159) X = D, Y = H Scheme 22

N Fullerene 0

.

i

Do ;(Ow2

0

H C02Me

(162) R',R2 = OPi, Ph

R2" R ' , 8 d NMe, + R3CH2CH2MgBr (164) R',R2 = OPr', Ph

(163)

MeTi(OPr'),

~

~

1

,

N f Me2d

~

R2" (165)

been prepared by the reaction of Cb0with tetraethyl methylenediphosphonate in the presence of iodine and sodium hydride."' A range of 3-hydroxy- (163) and 3-dimethylamino- (165) 3-(cyclopropy1)-propylphosphonates have been prepared in moderate to good yield by the reaction of Grignard reagents with esters (162) and amides (164), respectively, of 3-phosphorylpropanoic acids in the presence of titanium alkoxides."*

~

126

Organophosphorus Chemistry

1-Arylethyl-1,2-bisphosphonates (166) have been synthesised by palladiumcatalysed bis-hydrophosphorylation reactions of terminal ary1alk~nes.l~~ A discussion of the mechanism of the reaction is included in the report. A new approach offers a one-pot synthesis of thienylmethylphosphonates directly from the corresponding thiophene (Scheme 23).lI4Yields are moderate to good and the reaction works on a variety of thiophene structures. The first example of a polythiophene (167) containing a phosphonate group has been rep~rted."~ Unusually for polythiophenes, (167) is soluble in both protic and aprotic solvents and solutions in DCM/MeOH show solvatochromic properties. New derivatives of oligoarylenevinylene (168) carrying terminal phosphonate and trialkoxysilyl groups have been prepared in order to investigate their optical properties.ll6

R

R

I1

Reagents: i, BuLi, -78 "C; ii, CuI, -20 "C; iii, ICH2P(OEt)2 Scheme 23 0 II

(CH2)11P(OEt)2 h

0 It R'YNa + R2C=C-P(OEt)2 Y = S , Se, Te

-

R2

R'

E(OEt)2 (169)'

3.1.2 Alkenyl, Alkynyl, Aryl, Heteroaryl and Related Acids. Vinylphosphonates and -phosphinates are extremely useful intermediates in the synthesis of a wide range of organophosphorus compounds. A major reason for the lack of exploitation of these compounds is the shortage of general, convenient routes to them. A number of new routes have been reported but most appear to be specific. Alkyland aryl-substituted group 6 anions react with alkynylphosphonates to give the corresponding substituted vinylphosphonates (169) in moderate yield and predominately as the Z-i~omer."~ A series of a-phosphonovinyl nonaflates (170) have been prepared from the corresponding acylphosphonates;' l8 attempts to make the triflates were only partially successful. Compounds (170) undergo Pd-catalysed coupling with acetylenes to give phosphono-enynes and -dienes (Scheme 24). The 3-cyanoallylphosphonate ester (171) is reported to react with N-tosylsulfonylimines in the presence of catalytic amounts of DBU to give

127

4: Quinquevalent Phosphorus Acids

R3

!

(170) Nf = :.(CF&CF,

:Base, THF; ii,R3C=CH, Pd(Ph3P)4,THF, LiCl 0

Reagents: i, CF,(CF,),fF,

Scheme 24

0

R - 0

+ r(’

7P3(PEt)2 0

1.2 x Pd(OAC)* CaCO,, MeOH)

v

i

(

O

d

0 II

NBS

CCI,

t

)

2

(174)

(Et0)2pq -

-

(Et0)2pT;2

E

?

0 II

Et

R’

Ag(OAc)z AcOH

R2

R’

Br

R2

0

0

(176)

(175)

3-cyanobuta-1,3-dieneylphosphonate esters (172) in good yield.’19A convenient, high yielding route to styrylphosphonates (174) is available via a Heck reaction of vinylphosphonate (173) with diazonium salts.’” A new approach to substituted 3-phosphoryl-2,5-dihydrofuran-2-ones (176) involves the functionalisation and cyclisation of the product (175) from a Knoevenagel condensation of ethyl phosphonoacetate.121 Using a similar starting material (177), again prepared by a Knoevenagel reaction, as a heterodiene, phosphonylated 3,4-dihydro2H-pyrans (178) have been prepared.122The reaction sequence to give (178) can be accomplished in one-pot without isolation of (177). 0

(A10)21,J-(

0

0

piperidine

Y

+ ArCHO

PhH,reflux

b

0

(R1O)Afy Ar

FOR, Ar

(177)

X = CI,Br, I ; Y = H,Br X = Br, Y = F

9

(R10)255

-

Reagents: i, (EtO),PH, BU’OK, DMF, hv(354 nm) Scheme 25

OR2 (178)

128

Organophosphorus Chemistry

Reports of syntheses of arylphosphonates include that of (179) by direct phosphorylation of mono- and di-halogenoanilines by dialkyl phosphonates under UV irradiation (Scheme 25)123and that of the novel phosphonic acid monomer (18 l), for use in dental composites, via base-catalysed rearrangement of the corresponding arylphosphonate ( 180).124 A number of cyclophanes (182), containing a chiral spirobisindanol phosphonate group, have been prepared and their structures, resolution and clathration properties studied.125The ligand (183) has been synthesised with a view to producing, once (183) has been bound to a metal (e.g.Zn2+or Cu2+),a hydrophobic c a ~ i t y . ' ~Interestingly, ~,'~~ the nature of this cavity depends strongly on the nature of the metal used and it is suggested that these results offer the opportunity for sensor tuning of affinity and selectivity for either metal or guest. 0

(182) Ar =

,o

...a, a, MeaMe , 0

Ar

Me

R'~N

0.-'PPh2

QCH1 .. t

CI R = Ph, OEt

Scheme 26

129

4: Quinquevalent Phosphorus Acids

The 1,4-conjugate addition of enamines to the 4-phosphorylated 1,2-diazabuta-1,3-diene (184) provides a route to substituted l-aminopyrroles (185) which can be further converted into l-aminopyrroles (186) by basic hydrolysis (Scheme 26).12*Moderate to good yields of 2,6-diphosphonylated- 1,2-dihydropyridines (187) have been obtained in a one-pot reaction from either 1,4dihydropyridines or pyridinium salts (Scheme 27).129

3.1.3 Halogenoalkyl and Related Acids. In view of their extensive applications as, for example, phosphate mimics, new routes to a-mono- and -di-fluoroalkylphosphonates are always welcome and during the period of this review a substantial number have been reported. A variety of functionalised examples of such compounds have been prepared from the readily available difluorophosphonate (188).130For example, the monofluoro analogue (191) of serine phosphate has been synthesised by the reaction of (188) with organocopper reagents to give (190) followed by reduction and further functionalisation (Scheme 28). The

-

F (EtO),F&coy

ii-v

0 ( E t I1 0 ) 2 p ~ c o Y

(190) Y = (2S)-borane-[lO, 21sultam Reagents: i, R2CuLi,LiX; ii, H2/Pd; iii, NaHDMS,

c>(:p,

F (191)

NBBoc

THF; iv, Zn, AcOH; v, ( B o c ) ~ ~

Scheme 28

original target of the organocopper reaction was the Michael addition product (189) but this was not formed. The reaction of a similar starting material, (192), with sulfur ylides, e.g. (193), gives good yields of cyclopropanes, e.g. (194), and aviods the use of diaz~methane.'~~ Compound (194) can be reduced by LiBH4to the corresponding cyclopropanol (195), chain extension of which offers the homologous cyclopropane (196). 2,2-Dihydroxy-1,1-difluoroethylphosphonate (197), readily prepared in high yield from difluoromethylphosphonate, reacts with a range active methylene compounds to give activated alkenes (198) containing the difluoromethylphosphonate group (Scheme 29).'32The protected mono-( 199) and di-(200) fluoropropargylphosphonates have been synthesised and used as starting materials to prepare fluoroenynes, y-substituted-a-fluoroalkylphosphonates, a-fluoroallenylphosphonates, and fluoro-vinylphosphon-

Organophosphorus Chemistry

130

0

I1

(Et0)2PCHF2

i-iii

0

(EtO)$CF2CH(OH)2 (197) Reagents: i, LDA, CeCI3,THF; ii, DMF; iii, HCI, H20; iv, H2CXY Scheme 29

?

(Et0)2PCF&Hd (198)

Y

x

R3Si/L (199) X = H (200) X = F

ate^.'^^ The dimerisation of a-fluoroallenylphosphonate (201) to give (202), and the Diels-Alder reactions of (201) with a variety of dienes, have been reported.'34 The latter reactions provide a diastereoselective route to cyclic and bicyclic, e.g. (203), a-fluorovinylphosphonates (Scheme 30). The difluoromethyl-(205) and methyl-(207)phosphonate analogues of D-galactofuranosylphosphate have been synthesised from difluoroalkene-(204) and iodomethyl-(206) derivatives of proCompounds (205)and (207) show intertected D-galactofuranose (Scheme 3 1).135 esting biological activity. F 10

Sealed tube. THF

(202)

(203) Scheme 30

A series of conformationally-restrained phosphonate analogues, e.g. (209), (210), and (21l),of D-glyceric acid 1,3-bisphosphate (208) have been synthesised as potential inhibitors of phosphoglycerate kinase (3-PGK).'36A number of

4: Quinquevalent Phosphorus Acids

131

KO

o'.sc-+ F

0 II

-

TBDMS (204) 'OTBDMS

HO

HO

(205)

'OH

(207)

Reagents: i, HP(0)(OEt)2, But02COBut; ii, TMSI, CCI4; iii, (Me0)3P

Scheme 31

aryldifluoroalkylphosphonates have been prepared, primarily as tyrosine phosphate analogues. These include a range of novel, photoregulated, hydrolytically stable amino acid analogues, e.g. (212), for use in peptide ~ynthesis'~'and the non-hydrolysable phosphotyrosyl mimic (213).138The latter compound is suitably protected for solid-phase synthesis and the ultimate aim of the work is the preparation of signal transduction inhibitory peptides. Difluoromethylphosphonate analogues of tyrosine phosphate are highly potent inhibitors of protein tyrosine phosphatases (PTPs) and structural evidence suggests that an important interaction in the binding of these compounds to PTPs is with the pro-Rfluorine atom. To test this proposal, one of very few syntheses of single enantiomers of a-fluoromethylphosphonates has now been developed and applied to the synthesis of (214),(215),and (216).139 The route involves electrophilic fluorination of the (-)-ephedrine derivatives of the these phosphonic acids to give d.e.'s of up to 58% (Scheme 32). Chromatographic separation and deprotection gave the enantiomerically pure monofluoro-methylphosphonicacids. A related route has been used to a-chloroalkylphosphonic acids (218).I4O Diastereoselective alkylation of the camphor-derived oxazaphospholanes (217),followed by deprotection gave (218) with e.e. values of up to 90% (Scheme 33).

132 0 II ArCH2P(OH)2

Organophosphorus Chemistry

-

- /Nl - y! H F

ArCH2,piNl Me ol'/

\o

cis + trans

Me

Me Me

i

Ph

ii, iii

Ar

Ph

oQp\o

Ar P(OH)2 (214) Ar = 2-naphthyl (215) Ar =

Reagents: i, (trans isomer) Base, NFSI, THF; ii, TFA, MeOH; iii, TMSBr, CH2CI2 Scheme 32

P

h

q

(216) Ar = Ph

I (218) R = Me, Et, CH2CH=CH2, PhCH2 (217) CI Reagents: i, LDA, -90 "C, THF; ii, RBr, -90 "C; iii, MeOH; iv, 4N HCI, THF Scheme 33

?\ ,OR1 I'2\'

?'OCH*OCO+ ,OR2 P \0CH20CO+

d'

+ +,

(220) R' = R2 = CH20CO (221) R' = CH20CO

R2 = NR4

3

(222) R' = R2 = H2N

The synthesis and evaluation of a variety of prodrugs, e.g. (220), (221), and (222),141of clodronic acid (219) have been the subject of a number of r e p o r t ~ . ' ~ ~ - ~ ~ ~ These include a convenient synthesis of the prodrug (223) from tetramethyl methylenebisphosphonate (Scheme 34).142 The triester (224) of clodronate reacts with acetyl chloride to give the dimer (225), the structure of which was confirmed by X-ray analysis.143Although (225) is a potential prodrug of clodronate it is resistant to enzymic hydrolysis, and chemical hydrolysis in 50 mM aqueous phosphate buffer at 37°C gives the hydrolytically stable acyclic dimer (226). A number of chlorophosphonates, (227), (228), and (229), incorporating a 1,3,2dioxaphosphorinane ring, have been synthesised and used in alkene synthesis to provide a new route to 5-chlorofurfuryl-substituted alkenes and chloro-substituted d i e n e ~ . ' ~ ~ 3-Iodoalkyl-(231) and 3-iodoalkenyl-(232) phosphonates have been synthesised from the 1-iodoalkylphosphonates (230) by an iodine atom-transfer addition reaction (Scheme 35).'45 3.1.4 Hydroxyalkyl and Epoxyalkyl Acids. The addition of organometallic (Zn or Mg) reagents to P-ketophosphonates (233) offers a new route to P-hydroxyphosphonates (234) containing a tertiary alcohol f ~ n c t i 0 n . lYields ~ ~ are variable, excellent in the best cases, and can be improved in the Grignard examples by the addition of BF3.Et20.What is claimed to be the first catalytic asymmetric

4: Quinquevalent Phosphorus Acids

133

r

0

R

d.Rri[j

(230)

0

1

//L

0

J iv 0 II

( E t o ) R2 p P I f R1 (231)

R

i

(232)

Reagents: i, AIBN; ii, P R 1 ; iii, R C S H ; iv, (230)

Scheme 35

synthesis of (S)-a-hydroxy-H-phosphinates (235) and (S,S)-a&-dihydroxyphosphinates (236) has been achieved by e reaction of methyl phosphinate with aldehydes in the presence of a BINOL complex.'47A new highly diastereoselective route to 1-hydroxy-2-aminoalkylphosphonates (238),involving reduction of the protected a-ketophosphonate (237) with boranes, has been reported (Scheme 36).14* Reports of phosphonates derived from carbohydrates include the synthesis of

134

Organophosphorus Chemistry 0

OH R2 &!(OEt)2

M = MgX, ZnBr

R' (233)

R' (234) 22-99%

II

II

RCHO + H2POMe

XSH2PoMe

I

OMe (236)

0

PhthN

0

PhthN

II L i\,P(OEt)2

R / y b E t ) 2

-

NH2 P(OEt)2

R+ I

I

0

OH

OH (238)

(237) Ph Ph

Reagents: i,

@o

-

N B'

, -60

"C,PhMe;

ii, H2NNH2.H20, EtOH

Scheme 36

OH (239) /J = 0, 1, 2 Reagents: i, Fructose 1,6-bisphosphate, Fructose 1,6-bisphosphate aldolase, triose phosphate isomerase; ii, acid or alkaline phosphatase Scheme 37

deoxysugar w-phosphonic acid esters, e.g. (239), by chemoenzymic methods (Scheme 37).149Potentially the addition of lithiated methylphosphonate esters to glyconolactones (240) followed by removal of the a-hydroxy group provides a highly convenient route to isosteric phosphonate analogues (241) of glycosyl l-phosphates. Unfortunately attempts to achieve the final reductive step using Et3SiH and BF3.Et20have failed. It is now reported that this reduction can be achieved by the use of Et3SiHand TMSOTf (Scheme 38).I5OThe vinylphosphonate (242) formed as a by-product is readily converted into (241) by catalytic hydrogenation and overall the method gives excellent p-stereoselectivity. CGlycosidic phosphonates (243) have been prepared by the diastereoselective addition of glycosyl radicals to vinylpho~phonates.'~'Compounds (243) are useful substrates for the synthesis of complex, higher carbon sugars related to tunicamycin. A variety of glycophostones, e.g. (244) and (245), that are cyclic phosphonate analogues of sugars, have been synthesised, mainly by Arbusovtype chemistry.'52

135

4: Quinquevalent Phosphorus Acids

f Reagents: i, LiCH2P(OMe)2,THF, -70 '+ -40 "C; ii, Et3SiH,TMSOTf, CH2C12

(242)

Scheme 38

R' (243) R' = C02Me, H

HO I

(244)

OH

HO (245)

Enantiomerically pure epoxyalkylphosphonates, e.g. (247), are potentially useful synthons for the synthesis of a variety of functionalised phosphonates. Unfortunately, basic methods of oxirane ring-closure isomerise some of these epoxides; for example, 2,3-epoxypropylphosphonatesto 3-hydroxy-l-propenylphosphonates. Two recent reports describe a solution to this problem through hydrolytic kinetic resolution of the racemic epoxide by water in the presence of a chiral 154 The racemic epoxide (246) can be converted into the (S)epoxide (247) and the (S)-diol (248), with e.e.'s of 82% and 96%, respectively, using Jacobsen's (R,R)-salen-Co(II1)-OAccatalyst (Scheme 39).153The racemic epoxide (249) is similarly converted into the (R)-epoxide (251) using (250).'54 Ring-opening of (251) with benzylamine followed by hydrolysis and hydrogenolysis provides a synthesis of (R)-2-amino-l -hydroxyethylphosphonic acid (252)(Scheme 40). 3.1.5 Oxoalkyl Acids. Efficient methods of oxidising the readily available a-

hydroxyalkylphosphonates to ketones are still required. It is now reported that alumina-supported C r 0 3 will oxidise such hydroxy compounds, including the more difficult alkyl examples, to acylphosphonates (253)in the absence of solvent and in good to excellent yield.'55A one-pot synthesis of trialkyl phosphonothiolformates (255) has been r e ~ 0 r t e d . The I ~ ~ route involves the reaction of phosgene with thiols to give chlorothioformates (254) which form (255) on reaction with

136

Organophosphorus Chemistry

(246) (247) 82% e.e. Reagents: i, 0.2 mol% (R,R)-Salen-Co(1II)-OAc,0.55 eq. H20 Scheme 39

(248) 96% e.e.

ci:

N

H

0

(249)

i

0 ~ P ( II0 E t ) pii-iv

O

>Ci

N

NH2 0

O

H OH (251) (252) Reagents: i, H20, (250), 4 days, RT; ii, PhCH2NH2; iii, 12M HCI; iv, H2, Pd Scheme 40

t (250)

trialkyl phosphites. Yields are good and the reaction sequence is carried out at 0°C. Derivatives of phosphonoformate (PFA) (256) have been the subject of extensive studies due to their potent antiviral properties, particularly in relation to AIDS. The aim of many of these studies is to overcome the poor bioavilability of PFA due to its polyanionic nature at physiological pH. The synthesis of a variety of novel cyclic diesters (257) of PFA and an investigation of their use as prodrugs has now been r e ~ 0 r t e d . l ~ ~

t

0 R

(EtO)pPy OH

II

cr03'A1203,

(Eto)2pY 0 (253) R = aryl, alkyl

Two convenient approaches to (dipheny1phosphono)acetic esters (258) have been r e ~ 0 r t e d . lOne ~ ~ approach involves the reaction of chloroformate esters with the carbanion of diphenyl methylphosphonate and the other a MichaelisBecker reaction of bromoacetic esters (Scheme 41); the former reaction gives better yields than the latter. Olefination reactions of (258)with benzaldehyde and

4: Quinquevalent Phosphorus Acids

137

with aliphatic aldehydes gave excellent yields and high (87-95 %) (2)-selectivity. 4-0x0-2-alkenylphosphonates(259) have been prepared from alkenylphosphonates by cycloaddition reactions with nitrile oxides, reduction and deprotection (Scheme 42).'59The approach offers a new method for regioselective yacylation of allylicphosphonates. 0 II

::?

(PhO)2PMe

(Ph0)2PCH2COR (258) (Ph0)2PH

Reagents: i, CIC02R, THF, -78

"C;ii, LDA; iii, BrCH2C02R,Et3N, CH2C12 Scheme 41

0

R2

(Et0)25/&

+ [R3C=h-O-]

-

0

0-N

( E t O ) $ w R 3

R'

i-iii

R2 (EtO)2!+COR3

R'

R' (259)

Reagents: i, LDA, THF; ii, AcOH; iii, TiCI3, HCI, DMF, H20

Scheme 42

3.1.6 Aminoalkyl and Related Acids. A further development of the classical three component route to aminoalkylphosphonates has been reported. The reaction of aldehyde, amine, and triethyl phosphite in water using scandium tris(dodecy1 sulfate) as both Lewis acid catalyst and sufactant gives N-protected aaminophosphonates (26O).l6OThe use of chiral amines in a similar reaction gave at best moderate diastereoselectivities. The widely used addition of secondary phosphites to imines has been used to prepare N-alkyl-(a-aminoalky1)phosphonates (261) as potential HIV-protease inhibitors.161Yields are moderate and diastereoselectivity poor. In a more novel approach the addition of the P-H bond of chiral tetraoxyspirophosphoranes (262) to long-chain imines, followed by hydrolysis, has been applied to the synthesis of N-alkylaminoalkylphosphonates (263) (Scheme 43).162 Depending on the conditions and the substrates, high levels of diastereoselectivity can be obtained. 10 mol% SC(03SOC12H25)3

R'CHO + R2NH2+ (Et0)3P

H20, 30"c

0

(261)

The reactions of phosphorus(II1) compounds with halogenonitroalkanes and -alkenes have a long history and have been the subject of several conflicting reports. The most recent contribution is the synthesis of (l-hydroxyiminoalky1)phosphonates (264) by the reaction of trialkyl phosphites with l-bromonitr0a1kanes.I~~ Yields are moderate to good and the results provide an alternative

138

Organophosphorus Chemistry 0

0

I

0

HCI, H20

0 R2 II

I

(H0)2P-CH-NH(CH2),Me

(263)

Scheme 43

approach, via reduction of (264),to a-aminoalkylphosphonates. There have been a number of reports aimed at the synthesis of l-aminocyclopropylphosphonates and the corresponding acids. A new, more efficient route to 1-aminocyclopropanephosphonic acid (266) involves a one-pot reaction of cyclopropanone ketal(265) with a benzylamine in acetic acid/ethanol, followed by the addition of triethyl phosphite. Finally deprotection gives the free amino acid (Scheme 44).la The reaction is suggested to take place via an imminium 0

0

(265) Reagents: i, PhCHMeNH2, EtOH, AcOH; ii, (Et0)3P; iii, H2, Pd(OH)&, EtOH; iv, 6N HCI, 100 “C; v, -0 Scheme 44

Me,,+OMe (267)

OSiMe3

-

::

H

-

I

WR)2

A+ (268)

I “‘-‘o &OH),

Me’,

fl

NH2

(269) Reagents: if AcOH(cat), RNH2; ii, (R0)2P; iii, H2, Pd(OH)2/C,EtOH; iv, Me3SiI, CH2C12; v, -0 Scheme 45

EtOH

intermediate and the method has also been applied to the enantioselective synthesis of (1S,2S)-1-amino-2-methylcyclopropanephosphonic acid (269) from (2s)-methylcyclopropanone ketal (267), with the iminium ion (268) being the suggested intermediate in this case (Scheme 45).165,166 This approach is reported

139

4: Quinquevalent Phosphorus Acids

to give good to excellent d.e.'s. The phosphonic acid analogue (270) of ( - ) - d o norcoronamic acid has been synthesised in enantiomerically pure form from the cyclic sulfate of ( +)-(S)-propane-l,2-diol (Scheme 46).'(j7 Although rather long, the route offers a general approach to single enantiomers of a wide range of cyclopropylphosphonates. H

Me

Me

>'Ti, ii

C02Bu'

H "7OEt)n

0

0

0

(270)

II-

Reagents: i, (Me0)2PCHC02B~t;ii, NaH; iii, HC02H; iv, S0Cl2; v, NaN3; vi, PhCH20H; vii, TMSI; viii, /cp Scheme 46

A new method of preparing phosphonodipeptides (272) from N-terminal amino acids (27l),using the reaction of (271)with diethyl l-azidoalkylphosphonates and tertiary alkylphosphines, has been reported.16*The method offers moderate to excellent yields over a wide range of substrates. A number of macrocycles, (273), (274),'(j9and (275),170 carrying phosphonomethyl groups on ring nitrogen atoms have been reported. Compounds (273)and (274)were synthesised by phosphonylation of the corresponding N-unsubstituted macrocycle using formaldehyde and phosphorous acid. Attempts to prepare the corresponding phosphorus esters by an analogous method were unsuccessfu1.169 When layered with Co or Cd metal salts, compound (275) forms regular branched structures known as 'macrocyclic leaflet^'.'^'

7 N

(273) X = 0

f

(274) X = NCH2P(OH)*

Examples of P-aminoalkylphosphonatesprepared include the analogues (277) and (278) of the docetaxel C-13 side-chain (276).17' The diethyl esters have been synthesised previously but the authors claim that there are advantages in using the methyl esters in syntheses. Air-stable titanocene(1V) salt complexes, e.g. (279), have been prepared by the reaction of titanocene dichloride with phosphorus and sulfur p-amino acid ana10gues.l~~ The diastereoselective addition of metallated Schollkopf's bis-lactim ethers to

Organophosphorus Chemistry

140

0

+

&COpH Ph I

OH (276) R = Ph, Bu’O

OH (277) R = P h (278) R = Bu‘O

(279)

R’=Me, R 2 = H

/

0 =P(OEt)2 Reagents: i, THF, -78 “C; ii, 0.25M HCI, THF 24 h Scheme 47

(R’0)2F;Q0

:

H y -0-P(OR2)2 CH2 FmocN Hk 0 2 H (285) R’ = Bu’, R2 = MEM

CH2

H AC02H FmocN (286) R’ = R2= Pr‘

(E)- and (2)-1-propenylphosphonates(280) has been investigated, including semi-empirical quantum studies, and used in a synthesis of all four diastereoisomers of the glutamic acid analogues 2-amino-3-methyl-4-phosphonobutanoic acids, e.g. (281) and (282) (Scheme 47).’73A similar approach using the lithiated bis-lactim ether (283) has been used to prepare other phosModerate to good phonic acid analogues (284) of substituted glutamic

4: Quinquevalent Phosphorus Acids

141

diastereoselectivity was observed and optically pure examples of (284) were obtained by chromatographic separation of diastereomers and removal of the chiral auxiliary by acid hydrolysis. Compounds (281),(282),and (284)can also be considered as phosphonate analogues of substituted serine phosphates and two similarly protected derivatives (285) and (286), in this case of hydroxymethylene analogues of serine phosphate, have also been synthesised and incorporated into peptides by solid phase RNH

I

(287) n = 0. 1 OH Reagents: i, 4% K20~02(OH)4, 5% (DHQ)2PHAL, 3 equiv. RNCINa, MeCN, H 2 0 (or n-PrOH, H20) Scheme 48

Catalytic asymmetric aminohydroxylation using Os(VII1)and Sharpless' cinchona alkaloid ligand has been applied to a$- and P,y-unsaturated phosphonate substrates (Scheme 48).'76The reaction only works for the aryl substituted examples (287) and although initial e.e.'s are sometimes low, they can be increased to >90% by a single recrystallisation. The phosphonic acid analogue (288) of the anti-inflammatory drug Diclofenac, and a number of related phosphinic acids, have been synthesised from the corresponding hydroxy compound (Scheme49).'77None of the compounds prepared showed significant anti-inflammatory activity. The reaction of phosphorus nucleophiles with azetidinium salts (289) has been investigated and provides a convenient synthesis of, for example, 3-diethylaminopropylphosphonic acids (290).17* 0

(288) R = 2,6-dichloro Reagents: i, MsOH, (Me0)3P, CH2C12; ii, TMSBr, CH2CI2

Scheme 49

3.1.7 Sulfur- and Selenium-containing Compounds. A new route to a-thioalkylphosphonates (292)and -phosphinates (294)has been reported from the reaction of selenothioic acid S-esters (291) with phosphites and phosphinites, respectivel ~ .By-products ' ~ ~ (293), derived from the P(II1)ester alkylating the Se atom, are formed in many cases. a-Phosphono-P-substituted a,P-unsaturated dithioesters (296),prepared from diethyl phosphonodithioacetate (295),undergo Diels-Alder reactions with enol and thioenol ethers to give excellent yields of novel 5-

142

Organophosphorus Chemistry

phosphono-3,4-dihydro 2H-thiopyrans (297).l8’ The first synthesis of the [1,2] thiaphospholo[4,5-e][ 1,2,4]triazine ring system (298) has been achieved by the reaction of Lawesson’s reagent with 1,2,4-triazin-6-onesor -thiones.lgl 0*P(0R)2

SeR

( n O ) ; -

(294)

(293)

pxR0

(Etoh!+

0 (EtO)21,&

SEt +

ArcHhso)2

CICHZCOZH

PhMe Ar (296)

(295)

Meon

SEt

Ar XR (297) Ar = aryl, heteroaryl, X=OorS

AP5S

s5p‘s*

X

M

QOMe

e

o

“NH & P q N A p h

t

&LPh

n

(9

Ar x = o , s

Ar (298)

3.1.8 Phosphorus-Nitrogen Bonded Compounds. Chiral dendrimers act as efficient ligands for the enantiomeric addition of diethylzinc to N-diphenylphosphinylimines (299) to give N-diphenylphosphinylamines(300) with up to 94% e.e.lg2A number of approaches to N-phosphonamidothionate derivatives, e.g. (301), of glutamic acids have been in~estigated.’~~ The most efficient route involves reaction of phosphorus (1II)dichlorides with 3-hydroxypropionitrile, followed by coupling with glutamic acid diester, oxidation of P(II1) to P(V), and finally hydrolysis to give (301) (Scheme 50). N-Phosphinoylnitroso intermediates R V / N x P P h 2 + Et2Zn I1

0

dendritic chiral, ligand, PhMe

(299)

H

R

* yNvpt12 4

II

Et 0 (300)

i-iii

RPC12

Li+

(301) Reagents: i, HOCH2CH2CN,TEA; ii, HGlu(OMe)-OMe, TEA; iii, Sulfur; iv, LiOH Scheme 50

4: Quinquevalent Phosphorus Acids

143

(303) have been generated by periodate oxidation of the corresponding hydroxylamine (302), as evidenced by trapping with dienes to give (304).184Experiments using the chiral example (303, R' = Ph, R2 = Bu) gave adducts (304) with high d.e. values. Stereoselectiveroutes to N-diphenylphosphinoyl-protected cis(306) and trans-( 307) rneso-aziridinocyclohexene oxides from the known aziEnantioselective ridinocyclohexene (305) have been reported (Scheme 51).185 frearrangement of (306) and (307) induced by chiral bases gave the corresponding allylic alcohol with moderate e.e. values and demonstrated the stability of the N-protecting group to basic conditions. Ring-closingmetathesis catalysed by the ruthenium complex (309) has been used to prepare P-chiral phosphonamides, e.g. (3lo), and the analogous phosphonates, by a process of diastereotopic differentiation between side chains in, e.g., (308).'86

:0 80% trans

(307) Reagents: i, rn-CPBA, NaHC03, CH2C12; ii, Oxone, CF3COMe, Na2EDTA, NaHC03 Scheme 51

3.1.9 Phosphorus-containing Ring Systems. A full report has appeared of the synthesis of a variety of cyclic phosphorus-containing heterocycles, e.g. (31 l), with ring-sizes of 5, 6, and 7, by ring-closing rnetathesi~.'~' Phosphorus heterocycles (313) have been prepared as the product of the reaction of sulfur or selenium with the highly sterically hindered primary phosphines (312).'88An efficient synthesis of the phosphonamidate analogue (315) of the 1,4-benzodiazepine-2,5-dione ring system has been reporfed.lg9The key step is baseinduced cyclisation of the phosphonate (314). Compound (315) can be methylated at nitrogen and/or reacted with Lawesson's reagent to give a range of derivatives (316). New phosphonate-based cavitands, e.g. (317), have been de-

144

Organophosphorus Chemistry

signed and synthesised as sensors for the detection of alcohols.'90 An X-ray structure of one example is reported.

X

X

x (316) X = 0, S, R' = H, Me

(317) X = Br, Ar = Ph X=Br, Ar=OPh X = Me, A r = Ph

3.2 Reactions of Phosphonic and Phosphinic Acids and Their Derivatives. Cyclic 2-alkoxyvinylphosphonates (318) are reported to undergo [2 + 21 cycloaddition reactions with monochloro-(319) and dichloro-(320) ketene to give the bicyclophosphonates (321) in moderate yield.'" This is claimed as the first example of [2 + 21 addition of a ketene to a donor-acceptor substituted alkene. On treatment with zinc in acetic acid, (321) undergoes dehalogenation and cleavage of the central C-C bond to give the ring-expanded product (322). Palladium-catalysed acetoxylation of cyclic allylphosphonate diesters (323) in poor to good yields has been reported through the use of a palladium chloride catalyst in the presence of isopentyl nitrite, acetic acid and 0 ~ y g e n .A l ~mechan~ ism is proposed for the reaction. A new, catalytic asymmetric Mannich-type

4 : Quinquevalent Phosphorus Acids

145

reaction of the N-phosphinoylimines (324) with nitromethane, promoted by a new bimetallic BINOL complex has been r e ~ 0 r t e d .Enantiomeric l~~ excesses up to 9 1% were observed. While the relative rate of cyclisation to give five-membered rings is usually much greater than that to give six-membered rings, the two phosphinic acids (325) and (326) cyclise to give (327) and (328), respectively, at approximately the

Zn, AcOH

&O

F(OEt)2

R.T. 5 h

CI X=H, Y=CI X=Y=CI

-

r

(323)n = 1, 2,3

AcO

0 II

,pPh2 + 5X MeN02

A~AN

20 mol% YblKBlNOL

PhMeTTHF,-40 "C

' I :

* Ar , i , N , PPh2

(324)

H

rCHzBr (CH2)n

,?

LY'OH Ph (325)n = 0

- L y pq ) Et3N

A

(CH2)n

Ph

(327)n = 0 (328)n = 1

(326)n = 1

+, ,

rCH20H (CH2)n 0 Lf!NHPh Ph (329)n = O

(330)n = 1

same rate. A study of the alternative mode of cyclisation, where the nucleophile is on the carbon side-chain, to give (327)and (328) has now been r e ~ 0 r t e d . In l ~ this ~ case the rate of cyclisation of (329) is up to 70 x greater than that of (330),a result that corresponds to that observed with most types of cyclisation. The reasons for these differences are not clear. Interestingly, cyclisation of the thio analogues (331) and (332) occurs much less readily.'95For example, when treated with HCl in CDC13containing 1% methanol, (331)and (332)give only the acyclic products (333) and (334). As this result suggests, in the complete absence of nucleophiles cyclisation of (331) and (332)by a direct displacement mechanism is very slow. A study of transition state geometries for nucleophilic substitution reactions at nitrogen by carbon nucleophiles has used isotopically labelled phosphinate models, e.g. (339, with phosphinate leaving groups (Scheme 52).196The results CDCI?

Ph

Ph

(331)n = 0 (332)n = 1

(333)n=O (334)n = 1

4-

146 Ph\ I?

3

Organophosphorus Chemistry Ph\

i-iii

,? O-0

O-0

(335) Reagents: i, LDA; ii, H30+; iii, CH2N2

\

\

Scheme 52

support a trigonal bipyramidal T.S. for these substitutions. Metaphosphate (337) is the presumed intermediate in the neutral hydrolysis of the (E)-isomer (336) of the so-called troika acid, as evidenced by phosphorylation of the alcohol solvent. The (2)-isomer (338) cleaves by a different pathway to give (339). This process has now been initiated and studied using photo-induced fragmentation of ester (340) to generate the troika acid in both isomeric forms.'97

C02 + HCN + H20 +

0 II

( H o ) 2 P K C'oH N HO' (338) 0 -01 '1

ROH

0 Ho\II HO,P-OR

(337)

0 II

-

[)-OH]

-

C02 + H20 +

HO\I: P-CN HO' (339)

0 II

-o'pyc'om HO"

02N

(340) (337) + (339)

A new approach to the destruction of phosphorus-based nerve gases has been reported.19*The method incorporates ester exchange reactions between the phosphorus ester and polycarbonate and experiments using model compounds suggest that it may have practical application. Attempts at decontaminating the nerve agents VX (341) and GD (342) using gaseous ozone have been r e ~ 0 r t e d . l ~ ~ G D does not react under the conditions used and some of the products from reactions with VX still possess P-S bonds. Both results indicate that this is not a useful method of decontamination.

The acylation of a-fluorophosphonoacetate derivatives in the presence of magnesium chloride and triethylamine has been reported.*()(' Depending on the substrate structure simple acylation to give, e.g., (343) or acylation with P-C

4: Quinquevalent Phosphorus Acids

147

bond cleavage can occur. A new method of P-C bond cleavage of P-carbonylphosphonates in moderate to good yield has been published.201a,a-Disubstituted P-ketophosphonates (344) and a-carbamoylphosphonates (346) form ketones (345) and amides (347), respectively, on reaction of their lithium enolates with LiAlH4,followed by quenching with sulfuric acid (Scheme 53). The mechanism of the reaction is not entirelv clear and the authors suggest that the sulfuric Li .. 0 (EtO)2i+R3 0

[

1

' "\A\- '' 0.. (Et0)2P

0

Ri R2 (344)

0

\

"3

~1+~3

R3

R' R2

R2 (345)

Li .

r

1

I R' (346) Reagents: i, BuLi, THF; ii, LiAIH4,R.T.; iii, H30+; iv, R2NC0

Scheme 53

acid may play a role beyond simply neutralising the reaction mixture. Acylphosphonates react with aldehydes in the presence of semi-catalytic amounts of samarium metal or samarium diiodide to give acyloxyphosphonates (348).202 Compounds (348) react with aldehydes or ketones in a SmI2-catalysed reaction to give P-hydroxyphosphonates (349). The reaction can also be carried out as a three-component, one-pot reaction.

0 R'

-A

0

O Ri'

SmI,

$ K R 4

+ R~CHO

A

;(OEt)2

R2

0

t

"OfR4

Sml,, THF, RT

y E t h 0

R2

;(ow2

0

(348)

(349)

A variety of C2-symmetric diphenyl-phosphoramides, -thiophosphoramides and -selenophosphoramides have been used as chiral catalysts in alkylation reaction^?^^-^^^ Compounds (350) and (35 1)203and the selenophosphoramidates (352), (353), and (354)204act as ligands in Ti(1V)-catalysed asymmetric addition reactions of diethylzinc to aldehydes to give secondary alcohols with e.e. values of 40 to 83%. The diphenylthiophosphoramidates(35 l),(355), and (356) similarly act as ligands in Ag(1)-promoted enatioselective allylation of aldehydes with X

X II

0,

X (350) X = 0 (351)X = S (352) X = S e

X (353) X = S e (355) x = s

I'

II Y

(354) X = S e (356) X = S

(357)

Organophosphorus Chemistry

148

allyltrib~tyltin?~~ In this last case e.e. values are very variable and at best moderate, from 9 to 63%. A mechanistic investigation, involving 31PNMR and X-ray crystallography, of the enantioselective addition of diethylzinc to aromatic aldehydes catalysed by o-hydroxyaryldiazaphosphondiamides,e.g. (357), has been reported.206Hanessian and co-workers have used their diastereoselective route to substituted cyclopropanes from chloroallylphosphonamide (358) to

I

(358)

ii

Scheme 54

prepare (359), the key intermediate in a total synthesis of the secosequiterpene (-)-anthopalone (Scheme 54).207New water-soluble rhodium and iridium complexes of the tetra sodium salt of 2,2'-bipyridine diphosphonic acid (360) are reported to show excellent catalytic activity in the hydrogenation of various substituted acetophenones.208Incorporating a metal catalyst and a transition state analogue together with polymer imprinting provides a highly efficient catalyst for transfer hydrogenation of aryl ketones.209The complex (361) is co-polymerised with ethylene glycol dimethacrylate, followed by selective cleavage and removal of the phosphinate group to give the catalytic cavity. The triaza-lhs-phosphabicyclo[5.3.0ldecanes (362) undergo methanolysis to give different products, (363) or (364), depending on the conditions.210The results are explained in terms of the relative stability of the trigonal bipyramidal intermediates and the relative apicophilicity of the substituents on phosphorus. The effectiveness of 2-propanephosphonic acid anhydride (365) has been compared with that of the guanidinium derivative (366) as a peptide coupling reagent.*'l Compound (365) has a number of advantages and is particularly effective in the cyclisation of sterically hindered peptides. trans- Disubstitutedazetidines (367), -pyrrolidines (368), and -piperidines (369) react with diphenylthio- or diphenylseleno-phosphinic chlorides in the presence of potassium carbonate with an unexpected insertion of carbon dioxide to give the carbamate derivatives (370), (37l), and (372), respectively. *12 The corresponding cis-analogues do not give similar products and no reaction takes place with diphenylphosphinic chloride. Air and moisture-sensitive, phosphorus-containing triselenapenatalenes, e.g. (374), have been obtained in poor yield by the reaction

4: Quinquevalent Phosphorus Acids

149

of the diselenadiphosphetane (373)with dialkylcyanamides?’’ A new synthesis of trans-24 1-aryl-1-methylethyl)cyclohexylamines (375) incorporates the first example of ring-opening of a secondary aziridine with a tertiary carbanion (Scheme 55).*14Biaryls (376) have been prepared by a new route involving an intramolecular radical transfer reaction of aryl phosphinates with stannanes in the presence of a radical initiator (Scheme 56).215

LNM H

?\ ,o,

Pr‘-P

0 // . P-Pr‘

(365)

:

R’c(

)--

I

PhZPCI

yo

+

o,p5x

(X = S, Se) K,CO,, MeCN

N H

P i ‘Ph

(370)n = 1 (371)n = 2 (372) n = 3

(367)n = 1 (368)n = 2 (369) n = 3 Se

I

Se

Ar

(373)

o N i p h 2

a, 0,::; (374)

-

0

HI I

NPPh2 Me

2

r(Ar Me Me Reagents: i, ~ r 4 K-+ , 5 days; ii, CF3C02H, CHZCI2; iii, K2CO3, EtpO Me

Me

(375)

Scheme 55

Highly stable, 1:1 non-covalent, spherical complexes, e.g. (377), are formed from 1,3,5-tris(methyl phosphonomethy1)benzene and triammonium compounds.21

&

150

-&

Organophosphorus Chemistry

I:

O-PAr2

ilii

OH

R

R

X=N,CH Reagents: i, R3SuH, AIBN; ii, K2C03, MeOH

I

Y c;I

OMe

(376)

Scheme 56

I

(377) 0

3.3 Selected Biological Aspects. - Phosphonate and phosphinate functions continue to be widely used as transition state analogues in hapten structures and in the search for enzyme inhibitors. For example, a monoclonal antibody raised against the hapten (378) initiates chemiluminescence from SpiroCadamantane2,3’-(1,2-dioxetane)] substrates (379) by selectively cleaving the benzoate ester.217 The haptenic diphosphonate (380) has been used to generate esterolytic abzymes.21sThe latter approach has the advantage over previous attempts in that it should generate abzymes more closely analogous to natural enzymes where mechanisms operate in concert. Evidence is presented suggesting that abzymes generated in this way do have enhanced catalytic activity over those using other approaches. A number of a-methyl-substituted phosphonylphosphonates (381) have been synthesised as potential transition-state mimics of (382), an intermediate in, for example, the action of ornithine transcarbamoylase (OTC) on ornithine.*I9Surprisingly all compounds (381) studied were poor inhibitors of Streptococcus faecalis OTC. A variety of pseudo-tripeptides (383) containing a phosphinic acid function have been synthesised and evaluated as inhibitors of a number of metalloproteinases.220Structure related selectivity between different metalloproteinases was observed although compounds, e.g. (383)(R2 = (CH2)3Ph),containing long-

4: Quinquevalent Phosphorus Acids

151

0

Reagents: i, (BnO)zkHzLi+,EtO3.BF3, THF; ii, DCC, py/DMSO, CF3C02H Scheme 57

chain aryl-alkyl substituents at the P'-position acted as highly potent inhibitors towards a majority of the metalloproteinases studied. The phosphonate isostere (385) of D-erythrulose 1-phosphate has been prepared from (2R,3S)-3,4-epoxy1,2-O-isoprpoylidenebutane-1,2-diol(384) (Scheme 57) and used as a probe to investigate the reaction mechanism of slow binding inhibition of rabbit muscle aldolase by D-erythrulose l-phosphate.221The results are consistent with a phosphate p-elimination reaction through an enamine intermediate and the suggested mechanism takes acount of the stereochemistry and the recovery of enzyme activity observed. The phosphonates (386) have been prepared as acylglycerol analogues for use as inhibitors in a study of Human Pancreatic and Gastric lipases.222 0

(386)

4

N02

Structure

Theoretical studies of a variety of oxygen-containing phosphorus compounds, including P(V) acids and esters, by molecular mechanics (MM3) force field and of the interactions of phosphate, phosphonate, phosphinate and phosphine oxide ligands with lanthanide cations in the gas phase have been

152

Organophosphorus Chemistry

reported.224In the latter case steric effects are the major factor influencing the relative strength of the ligand-metal binding. Chiral phosphoramides, particularly C2-symmetricexamples, are widely used in asymmetric synthesis (see section 3.2). One example is the asymmetric catalysis of Aldol reactions, where the phosphoramide catalyst is used in combination with a Lewis base. A solid state and solution study of the structure of chiral phosphoramide-tin complexes used in such reactions has now been A number of chiral, non-racemic cyclic phosphoramide receptors (387)have been synthesised and their interactions with homochiral amines studied using electrospray ionisation MS. Although (387) bind the amines strongly, no evidence of chiral selectivity was found.226Evidence from a combination of its X-ray structure, 31PNMR, and ab initio calculations suggests that the cyclen phosphorus oxide (388) has an N-P transannular interaction in the solid state.227A series of isomers of 1,3,2-oxazaphosphorino[4,3-a]isoquinolines (389), containing a novel ring-system, have been prepared and their stereochemistry and conformation studied by ‘H, 13C,and 31PNMR spectroscopy and X-ray crystallography.228

The pK, of the 2’-hydroxy group in the ribose phosphate diester (390)has been determined as 14.9 by theoretical methods.229Since ribozymes and ribonucleases employ mechanisms involving deprotonation of a 2’-hydroxyl group this result is of interest in the study of a wide range of biological systems. The solute-solvent interactions in crystals of the dithiophosphoro-substituted carbohydrate (391) have been investigated using X-ray and solid state NMR methods.230The conformation in solution of a number of pseudodisaccharides that incorporate structural motifs previously proposed for inositolphosphoglycan mediators of intracellular signalling processes have been investigated by NMR and theoretical methods.’31Structures studied include a number of phosphates, e.g. (392).

u I

-0, -0,/? I ?

I

0 OH 0 I OH O=P-0OMe

(390)

S S (R0)2;’s‘S’

(391)R =

0 0 ;(OR), ;(OR),

H

O HO

G

o ‘NH3

& Ho

(392)

OH

OH

153

4: Quinquevalent Phosphorus Acids

The addition of photochemically-generated phosphoryl radicals to [76] fullerene has been studied by EPR.232Seven of the nineteen possible radical adducts were observed, six of which are stable. The study was supported by semi-empirical MNDO/PM3 calculations. Two new, cyclic phosphinylhydrazyl radicals, (393) and (394),have been generated by the oxidation of the corresponding hydrazines and their structures, and their interactions as guests in cyclodextrins, studied by EPR.233 R

R BU‘OOBU‘ P

hv

(393)X=O, R = H (394)X=CH2, R = Me 0

CI-P

(395)

//

‘b

(396)

Simultaneous determination of enantiomeric purity and erythrolthreo ratios in chiral 1,2-aminoalcohols can be achieved by NMR using (R)-(+)-t-butylphenylphosphinothioic acid (395) as a complexing agent.234The interactions of phosphate and pyrophosphate anions with a number of cyclic and acyclic polyammonium cations in aqueous solution have been studied by potentiometIn two cases X-ray crystal ric, microcalorimetric and NMR structures were also determined. The first spectroscopic study of free gas-phase phosphenic chloride (396), generated by passing an electric discharge through a mixture of PC13and 02, has been reported.236

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156

Organophosphorus Chemistry

80. M. Hodgson, P. A. Stupple and C. Johnstone, Chem. Commuiz. (Cambridge), 1999, 2185. 81. M. Mizuno and T. Shioiri, Tetrahedron Lett., 1999,40,7105. 82. M. S. Hemenway and H. F. Olivo, J . Org. Chem., 1999,64,6312. 83. M. Felemez, P. Bernard, G. Schlewer and B. Spiess, J . Am. Chem. SOC.,2000,122, 3156. 84. H. I. Park and L-J. Ming, Angew. Chem., Int. Ed. Engl., 1999,38,2914. 85. C-G. Zhan, 0.N. de Souza, R. Rittenhouse and R. L. Ornstein, J . Am. Chem. SOC., 1999,121,7279. 86. M. Merkx and B. A. Averill, J . Am. Chem. SOC.,1999,121,6683. 87. X. Wang, R. Y. N. Ho, A. K. Whiting and L. Que, J . Am. Chem. SOC., 1999, 121, 9235. 88. R. H. Hoff, P. Mertz, F. Rusnak and A. C. Hengge, J . Am. Chem. SOC., 1999,121, 6382. 89. R. H. Hoff, L. Wu, B. Zhou, Z-Y. Zhang and A. C. Hengge, J . Am. Chem. SOC., 1999, 121,9514. 90. J. Haddad, S. Vakulenko and S. Mobashery, J . Am. Chem. SOC.,1999,121,11922. 91. L. Kaustov, S. Kababya, S. Du, T. Baasov, S. Gropper, Y. Shoham and A. Schmidt, J . Am. Chem. Soc., 2000,122,2649. 92. 0. Brummer, P. Wentworth, Jr., D. P. Weiner and K. D. Janda, Tetrahedron Lett., 1999,40,7307. 93. C. Gao, 0. Brummer, S. Mao and K. D. Janda, J . Am. Chem. Soc., 1999,121,6517. 94. K. A. H. Chehade, D. A. Anders, H. Morimoto and H. P. Spielmann, J . Org. Chem., 2000,65,3027. 95. N. Khaleeli, R. Li and C. A. Townsend, J . Am. Chem. SOC.,1999,121,9223. 96. L. Charon, C. Pale-Grosdemange and M. Rohmer, Tetrahedron Lett., 1999, 40, 7231. 97. E. Cane, S. Du and I. D. Spenser, J . Am. Chem. Soc., 2000,122,4213. 98. D. E. Cane, S. Du, J. K. Robinson, Y. Hsiung and I. D. Spenser, J . Am. Chem. SOC., 1999,121,7722. 99. K. Ghosh, S. Khan and D. Farquhar, Chem. Commun. (Cambridge), 1999,2527. 100. Eymery, B. Iorga and P. Savignac, Tetrahedron, 1999,55,13109. 101. S. C. Fields, Tetrahedron, 1999,55, 12237. 102. L-B. Han, F. Mirzaei, C-Q. Zhao and M. Tanaka, J . Am. Chem. SOC.,2000, 122, 5407. 103. I. Hansen and J. Kehler, Synthesis, 1999, 1925. 104. R. Dalpozzo, A. De Nino, D. Miele, A. Tagarelli and G. Bartoli, Eur. J . Org. Chem., 1999,2299. 105. S. Kende, J. B. J. Milbank, F. H. Ebetino and M. A. delong, Tetrahedron Lett., 1999,40,8189. 106. S. Goumain, P. Jubault, C. Feasson and N. Collignon, Synthesis, 1999, 1903. 107. C. Duquenne, S. Goumain, P. Jubault, C. Feasson and J-C. Quirion, Org. Lett., 2000,2,453. 108. S. Goumain, P. Jubault, C. Feasson and J-C. Quirion, Tetrahedron Lett., 1999,40, 8099. 109. S. Yamazaki, Y. Yanase and K. Yamamoto, J . Chern. Soc., Perkin Trans. 1, 2000, 1991. 110. S-C. Chuang, D-D. Lee, K. C. Santhosh and C-H. Cheng, J . Org. Chem., 1999,64, 8868. 11 1. Cheng, X. Yang, H. Zhu and Y. Song, Tetrahedron Lett., 2000,41,3947.

4: Quinquevalent Phosphorus Acids

112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132.

133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146.

157

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158

Organophosphorus Chemistry

147. T. Yamagishi, T. Yokomatsu, K. Suemune and S . Shibya, Tetrahedron, 1999, 55, 12125. 148. Barco, S. Benetti, P. Bergamini, C. De Risi, P. Marchetti, G. P. Pollini and V. Zanirato, Tetrahedron Lett., 1999,40,7705. 149. G. Guanti, L. Banfi and M. T. Zannetti, Tetrahedron Lett., 2000,41,3181. 150. Dondoni, A. Marra and C. Pasti, Tetrahedron: Asymmetry, 2000,11,305. 151. H-D. Junker, N. Phung and W-D. Fessner, Tetrahedron Lett., 1999,40,7063. 152. S . Hanessian and 0. Rogel, J . Org. Chem., 2000,65,2667. 153. E. Wroblewski and A. Halajewska-Wosik, Tetrahedron: Asymmetry, 2000,11,2053. 154. P. B. Wyatt and P. Blakskjar, Tetrahedron Lett., 1999,40,6481. 155. B. Kaboudin, Tetrahedron Lett., 2000,41,3 169. 156. C. J. Salomon and E. Breuer, Synlett, 2000, 8 15. 157. C. G. Ferguson, B. I. Gorin and G. R. J. Thatcher, J . Org. Chem., 2000,65,1218. 158. Ando, J . Org. Chem., 1999,64,8406. 159. S. Y. Lee, B. S. Lee, C-W. Lee and D. Y. Oh, J . Org. Chem., 2000,65,256. 160. Manabe and S . Kobayashi, Chem. Commun. (Cambridge), 2000,669. 161. E. Alonso, E. Alonso, A. Solis and C . del Pozo, Synlett, 2000,698. 162. Vercruysse, C . Dejugnat, A. Munoz and G. Etemad-Moghadam, Eur. J . Org. Chem., 2000,28 1. 163. K. S. Kim, E. Y. Hurh, J. N. Youn and J. I. Park, J . Org. Chem., 1999,64,9272. 164. Fadel, J . Org. Chem., 1999,64,4953. 165. Fadel and N. Tesson, Eur. J . Org. Chem., 2000,2153. 166. Fadel and N. Tesson, Tetrahedron: Asymmetry, 2000,11,2023. 167. Hercouet, M. Le Corre and B. Carboni, Tetrahedron Lett., 2000,41,197. 168. D. Sikora and T. Gajda, Tetrahedron, 2000,56,3755. 169. J. L. W. Griffin, P. V. Coveney, A. Whiting and R. Davey, J . Chem. Soc., Perkin Trans. 2,1999,1973. 170. V. K. Sharma and A. Clearfield, J . Am. Chem. Soc., 2000,122,1558. 171. E. Wroblewski and D. G. Piotrowska, Tetrahedron: Asymmetry, 2000,11,2615. 172. S . A. Shackleford, D. F. Shellhamer and V. L. Heasley, Tetrahedron Lett., 1999,40, 6333. 173. V. Ojea, M. Ruiz, G. Shapiro and E. Pombo-Villar, J . Org. Chem., 2000,65, 1984. 174. Ruiz, V. Ojea, M. C. Fernandez, S. Conde, A. Diaz and J. M. Quintela, SynEett, 1999, 1903. 175. Wiemann, R. Frank and W. Tegge, Tetrahedron, 2000,56,1331. 176. A. Thomas and K. B. Sharpless, J . Org. Chem., 1999,64,8379. 177. Mugrage, C. Diefenbacher, J. Somers, D. T. Parker and T. Parker, Tetrahedron Lett., 2000,41,2047. 178. Bakalarz, J. Helinski, B. Krawiecka, J. Michalski and M. J. Potrzebowski, Tetrahedron, 1999,55, 12211. 179. T. Murai, C. Izumi, T. Itoh and S. Kato, J . Chem. SOC.,Perkin Trans. I , 2000,917. 180. H. Al-Badri, N. Collignon, J. Maddaluno and S . Masson, Tetrahedron, 2000, 56, 3909. 181. Y. A. Ibrahim, A. M. Kadry, M. R. Ibrahim, J. N. Lisgarten, B. S. Potter and R. A. Palmer, Tetrahedron, 1999,55,13457. 182. Sato, R. Kodaka, T. Shibata, Y. Hirokawa, N. Shirai, K. Ohtake and K. Soai, Tetrahedron: Asymmetry, 2000,11,2271. 183. H. Lu, K. L. Mlodnosky, T. T. Dinh, A. Dastgah, V. Q. Lam and C. E. Berkmann, J . Org. Chem., 1999,64,8698. 184. R. W. Ware, Jr. and S. B. King, J . Am. Chem. Soc., 1999,121,6769.

4: Quinquevalent Phosphorus Acids 185. 186. 187. 188. 189. 190.

159

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160

Organophosphorus Chemistry

221. Page, C. Blonski and J. Per%, Eur. J . Org. Chem., 1999,2853. 222. Marguet, J-F. Cavalier, R. Verger and G. Buono, Eur. J . Org. Chem., 1999,1671. 223. E. L. Stewart, N. Nevins, N. L. Allinger and J. P. Brown, J . Org. Chem., 1999,64, 5350. 224. Schurhammer, V. Erhart, L. Troxler and G. Wipff, J . Chem. SOC.,Perkin Trans. 2, 1999,2423. 225. E. Denmark and X. Su, Tetrahedron, 1999,55,8727. 226. R. C. Smith, A. J. R. Heck, J. A. Kenny, J. J. Kettenes-van den Bosch and M. Wills, Tetrahedron: Asymmetry, 1999,10,3267. 227. N. Oget, F. Chuburu, H. Handel and L. Toupet, J . Chem. Res. ( S ) , 1999,526. 228. Martinek, E. Forro, G. Giinther, R. Sillanpaaand F. Fiilop, J . Org. Chem., 2000,65, 316. 229. D. Lyne and M. Karplus, J . Am. Chem. SOC., 2000,122,166. 230. M. J. Potrzebowski, K. Ganicz, W. Ciesielski, A. Skowronska, M. W. Wieczorek, J. Blaszczyk and W. Majzner, J . Chem. Soc., Perkin Trans. 2, 1999,2163. 231. M. Martin-Lomas, P. M. Nieto, N. Khiar, S. Garcia, M. Flores-Mosquera, E. Poirot, J. Angulo and J. L. Mufioz, Tetrahedron: Asymmetry, 2000,11,37. 232. 0.G. Kalina, B. L. Tumanskii, V. V. Bashilov, A. L. Christyakov, I. V. Stankevich, V. L. Sokolov, T. J. S. Dennis and R. Taylor, J . Chem. SOC., Perkin Trans. 2, 1999, 2655. 233. M. Lucarini, G. F. Pedulli and D. Lazzari, J . Org. Chem., 2000,65,2723. 234. K. G. Gunderson, M. J. Shapiro, R. A. Doti and J. W. Skiles, Tetrahedron: Asymmetry, 1999,10, 3263. 235. Bazzicalupi, A. Bencini, A. Bianchi, M. Cecchi, B. Escuder, V. Fusi, E. GarciaEspaiia, C. Giorgi, S. V. Luis, G. Maccagni, V. Marcelino, P. Paoletti and B. Valtancoli, J . Am. Chem. SOC.,1999,121,6807. 236. Brupbacher-Gatehouse, J . Am. Chem. Soc., 2000,122,4171.

5 Nucleic Acids and Nucleotides; Mononucleotides BY M. MIGAUD

1

Introduction

This past year has been highlighted by the development of novel phosphate protecting groups and their use in nucleotide and chiral nucleoside thiophosphate chemistry. Concise methodologies have been described for cost effective syntheses of oligonucleotide building blocks. Finally, the collection of unnatural nucleotides reported to have been synthesised has been expanded significantly.

2

Mononucleotides

2.1 Nucleoside Acyclic Phosphates.- 2.1.I Mononucleoside Phosphate Derivatives. A preliminary study on a novel solid phase reagent (Scheme 1) for the capture phosphorylation of nucleosides has been described. The 1YOcross-linked divinylbenzene-polystyrenecopolymer, containing cyanoethoxy N,N-diisopropy1 phosphine was used for the selective phosphorylation of uridine to 5'uridine monophosphate (UMP) in 67% yield.' 1. ROH, 1Ktetrazole

2. BU'O,H 3. DBU 4. MeONa

0 II

* -0-p-oI

OR

Scheme 1

Novel phosphate-protecting groups for oligonucleotide synthesis, the 2(phenylcarbamoyloxy)ethyl, the 2-[(4-dimethylamino)phenylcarbamoyloxy] ethyl and the 2-[(1-naphthyl)carbamoyloxy]ethyl groups, have been developed by Guzaev. The 2-[( 1-naphthyl)carbamoyloxy]ethyl (NCE) group was reported to be the most convenient phosphodiester protecting group amongst these three Organophosphorus Chemistry, Volume 33

0The Royal Society of Chemistry, 2003 161

162

Organophosphorus Chemistry

2-(arylcarbamoyloxy)ethyl groups when they were tested for their effects on coupling yields, deprotection kinetics and hydrolytic stability of the thymidine phosphoramidite building blocks (la-c) used in DNA synthesis.2 The same group also reported the 2-benzamidoethyl derivatives (2a-h) and (3a-c) as two effective and versatile classes of protecting groups for phosphodiester functions. Along with high coupling yields, a wide range of conditions for removal of these protecting groups, depending on the aryl substitution, could be employed in oligonucleotide ~ynthesis.~ Furthermore, it was shown that the mechanism by which these protecting groups were removed proceeded via intramolecular cyclisation.

0 ’ I

Yo

.,p\o-o

Pi2N

R”H

(1)a R = P h (1) b R = 4-(Me2N)C6H4 (1) c R = 1-Naphthyl

H

O Y N Y O

D M T o P N A

7’ PG =

i

i R

PG =$R f+‘: O

S

a R=R~=R~=H (3)a R = 1, R = P h b R = R’ = H, R2 = 4-OMe (3)b n = 1, R = NHPh (3) c n = 2, R = Ph c R = R’=H, R2=3-N02 d R=Me, R ’ = R 2 = H e R = R 2 = H , R’=Me f R = H, R’ = Me, R 2 = 4-OMe g R = H, R’ = Me, R2 = 4-N(Me)2 h R = H, R1 = (Me)2CH, R2 = 4-OMe

Another phosphoramidite protecting group, the 2-(N-formyl-Nmethy1)aminoethylgroup, has been developed for the cost effective preparation of therapeutic oligonucleotides. This protecting group (4)was evaluated against other known similar amide- and carbamate-based groups for the rapid production of dithymidine phosphodiesters. Unlike the previously reported phosphoramidite protecting groups, 2-(N-formyl-N-methyl)aminoethyl could be cleaved via a unique thermolytic cyclodeesterification process at pH 7 (Scheme 2).4 Beaucage also reported the use of the 4-[N-methyl-N-(2,2,2-trifluoroacetyl)amino] butyl group as an alternative to the cyanoethyl group in phosphate protection (5a-d) to completely prevent nucleobase alkylation by acrylonitrile occasionally occurring at the deprotection stage. The butyl derivative was easily removed under mild basic conditions in two steps, deacylation followed by cyclodeesterification. 31PNMR studies showed that the cleavage of the N-trifluoroacetyl group was the rate-limiting step of the depr~tection.~ The use of 2-cyano-1-t-butylethyl- and 2-cyano- l-(l,l-diethyl-3-butenyl)ethylphosphorimidazolidite as new phosphitylating reagents has been reported for

163

5: Nucleic Acids and Nucleotides; Mononucleotides

-gy N

pH 7.0

90 “C

.O

/

0’ I

o=p-xI

O

F

Y

?nryc

Scheme 2

DMToF I

(5) a (5) b (5) c (5) d

0 B =Thy B = BzCyt B=BZAde B = tBUGua

DMToT

DMTO

B

E

Pr‘Nh,

HO w

R’ 0 X = lmidazolyl

DMTO

NHP~ (6) a B = ABz (6)b B = T

NHPr’ (7)a B = cBZ (7)b B = T ( 7 )B~= AB’ (7) d B=GlBU

Scheme 3

the in situ preparation of the 2-cyano-1-t-butylethyl- and 2-cyano-1-(l,l,-diethyl3-butenyl)ethyl-3’-O-phosphorimidazolidite of 5’-O-protected nucleosides (Scheme 3). The resulting phosphoribosimidazolidites (6a-b) and (7a-d) were used for the selective formation of 3’-5’ internucleotide linkages when treated with a 3’,5’-O,O-unprotectednucleoside.6 P-Heteroaryl-substituted ethanols, pyridine 2-ethanols and pyridine 4-

164

Organophosphorus Chemistry

ethanols (8a-j) were also developed as new types of phosphate-protecting groups in the synthesis of oligonucleotides using the phosphotriester approach. These groups showed a broad range of stability towards base treatment in aprotic solvents depending upon the activation of the H-C(P) atoms by the heterocyclic moiety. They could be removed selectively after dinucleoside 3',5'-phosphodiester bond formation by acid, oximate and DBU treatment, depending upon the nature of the blocking groups (9a-e).7 H

O Y N Y O

D O=P-OR I M T o Y N d

Q

NO2

2,4-Dinitrophenol has been shown to be a remarkably efficient activator in the reaction of P(II1) amides with nucleosides to give P(II1) triesters in excellent yield. Using 2,4-dinitrophenol, the diastereomerically pure fluorophosp horamidit e of 5'-dimet hox yt rit yl t hymidine reacted with 3'-dimet hoxytrityl-

5: Nucleic Acids and Nucleotides; Mononucleotides

165

thymidine in the presence of dinitrophenol yielding the dinucleoside phosphorofluoride in a non-stereoselective way but in high yield. The mechanism for activation by dinitrophenol was thought to proceed in a similar manner to that by tetrazole. Furthermore, P(III)-2,4-dinitrophenyl triesters used as phosphitylating reagents did not require activation.* Phosphonates (10) and phosphine oxides (11) were prepared for use in the synthesis of a series of new alk-1-enyl derivatives of adenine and thymidine (Scheme 4) via Horner reactions and Horner-Wadsworth-Emmons reactions on carbonyls.' This approach, complementary to the previously reported methods for the preparation of N-(alk- 1-enyl) nucleobases, offers a novel general strategy to access trisubstituted alkenyl nucleobases. B

1. NaH

or PO(OEt)2 (10)a B = B 1 (10)b B = B 2

R'

Ph20P (11)a B = B 1 (11)b B = B 2 ( 1 1 ) ~B = B 3

Scheme 4

Pyrimidine nucleoside 5'-phosphoramidites (12, 13) protected at the 3'-position with the photoremovable nitrophenylpropyloxycarbonyl (NPPOC) group have been synthesised to provide oligonucleotides in high cycle yields via reverse (5'-3') light-based solid phase synthesis. Isobutyroyl deoxycytidine was unreactive under the photochemical deprotection conditions. This methodology has the potential to afford high fidelity in nucleic acid analysis when coupled to DNA microarray fabrication technology, photolithography and enzymatic processing of probes."

CCN Pri2N

CCN Pri,N'

0

166

Organophosphorus Chemistry

The 5’-phosphoramidite of the novel bicyclic nucleoside (14), restricted to an S-type conformation, has been synthesised in eight steps via double inversion of configuration at the C4’ position of protected 1-(3’-deoxy-P-~psicofuranosy1)uracyland introduction of an azide moiety. The secondary amino group at C4’ permitted the subsequent incorporation of (14) into oligonucleotides via a 5’-3’directed variation of the standard phosphoramidite approach for synthesis of oligonucleotides. Thermal denaturation studies showed rather large decreases in duplex stabilities toward complementary DNA and RNA.” The synthesis and chemical properties of the naturally occurring O-P-Dribofuranosyl-( 1”-2’)-adenosine-5’‘-0-phosphate (15) have been reported. This was further converted into the corresponding 3’-phosphoramidite of 5’-0-(4,4’dimet h o xy t r it y1)-0- p-D -r i b ofu r an osy 1-( 1”- 2’)-ad en o sine - 5”-0- bis(p-n i t r o phenylethy1)phosphate for its incorporation into oligonucleotides.’* Matsuda reported the synthesis of a series of 5’-modified novel analogues of the clinically useful immunosuppressant bredinin. These analogues, including the 5’-phosphate (16), were prepared via a novel photochemical imidazole ring cleavage reaction as the key step.13

0

(18)a R = M e (18) b R = Et (18) c R = Me3CCH2 (18) d R = PhCH2 (18) e R = Pr‘ (18) f R = C6Hll (18) g R = cholesteryl (18) h R = B d (18)i R=Ada

Oxanosine, a novel guanosine analogue antibiotic has been phosphorylated according to the Yoshikawa procedure to yield (17) and evaluated for in vitro antiviral activity against HIV pr01iferation.l~Compound (17) reduced the number of HIV particles in CEM cells to almost the same level as ddI.

5: Nucleic Acids and Nucleotides; Mononucleotides

167

A series of alkyl ester hydrogenphosphonate derivatives of AZT, d2A and d4T (18), (19) and (20) have been synthesised to investigate the metabolic pathway by which the hydrogenphosphonate (18, R = H) is transformed to AZT inside the ~e1ls.l~ It was found that ester residues containing primary and secondary alcohols were oxidized and hydrolysed to give AZT, whereas those containing tertiary alcohols were hydrolysed to AZT-5’-H-phosphonate. The same observations were reported for d2A and d4T. Perigaud has extended his work on the synthesis and biological activities of phosphotriester derivatives of AZT bearing a phenyl group or L-tyrosinyl residues. The novel AZT-derivatives (21a-d) also incorporating one S-pivaloyl-2thioethyl residue were obtained via either P(II1) or P(V) chemistry from the appropriate aryl precursors and evaluated for their in vitro anti-HIV activity. EC50values for their ability to inhibit HIV-1 replication in various cell culture experiments ranged between micro- and the nanomolar concentrations. SPivaloyl-2-thioethyl aryl phosphotriester derivatives of AZT were able to allow the efficient intracellular delivery of the parent nucleotide via their successive intracellular hydrolysis by an esterase and a phosphodiesterase.’6 Further work has also been carried out on the synthesis and biological evaluation of novel amidate prodrugs of PMEA and PMPA. To synthesise (22a-i), PMPA and PMEA were converted under mild conditions into their corresponding dichloridate using thionyl chloride and pyridine. The desired compounds were obtained only when the addition of the phenols and the amino acid methyl esters in the presence of triethylamine were performed in that order.17

0

YNHR (21) a (21) b (21) c (21)d

R’ &O R = ‘BOC, R’ = OBU‘ R = ‘Boc, R’ = OMe R = H, R’ = OBU‘ R = H , R’ =OMe

(22) a (22) b (22) c (22) d (22) e (22) f (22) g (22) h (22) i

R’ R’ = Me, R2 = L-Ala-Me-ester, R3 = PhO R’ = Me, R2 = Gly-Me-ester, R3 = PhO R’ = Me, R2 = D-Ala-Me-ester, R3 = PhO R’ = Me, R2 = L-Phe-Me-ester, R3 = pCI-PhO R’ = Me, R2 = L-Ala-Me-ester, R3 = pCI-PhO R’ = Me, R2 = R3 = PhO R’ = H, R2 = L-Ala-Me-ester, R3 = PhO R’ = H, R2 = Gly-Me-ester, R3 = PhO R‘ = H, R2 = D-Ala-Me-ester, R3 = PhO

0 II

HN-P-0 Me02C--(

OPh Me

HO (23)

168

Organophosphorus Chemistry

The synthesis of the phosphoramidate pro-drug of 6-thio-7-deaza-2‘deoxyguanosine (23), a precursor to the potent inhibitor of human telomerase TDG-5’-triphosphate, has been achieved by selective phosphorylation of TGD with phenyl methoxyalaninyl phosphochloridate in the presence of N-methylimidazole at -70°C. Compound (23) was effective in producing measurable levels of TDG-TP in A539 cells.’* An alternative strategy, reported by Stec, to access 5’-aminoacidophosphoramido-thioates and -dithioates of AZT (24) with satisfactory yields has been based upon 1,3,2-0xathia(dithia)phospholane chemistry. It consisted of the derivatisation of the corresponding amino acid-methyl esters either with 2-chloro1,3,2-oxathiaphospholaneor 2-chloro- 1,3,2-dithiaphospholane, followed by the reaction of the resulting N-phosphorothioylated amino acid esters with AZT.I9 Two glutaminyl adenylate analogues (25a,b)have been synthesised and evaluated as inhibitors of glutaminyl-tRNA synthetase. In spite of the reduction of the ester to an ether group, the free acid (25a) was a potent inhibitor of the synthase (Kj = 280 nM). A 50-fold decrease in potency was observed for (25b).*’ R

(24)a (24) b (24) c (24) d

n

R=Ph, Y = O R = Ph, Y = S R = 3-lndoly1, Y = 0 R = 3-lndolyl, Y = S

n

HO’ (25) a R = H (25) b R = M e

(27)a (27) b (27) c (27) d (27) e (27) f

\

OH

I\-’-

R=Ph R = CH(Me)CHzMe R = CHMe2 R = L-CHzPh(pOH) R = D-CH2Ph(pOH) R = CHzCHzSMe

Working on the assumption that the P-N bond of an N-acyl phosphoramidate linkage was stable under physiological conditions, Sekine has reported the synthesis of a series of novel amino acid-AMP analogues (26,27a-f) bearing such a linkage.21These aminoacyloamido-AMP, true and stable isosteres of amino acid-AMPS, were expected to be useful as material for studies on the recognition mechanism of the aminoacylation of tRNA by acting as potential specific inhibitors. The key step in the preparation of such analogues was the construction of the N-acyl phosphoramidate linkage. TBTr (4,4’,4”-tris(benzoyloxy)trityl) and TSE (2-(trimethylsily1)ethyl) groups were used for the protection of the amino group of the amino acid amides and the phosphorimidite group, respectively. Condensation of phosphoramidites and protected amides in the presence of 5-(3,5-dinitrophenyl)-l-H-tetrazole offered the fully protected aminoacyloamido-AMP derivatives. The fully deprotected adenosine deriva-

’

5: Nucleic Acids and Nucleotides; Mononucleotides

169 0

0 II

% H 2 !(0 ):

OH HO R2 (31)a R’ = H, R2= OH, R3= U (31) b R’ = H, R 2 = OH, R3= C ( 3 1 ) R’ ~ =OH, R 2 = H, R3= C

HO

R2

(32)a R’ = H R2 = OH, R3 = U (32)b R’ = H: R2 = OH, R3 = C (32)c R’ = OH, R2 = H, R3 = C

tives (26,27a-f) were found to be stable under acidic (pH l,O.l M HCl) and basic (pH 13,O.l M NaOH) conditions. The preparation of the phosphorane (28), obtained quantitatively from the 5’-diisopropylphosphite of 2’,3’-di-O-acetyluridinein the presence of tetrachloro1,2-benzoquinone, was reported. Compound (28) is a proposed analogue of the intermediate occurring during RNA hydrolysis.22 The syntheses of carbocyclic analogs of phosphononucleosides (29) and (30a-c) have been reported. Phosphonic acid (29) was obtained by introduction of the benzoylated thymine on the 2(4-hydroxycyclopent-2-enyl)ethylphosphonic acid diisopropyl ester under Mitsunobu conditions while (30a-c) were prepared by building-up the base around a phosphono-cyclopentylamine moiThe vinylphosphonate derivatives of uridine, cytidine and cytosine arabinoside (3 la-c) have been prepared by Wittig condensation of [(diethoxyphosphinyl)methylidene]triphenylphosphorane with the appropriately protected 5aldehydic nucleoside derivatives. Dihydroxylation of the novel vinyl phosphonates offered the dihydroxylated phosphonate derivatives (32a-c). Each of these novel compounds was evaluated as substrates for the enzyme nucleotide monophosphate kinase, and their toxicity to K562 cells. All analogues were found to be poorly phosphorylated by the kinase and exhibited poor in vivo A rapid and high yielding synthesis of 5’-deoxy-5’-thioguanosinephosphorothioate (GSMP) (33) and its application in introducing a 5’-terminal sulfhydryl group in large RNA molecules via an enzymatic step has been reported. Compound (33) was prepared by treatment of 2’,3’-O,O-isopropylidene-

Organophosphorus Chemistry

170

DMTO

DMTO

CN (34) a BASE = BZAde (34) b BASE = %yt (34) c BASE = Ura

(35) R = H (36) R = BZ

OR

OCH2COOR (37)a R = M e (37) b R = Ally1

5’-deoxy-5’-iodoguanosine with trisodium thiophosphate and isolated in 68 % yield after 2.5 days. The in vitro transcription of (33) with T7-RNA polymerase yielded 5’-(GSMP)-RNAwhich was then converted into 5’-SH-RNA by dephosphorylation with alkaline p h o ~ p h a t a s e . ~ ~ An improved procedure for the preparation of isotopically labeled D-[ 1-I3C] ribonucleoside 3’-phosphoramidites (34) has been reported. This method, which employed the regioselective 2’-O-silylation of the ribonucleoside via a selective protection and subsequent removal of the 3’,5’-di-tert-butylsilanediylgroup, avoided the undesired 3’-O-silyl-2’-O-phosphoramidite nucleosides usually detected with standard p r o c e d u r e ~ . ~ ~ ~ ~ ~ The synthesis of nucleotide building blocks containing electrophilic groups in the 2’-position has been described. The phosphoramidite derivative of 2’-0(2,3,dihydroxypropyl)uridine (35) has been synthesised via (36) and incorporated in an oligonucleotide, to then be oxidized by NaI04 to form the aldehydic side-chain-containing oligonucleotide. Such modified oligomers could then interact with compounds containing nucleophilic groups. Unlike that of 2’-deoxy2’-(2,3-dihydroxypropyl)uridine, the t hermost ability of the DNA duplexes incorporating the resulting aldehydic side chain hardly differed from that of the natural DNA duplexes. The same group also reported the synthesis of (37a) and (37b) and their incorporation into synthetic n u ~ l e o t i d e s . ~ ~ ~ ~ ~ In order to preserve optimal stability in the hybridization of RNA by sugarmodified oligonucleotides, nucleosides substituted at the 2’-position must retain a C3’-endo puckered conformation. To this end, the 2’-0-{2-[N,N(dimethylamino)oxy]ethyl} and the 2’-0-{ 2-[N,N-(diethy1amino)oxyl-ethyl}3’phosphoramidite derivatives of thymidine (38a, 38b) have been synthesised. The nucleoside precursors were prepared from a phthalimido-derivative obtained from 2,2’-anhydro-5-methyluridinewhich had been treated, after appropriate protection, with a borate ester generated in situ and then reacted with PPh3, DEAD and N-hydroxyphthalimide. The incorporation of (38a) and (38b) in oligonucleotides and oligodeoxynucleotides resulted in high binding affinity for

171

5: Nucleic Acids and Nucleotides; Mononucleotides H

O Y N Y O

DMTo%B Pi2N--6I

P-NPr‘2 dCH&H&N (38) a R = Me (38) b R = CH2Me

CN (39) a (39) b (39) c (39) d

CN (40)a B = U, R=CH20Si(Pr$, (40) b B = Bz‘A, R = CH20Si(Pr‘)3 (40) c B = Ac2G, R = CH20Si(Pr‘)3 ,

s&-o

CN B = uBZ B=ABZ. B = CBu’ B = GCerPa

CN (41) a B = U, R = CH20CH2CH2CH2Br (41) b B = Bz‘A, R = CH20CH2CH2CH2Br (41) c B = Ac2G, R = CH20CH2CH2CH2Br

RNA but not for DNA, respectively. A marked enhanced stability to nucleases was recorded.’O Extensive work in the development of suitable phosphate protecting groups for the synthesis of nucleoside phosphoramidites possessing a phosphate moiety at the 2’-position and incorporable into oligonucleotides, has been reported. Such protecting groups were designed so that the common 2‘,3’-migration of the phosphate group was prevented during the synthesis. Sekine et al. reported that the use of the 2-cyano-l,l-(dimethyl)ethylprotecting group provided easy access to (39a-d) via 3’,5’-unprotected 2’-bis(2-cyano- 1,l-dimethylethoxy)-t hiophosphorylated nucleoside derivatives without formation of the regioisomer obtained by migration of the thiophosphate The syntheses of the 6’-O-(bromopenty1)-substitutedallofuranosyl-purine and -pyrimidine phosphoramidite (40a-c) and the 2’-0-[(3-bromopropoxy)methy1] substituted allofuranosyl-purine and -pyrimidine phosphoramidite (41a-c) have been reported. Such modifications of the sugar moiety presented opportunities for the functionalisation of oligonucleotides with a variety of soft nucleophiles while the fully protected sequence was still on the solid Leumann reported the syntheses of 5’-C-butylthymidine, 5’-C-butyl-2’-deoxyThese ana5-methylcytidine and 5’-C-isopentyl-2’-deoxy-5-methylcytidine. logues were prepared from natural thymidine using Wittig chemistry on thymidin-5‘-al, followed by epoxidation of the alkene and reduction to the 5’-alcoh01.~~ The 3’-phosphoramidite derivatives (42a,b) and (43a,b) were prepared for their incorporation into oligodeoxynucleotides, so as to investigate the effects of these 5’-modified nucleosides on the stability of the DNA double helix

172

Organophosphorus Chemistry

and their effects on minor-groove hydration. The same group has also described a novel method for the synthesis of pyrrolidino C-nucleosides. In this approach, N-protected 2-pyrroline was coupled to 5-iodouracyl via a palladium(0)-mediated reaction. Numerous attempts were made and the most successful conditions (Pd(OAc)z,NBu3, AsPh3, DMF) offered the product in 58% yield. The Heck-coupled product was then deprotected, reduced, alkylated and selectively protected to offer the amidites (44a,b) following standard cyanoethyl chlorophosphoramidite treatment .34 The phosphoramidite derivative of a modified nucleoside containing an adenine and a 6-membered azasugar (45) has been synthesised from N-benzhydryl-ldeoxynojirimycin and nucleophilic displacement of a mesylate by benzoylated adenine. Oligonucleotides incorporating (45) exhibited strong hybridization with RNA depending on the location and number of incorporations within the ~equence.3~

NHBz

pi," (42) a R = CH2CH2Me (42) b R = Me2CHCH2

Pll," (43) a R = CH2CH2Me (43) b R = Me2CHCH2

? DMTO

CN (44) a R = H (44) b R = M e MTrO,

The cyclohexene ring, known to be less rigid than the cyclohexane ring, displays flexibility and conformation similar to those of a furanose ring. This

5: Nucleic Acids and Nucleotides; Mononucleotides

173

structural backbone has therefore been integrated in the new nucleic acid structure (46). An evaluation of the stability of DNA/RNA hybrids formed with the DNA sequences incorporating (46) was reported. The oligodeoxynucleotides incorporating (46) were found to be stable against degradation in serum while analogue-DNA/RNA hybrids were shown to activate E . coEi RNase H, resulting in cleavage of the RNA The synthesis of a nucleotide-like phosphoramidite building block in which the nucleic base has been replaced by a tert-butyldimethylsilyl-protected styrene glycol (47) has been described. After its incorporation in an oligonucleotide by automated synthesis, the terminal alcohol has been oxidized with NaI04 after fluoride deprotection. A similar phosphoramidate in which the nucleic base has been replaced by an alkyl diol(48) has been incorporated in an oligonucleotide and further conjugated with biotin after oxidation to the aldehydic functionalOTBDMS

DMTO

CN F3C”N’

I

Further modifications to the nucleic base of oligonucleotide building blocks have been described. Spermine-containing oligodeoxynucleotides have been prepared from the trifluoroacetylated phosphoramidite derivative of 2-(4,9,13triazatridecyl)-2’-deoxyguanosine(49). The stability of the hybridisation duplexes increased with the increased content of spermine residues and this stability was neither sequence nor position-dependent.” The novel modified thymidine monomer (50)has been synthesised to facilitate the efficient incorporation of reporter groups into oligonucleotides at specific

174

Organophosphorus Chemistry

sites. The Fmoc-protecting group could be removed during or after solid-phase oligonucleotide synthesis to offer the free primary hydroxyl group and allowed to react with any chosen phosphoramidites. The monomer (50)was prepared from 5’-0-(4,4-dimethoxy)trityl-5-iodo-2’-deoxyuridine which had been treated with propargylamine under Sonagashira conditions (CuI, 12, Pd(PPh3)4,Et3N, DMF) without the need for prior protection of the amine. Subsequent treatment with succinic anhydride, followed by addition of 7-O-Fmoc-heptanolamine, offered the nucleoside precursor which was phosphitylated using 2-0-cyanoethyl-N,N-diisopropyl chlorophosphine in the presence of DIPEA to yield (50).39 The synthesis of a novel bis-amino-modified thymidine monomer (51) for use in DNA triplex stabilization has also been reported. This analogue contained a 5-aminopropargyl modification on the pyrimidine ring and an aminoethoxy group at the 2’-position. The presence of the two amino groups on the same nucleoside enhanced triplex stability. In the synthesis of (5 l),the 2’-aminoethoxy group was introduced on the sugar prior to the introduction of the 5-iodouracyl moiety, which was accomplished under Vorbruggen conditions. The resulting 3’,5’-0-acetyl-2’-aminoethoxy-2’-deoxy-5-iodouridine was then coupled to N trifluoroacetylpropargylamine using palladium(0) in high yield. After removal of the acetyl group, conventional phosphitylation of the 3’-hydroxy group using 2-cyanoethoxy (N,N-diisopropy1amino)chlorophosphine afforded the phosphoramidite (5 l).40 Two novel phosphoramidite derivatives of 2’-deoxynucleosidesincorporating a pyranose-modified nucleic base have been synthesised and incorporated into short DNA sequences. The galactose-modified deoxyuridine phosphoramidite (52) was synthesised via a Heck reaction between 3’,5’-0,0-bis(tert-butyldimethylsilyl)-5-iodo-2’-deoxyuridine and 2,3,4,6-tetraacetyl-1-(6-hex-1-ynyl) galacto-pyranoside. Subsequent deprotection, 5’-0-tritylation and treatment with 2-O-cyanoethyl-N,N-diisopropyl chlorophosphine in the presence of DIPEA offered (52)which was used for solid-phase synthesis of a new type of oligo DNA-galactose onj jug ate.^^ As part of his on-going programme to study the biosynthesis and biological function of glucosylated DNA, van Boom reported the synthesis of the phosphoramidite building blocks (53) and (54),derivatives of cytidine, and their incorporation into oligodeoxynucleotides. Compound (53) was prepared from the suitably protected thymidine, which was radically brominated and subsequently treated with CsAc in DMF to afford the fully protected thymidine derivative. Treatment with triazole and POC13, followed by removal of the triazole, benzoylation and selective protection offered the modified 2’deoxycytidine, precursor to (53). Compound (54)was prepared in a similar fashion from a sugar-uracyl Hunziker described the synthesis of aromatic analogues of (54),uracil derivative (55) and cytidine derivative (56), and their incorporation into oligodeoxynucleotides. To avoid the cumbersome hydroxymethylation of 2’deoxyuridine, uracil was hydroxymethylated with paraformaldehyde under basic conditions and the resulting alcohol was benzylated. The modified nuc-

5: Nucleic Acids and Nucleotides; Mononucleotides

175

FmocO.

O , Ac

I

?'

CN

.

P-NPr'2

(52)

leobase was then treated under Vorbruggen conditions with 1,2,3,5-tetra-Oacetyl-D-ribose. After deacetylation and selective silylation of the 3',5'-hydroxyl groups, the 2'-OH was removed via Barton-McCombie reduction and further conversion into the deoxycytidine derivative was accomplished with triazole and POcl3. Subsequent deprotection of these two base-modified nucleosides and selective phosphitylation offered (55) and (56).43 The syntheses of six different ribonucleoside phosphoramidites with fluorobenzenes or fluorobenzimidazoles as nucleobase analogues and of one inosine analogue have been described. Lithiation of the required bromoarene with BuLi was followed by its addition to 2,3,5-tri-O-benzyl-~-ribono1,4-lactone to yield an intermediate lactol which was directly dehydroxylated with triethylsilane and BF3-OEt2 to afford stereoselectively the respective precursors to (57a-f).44 Three parallel strategies have been developed to access oligodeoxynucleotides

176

Organophosphorus Chemistry

HO

Ho\

l

I

o, P-NPr‘2

CN

P-NPr‘2

i

CN

(53)

(54) 0

I

0,P-NPr‘2

i

NHBz

(56) R =

CN

incorporating modified nucleosides for which the nucleobase was converted into a 4-guanidino-2-pyridinone. The first approach used the 4-triazolyl-2-pyri-dinone-nucleoside 3’-H-phosphonate (58), which could be transformed into the desired guanidine derivative in a single step using KIC03after its incorporation in the oligonucleotide and before the final deprotection and cleavage of the oligonucleotide from the resin. In the two other strategies, the guanidine-derivatives (59) and (60a-d) were used as synthons in the oligonucleotide assembly. The main differences between these two approaches were the protection of the guanidine group as either a benzoylamide or a methylamine and the nature of the precursors to the internucleoside phosphate linkage, a 3’-phosphoramidite or a 3’-Hphosphonate derivative, re~pectively.4~ The functionalisation at the N1-position of 2’-deoxy-pseudouridine by Michael addition of methyl acrylate offered access to the phosphoramidites (61). The precursor to (61) was also functionalised as an amine derivative, which was transformed into the fluorescein-labelled phosphoramidites (62a-b). Fluorescent oligonucleotides were synthesised either from these latter building blocks or by post-synthetic modifications of oligomers containing the 2’-deoxypseudouridine- 1-propanoate The synthesis of nitropiperonyl2’-deoxyriboside phosphoramidite (63) and its incorporation into an oligodeoxynucleotide has been described. This C-nucleoside analogue combined the attributes of two recent significant oligonucleotide interests, the design of universal/non hydrogen-bonding base analogues and the ability to photochemically cleave DNA-backbone. Oligonucleotides incorporating such modified nucleosides could serve as light-based DNA scissors!’ A mechanism, based on the well precedented nitrobenzyl photochemistry, has been

177

5: Nucleic Acids and Nucleotides; Mononucleotides

H

O Y N Y

NvNR’

?

H-P=O I

OH-N(C2H5)3 (60) a R’ = R2 = R3 = H (60) b R’ = Me, R2 = R3 = H (60) c R’ = H R2 = R3 = Me (60) d R’ = R2 = Me, R3 = H

proposed to explain the photochemical cleavage of oligonucleotides containing (63), yielding the 3’-phosphate and 5’-phosphate cleaved residues. An alternative DNA base pair has been reported for the novel base-pairing mode assisted by borate formation observed in oligonucleotides incorporating catechol-bearing nucleosides. The phosphate derivative of catechol-bearing nucleoside (64a) was prepared by the triphosphate ester approach using p-chlorophenyl2-cyanoethyl chlorophosphate and N-methylimidazole, while the phosphoramidite (64b) was prepared using the standard methodology that employs 2-cyanoethyl diisopropyl-chlorophosphoramidite and diisopropylethylamine?’ The synthesis of the phosphoramidites (65a-c) has been described. They have been designed to be incorporated into oligonucleotides so as to create analogues with a nucleobase-including backb0ne.4~The purine derivatives have been prepared from C(8)-hydroxymethylation of an appropriately protected 2deoxyadenosine by deprotonation with LDA and treatment with DMF followed by reduction with NaBH4. Selective protection and deprotection offered suitable

178

Organophosphorus Chemistry

‘0

I

P-NPr‘2

.

P-NPr‘2

0’

0’

(611

LN

CN

(62) a n = 0 (62) b n = 1

OAc

/

DMTO

\

P -NPrI2 CEO/ (63)

RO (64) a R = (CENO)(pCI-Ph0)OPO (64) b R = (Pt‘2N)(CENO)P

precursors to (65b,c) which were then submitted to standard phosphitylation conditions. Similarly, the pyrimidine phosphoramidite derivative (65a) was prepared from 2’-deoxyuridine,which after silylation was hydroxymethylated in the presence of LDA, DMF and NaBH4, and subsequently phosphitylated using standard conditions after suitable protection. It has been demonstrated that it is possible to insert paramagnetic probes into nucleic acids in a site- and type-specific manner. To this end, the 2,2,6,6-tetramethyl- 1-piperidinyloxy free radical-labelled phosphoramidites of 2-amino-2’deoxyadenosine, 2’-deoxyadenosine, 2’-deoxycytosine and 5-methyl-2’deoxycytosine have been prepared and used for the automatic synthesis of mono-labeled oligodeoxynucleotides which proved active by EPR. The phosphoramidites carry a nitroxide spin-label directly linked to the exocyclic amino group. Starting from appropriately protected 2’-deoxyguanosine or 2’deoxyinosine, the precursors to (66a) and (66b) were obtained by nucleophilic

5: Nucleic Acids and Nucleotides; Mononucleotides

I

179

I

.

P-NPrI2

P-NPr'2

O/

i

CN

CN

(65) b R=DMT, R ' = B z ( 6 5 ) ~R = B z , R'=DMT

(65) a

DMToP 0

0

P-NPr'2

0'

?

CN CN

(66)a R=NHCOPi (66) b R = H

-NHBU'

% : "7

0

DMTo-N

(66) c R = H (66) d R = Me

I

P-NPr'2

P-NPr'2

O/ I CN

NMe2

O/

(67)

substitution of the respective 6-0-sulfonylated purines with tempamine. Compounds (66a) and (66b) were obtained using standard phosphitylation methods. The pyrimidine derivatives (66c) and (66d) were obtained following a similar procedure?' Saito reported the synthesis of the 3'-phosphoramidite of the "-modified 2'-deoxyguanosine (67), this acting as a strong electron-donating nucleobase, since the nucleobase exhibited a smaller oxidation potential than guanine and 7-deaza-guanine." Another phosphoramidite derivative of a guanine-modified nucleoside (68) has been reported in which the sugar moiety has been attached to the 8-position of 7-deazaguanine. Glycosylation of the unprotected 7-deaza-guanine base with

180

Organophosphorus Chemistry

1-0-acetyl-2,3,5-0-benzoyl-b,d-ribofuranose in nitromethane in the presence of SnC14 yielded the benzoyl-protected C8-ribonucleoside precursor to (68). Removal of the esters and selective protection of the 3’,5’-hydroxyls with a bis-silyl group, were followed by dehydroxylation of the 2’-OH using the Barton-McCombie conditions. Subsequent desilylation, selective protection and phosphitylation using the standard conditions offered (68).52 The synthetic procedure developed to introduce oxidative and reductive probes at the C8 position of adenosine and offer the phosphoramidites (69) and (70) has been described. To enable the efficient introduction of such groups, N-benzoyl-5’-O-dimethoxytrityl2’-deoxy-2-bromoadenosine was coupled with alkynylanthraquinone and alkynylphenothiazine derivatives using Pd(PPh& and CuI in DMF. Subsequent phosphitylation at low temperature offered the oxidative probe-containing phosphoramidite (69) and the reductive probe-containing phosphoramidite (70), which were both to be kept under inert atmosphere c o n d i t i o n ~ . ~ ~

5$

0

aSx) N

/

I

0‘ I

I

P-NPr‘Z

.

P-NPr‘2

0’

i

CN

(69)

CN

(70)

An improved protocol for the efficient conversion of inosine into its 3’phosphoramidite synthons for solid-phase oligonucleotide synthesis has been described. This procedure, which almost doubled the literature reported overall yields starting from inosine, was optimized for scale-up to multigram quantities. The portion-wise addition of DMT-Cl to a solution of inosine in DMSO and pyridine prevented multiple-site protections, which was also reported to occur in the presence of DMAP or triethylamine. Treatment with TBDMSCl in the presence of silver nitrate and pyridine in THF offered a mixture of the 2’- and 3’-substituted nucleosides from which the 5’-O-dimethoxytrityl-2’-O-tert-butyldimethylsilyl-protected inosine was crystallized in ethyl acetate. The mother liquor was enriched with the 2‘-isomer by treatment with triethylamine in methanol. Standard conditions for phosphitylation were then applied to yield

181

5: Nucleic Acids and Nucleotides; Mononucleotides

the phosphoramidite (71) in 54% overall yield from i n ~ s i n eNovel . ~ ~ fluoridelabile nucleobase-protecting groups developed for the synthesis of 3'-(2')-0aminoacylated RNA sequences have been described. The preparation of the phosphoramidites (72a-d) of all four nucleobases incorporating the 2'-0[(triisopropylsilyl)oxy]methyl sugar protecting group and the N-{ { 2-[(triisopropylsilyl)oxy]benzyl}oxy}carbonyl base-protecting group was d e ~ c r i b e d . ~ ~ The synthesis and oligonucleotide-incorporation of the phosphoramidite (73) in which (R*,S*)-5-hydroxyhydantoinhas replaced the nucleic base has been reported. Compound (73) was prepared to assess the mutagenic features of l-[2-deoxy-~-~-erythro-pentolfuranosyl]-5-hydroxyhydanto~n, the major oxidation product of 2'-deoxycytidine upon exposure to OH-radicals, excited photosensitisers or ozone.56 0

VNH

H

0

OTBDMS

I

P-NPr'2

0'

i

i

CN

CN

CN

(71)

CN

(72) b

(72) a

(72) c

LevoHo

DMToTNTNH 0 I

.

P-NPr'2

0'

0'

i

CN

(72) d

CN

(73)

Transformations of nucleoside H-phosphonate monoesters into their corresponding H-phosphonothioate and H-phosphonodithioate derivatives and the nature of the side-reactions that may accompany these processes have been

Organophosphorus Chemistry

182

investigated using 31PNMR spectroscopy. The development of efficient methods for the preparation of such nucleoside derivatives has been based on a proposed mechanism deduced from these spectroscopic investigations. The H-phosphonothioates (74a-e) were obtained in high yields by reacting the in situ generated nucleoside aryl H-phosphonates with hexamethyldisilathiane while the H-phosphonodithioates (75a-e) were either prepared by treating the H phosphonate nucleoside monoesters with diphenylchlorophosphate in the presence of hydrogen sulfide or by sulfohydrolysis of the in situ generated nucleoside diary1 phosphite. All these transformations could be carried out as one-pot

reaction^.^^ Stec extended his work on P-chiral phosphorothioates and described the synthesis of P-chiral, isotopomeric deoxyribonucleoside-phosphorothioatesand -phosphates (76a-p) labelled with an oxygen isotope. To obtain stereodefined PS”0-oligos, the 5’-O-DMT-nucleoside-3’-O-(2-thio-‘spiro’-4,4-pentamethylene- 1,3,2-[018]oxathiaphospholaneswere synthesised by phosphitylation of the correct protected nucleoside with chirally pure [018]oxathiaphospholane, with subsequent sulfurisation. The resulting oxadithiaphospholanes were separated by chromatography into diastereomerically pure forms and individually treated with SeOz to yield the oxathiaphospholanes?* Cook reported the syntheses of phosphonamidite and H-phosphonates derivatives of 3’Cmethylene modified thymidines (77a-e), 3’-C-methylene 5methyl-N-pyrrolidine-modified cytosine (78) and 3’Cmethylene 5-methyl modified uridine (79) having methoxy, fluoro, hydrogen and methoxyethoxy substituents at the 2’-position~.~~ The H-phosphonates were synthesised from the corresponding key intermediate 3’-C-iodomethyl nucleosides through an

0’ I

S=P-H (74) a B = T, (74) b B = A, ( 7 4 ) ~B = C , (74)d B = G , (74)e B = U ,

I XR = H, X = 0 R = H, X = 0 R = H, X = O R=H, X = O R=OTBDMS, X = O

(76) a 6 = T, X = S, *R (76) b B = T , X = 0, *R (76) c B = T, X = S, *S (76) d 6 = T X = 0, ‘S (76) e B = X = S , ‘R (76)f B=BZC, X = O , *R (76) g B = %, X = S, ‘ S (76) h B = BzC, X = 0, *S

‘R

S=P-H I

(75) a B = T , (75) b B = A , ( 7 5 ) ~B = C , (75)d B = G , (75) e B = U,

XR = H, X = S R = H, X = S R = H, X = S R=H, X=S R = OTBDMS, X = S

(76)i B = B Z A , X = S , *R (76)j B = BzA, X = 0, ‘R (76) k B = BzA, X = S, *S (76)l B = B Z A X = O , *S (76) m B = te’G, X = S, ‘R (76) n B = tBuG, X = 0, *R (76) o B = tBuG, X = S, *S (76) p B = tBuG, X = 0, ‘S

183

5: Nucleic Acids and Nucleotides: Mononucleotides

O=P-H I

0- +HNEt3 (77) a B = T, R = OMe, PG = DMT (77) b B = T, R = F, PG = DMT (77) c B = T , R = OMe, PG = MMT (77) d B = T, R = F, PG = DMT (77) e B = T R = OCH2CH20Me, PG = DMT R = OMe, PG = MMT (78) B = MeCPYRo, (79) B = T , R = H , PG=DMT

Arbuzov reaction with HP(OSiMe& as the reagent and were converted into the corresponding 3'-methylene modified phosphonamidates using Ph3PC12 in p yridine. 2.1.2 Polynucleoside Phosphate Derivatives. A convenient method for the oxidation of nucleoside phosphite triesters into phosphate triesters under non-basic and non-aqueous conditions using commercially available ethyl(methy1)dioxirane has been reported (Scheme 5).60This oxidation method could be used with both N-protected and N-unprotected nucleosides (8Oa-m), and was efficiently applied to nucleotide synthesis both in solution phase and on solid support.

DM'"

P

O\ RO-P .,

% CHPCI,

,w *

O\ RO-P=O \

R'O (80) a B = Ade R = NCCH2CH2, R' = TBDMS (80) b B = AdeAoc, R = NCCH2CH2, R' = AOC (80) c B = AdeBz, R = NCCH2CH2, R' = TBDMS (80) d B = Cyt R = NCCH2CH2, R' = TBDMS (80) e B = Cyt" R = NCCH2CH2, R' = TBDMS (80) f B = CytAo'. R = NCCH2CH2, R' = AOC (80) g B = CyfEz, R = NCCH2CH2, R' = TBDMS (80) h B = Gua, R = NCCH2CH2, R' = TBDMS (80) i B = GuaA"**OC,R = NCCH2CH2, R' = AOC (80) j B = Guadm', R = NCCH2CH2, R' = TBDMS (80) k B = GuaIBU,R = NCCH2CH2, R' = TBDMS (80) I B = Thy, R = CHpzCHCH2, R' = AOC (80) m B = Thy, R = NCCH2CH2, R' = TBDMS Scheme 5

To explore whether incorporation of native DNA structural elements such as the sugar-phosphate backbone into synthetic binders could be employed to dictate the formation of defined complexes such as helicates, the dinucleoside mimic (81)has been synthesised. In (81),the nucleic base has been replaced by the metal-binding ligand 2,2'-bipyridine, linked to the sugar by a methylene bridge

184

Organophosphorus Chemistry

to allow for a more relaxed structure and dimensions similar to the DNA double helix. Compound (81) was prepared using the standard phosphoramidite methodology in which the coupling was catalysed by 1-H-tetrazole, and the resulting phosphine oxidized with an iodine-water-pyridine mixture. In the presence of Cu2+,Pd2+ and Ag+, double stranded structures were detected as well as single stranded assemblies.61 A facile synthetic method for the preparation of a phosphorothioate dimer building block has been described. Dinucleoside phosphite triester intermediates were obtained in the one-pot coupling reaction between a protected nucleoside bearing a free 5’-OH and a protected nucleoside bearing a free 3’-OH in the presence of phosphorus trichloride and 1,2,4-triazole.These intermediates were easily sulfurised to afford (82a-h) in good yields (Scheme 6).62 Stec applied the above-described oxathiaphospholane approach to synthesise stereoselectively the phosphorothioates of the locked nucleic acids (84a) and (84b) from (83a) and (83b), respectively (Scheme 7).63The oxathiaphospholane ring opening condensation reaction proceeded in acetonitrile in high yield and with 96% stereoselectivity. One of the two diastereomers thus prepared was found to be readily digested by snake venom phosphodiesterase, an enzyme known to be an Rp-specific nuclease. However, neither diastereoisomer was hydrolysed by nuclease P1, an enzyme known to preferentially hydrolyse phosphorothioate linkages of Sp-configuration.

-0 --‘P =0 \ 0

l a PCI,, 1,2,4-Triazole, Nmethyl-morpholine, THF, 0 “C l b 0°C

DMToy

Ho=B’

T02

DMTO

L

HO

2\13

1C NCCH&H,OH, 0 “C 2a S,, pyridine 2b AcOH, HzNNH2.HzO

Scheme 6

~

0 CENO+~ 0’

eB’

HO (82) a B’ = B2 = T (82) b B’ = CBZ, B2 = T (82) c B’ = ABz, B2 = T (82) d B’ = GiBu, B2 = T (82) e B’ = T, B2 = CBz (82)f 6’ = T , B 2 = ABz (82) g B’ = T, B2 = GiBu (82) h B’ = ABz, B2 = CBZ

185

5: Nucleic Acids and Nucleotides; Mononucleotides

To avoid the P-elimination-promoted rearrangements observed when the promising indolooxazaphosphorine approach was applied to solid phase synthesis of PS-oligos, Just developed a set of chiral auxiliaries, derived from D- and L-tryptophan, that could be removed by direct displacement of the primary H

o

DMTo3T s=x-M HO

t

1 DBUNeCN 2 Deprotection

I

p

d

Pc HO

Scheme 7

-i)l/oH T

(84)a ' S (84)b *R

t

Conc. NH, EtOH

0

o=p*-s-

(83)a *S (83)b *R

0

p

H2N 0

/

HO/

O

Scheme 8

s,

OTy I

Pri2N

X (86)

DMTo-P DMT 9 MeSe-P=X 1

(v

DMTO

(89) X = O (90) x

=s

AgF or Et3NHF

. )

F-P=X

1

(v

DMTO

(87)X = 0 (88)X = S

186

Organophosphorus Chemistry

alcohol (Scheme 8).64The chiral ligand reacted with PC13 and triethylamine to yield a cyclic chlorophosphinamidite, which was then treated with 5’-O-tertbutyldimethylsilyl-thymidine. The resulting cyclic phosphoramidite was a single isomer and stable enough to be purified by silica gel chromatography. The thymidine cyclic phosphoramidite was then treated with 3’-O-tert-butyldimethylsilyl-thymidine in the presence of DBU, followed by Beaucage’s reagent, to afford the chirally pure dithymidine phosphorothioate (85) after stereospecific removal of the protecting groups. The same sequence was applied successfully to the solid phase synthesis of both enantiomerically pure dithymidine phosphorothioates. Just also reported a study on the diastereoselective synthesis of dithymidine phosphorothioates (86) through a D-xylose-derived chiral auxiliary, l,2-di-O-isopropylidene-3-C-cyanoethyl-5-deoxy-5-isopropyl-amino- Dxylof~ranose.~~ It was later reported that the reaction proceeded with highest diastereoselectivity when 2-mesityl-4,5-dicyanoimidazole, instead of 2-bromo4,5-dicyanoimidazole, was used as catalyst and the coupling reaction was carried out at low temperature.66 The sugar auxiliary was easily removed with either concentrated ammonia or 3% TFA in aqueous solution. It was reported that studies were underway to establish the mechanism for the coupling, in particular whether the azole served only as a proton source to protonate the nucleoside phosphoramidite (inversion of configuration) or whether it acted as a nucleophile, giving rise to the formation of an azolide intermediate (retention of configuration). The syntheses of dithymidylyl-3’,5’-phosphorofluoridate and phosphorothiofluoridate (87) and (88) have been described. These involved the fluorinolysis of the P-Se bond in the bis-dimethoxytrityl selenomethyl esters (89) and (90). Compounds (87) and (88) were reported to be hydrolytically unstable, with no inhibitory activity on the snake venom and spleen phosphodiesterases and alkaline phosphatases. Finally, neither was considered as a highly toxic dinucleotide.67 The synthesis of vinylphosphonate-linked nucleotide dimer (93) has been achieved using an olefin-metathesis reaction step between the vinylphosphonate (91) and the 5’-alkene derivative of thymidine (92). The second-generation Grubb’s catalyst was reported to be the superior catalyst for this conversion in which no vinyl phosphonate homo-coupling was detected.68 Simple alkyl phosphonate diesters bearing a 2-pyridyl moiety are known to display a wide range of biological activities as well as having numerous technological applications. This functionality has now been incorporated in phosphonate nucleotide dimers (94). The bis([4,4‘-dimethoxy]trityl)-dithymidine H-phosphonates afforded (94) quantitatively upon treatment with N methoxypyridinium tosylate in the presence of DBU. The reaction was rapid and proceeded ~tereospecifically.6~ Wang reported the synthesis of dinucleosides, dinucleotides and oligodeoxynucleotides containing 3’-amino-3’-deoxy-3’-N,S’-(R)-Cethylenethymidine. The bicyclothymidine was prepared from 3’-azido-3’deoxythymidine and condensed with 5’-O-(H-phosphonyl)thymidinein the presence of triethylamine and 5’-O-(p-nitrophenoxycarbonyl)thymidine derivatives

187

5: Nucleic Acids and Nucleotides; Mononucleotides H O Y N Y O TBDMSO

0

TBDMSO

I

Grubb’sCatalyst II

TBDPSO

0 I

TBDPSO

(92)

(93)

DMTo DM DMToT o!po O=P-0

w

Po

d

d

A/

P

DMTO (94)

?P-OCH2CH2CN

PS2N (95) R = Me (96) R = C E N

?

O w P -0CH2CH2CN Pt2N‘

(97)

to give the dinucleotides (95) and (96) and dinucleoside (97). Duplexes of both DNA and RNA formed from oligonucleotides incorporating these locked C3’endo sugar puckered dimers were found to be destabilised to varied degree^.^' The methylene(methylimin0) (MMI) modification in which a methylene group replaces the 3‘-oxygen atom and a N-methylhydroxamine replaces the phosphodiester group in dinucleotide building blocks has been shown to be a promising modification of the backbone of antisense oligonucleotides. A new approach and the syntheses of for the syntheses of 3’-deoxy-3’-C-formyl-ribonucleosides alternating methylene(methylimin0) linked phosphodiester backbone-containing oligonucleotides has been reported. The 3’-phosphoramidite derivative of the methylene(methy1imino) linked dinucleoside was synthesised from a 3-Cdithiane-1,2-0-diacetylpentofuranose, present in the ribo-conformation. This intermediate was then converted into the corresponding nucleoside derivative in the presence of silylated thymine via Vorbruggen coupling. Subsequent deprotections offered the 3’-aldehydic thymidine derivative, which was reductively coupled to 2’-0-methyl-5’-O-methylamino-5-methyluridine to yield the riboMMI-dimer that was further converted into the phosphoramidite (98) after appropriate p r ~ t e c t i o n . ~ ~ The synthesis and characterization of a tetranucleotide analogue containing

188

Organophosphorus Chemistry

alternating phosphonate-amide backbone linkages has been reported. The tetranucleotide 5’-dC-phosphonate-T-amide-T-phosphonate-dC(III) (99) was prepared from the peptide-coupling of two 5’-dC-phosphonate-T units, one possessing a thymine linked to the terminal amine and the other a thymine linked to the terminal carboxylic acid. The phosphonate linkage was formed by coupling of a peptidyl phosphonate containing the nucleobase to the 4-benzoyl-2’-deoxy-5’-0TBDMS-cytosine in the presence of adamantanecarbonyl The replacement of the two backbone oxygen atoms of the phosphodiester linkage of DNA with carbon and nitrogen in the form of a phosphonamidate ester linkage has been described. Both regioisomers, (100) and (101),have been synthesised and characterised, and each respective diastereoisomer has been separated prior to oligonucleotide incorporation. The 5’-homologated H-phosphinate precursors were obtained from a boron trifluoride-catalysed oxetane ring-opening with a phosphinate-stabilised carbanion. The 3’-homologated H -

NMe

d

Yr

Pr’,N, P - 0 NCV-6

OMe

(98) T

‘“q0 C

T

C

0-

(99)

DMTo-w DMT O=P-0 HN

b 0 \

P-OCH2CH2CN Pri2N’ (100) a *R, R = Me (100) b *S, R = Me (100) c *R, R = Et (100) d *S, R = Et

HN\ O=P-0

b

O; P - OCH2CH2CN Pri2N‘ (101)a *R (101) b *S

189

5: Nucleic Acids and Nucleotides; Mononucleotides

phosphinates were made available from the 3’-formylated thymidine, which, after reduction and iodination of the alcohol with methyltriphenoxyphosphonium iodide, reacted with the potassium salt of a protected hypophosphorous acid to give the alkyl3’-H-phosphinates. Formation of the dimers (100) and (101) was achieved upon bis(trimethylsily1)-trifluoroacetamide-catalysedreaction of the H-phosphinates with the appropriate azidonucle~sides.~~ 2.1.3 Mononucleoside Phosphate Sugars. The syntheses of novel base- and sugarmodified cytidine monophosphate N-acetylneuraminic acid (CMP-Neu5Ac) analogues (102a-i) have been reported. The 2-phosphitylated sialyl sugar derivatives were reacted with acyl-protected riboside 5-phosphorous acids without addition of a catalyst and yielded, under phosphite/phosphate exchange conditions, the corresponding P-configured sialyl riboside monophosphate derivatives. Subsequent mild deprotections offered the CMP-NEU5Ac derivatives (102a-i). The modifications on the neuraminic residue, though not the modifications of the base, were tolerated by rat liver ~t(2-6)-sialyl-transferase?~ The synthetic utilities of sialyltransferases as alternative methods to sialylate oligosaccharide and glycoconjugates have been further explored by Halcomb who described the synthesis of a novel anomeric sulfur analogue of CMP-sialic acid (103). The key step in the synthesis of this novel CMP-sialic acid was a tetrazole-promoted coupling of a cytidine-5’-phosphoramidite with a glycosyl thiol of a protected sialic acid. The rate of solvolysis of (103) in aqueous buffer was reported to be 50-fold slower than that of CMP-sialic acid. Thioester (103) was a substrate for the transferase with a K , three-fold higher than the K , of the true substrate, but a K,,, two orders of magnitude lower compared to that of CMP-sialic

Hd

HO (102) a R’ = NHAc, R = OMe (102) b R’ = NHAc, R

=“Do’ t

(102) h R 2 = H, R3 = Me (102) i R2 = (HO)*PO-, R3 = H

(102) c R’ = NH3+, R = Cyt (102) d R’ = C~HSCONH-, R = Cyt (102) e R’ = +H3NCH2CONH-, R = Cyt (102) f R’ = EtOCONH-, R = Cyt ( 1 0 2 ) ~R’=OH, ~ R=Cyt

n

0

HO

AcNH

“2-

HO

HO

OH

Organophosphorus Chemistry

190

2.2 Nucleoside Cyclic Phosphates. - The previously reported conformationally rigid 5'-cyclouridylic acid derivatives (104a-d) have been shown to fix They were also incorporated torsion angles in RNA duplexes without into dimer building blocks (105a-d) of established chirality at the phosphate triester position for RNA i n c ~ r p o r a t i o n .The ~ ~ 5'-O-dimethoxytrityl-2'-0methyluridine 3'-phosphorodiamidite, prepared from the uridine derivative and treatment with bis(diisopropylamino)chlorophosphine,was condensed with 3'O-acetyl-5-[2-(hydroxypropyl)]-2'-O-methyluridineto give the phosphate triesters after oxidation with tBuOOH (105a,b) and the phosphorothioate triesters after oxidation with elemental sulfur (105c,d). Each diastereomer (104a-d) and (105a-d) was purified by silica gel chromatography and the respective 3'-phosphoramidite derivatives were prepared for RNA incorporation using solid support chemistry. The syntheses of thymidine cyclic phosphotriester (106) and that of a novel dithymidine derivative incorporating a conformationally constrained phosphotriester linkage (107) have been reported. In these syntheses, a ring-closing metathesis reaction using the first and second-generation Grubb's catalysts and the appropriate allyl-substituted phosphate triester was a ~ h i e v e d . ~ " ~ ~

HO'

HO' (104) a (104) b (104) c (104) d

'OR R = H, 'R R = H, 'S R = Me, 'R

HO (105) a (105) b (105) c (105) d

R = Me, 'S

OMe X = 0 ,'R X = 0, ' S X = S, 'R X = S, *S

HO (107)

Three novel analogues of cyclic-AMP have been reported. The cyclic phosphinate ester (108) was prepared by using a double Arbuzov-type condensation of bis-trimethylsilyl phosphinite with a dibromo-sugar, which was subsequently treated with SnC14and adenine after appropriate acetylation.*' Shaw reported a general procedure for the preparation of cyclic

191

5: Nucleic Acids and Nucleotides; Mononucleotides

boranomonophosphates and its application to the first synthesis of a 3’,5’-cyclic boranomonophosphate adenosine. This method, which employs a phosphite approach and subsequent treatment with Me2S:BH3,offered the two diastereoisomers (109a,b) that could be separated by chromatography.8l The first boron-containing 2’,3’-cyclic phosphate uridine derivatives (110) were synthesised via cyclophosphorylation of 5’-0-dimethoxytrityl-uridine by diphenyl H-phosphonate. The resulting uridine 2’,3’-cyclic H-phosphonate was silylated and treated with DIPEA-BH3 followed by acid catalysed hydrolysis to yield (110).The two diastereoisomers (11Oa) and (110b)were separated by C18 reversed phase HPLC.82

?*

/,PLO OH 0 1 BH3(109) a *R (109) b *S

0 , p //

\

0 BH3(110) a ‘R (110) b *S

2.3 Nucleoside Pyrophosphates. - 2.3.1 Nucleoside Diphosphate Analogues. A large variety of esters with different nucleoside and alkyl moieties (11la-j) have been synthesised in small amounts using different combinations of nucleoside triphosphate, alcohols and snake venom pyrophosphatase. Potato tube pyrophosphatase was also reported as being a possible practical biocatalyst to synthesise such nucleotide pyrophosphate-0-alkyl esters, but using more stringent reaction requirements than that of the snake venom enzyme.83 A series of eight different non-hydrolysable G D P analogues (112a-h) has been used in an affinity study between the G-protein of the visual photoreceptor, transducin, and GDP. The imidodiphosphate derivative (112e) exhibited good affinity to transducin. This very important heterotrimeric G-protein was shown to be highly restrictive with regard to the structural nucleotide modifications at the pyrophosphate moiety, at the 3’-position of the ribose and at the N’ position of the purine.84 The synthesis and biological activity of the new acyclic heterodinucleo tide (113) that consists of both an antiherpetic (acyclovir) and an antiretroviral (2(phosphonomethoxy)propyl-adenine)drug linked by a pyrophosphate bridge were reported. The heterodinucleotide (113), prepared from the reaction of a morpholidate derivative of PMPA and the tributylammonium salt of acyclovir monophosphate in the presence of pyridine, behaved as a pro-drug in macrophages. Anti-HIV and anti-HSV activity of this compound were demonstrated in HIV- lBa-L and HSV- 1-infected macro phage^.^^ A novel extremely potent inhibitor of trypanosomal glyceraldehyde phosphate dehydrogenase has been reported. N6-Naphthalenemethyl-2’methoxybenzamido-P-NAD (114) was synthesised by selective phosphitylation of N6-naphthalenemethyl-2’-methoxybenzamido-adenosineusing bis(2-cyanoethoxy)(diisopropylamino)phosphine in the presence of 5-ethylthio-1H-tetrazole. The resulting phosphotriester was purified by silica chromatography

Organophosphorus Chemistry

192

NH2

0 -0,I I

HO (111) R

=a H

O

Y

-

, b C12CH-$,

OH

c CICH2-$,

,e'-eM

d HOCH,-$,

f Me-,'

OH

9 Mfe,

,h H 0 2 C y 3

H

O

T

'

I

OH

2-0,p'O

'NH,

OHH OH II

0

0

II

0 Ho

OH ( 1 1 2 ) f

n U

NH2

0

(112) R = a HO

0

0

0,

OH

0

OHH OH II

NH2

II

HO II

ll

0

0

OH

(112) h

after oxidation and deprotected to give the free acid. The adenosine monophosphate derivative was converted into the phosphoromorpholidate derivative and coupled to nicotinamide mononucleotide in the presence of MnClz in formamide. The NAD derivative (114) was purified by C18-reversed phase HPLC.86 The reaction of O-nucleosid-5'-yl-O-alkyl H-phosphonate diesters with Llysine methyl ester dihydrochlorides in the presence of triethylamine and tetrachloromethane produced the corresponding N*,N'-lysine linked 5',5'-dinucleotides (115a) in excellent yield. The N",N'-lysine linked 3',3'-dinucleotides (115b) were prepared starting from the O-nucleosid-3'-yl-O-alkyl H-phosphonate diesters. These novel molecules (115a) and (1 15b) could be considered as the

193

5: Nucleic Acids and Nucleotides; Mononucleotides 0

I

-P=O

Meo2cY-NH /

O=P-OPI-'

HN

I

OH

.

..Th

I

0

b HO

O Y T h Y OH T

h

y (115) a

HN

I

0 O=P-NH I bPl'

-C02Me (115) b

analogues of P1,Ps-di(nucleosid-5'-yl)-pentaphosphates in their inhibition of nucleotide k i n a ~ e . ~ ~ 2.3.2 Nucleoside Diphosphate Sugars. Recombinant enzymes occurring in the non-mevalonate isoprenoid pathway have been employed for the efficient onepot preparation of I3C- and I4C-labeled 4-diphosphocytidyl-2C-ethyl-~-erythritol(ll6) in millimole quantity.88 Liu reported the first chemical synthesis of uridine S-diphospho-P-~-arabinofuranose (117), a possible donor of L-arabinofuranose residue. Compound (117)underwent interconversion with UDP-P-L-arabinopyranose, the likely precursor of L-arabinofuranose in vivo, when incubated with UDP-galactopyranose mutase. This result provided insights into the biogenesis of L-arabinofuranose in plant sg9 Based on the recent re-evaluation of the substrate specificity of Salmonella

194

Organophosphorus Chemistry

HO'

'OH

(116)

OH

HO

OH

(117)

HO

0 I

OH

OH

(118)a B = T (118)b B = U

Ho

OH

( 1 1 8 ) ~B = T (118)d . . B=U

HO'

'OH

HO'

'OH

HO

OH

HO

0

0

II

HO

I

OH

OH

(118)e B = T (118)f B = U

HO

OH

(118)g B = T (118)h B = U

0

HO

(118)i B = T (118)j B = U

HO

OH

0

(118) k B = T (118)l B = U

HO

0 OH

OH

Ho

(118)m

HO

OH

0

OH OH

OH

OH

(118) n

HO

OH

195

5: Nucleic Acids and Nucleotides; Mononucleotides

enterica LT2 a-D-glucopyranosyl phosphate thymidylyltransferase that can con-

vert a wide array of a-D-hexopyranosyl phosphates into their corresponding UDP- and TDP-nucleotide sugars, Thorson reported a general chemoenzymatic method to rapidly generate novel sugar nucleotide diphosphates (118a-p). Rapid access to such activated sugars is of significance in providing substrate sets for developing in vitro glycosylation Another methodology to rapidly access a- and P-configurated UDP sugars (119a-f) that employed the direct reaction between sugar epoxides and uridine diphosphate has been described. The sugar epoxides were obtained from the appropriately protected glucals using DMDO in dichloromethane. The nucleo-

0 0

B

" o BnO

W

q

0

0

II .. n

OH

~

(1 19) e

BnO

OH

HO

OH

BnO

\

HO

OH

(119) f

HO HO HO OH

HO HO

OH

(120) a

HO

OH

HO

OH

0

0

OH

OH

(120) b

Ho'

'OH

Ho

OH

HO

HO HO

0 II

0

I

OH

(120) c

(120)d

HO

OH

(121)

HO

OH

OH

196

Organophosphorus Chemistry

side diphosphate in its free acid form was converted into its tetrabutylammonium salt, dispersed in dichloromethane and added to a solution of a glycosyl donor. The resulting UDP-sugars (119a-f) were purified by anion exchange chromatography and isolated as anomeric mixtures.” The two anomers of ADP-L-glycero- and D-glycero-D-manno-heptopyranose (120a-d) have been synthesised in order to establish the substrate specificities of bacterial heptosyltransferases. The monotriethylammonium salt of O-pentaacetyl a-heptosyl-1-phosphate was coupled to AMP-morpholidate in pyridine in 90% after purification by anion-exchange chromatography. The same treatment was carried out on the monotriethylammonium salt of 0-pentaacetyl P-heptosyl-1-phosphate. Subsequent deacetylation with MeOH/H20/Et3Nafforded (120a-d) in moderate to excellent yields.92The first chemical synthesis of uridine 5’-(2-acetamido-2,6-dideoxy-~-~-galactopyranosyl) diphosphate (121), the putative biological precursor to N-acetyl-L-fucosamine, has been reported. 3,4-di-0-acetyl-2-azido-2,6-dideoxy-~-~-galactopyranosyl dibenzyl phosphate, prepared from the product of the reaction between the corresponding a-glycosyl nitrate and caesium dibenzylphosphate, was hydrogenated and treated with uridine 5’-phosphoimidazolide in DMF. N-Acylation under mild conditions using N-acetoxysuccinimide and selective deacetylation offered (121)after purification on TSK HW-40 HPLC column.93

3

Nucleoside Polyphosphates

3.1 Nucleoside Pyrophosphates. - The synthesis of 8-aryl-3-p-~ribofuranosylimiazo[2,l-i]purine 5’-phosphates (122) from AMP or ATP has been described. To access these fluorescent nucleotide derivatives, a combination of Kornblum oxidation reaction and imidazole formation was employed. For this conversion, the appropriate adenosine phosphate, present in its free acid form, was treated with p-nitro-acetophenone in DMSO in the presence of DBU.94 Treatment of a 5-(chloroethyl)-4-(triazole-1-yl)pyrimidine-nucleoside with benzylhydrazine offered the 6,6-bicyclic pyrimido-pyradazin-7-one, the precursor to (123). This triphosphate was used as a substrate for DNA polymerase~.”’ The efficient synthesis of 3’-deoxy-5’-0-(4,4’-dimethoxytrityl)-3’-[(2-methyl-lt hiopro pyl)amino] th ymidine ( 124) and 3'-deox y - 5’-0-(4,4’-dimet h oxytrit y1)-3’[{ 6-{ [(9H-fluoren-9-ylmethoxy)carbonyl]amino}1-thiohexyl}] thymidine (125a) from a 3’-amido-tethered nucleoside precursor by regioselective thionation using Lawesson’s reagent has been reported. Compound (125a) was further modified by the removal of the Fmoc-protecting group (125b) and derivatised with fluorescein to yield (125c). These modified nucleoside 5’-triphosphates were substrates for the Tap DNA polymerase; however, specific incorporation did not occur.96 8-0x0-dGTP (126), generated by the oxidation of 2’-deoxy-guanosine during normal cellular metabolism, is believed to play a significant role in aging and cancer. A high yielding chemical synthesis of (126) has been achieved, starting

197

5: Nucleic Acids and Nucleotides; Mononucleotides NO2

N HO

’

d

OH

(122) a X = P03Na2 (122) b X = P30gNa4

HO

OH

(122) c X = P03Na2 (122) d X = P309Na4

(124)

b09P3?

RAN

Why H

(125) a R = F ~ O C N H ( C H ~ ) ~ (125) b R = H2N(CH2)5

S

(125) c

from 8-benzyloxy-2’-deoxy-guanosine. The triphosphate ester was prepared by reacting 8-oxo-2’-deoxyguanosine with P o c l 3 in triethylphosphate followed by simultaneous addition of tri-n-butylamine and bis-tri-n-butylammonium pyroph~sphate.~’ The synthesis and enzymatic DNA-incorporation of the 5’-triphosphates of 2’-deoxyribosyl pyrrole 3-monocarboxamide (127a) and 2’-deoxyribosylpyrrole 3,4-dicarboxamide (127b) has been reported. Their preparation was achieved after treatment with POC13 of the respective nucleoside, followed by reaction with Pz07Hz(HNB~3)2.98 Mikhailopulo described the synthesis of l-(2-deoxy-3-O-phosphonomethyl-~D-erythropentofuranosy1)thymidineand its a-anomer (128a,b).To prepare both anomers of l-(2-deoxy-3-O-(pyrophospho-ryl)phosphonomethyl-~-~-erythropentofuranosyl) thymidine (129a) and (129b), (128a) and (128b) were treated with inorganic pyrophosphate activated with Im2C0, respectively. Neither (129a) nor (129b) were substrates for calf terminal deoxynucleotidyl transferase nor for AMV reverse transcriptase and showed moderate substrate activity with E. coli DNA polymerase I.99

198

Organophosphorus Chemistry

Me

Me

I

C H2PO(OH), (128) a

CHzPO(OH)2 (128) b Me

Me

I

)

O=P-OH \ 0 O=P-OH \ 0 O=P-OH \ OH (129) a

)

0 =P -, OH

b 0 =-P , OH

/I\

HO OH (129) b

3.2 Nucleoside Polyphosphates. - The preparation of the phosphonate analogues of Ip41and Ip,I (130) and (1 3l) has been described. Various methods for the efficient synthesis of these compounds have been examined. The most convenient method employed tris(imidazo1ido)phosphate and inosine 5'-methylenediphosphonate, which had been prepared from 2',3'-isopropyledeneinosine and methylenebisphosphonic dichloride."' A novel series of dinucleoside 5'-polyphosphates UpnU (132a-f) has been reported. These dinucleoside derivatives were prepared from the 5'-phosphoimidazolidate derivative of uridine which was either treated with UMP to yield (132a) and (132b) or from UTP, which upon activation to cyclic uridine 5'trimetaphosphate, reacted with U M P to yield (132c) and (132d). Compound (132c)could also be prepared from the phosphoimidazolidate derivative of UDP. Reaction between cyclic uridine 5'-trimetaphosphate and U D P offered (132d) while (132e) and (132f) were generated as minor by-products."' Three novel bisubstrate analogues (133a-c) acting as potent inhibitors of 6hydroxymethyl-7,8-dihydropterinpyrophosphokinase have been synthesised and used in the co-crystallisation of the kinase. These compounds were synthesised by coupling adenosine nucleotides (AMP, ADP and ATP) to 6-hy-

199

5: Nucleic Acids and Nucleotides; Mononucleotides

HO,

,OH

(132) a (132)b (132) c (132) d (132) e (132) f

n= 1 n=2 n= 3 n= 4 n= 5 n= 6 Nr N \ y N H *

(133)a n = l (133) b n = 2 (133) c n = 3

Ho

OH

droxymethylpterin monophosphate activated with 1,l'-carbonyldiimidazole.102 Sekine reported an improved method for the preparation of 4-thiouridine, 6-thioguanosine and 6-thioinosine 3',5'-bisphosphates (134, 135, 136). These three thionucleoside bis-phosphates were substrates of T4 RNA ligase and examined as donors for ligation with m32,2~7G5'pppAmUmAm.'03 A novel series of adenophostin analogues, in which the adenine ring was removed, have been reported. The synthesis of clustered disaccharide analogues of adenophostin (137 a-c) has been achieved via the Sonogashira coupling of propargyl 2-0-acetyl-5-0-benzy1-3-0-(3,4-d~-O-acetyl-2,6-d~-O-benzyl-~-~glucopyranosy1)-P-D-ribofuranosidewith iodo-, diiodo-, and tetraiodo-benzene. These compounds were capable of evoking Ca2+ -release from permeabilised hepat ocytes.lo4

200

Organophosphorus Chemistry

SH

SH

SH

I

'vv\I

R

R

(137) a

(137) b

(137) c

References 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11. 12. 13. 14. 15.

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5: Nucleic Acids and Nucleotides; Mononucleotides

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

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Organophosphorus Chemistry

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6 Nucleotides and Nucleic Acids; Oligo- and Polynucleotides BY D. LOAKES

1

Introduction

The number of publications on oligonucleotides continues to increase, as has the range of applications. This present review covers a two-year period, and the two major areas of publication for this period have been in modified base analogues and NMR structural studies. There have been many new analogues that have been incorporated into oligonucleotides which have a variety of functional groups attached. Previously such modified analogues would have been studied principally in hybridisation experiments, but the range of applications has increased to cover many new areas, such as electron transport, photoreactive groups and chelating groups to incorporate metal ions. In addition there has been a growth in the number of unnatural base analogues to study the various interactions that occur within duplex and other tertiary structures. The advances in NMR technology have also led to a growth in the number of oligonucleotide structures that have now been solved in solution. There have also been many developments in internucleotide linkages and sugar modifications leading to a variety of novel structures, for example the advances in peptide nucleic aids (PNA),locked nucleic acids (LNA)and nucleotides in which the 5-membered furanose ring is replaced by a 6-membered ring. Conjugation to oligonucleotides is also a rapidly developing field as reflected by the number of publications reported. There have been developments in two other areas, namely DNA microarrays and the attachment of oligonucleotides to solid surfaces, and in the generation of DNA and RNA aptamers that not only bind to the target, but also catalyse chemical reactions. These two growth areas are discussed separately. 1.1 Oligonucleotide Synthesis. - 1.1.1 D N A Synthesis. There have been a number of improvements to solid phase DNA synthesis. These improvements are concerned with new supports, and in new protecting group chemistries. A uridine based linker attached to polystyrene beads via the 5’-hydroxyl has been used as a universal support for DNA synthesis.’ The oligomer is extended from the 2’-OH of the uridine support, and cleavage is reported to be faster than other vicinol diol universal supports. The method also provides DNA free from 3’-modified contaminants. A protocol for the preparation of high loading supOrganophosphorus Chemistry, Volume 33

0The Royal Society of Chemistry, 2003 204

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205

ports suitable for large scale DNA synthesis has been reported,2and found to be suitable for synthesis of DNA comparable to commercial supports. A fairly recent and growing area of research is the synthesis of peptide-oligonucleotide conjugates. New solid supports have been prepared to synthesise oligonucleotide-peptide conjugate^.^ The supports are designed to link the 3'-end of an ODN to the carboxyl end of a peptide via a phosphodiester or phosphorothioate bond. A support for the synthesis of symmetrical ODNs containing a bipyridine ligand (1) at the 3'-3' inversion site is reported." The support is designed to act as a chelating agent for a variety of applications. For large-scale liquid phase O D N synthesis: a method based on oxidative coupling in the presence of NBS of alkyl H-phosphonate monomers, and using PEG-5000 as a soluble support has been reported. Guzaev et al. report that the synthesis of ODNs without phosphate protection of the growing ODN may be carried out, with few side reactions, by converting the phosphate (or phosphorothioate) into its 4-(N,N-dimethylamino)pyridinium salts: The advantage of this system is that it allows ODN synthesis using both phosphoramidite and H-phosphonate chemistries. The internucleotide phosphate or thiophosphate has been protected with allyl groups (P-0-allyl-phosphoramidites) for the synthesis of DNA,' which may be used alone or in conjunction with P-cyanoethyl-phosphoramidites. The allyl group is removed under mild conditions with nucleophiles. A novel phosphate/thiophosphate protecting group for DNA synthesis, 2-(N-formyl-Nmethy1)aminoethyl (2), undergoes a thermal de-esterification, thus eliminating the use of ammonia for deprotection.' A protocol for the preparation of phosphorothioate ODNs substituted at the 5'-end with a protected thiol function and at the 3'-end an amino function is reported.' Special deprotection conditions are required which deprotect the terminal functional groups in addition to all side chain protection groups. A new phosphate protecting group for ODN synthesis, 2-[( l-naphthyl)carbamoyloxy]ethyl(3), gave the best yields for a range of aryl derivatives, best deprotection kinetics (aqueous ammonia) and greatest stability of the phosphoramidite monomer.1o Commercially available 'fast-deprotection' phosphoramidites are used to prepare ODNs containing base-sensitive nucleotides, which are deprotected using K2C03/MeOH.However, trans-amidation can still occur, particularly with dG. Use of trimethylacetic anhydride as capping agent is shown to eliminate this problem." A set of amidites using P-cyanoethyl carbamates as protection for the amino groups of the nucleobases allows DNA synthesis and deprotection under mild aprotic conditions using triethylamine/DMF.I2 New phosphoramidite building blocks using either 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) or (2-dan3' sy1ethoxy)carbonyl (dnseoc) protecting groups have been devised for 5' oligonucleotide ~ynthesis.'~ Using these monomers, ODNs were prepared in good yield, including ODNs conjugated to cholesterol or vitamin E, and ODNs containing 3'-3' and 5'-5' linkages. Synthesis of DNA in the 5' -+ 3' direction requires both N2- and 06-protectionof the guanine base to prevent unwanted phosphitylation of free 06-residues.14 A method for the modification on solid supports of DNA substituted at the

-

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Organophosphorus Chemistry

0.

DMTo 0

'Pr2N,p,0

I

I

OMe

2'-position has been described using the phosphoramidites (4, 5).l5,l6The synthesis requires the use of 2,2,2-trimethylacetic anhydride as capping agent. The o-nitrobenzyl protecting group is then removed by two photolysis steps to leave a free amino group. This was then modified using aryl isocyanates or alkyl carboxylic acids with a-methylene groups to prepare a variety of conjugates. Whilst there are many reports of masked phosphate nucleotides, there has been little reported on the synthesis of phosphate protected oligonucleotides. Imbach and co-workers have developed their S-acetylthioethyl (SATE) protected nucleotides to the synthesis of oligonucleotides. The first synthesis of SATE protected ODNs (pro-oligonucleotides) has been reported using both H-phosphonate and phosphoramidite chemistrie~.'~-'~ The synthesis requires the use of photocleavable base protecting groups. SATE protected pro-oligos have also been examined for their protein-binding properties.'' SATE pro-oligos were shown to have decreased affinity for serum proteins and lactoferrin compared to parent ODNs. The cellular uptake of oligonucleotides is hampered by their

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207

instability to biological fluids and poor cellular penetration. The SATE protecting group has been used to improve the cellular uptake of nucleoside phosphates. More recently, the SATE protecting group has been used to improve the lipophilicity and hence the cellular uptake of short oligonucleotides. TI2-mers have been prepared containing up to ten SATE phosphate protecting groups and it was demonstrated that these oligomers were efficiently internalised in HeLa cells.2o A solid phase enzymatic synthesis of ODNs has been reported?l After attaching a trinucleotide to a solid support, chain extension is carried out using T4 RNA ligase and nucleoside 3’,5’-diphosphates. The terminal phosphate is removed with alkaline phosphatase ready for the next extension. 1.I .2 D N A Microarrays. Since the technology to synthesise DNA on microchips . have ~ ~been ~ tremendous developments was developed, e.g. by Fodor et ~ 1 there in the various chemistries for attaching DNA to surfaces, the size of the array and the different types of surface which oligonucleotides can be attached to. This is still a fast growing area of research, although DNA microchip technology has become routine. In this review are reported new methods of attachment, methods for attachment to different surfaces and some methodology. A-A

-

O ‘ S i A NH V B -O’& 0

Slide

r

‘CCAGGGATTCTTATGAC-3l GGTCC-51

A\

A-A’

(6)

An ODN containing a hairpin stem-loop with multiple phosphorothioate linkages in the loop has been used for immobilisation onto activated glass surfaces. The glass surface is activated with bromoacetamidopropylsilane to give (6), and then used to attach the phosphorothioate ODN.23The advantage of attachment via the stem loop of the ODN is that it leaves both 3’- and 5’-termini free for further elaboration. Glass surfaces are commonly used for the construction of DNA arrays, but the characterisation of the DNA is very difficult, due in part to the sub-picomolar quantities available. LeProust et al. have studied the various steps of DNA synthesis on glass plates, characterising the DNA, after cleavage from the surface, by 32P-labellingand PAGE.24The authors found that there was a much lower yield of DNA than that obtained by synthesis on CPG. Analysis of each cycle of the synthesis allowed the authors to conclude that the low yield is due to inefficient reactions close to the surface of the glass plate. Reaction yield increases as the synthesis proceeds, but by-products due to incomplete reactions early in the synthesis lead to many shorter products. The attachment of ODNs to silicon wafers is described2*in which hydrogen terminated Si(II1) surfaces are modified with w-unsaturated alkyl esters. Deprotection with tBuOK yielded a carboxyl modified surface, which was used to attach DNA. The silicon wafers were shown to exhibit excellent specificity and stability. UV-mediated attachment of alkenes has been used to functionalise silicon surfaces using t-BOC protected 10-aminodec-1-ene. After removal of the

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Organophosphorus Chemistry

t-BOC group, thiol modified DNA was used to prepare DNA arrays on the silicon surface. The arrays were very stable and performed well in DNA hybridisation assays.26 Thymidine and 2’-deoxycytidine phosphoramidite monomers have been prepared using 3’-[2-(2-nitrophenyl)propyloxycarbonyl] protecting groups, which are removed photochemically, to allow for 5’ 3’ DNA synthesis by photolithography on m i c r o ~ h i p sThe . ~ ~ binding of 8-mers modified with the 2’-O-methylribosides of adenine and 2,6-diaminopurine and 2,6-diaminopurine-2’deoxyriboside to a generic microchip containing all 4096 hexamers has been studied.28The use of three substituted adenine derivatives resulted in increased mismatch discrimination, with the best discrimination achieved using 2,6-diaminopurine-2’-O-methylriboside. Koch et al. have devised a photochemical method for immobilising ODNs to a solid surface.29An anthraquinone phosphoramidite is attached to the 5’-end of ODNs during DNA synthesis. The modified ODNs may then be conjugated to microtitre plates by photolysis. The ODNs may then be used in, for example, PCR. Taton3’ describes a method for analysing DNA arrays using ODN-modified gold nanoparticles and a flatbed scanner. The labelling of ODNs with nanoparticles rather than fluorophores substantially alters the melting profiles of the targets on an array, giving a %fold increase in selectivity compared to fluorophores. ODN-capped gold nanoparticles have also been attached to quartz crystal surfaces under shear oscillation to give a uniform monolayer or islands of multilayer~.~~ This provides a 3-D assembly of ODNs which give improvements in the extent of hybridisation. A method has been reported for the synthesis of DNA on polystyrene beads in 5’ direction and then reversing their orientation in sit^.^^ the standard 3’ Polystyrene beads are first treated with a mixture of triethyleneglycol and levulinyl-protected triethyleneglycol phosphoramidites. Oligonucleotides are synthesised via the triethyleneglycol linker and detritylated. The free 5’-OH group is then allowed to react with 0-chlorophenylphosphorobistriazolide,and selectively hydrolysed with 0.3 M TEAB. Removal of the levulinyl group with hydrazine, followed by MSNT coupling yielded oligomers attached to the beads at both 3’- and 5’-ends. Removal of the phosphate-protecting group followed by ammonia deprotection yielded oligonucleotides attached to the beads via their 5’-end. The authors claim that this process also allows for purification of the oligonucleotides whilst on support. DNA sequence analysis using MALDI mass spectrometry has been carried out with a microarray of gel immobilised O D N S .The ~ ~ microarray consisted of 8-mers, which formed a nested overlapping set complementary to the target sequence. A second round of hybridisation used 5-mers, which when contiguous with the 8-mers formed a more stable complex. The sequence of the 5-mers was characterised by MALDI MS to aid identification of the sequence. DNA sequencing has also been performed on 16-channel capillary electrophoresis m i c r o ~ h i p sThe . ~ ~ advantages of the system include uniform signal intensity and tolerance of high DNA template concentrations. The system yields 450 bases in 15 minutes on all 6 channels.

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A variety of DNA dendrimers may be prepared using pentaethyleneglycol phosphoramidite and the doubling (7) and trebling synthons (8).35These were associated with complementary oligonucleotides, in solution or on a solid support, and shown to have higher stability than those of un-branched oligonucleotides. The authors suggest that this may have applications in DNA microarrays where higher hybridisation temperatures are required. 0

iPr2N,p-o$~oDMT O

~

O

D

M

T

HNFoD 0

NC-o’

Doubling synthon (7)

-0DMT

Trebling synthon

(8)

Transcripts representing mRNAs of three Xenopus cyclins were hybridised to arrays of ODNs, and the first 120nt of the coding region scanned for the ability to form duplexes with the ODNs that produced high heteroduplex yield were assayed for their ability to effect translation of cyclin mRNAs. Excellent correlation was found between antisense efficiency and affinity of ODNs as measured on the array.

1.2 RNA Synthesis. - Most of the recent developments in RNA synthesis concern the use of new protecting groups, in particular for the 2’-position, and improved methods of automated synthesis. A new photolabile 2’-OH protecting [(R)-1-(2-nitrophenyl)ethoxy]methylhas been demonstrated for the synthesis of RNA.37The protecting group is removed by photolysis, though the presence of the protecting group in duplexes has little effect on the thermal stability. Fluoride labile nucleobase and sugar protecting groups have been reported for the synthesis of O-aminoacylated RNA sequences.38The sugar protecting group used is triisopropylsilyloxymethyl (TOM) and nucleobase amino groups are protected with { 2-[(triisopropylsilyloxy)oxy]benzyloxy}carbonyl (tboc). It has been reported that for the synthesis of long ribooligonucleotides (>40-mers), the yield and purity of RNA can be substantially improved using 4,5dicyanoimidazole as coupling agent in place of 1 H - t e t r a ~ o l eA. ~set ~ of building blocks (9) has been prepared for the incorporation into RNA nucleotides containing O’-phosphate groups?’ As RNA synthesis has become routine, the synthesis of more complex oligomers has been investigated. One particular area of interest in RNA synthesis is the formation of cyclic and lariat RNA. The use of a protected universal building block containing the selectively activated 2’-H-phosphonate and 3’chlorophenylphosphate has been used to prepare branched oligoribonucleotides and lariat structures?’ The synthesis of small to medium cyclic RNA can be carried out, providing that the linear precursor attached to the support has a

Organophosphorus Chemistry

210

-

I

I

NCH& 2iC l

x : --(+ 0 -P -0

0

‘Pr2N

0

l o

Me

Me

CH2CN

Me

Me CH2CN

(9)

2’-deoxy- or 2’-O-methylribonucleoside at the 3’-end.42Cyclisation of the ODNresin with MSNT affords cyclic ODNs, which are cleaved and deprotected with oximate. A method for the synthesis of cyclic oligoribonucleotides has been de~cribed.4~ A TOM-protected RNA phosphoramidite is attached to a CPG linker via 3-chloro-4-hydroxyphenylacetic acid, attached to the phosphoramidite, which is then oxidised to yield the phosphotriester attached to the solid support. RNA synthesis is carried out in the usual manner, and cyclisation of the terminal 5’-hydroxyl group to the 3’-phosphodiester occurs using MSNT. A variety of cyclic ODNs were prepared, though cyclisation yields were only of the order of 15%. Using ribonucleotide 5’-phosphoro-2-methylimidazolidemonomers, non-enzymatic transcription has been demonstrated from a DNA hairpin template.44 The primer strand of the hairpin was substituted with rG at the 3’-end. The template strand incorporated an isoguanosine (iso-dG) residue, and the experiments demonstrated that iso-dG could act as a template for isocytidine.

1.3 The Synthesis of Modified Oligodeoxyribonucleotides and Modified Oligoribonucleotides. - I .3.I Oligonucleotides Containing Modified Phosphodiester Linkages. There have been many developments in the synthesis of oligonucleotides with modified backbones, with the largest area of research being in linkages related to peptide nucleic acids (PNA). Phosphorothioate linkages have also been examined in more detail given their stability in cell extracts for use as antisense agents, in addition to the more recently developed phosphoramidate chemistry. These, as well as more established linkages, have frequently been used in chimeric oligonucleotides. Chimeric ODNs containing phosphodiester, phosphorothioate and phosphoramidate linkages have been reported using H-phosphonate monomers of 2’-0-(2-rnethoxyethyl) ribonucle~sides!~ Phosphodiester linkages were introduced by oxidation with 0.1 M Et3N in CC14/pyridine/H20. By using N4-acetyl dC-3’-H-phosphonate monomer, phosphoramidate linkages were introduced without transamination during the oxidation step. 2’-O-methyl RNA containing alternating methylphosphonate and phosphodiester linkages have been reported to be remarkably stable to exo- and endo-nucleases, despite the presence of phosphodiester bonds.46 They also have very high affinity towards RNA as demonstrated by binding to HIV- 1 TAR RNA. Similarly phosphoramidate RNA oligomers show enhanced nuclease stability and binding affinity towards target RNA!7 A methylphosphonate/DNA chimera and a neutral methylphos-

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

21 1

phonate ODN have been targeted to a rib~zyme.~* Using only hexamers, the dissociation constant of the methylphosphonate ODN gave 30,000-fold binding enhancement by tertiary interactions than for native DNA. Using 5’-psoralen-conjugated ODNs the effects of backbone modification of triplex forming oligonucleotides (TFOs) targeted to a purine tract of HIV env-DNA have been e~amined.4~’~’ TFOs containing chimeric methylphosphonate linkages form stable triplexes with the target DNA, and are compatible with the introduction of other modifications, such as 2’-O-methyl or 5-propynyl. Although the stability of these triplexes is less than that formed by phosphodiester linkages, the methylphosphonate linkages have enhanced nuclease resistance. Chimeric RNA/DNA oligonucleotides have been used to repair or modify DNA sequences in 3’-C-methylene thymidine phosphoramidites and H-phosphonates (10)have been incorporated into DNA targeted towards RNA.54These analogues show increased stability compared to DNA, and ODNs containing the analogues were resistant to digestion with SVPDE. Isothermal titration calorimetry has been used to examine the effects of modifications to a third strand on triplex ~ t a b i l i t yModifications .~~ of the phosphate backbone (phosphorothioate and 2’-0-Me) are more detrimental to triplex stability than are base modifications. I

0

H I

9 (10) R = H, OMe

0

i

Me.N+-N-7=o

o.,

Me’ (11)

The introduction of the positively charged backbone N , N dimethylaminoethylphosphoramidate (11) was introduced into positions in a TF0.56It was found to be destabilising, probably due to steric effects. 2‘-OH modification with (N,N-dimethy1amino)propylgroups has also been reported,57 though for incorporation into antisense ODNs, where the analogue generally aided duplex stabilisation. The incorporation of many consecutive substitutions was detrimental. Phosphorothioate linkages are still the most common modified backbone, applications of phosphorothioate nucleotides and the synthesis of stereo-enriched isomers forming the main area of research. Water-soluble carbodiimides have been used to prepare phosphorothioate linkages from ODNs containing phosphorothioate diesters with non-bridging sulphur, leading to stable ligated ODNS.~* Nucleotide analogue interference mapping (NAIM) has been used to study the hairpin r i b ~ z y r n eThe . ~ ~ aim was to identify functional groups important for folding and catalysis of the ribozyme using 18 phosphorothioate tagged analogues. The stereo-reproducibility of phosphorothioate linkages during ODN syn-

212

Organophosphorus Chemistry

thesis has been extensively studied, but found to be inherently process controlled, with Rp/Sp ratios between 40:60 to 60:40.60The effect of phosphorothioate substitution (Rp and Sp) at positions in a RNA hairpin have been studied by NMR.61Whilst at most positions substitution had little effect on the structure, it was shown that at certain positions it can substantially alter the RNA conformation. This may complicate substitution-interference experiments studying RNA structure and function. A similar effect has been observed for an RNA GAAA tetraloop hairpin structure, where an unexpected stabilisation was observed.62 The effect of phosphorus chirality in phosphorothioate ODNs has been investigated with respect to the ability to adopt a left-handed conformation at varying salt c ~ n c e n t r a t i o nAt . ~ ~high Na+ concentrations the phosphorothioate ODNs d(CG)4and d(GC)4convert to a Z-form, whilst the unmodified ODN does not. Stereoenriched Rp and Sp phosphorothioate ODNs have been synthesised using oxazaphospholidine monomers (12, Rp isomer shown).64A comparison of duplexes containing stereoenriched Rp, Sp and stereo-random ODNs has been made by hybridisation studies. The binding affinities were found to be in the order Rp > stereo-random > Sp, whilst the in uitro nuclease stability was the reverse order. All ODNs activated RNase H activity, though Rp phosphorothioates were the most efficient. A met hod for the preparation of ODNs containing terminal 2’-S,3’-O-cyclic phosphorothiolate has been d e ~ c r i b e dSuch . ~ ~ modified ODNs would be of use to study metal interactions with metalloenzymes. 5’-Deoxy-5’-thioguanosinemonophosphorothioate has been prepared66and incorporated into the 5’-terminus of RNA using T7 RNA polymerase. This can be dephosphorylated (alkaline phosphatase) to leave RNA with a free 5’-SH for further modification. 3’Phosphoselenoates undergo facile selenium mediated autoligation of DNA or The method also provides a means RNA strands with 5’-deo~y-5’-iodo-ODNs.6~ for incorporation of heavy atoms into ODNs suitable for X-ray crystallography. A phosphorothioate antisense O D N targeted at the chemokine receptor CXCR4 gene in HIV-1 infected HeLa-CD4 cells showed a reduction of up to 50% of surface levels of the receptor.68The anti-gene effect of a TFO incorporating an increasing number of phosphorothioate linkages has been studied.69 Increasing the number of phosphorothioate linkages increases the nuclease resistance of the O D N but also reduces the tendency of the O D N to aggregate. The replacement of a phosphodiester linkage with the 3’-N-sulfamate group (13, X = 0)has little effect on stability when targeted towards either DNA or RNA.70However, substitution by the sulfamide group (X = NH) causes destabilisation of duplexes, and this may be due to poor hydration and a steric clash with the 5’-NH and a neighbouring H2’ atom. A similar analogue to (13, X = 0)incorporating an N-acylsulfamide linked thymine dimer has been prepared and incorporated into DNA,71but this analogue was also destabilising towards an RNA target. An O D N incorporating the pyrrolidine-amide (14) shows enhanced binding to both complementary DNA and RNA (compared to native ODNs), and the binding kinetics have shown that it is able to bind selectively with RNA over DNA.72

213

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

I

HN

NH

OH

o=s=o I

HN

OH (12)

(13) X = O , NH

(14)

Y

HN

OH

(15 )

Phosphoramidate linkages are a growing area of research, as they have been shown to be effective in a number of different applications. The incorporation of the four natural and 2,6-diaminopurine ribonucleosides containing N3’ P5’ linkages, increases the thermal stability of duplexes containing them. The hydrolysis rates by RNase A and T I have also been described.73RNA phosphoramidate oligonucleotides were 0.5-1 “C more stable per substitution than for DNA phosphoramidate oligon~cleotides.~~ 2,6-Diaminopurine-based phosphoramidate oligonucleotides are considerably more stable (7°C per substitution) and show selectivity for RNA over DNA. Oligoribonucleotides containing N3’ P” linkages (15) are hydrolysed by both RNases with similar rates to those containing natural phosphodiester backbones. 2,6-Diaminopurine with N3’--+ P5’phosphoramidate linkages in DNA have also been shown to increase stability towards DNA and in particular RNA.75The synthesis of uniformly modified ODNs containing N3’ P5’ thiophosphoramidates has been In duplexes they have superior thermal stability compared to ODNs with a phosphodiester linkage, but have similar stability to N3’-+ P” phosphoramidates. Psoralen-modified TFOs form covalent triplexes upon UV irradiation. Such modified triplexes are not repaired in either HeLa cells or HeLa nuclear extract, allowing for persistent intracellular damage and transcription inhibition.” A similar effect was observed using psoralen-modified TFOs with N3’-P5’ phosphoramidate linkages.7*A new method for introducing phosphoramidate linkages is Using cyanoethyl-protected phosphodiesters, the cyanoethyl group is removed with piperidine and the phosphodiester activated with tosyl chloride. Amine nucleophiles can then be used to displace the tosyl group. TFOs containing phosphoramidate linkages significantly increase the triplex stability at neutral pH, and increase the binding constant by almost two orders of magnitude.*’ In addition to the phosphoramidate linkage, there are a few other amino-type modified backbones. The phosphodiester bond between U4 and G5 of a modified hammerhead ribozyme was replaced by an amide backbone.*’ There was little effect of this ribozyme’s cleavage activity, and the ribozyme was stable to endonucleolytic digestion at this position. ODNs bearing either hydroxamatex2 or N-hydroxycarbamate linkages,83(16), have been studied. Whereas the hydroxamate linkage had a slightly stabilising effect against both complementary DNA and RNA, the N-hydroxycarbamate linkage was destabilising in DNA

-

-

-

Organophosphorus Chemistry

214

duplexes. A thymine dimer involving a methylene(methylimin0) (MMI) linker (17) has been incorporated into antisense ODNS,'~where it was found to have high binding affinity towards target RNA. Oligomers containing the cationic S-methylthiourea, DNmt, (18) bind with high affinity to poly dA, and forms triple~es.'~ Triplexes are stabilised by electrostatic interactions between the polycation and the poly dA phosphate backbone. Solid-phase synthesis of DNmt oligomers, and the neutral analogue containing a thiourea backbone have been reported.86 \

Ho'Nv ?OH

O Y X

\

-

Me-N,

x

O\

\

\

(1 6 ) X = CH2, hydroxamate X = 0, hydoxycarbamate

OMe

I (18) OH

(17 ) \

Since Nielsen et ~ 1 . ' ~introduced peptide nucleic acids (PNA), this area has received vast attention, and continues to do so. More recently, the main area of interest has been in novel analogues, and many new ones have been reported. The solid phase synthesis of DNA-3'-PNA chimeras have been described, in which the DNA is attached to the amino terminal of the PNA via the 3'phosphate or thiophosphate." All chimeras were shown to have superior thermal stability towards either DNA or RNA than a DNA oligomer, and the phosphodiester linkage was more stable than the phosphorothioate. Hybridisation studies with PNA and PNA-DNA chimeras demonstrate that there is a sequence effect for the junction between PNA and DNA on duplex ~tability.'~ A decamer pyrimidine bis-PNA oligomer, separated by a linker, when targeted to complementary dsDNA formed three distinct structure^.^^ One structure contained two bis-PNA units, and the other two were believed to be structural isomers. PNA occurs as both E- and 2-rotamers in un-complexed forms, but in duplexes it is uniformly oriented in the 2-form. Schutz et have prepared olefinic PNA (OPA) in which the amide bond is replaced by the isostructural C-C double bond in both E- and 2-configurations (19, 20). Incorporation of either isomer into OPA resulted in a decrease in thermal stability against DNA with similar affinity. Homopolymers of OPA also did not form triplexes. OPA also binds preferentially in the parallel mode. A PNA oligomer to which has been attached diethylenetriamine (DETA) via a urea bond was shown to cleave an RNA target at micromolar concentrations under physiological conditions?'

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

215

Pseudo-complementary PNA containing diaminopurine-thiouracil base pairs have been shown to bind with high specificity to complementary targets in dsDNA by a mechanism termed double duplex invasion.93By this mechanism, the DNA duplex is unwound and both DNA strands are targeted simultaneously by the two pseudo-complementary PNAs. Antisense PNA oligomers targeted at HIV-1 TAR RNA are able to prevent Tat-TAR interaction by efficient sequestration of the RNA.94Antisense oligomers with PNA, 2'-O-methyl and phosphoramidate backbones have been targeted against Ha-ras mRNA.95Amongst these, the PNA antisense oligomer showed the highest stability and acted specifically in vitro to inhibit mRNA translation by a steric blocking mechanism. Pyrrolidine PNA-DNA chimeras incorporating (21) have been prepared to investigate the function of a positive charge in the ODN backbone.96The pyrrolidine unit was found to be destabilising, particularly at the centre of a duplex. A similar pyrrolidine-derived polyamide PNA d e r i v a t i ~ was e ~ ~reported to bind specifically with RNA with only slightly reduced affinity compared to DNA. The four stereoisomers of a cyclic pyrrolidinone PNA (pyr-PNA) analogue (22) have been and the thermal stability of the pyr-PNA measured against complementary DNA, RNA and PNA. The 3S,5R isomer had the highest affinity toward RNA and PNA. However, pyr-PNA was found to be slightly destabilising compared to PNA, and the authors suggest that the 5membered ring may not be the optimal modification to restrict PNA. An adenine pyrrolidine PNA analogue has also been and preliminary hybridisation data suggests that it has good affinity for both DNA and RNA. \ \

B

"NV

HNYNH2

The chimeric deoxynucleic guanidine-PNA (DNG/PNA) oligomer (23) introduces a positive charge into the PNA Hybridisation studies showed that (DNG/PNA)2-DNA triplexes are more stable than DNA-DNA triplexes. The inclusion of an internal DNG unit results in destabilisation of the triplex, but DNG units at both termini of the PNA strand result in a triplex which is about as stable as (PNA)?-DNA.The DNG/PNA oligomer was shown to associate faster with DNA than PNA. The use of guanidinium linkages has also been extended to ribonucle~tides,'~~ though few data are available at present.

216

Organophosphorus Chemistry

Ester, N-methylamide and trans-4-hydroxy-1-proline PNA homo-thymine oligomers have been prepared and evaluated against DNA and RNA targets. All polymers were found to be less stable than PNA except for the proline 01igomer.'~~ Acyclic serine-linked thymine analogues have been prepared, and incorporated into DNA, substituting for thymidine residues.Io5With complementary DNA or RNA, there was a decrease in Tm, reflecting the increase in flexibility of the oligomers. All four threolerythro stereoisomers of 2(R/S)-(Nthymin-1-ylacety1)-amino-l(R/S)-aryl1,3-propanediol, e.g. lS,2S-threo (24)have been prepared and incorporated into ODNs.lo6When incorporated into either duplexes or triplexes, they had little or slightly destabilising effect on thermal stability, with (24)being the most effective. Cyclic oligonucleotides have been prepared using a number of different analogues. ODNs have been prepared containing a conformationally rigid 5'-cyclouridylic acid derivative,'" (25). ODNs containing these analogues were resistant to SVPDE and nuclease P1. However, duplexes containing them showed considerable destabilisation. When the 2'-O-methyl derivative was incorporated at the 5'-end of an ODN, it increased the stability of duplexes bound with RNA but not with DNA.lo8The cyclic dinucleotide (26), designed to mimic the intraresidual H-bonding in the anticodon loop of E. coli tRNAArg,has been incorporated into DNA to study DNA bending.'" The distortion of DNA by the analogue was confirmed by NMR and PAGE. U O A

,o

0

'X

HO OR (25) R = H, Me

Two building blocks, derived from glycerol (27) and cis,cis-1,3,5-cyclohexanetrio1 (28) have been prepared for the synthesis of ODNs with a 3'-3' linkage.'" The building blocks allow for either symmetric or asymmetric ODN synthesis; for asyrrmetric synthesis, reilloval of the DMT group allows for first strand synthesis which is then capped with benzoyl chloride. Removal of the silyl protecting group then allows second strand synthesis. Jiang et al."' have described a novel antisense ODN strategy using pseudocyclic OLINs. Two ODNs are attached through their 3'-3' or 5'-5' ends, one is complementary to a mRNA sequence, the other complementary to a section of the antisense ODN. In the absence of target mRNA, the linked ODNs form an intramolecular pseudo-cyclic structure (29), but in the presence of mRNA, the antisense ODN preferentially forms a duplex with the mRNA. These pseudocyclic ODNs activate RNase H cleavage, and are more stable to nucleases. They have also been successfully used with fluorescent tags in real time PCR experi-

217

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

DMTO

ODMT

DMTO

OTBDMS

DMTO

DMTO

"GCGTGCCTCCTCACTGGC'/

3'CGCACGG5'

Linear form

1 Hybridised form

(CGCACGGS

1

In presence of target rnRNA

CGGTCACTCCTCCGTGCG 'ACCGCCGCCAGUGAGGAGGCACGCAGCGUU3'

(29)

ments.'12 An ODN has been circularised around a plasmid DNA, using a third strand forming a triplex to the plasmid sequence, a so-called padlock ODN.'13 The ends of the duplex may be joined using T4 DNA ligase creating a circular DNA catenated to the plasmid with the target sequence. Fujimoto et al. have reported a method for circularisation of DNA. 5-Vinyl dC or dU at the 5'-end of an ODN will undergo a template-directed photocircularisation at 366 nm with a thymidine residue at the 3'-end of the oligomer, to give a thymidine photo a d d u ~ t . "Irradiation ~ at 302 nm reverses this process. 5-Vinyl-dC is more efficient for this process than 5-vinyl-dU. This photocircularisation will also occur when the vinyl pyrimidine is present as the third strand of a triplex."' The photolysis reaction time for these analogues is quite long; however, using 5-carboxyvinyl-dU, much shorter reaction times are achieved.'I6 The same group has also prepared ODNs containing 7-vinyl-7deazaguanosine, and demonstrated that the analogue enhances duplex stability."' To study the codon-anticodon pairing properties, a model system has been prepared in which the codon and anticodon nucleotides are synthesised in a

218

Organophosphorus Chemistry

cyclic mini-helix linked by ethylene diol linkers."' This stabilises the duplex to allow for physical characterisation. Two model systems were prepared, corresponding to the codon for tRNAphe,and involved the modified l-methylguanosine (m'G) (5'-GAAm'G). To increase the nuclease stability of ODNs, end-capping using propane- 1,3-diol, 1,6-hexanediol and the acyclic nucleoside derivative, 2',3'-secouridine has been investigated."' Each of these substitutions was found to enhance the stability of ODNs by more than twelve-fold compared to native DNA, even when carried out in cell culture. A homo-pyrimidine-homopurine duplex ODN linked at each end via a hexaethylene glycol linker in which the cytosine residues are replaced with 5-methylcytosine showed an exceptionally high T, above 90"C.'20The duplex also formed a triplex with a homopyrimidine strand even at neutral pH. The first boranophosphorothioate mimic of a phosphodiester has been synthesised and shown to be more lipophilic and nuclease resistant than natural phosphodiesters or phosphorothioates.121The pairing properties of ODNs with a phosphinato linkage between a C H 2 0group attached to either C' of dA or C6 of dU and containing either a 2'-deoxyribose sugar"2 (ODNs having a free 5'-CH20Hgroup) or a 2'-deoxy-~-erythrose'~~ (30,3 1)have been examined. Each analogue caused a destabilisation of up to 8°C per modification, and the destabilisation was independent of the C4'-CH20H. Zhang and Taylor'24 have introduced a photocleavable 'caged' DNA strand break (32) into ODNs. Photolysis yields a 5'-phosphate strand and a 3'-OH strand, which can therefore be re-ligated. Caged DNA has also been prepared by cross-linking amino containing polycations with a bisimidoester cro~s-linker.'~~ This caged DNA is stable in salt solutions, and does not aggregate at high ionic strength. 1.3.2 Oligonucleotides Containing Modified Sugars. Developments in oligonucleotides containing modified sugars have, on the whole, been aimed at generating

.o

I

0

p o -0' \o (30)

R=CH20H, H

(32)

(31)

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

219

analogues with some improved property over the natural oligonucleotides. Generally this has been to enhance duplex stability or nuclease resistance. There have been many reports on oligonucleotides with modified sugars. Probably the two main areas of interest in these respects have been with locked nucleic acids, and nucleotides containing a hexose sugar or derivative. In addition to these, there have been a number of developments in analogues modified at the 2’position. This may again be to enhance the properties of the oligonucleotides, but also because the 2’-position is a convenient place to attach functional groups. 2’-Modifications have found many uses as oligonucleotides containing them often having enhanced binding towards RNA. This has been attributed to the analogues adopting a C3‘-endo conformation, leading to more stable A-form duplexes. This section will discuss sugar modifications, dealing first with analogues according to the position of modification, and finally discussing 6-membered ring sugar based oligonucleotide systems. The most common sugar modification is the 2’-O-methyl group. In a study of parallel intramolecular triplexes containing a DNA, RNA or 2’-OMe-DNA third strand, it was found that the 2’-OMe-DNA triplex was the most stable, followed by RNA.’26Mixed 2’-O-methyl and 2’-deoxy oligonucleotides show no advantage in terms of duplex stability compared to all 2’-deoxy-DNA. However, DNA with four 2’-O-methyl nucleotides at each end showed the same nuclease stability as an all 2’-O-methyl RNA 01igomer.~~~ 2’-O-Methyl oligonucleotides have been used to probe the helicase activity of HCV non-structural proteins (NS).12*NS3 and NS4A were not able to unwind (ds) 2’-0-methyl oligonucleotides, but RNA/2’-O-methyl chimeras were unwound provided the 2’-O-methyl modifications were at the 5’-end. RNA containing the modified analogue 2’-0methyl-2-thiouridine (s’Um) has been prepared and studied by thermal melting experiment^.'^^ It was shown that, against both RNA and DNA, the s2Um.Abase pair is more stable than USA,and that the wobble pair U.G is more stable than s2Um.G. The thermodynamics of hybridisation, binding kinetics and conformation of 2’-fluoro-, 2’-0-propyl-, 2’-O-methoxyethyl- and 2’-0-aminopropyl-ribose modified oligonucleotides have been studied.130 High stabilities were observed with 2’-fluoro-, 2’-O-propyl- and 2’-O-methoxyethyl modified duplexes, especially in the case of DNA-RNA duplexes. However, kinetics of binding was found to be slow. By contrast, the kinetics of binding with 2’-O-aminopropyl-ribosemodified oligonucleotides was rapid with both DNA and RNA targets, though the stability of the resultant duplex was lower. 2’-O-Methoxyethyl (2’-MOE) RNA has been used to inhibit human telomerase in immortal human prostate D U 145 cell ly~ate.’~’ IC50valuesof 5-10 nM were obtained, and inhibition of telomerase activity persisted for up to seven days after a single dose of 2’-MOE RNA. A fully modified 2’-MOE oligonucleotide targeted to the 3’-polyadenylation site of E-selectin was found to inhibit polyadenylation at that site, and redirect it to one of 2 upstream cryptic Manoharan et ~ 2 1 . ’have ~ ~ demonstrated site specific cross-linking to an abasic site in a duplex incorporating a nucleoside with a 2’-O-pentylamino linker after reductive amination. Oligonucleotides containing the modifications 2’-0-{2-

220

Organophosphorus Chemistry

[N,N-(dimethyl)aminooxy]ethyl} (2’-0-DMAOE) and 2’-0-(2-[N,N(diethyl)aminooxy]ethyl} (2’-0-DEAOE) (33) have been ~ynthesised.’~~ These oligonucleotides exhibit high binding affinity towards RNA, but not DNA, and enhance nuclease resistance. The incorporation of the 2‘-acylamido end cap (34) significantly increases duplex ~tabi1ity.I~~ This effect has been further studied by Kool and c o - w o r k e r ~(see ’ ~ ~section on modified bases).

(33) R = CH3,2’-ODMAOE R = CH*CH3,2’-ODEAOE

0 3 ” 0

(34)

HN

(35)

2’-Thio modifications have also been studied. The hammerhead ribozyme catalyses the cleavage of RNA by promoting attack of a distinct 2’-OH group onto the neighbouring phosphate group producing cleavage products with a cyclic 2’,3’-phosphate and a 5’-OH terminus. Remarkably, substitution of the 2’-OH group by a 2’-SH in the substrate strand of a ribozyme promotes attack of the adjacent C” displacing the nucleoba~e.’~’ The stability of DNA containing a 2’-thiohexyl side chain towards either DNA or RNA targets was decreased compared to unmodified controls.’38 Oligonucleotides incorporating 2’methoxycarbonylmethylthio-2’-dU have been used to functionalise oligonucl e o t i d e ~ . ’Reaction ~~ with ammonia or amines on solid supports gives rise to 2’-t hiome t h ylcarbamat e derivatives. Various 2’-modified nucleoside analogues, including 2’-fluoro, 2’-amino, 2’thio and 2’-arabino, have been used to probe conformational changes in hairpin ribozyme ~1eavage.l~’ DNA containing 2’-fluoro-P-~-arabinofuranosyl-adenine and guanine nucleotides exhibit almost the same affinity for complementary DNA and RNA.I4’When used in an in vitro transcription-translation assay, the RNase H mediated antisense oligomers containing these analogues is the same as that for all 2’-deoxyribose oligomers. The 2’-position has been used to attach other functional groups, either for detection or for further modification. The tertiary structure of TAR RNA has been investigated by the incorporation of the uridine analogue (35).’42The analogue incorporates a nitroxide spin-label and may be detected using electron paramagnetic resonance spectroscopy (EPR). A similar spin-label has been attached to the O6 of a guanosine residue, where it was used to monitor hybridisation by EPR.’43

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

22 1

Incorporation into RNA oligomers of uridine containing 2’-O-pyrenylmethyl, allows hybridisation and fluorescence properties to be in~estigated.’~~ When hybridised to either DNA or RNA, there is an increase in thermal stability. When hybridised to RNA, there is a large increase in fluorescence, which is not so significant when DNA is the target. This could be used to investigate RNA structures. A pyrene seco-pseudonucleoside, derived from 4-( 1-pyreny1)butane1,3-diol, has also been incorporated into DNA.145When incorporated as a dangling end of a duplex at either termini, there was a slight increase in stability. By varying the number of pyrene residues it is possible to alter the hydrophobicity and fluorescent properties of the oligomer. The fluorescent properties of pyrene have been used to probe the tertiary structure of RNA.146Attachment of pyrene to a 2’-amino modified nucleoside allowed the microenvironment of the pyrene to be monitored during hybridisation and folding events. An azobenzene unit has been attached to the 2’-OH group of uridine and incorporated into DNA.’47The azobenzene is normally present in the trans form, but on irradiation the double bond isomerises into the cis form, which causes a significant decrease in thermal stability. A series of oligonucleotides containing anthraquinone (AQ) linked to 02’of uridine were used to investigate charge transport in DNA.’48The oligonucleotides had GG steps symmetrically disposed around the AQ sites. On photolysis the AQ conjugates undergo piperidinemediated strand cleavage at the GG sites. Thus the effect of charge transfer can be measured by following the extent of cleavage. Carboxylic acid, 1,2-diol and aldehyde functional groups have been incorporated into DNA using 2’-modified phosphoramidite building in order to introduce reactive functional groups for further modification after oligonucleotide synthesis. The 2’-O-phosphate-3’-O-phosphoramidite monomers of U and A have been prepared which allows the synthesis of RNA with selectively placed 2’-O-phosphate groups.15oThe 2’-O-phosphate is protected as the t-butyl triester, and deprotected with 0.01 M HCl. Another common modification of the C2’ position is 2’-amino. 2’-Amino groups in ssRNA react more rapidly with activated esters than in duplexes or mismatches with RNA,151,’52 suggesting that 2’-amino-~ubstitutedRNA is more sensitive to local nucleotide flexibility; selective acylation was used to map the structure and Mg2+ ion-dependent conformational changes in tRNAAsptranscripts. 2‘-Aminoguanosine has been used to probe the electrostatic environment l ~ ~ conditions in of the active site of the Tetrahymena group I r i b 0 ~ y r n e . Under which the 2’-amino group is protonated, the binding affinity is increased by a factor of 200 compared to that using guanosine. Dimethylaminonaphthamide and fluorescein have each been attached to the C2’position of 2’-amino-2’-deoxyuridine as fluorescence energy donor and acceptor for FRET analysis.154The analogues were incorporated at the termini of DNA, and it was shown that the presence of the bulky groups at the 2’-position did not affect duplex stability or conformation of DNA duplexes, and they were effective in FRET analysis. Two different methods for introducing disulphide bonds or cross-links have been reported. In the first, an aliphatic isocyanate with a pyridyl-protected

222

Organophosphorus Chemistry

disulfide (36)has been used to prepare an interstrand RNA cross-link by reaction with a 2’-amino modified nucleotide within the d ~ p 1 e x . lIn ~ ~the second, a number of different functional groups (R = biotin, phenyl etc. in (37)) were introduced to the 5’-end of RNA by formation of a disulfide bond on a terminal guanosine phosph~rothioate.’~~ Modifications at C3’, C4’ and C5’ are much less common, though a few examples of each have been reported. ODNs containing 3’-O-methyl modifications (with 5‘ 2’ linkages) displayed lower Tmsthan unmodified ODNs, and showed a higher affinity for RNA targets than DNA, reflecting the fact that 3’-O-methyl modifications lead to a more A-like c~nformation.’~~ Such analogues are not substrates for RNase H, and are resistant to phosphodiesterases. The nucleoside triphosphates of 3’-amino modified analogues have been examined as chain terminators in DNA sequencing reactions.158The 3’-amino group was further modified via urea and thiourea linkers to which may be added fluorescent dyes. The analogues described were shown to be effective chain terminators in sequencing with ThermoSequenase. The C3’-hydroxymethyl-modified thymidine, containing an 02’methoxymethyl (MEM)(38)was found to have lower affinity towards both DNA and RNA when incorporated into a duplex than natural DNA.’59The presence of the 4‘-C- or 3’-C-aminoalkyl branched thymidine analogues (39), (40) in duplex DNA with complementary RNA had little or no detrimental effects.16’ The 4’X-modified analogue showed an increase in binding affinity compared to the 2’-deoxy analogue of these nucleotides. The incorporation of a 4-hydroxy-Nacetylprolinol nucleotide analogue at the 3’-end of an ODN or of 2-5A DNA significantly increased the 3’-exonuclease resistance.161 Such modifications had only a slight destabilising effect towards complementary RNA, and had no effect on RNase H activity.

+.

The incorporation of a 4’-a-C-aminoalkyl group into thymidine (41) gave a set of building blocks, which were incorporated into DNA.16*ODNs containing these modifications showed higher thermal stability towards DNA and RNA targets than unmodified DNA. The modified ODNs were also shown to be

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

223

resistant to both exo- and endo-nucleases, and were substrates for RNase H. These features make the analogues good candidates for antisense research. ODNs containing 4‘-C-aminomethyl-2’-O-methylor 4-C-aminomethyl-2’fluoro-modified thymidine showed increased affinity towards both DNA and RNA.163The presence of the 2’-substituent induces a conformational shift towards C3’-endo. The incorporation of lipophilic groups ( e . g . palmitic acid, cholesterol) via 4’-a-C-(2-aminoethyl)thymidine has been r e ~ 0 r t e d . lThe ~ ~ analogues increased thermal stability of duplexes with DNA complementary strands, but there was little effect with RNA compared to the control. ODNs (ss and ds) containing C4’-pivaloyl-modifiednucleotides have been shown to undergo photolytic strand ~1eavage.l~~ Photolysis causes loss of the pivaloyl group to generate an enol ether radical cation that is reduced to the enol ether by a single electron transfer from a guanosine residue up to four nucleotides away. Finally, there are three C”-modifications reported. A method for functionalisation of oligonucleotides on solid support has been d e s ~ r i b e d . ’ ~Using ~ , ’ ~ ~a P-D-allofuranosyl phosphoramidite with a bromopentyl side chain at 06’, oligonucleotides may be prepared incorporating the modified building block (42) which reacts with a variety of soft nucleophiles. Oligonucleotides containing a 5’-terminal phosphate or thiophosphate group undergo thermolysis at 90°C in 0.1 M NH40Ac to remove the terminal (thio)phosphate group.16*The thiophosphate group is more labile, being removed in a few hours. 3’- and 5’-Iminoacetic acid derivatives of thymidine as potential metal chelators have been prepared and incorporated into DNA.169 Locked Nucleic Acids (LNA) were first reported by I m a n i ~ h iand ’ ~ ~Wengel,17* the first group terming the analogues BNA. Since then there have been many reports on the synthesis and applications of a number of different locked nucleic acid derivatives. In an attempt to obtain analogues with enhanced affinity towards target complementary strands, the 2”s and 2”R analogues of (43) were synthesised and incorporated into oligonucleotides.172Oligomer 5’-2’’-S13T, exhibited RNA-selective binding with moderately enhanced thermal stability compared with the corresponding unmodified referen~e.’~~ Remarkably strong intermolecular self-pairing was observed for oligomer 5‘-2”-Rl3T, but not for the diastereoisomeric 5’-2’’-Sl3 T. The authors suggest that the formation of an intramolecular hydrogen bond between the (2”R)-2”-C-hydroxymethyl group and the C-2-carbonyl group in the thymine moiety leads to pre-organization of R-monomer allowing the formation of a very stable homo-complex based on T:T base pairing. The analogue (43) has also been used to prepare branched oligonucleotides for triplex formation, with the second strand extended from the 2’-0-3’-ethylene hydroxyl group.174These Y shaped ODNs showed increased thermal stability towards DNA compared to fully linear oligonucleotides. The eight stereoisomers of LNA-T, e.g. (44), have been prepared and their hybridisation properties evaluated against RNA target^.'^^-'^^ Each of the stereoisomers showed remarkable affinity towards RNA targets except that from a-L-xylo-thymidine, which did not show a melting transition. Each of the stereoisomers is compared. The a - derivative ~ of LNA-T has also been shown to

224

Organophosphorus Chemistry

(42)

(43)

(44)

be destabilising in duplexes with both DNA and RNA if a single substitution is made, but a fully modified a-LNA sequence shows a marked increase in stability and affinity towards complementary RNA.'78Similar results were found with the adenine derivative of ~ - L - L N A . ' ~ ~ Stopped-flow kinetics has been used to examine the duplex formation of DNA duplexes containing LNA substitutions.'" Fast second-order association reactions were observed, with association constants of around 2 nM compared to a DNA-DNA duplex (10 nM). A 5'-terminal LNA nucleotide does not have the same stabilising ability as an internal substitution. The increase in stability of LNA-containing duplexes is due not to association rates but rather to slower rates of dissociation. T or C nucleobases form triplexes with a C-G pair, and the O2oxygen is probably important in this interaction. To probe this, a 2',4'-LNA derivative containing 2-pyridone, which lacks the other hydrogen bonding groups of the pyrimidines, was prepared.'8' The results demonstrated that the pyridone derivative stabilised the C.G pair with selectivity over a T-A pair. The incorporation of the 3'-endo locked (4',2') dU analogue (45) in TFOs enhanced thermal ~ t a b i l i t y , ' ~and ~ , ' ~confirms ~ that the correct conformational pre-organisation of a T F O favours its interaction with a duplex. The introduction of a 2'-O-methyl group into LNA (46)has the opposite effect to DNA, in that the LNA derivative is considerably de~tabi1ised.l~~ The conformationally-locked 3'-amino thymidine derivative (47) was prepared and incorporated into DNA as a dimer unit, attaching the amino group via a carbamate or phosphoramidate linkage.185Both modifications were found to be destabilising towards both RNA and DNA targets. The hybridisation properties of an amino-modified bicyclic thymine nucleotide (48) have been examined.'86Using alternate T and (48) residues there is an increase in duplex stability with d(A),,, with no pH dependence. When the amino group is acetylated, the duplex stability is decreased. The locked C-nucleoside oxazole derivative (49)has been incorporated into TFOs where it was found to selectively enhance the stability with a C.G base pair.'"

HO

0

OMe

0+-0 I 0.5

HO

0

H

225

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

Oligonucleotides containing conformationally-constrained abasic sites (50, 51) have been prepared.’88These abasic sites, like natural abasic sites, behave as universal base analogues with high destabilisation. The presence of the conformationally constrained analogue does not confer additional stability to the duplex. At low salt concentrations, however, the conformationally constrained analogue shows a tendency to stabilise the cavity formed by the missing base compared to flexible abasic sites. When the DNA nucleobases are attached to the ring via an acyclic linker,’89it was shown that the entropic cost of attaching the base by the flexible linker is overcome if the sugar-phosphate backbone is conformationally restricted. Other locked abasic sites have also been investigated,Ig0(52-54) and it was shown that the locked abasic site also did not confer duplex stability. In addition, the acyclic nucleosides were even more destabilising than the equivalent natural acyclic derivative. The locked abasic site has also been incorporated into TFOs where it was destabilising.”’ The pseudorotationally constrained abasic site ( 5 3 , based on bicyclo[3.l.O] hexane, has been incorporated into the methyltransferase M.HhaI recognition sequence to probe the mechanism of base flipping.19*Binding affinity increases when the abasic sugar is constrained to the north configuration, and is related to the ability of the abasic sugar to flip out of the DNA duplex.

I O

4-

‘0

‘0

.R

Y -

0

I

(50)

3

O,

0

(51) R=OCHzOCH3 R = NH2 R = OCH2Base

\

ZL (52)

(53)

Oligonucleotides have been prepared incorporating a number of naturally occurring sugar residues, the most common of which are arabino derivatives. Recently it was shown that hybrids of RNA and D-arabinonucleic acids (ANA) are substrates for RNase H.’933’94 The stereochemistry at C2’(C2’-endo)is a key factor for the activation of RNase H, and C D measurements of ANA/RNA hybrids are more similar to DNA/RNA than RNA/RNA. It was further demonstrated that 2’-fluoro-ANA form more stable duplexes than ANA-RNA, and adopt an A-like structure more like DNA-RNA, and still induce RNase H activity.lg5In addition, 2’-fluoro-ANA also form stable duplexes with DNA, unlike ANA. By studying the crystal structures of duplexes composed of ANA derivatives to determine the factors affecting cleavage by RNase H, Minasov et ~ 2 . l have ~ ~ shown that the ANA analogues may not be able to adopt sugar puckers that are compatible with pure A- or B-form duplexes. Rather, the analogues adopt an 04’-endo conformation. They suggest that this feature may be used by the enzyme to differentiate between RNA duplexes and DNA/RNA hybrids. Arabinonucleic acids (ANA) form duplexes with complementary RNA, direct RNase H degradation and are resistant to 3’-exonucleases.

226

Organophosphorus Chemistry

Thymine oligonucleotides containing the isonucleosides derived from L- (56) and D-arabinitol(57) and L-mannitol(58) have been described.’97The analogues were all slightly destabilising in duplexes with d(A),, though the mannitol nucleoside was similar to dT. Each of the analogues was shown to have significant resistance to snake venom phosphodiesterase. Both the D- and L-forms of an RNA duplex have been shown to be degraded by SVPD,’98though the L-form was degraded 1800-fold slower. Substitution within a short DNA duplex amenable to Z-form DNA of two contiguous L-nucleotides stabilised the left-handed Z-c~nformation.’~~ The Lnucleotides induced, at low salt concentration, a local left-handed conformation different from the existing Z-DNA, but which contributed to the lower energy required for B- to Z-transition. The role of the 3’-5’ exonuclease activity of the tumour suppressor p53 protein has been examined by an in vitro assay in which ODNs were terminated with either p-D or p-L of ddAMP or 3’-thio-ddc (SddC).*” The affinity of the p53 protein was shown to be five-fold lower for p-L nucleotides. ~-a’-threofuranosyl-(3’+ 2’) (TNA) oligonucleotides are structurally the simplest of potentially natural oligomeric nucleic acid structures. TNA duplexes show thermal stabilities similar to that of DNA and RNA, and TNA also forms stable duplexes with both RNA and DNA.*’l Oligonucleotides consisting of 2’,5’anhydro-3’-deoxy-3’-thymin-l-yl-~-mannitol incorporated as either 1’ 4’ (59) or 6’ + 4’ (60) linkages have been examined.*02Both oligonucleotides were resistant to SVPDE. Whilst the 1‘ -.+ 4’ oligonucleotide formed stable duplexes with complementary DNA comparable to that of the native duplex, oligonucleotides with the 6’ 4’ failed to hybridise. The C6’-hydroxylgroup is predicted to be on the surface of the duplex and may help stabilise the duplex by providing additional hydrogen bonding.

-

-

How woH

.OH

OH

L-Arabinitol (56)

OH

HO

D-Arabinitol

OH L-Mannitol

1‘-4‘ linkage

(57)

(58)

(59)

T

6’-4’ linkage

(60)

Previously, carbocyclic nucleosides have been studied in some detail, but these analogues were often poor substrates for enzymes. This may be a reason for why there have been so few reports on carbocyclic derivatives in oligonucleotides. The carbocyclic L-nucleoside derivatives (61, 62) which are fixed in the antiglycosyl conformation, have been prepared to examine factors determining the helicity of dsDNA.*03The anti-conformer was prepared to determine whether

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

227

glycosyl conformation is a major factor determining helicity. The data suggest that duplexes containing the analogues adopted a right-handed double helix, and the authors suggest that the major factor affecting the helical sense of DNA is glycosyl conformation and chirality of the deoxyribose. Oligonucleotides have been prepared incorporating the carbocyclic oxetanocin derivatives (63).204,205 The adenosine oligonucleotide gave superior thermal stability against ribooligouridine than with the oligothymidine. It also forms a stable triplex with ribo-oligouridine. 6’-a-[N-Aminoalkyl)carbamoyloxy]-carbocyclic-thymidine derivatives (64) have been introduced into oligonucleotides to enhance nuclease resistance?06 The lower homologues ( n = 1) had little effect on duplex stability, but the longer chains caused a decrease in T m .

0-., (64)

ft=

1-3

This final section deals with nucleotides with 6-membered ring sugars or derivatives. The development of these nucleotide systems is led primarily by the groups of Eschenmoser and Herdewijn, who have synthesised and studied many different systems. With hexose-based nucleotides, there are many different linkage systems, and a number of these have been reported. The Ld-pyranosyl(4’ --* 3’) oligonucleotide backbone207(65) has been shown to exhibit cooperative base pairing even though it only has five bonds per repeat unit instead of six. Duplexes adopt a B-form, but are less stable than the 4’ --* 2’ system. The a - ~ lyxopyranosyl4’ 2’ oligonucleotide system has also been studied2’’ and found to be an efficient Watson-Crick base pairing system. A number of members of the pentopyranosyl(4’ --* 2’) family of oligonucleotides have been prepared, and the stability of duplexes of these pyranosyl oligonucleotides The authors also demonstrate efficient intersystem cross-pairing with these analogues, though not with DNA or RNA. It is deduced that the 4’ ---* 2’ pentopyranosyl family adopts a common form of duplex, probably a weakly twisted ladder. The incorporation of 1,5-anhydrohexitol nucleoside triphosphates (hNTPs) (66) by various DNA polymerases has been demonstrafed,2l0but only the family of B DNA polymerases (e.g. Vent DNA polymerase) was able to extend from an anhydrohexitol nucleotide at the 3’-end. An in-depth study using molecular dynamics and NMR has been used to investigate the stability of hexitol (HNA), altritol (also termed ANA, cf: arabinonucleic acid), mannitol (MNA) and ribose (RNA) nucleic acids.211These have been investigated as single-stranded nucleic acids as well as cross-pairs in duplexes. Introduction of a (S)-3’-OH group to HNA leads to altritol nucleic acid (ANA) (67). A comparison of duplex stability of HNA and ANA with DNA and RNA showed that ANA gives the highest Tms,

-

228

Organophosphorus Chemistry

Double stranded ANA is considerand higher Tmswith RNA than with ably stable. C D measurements indicate that ANA duplexes are A-form. 0 \

O=P,

,O‘

0

\

HO (69)OMe

(67)

Using 5’-phosphoro-2-methylimidazole guanosine as an activated monophosphate in non-enzymatic template directed synthesis of RNA, a set of template oligonucleotides have been Using DNA, RNA, ANA (altritol) and HNA (hexitol) oligomers as templates, ANA was shown to be the superior template for RNA synthesis. The superiority of ANA over HNA and RNA was consistent with the greater stability of ANA-RNA duplexes. The replacement of the furanose ring by cyclohexene214(CeNA) (68) has been reported in oligonucleotides to stabilise duplexes with both DNA and RNA. CeNA is also stable in serum, and a CeNA:RNA hybrid is also a substrate for RNase H resulting in cleavage of the RNA. The D- and L- forms of cyclohexanyl adenine and thymine have been incorporated into olig~nucleotides.~~~ D-CYClohexanyl oligonucleotides form more stable duplexes than DNA with both complementary DNA and RNA, but with RNA the duplex is particularly stable. L-Cyclohexanyl oligonucleotides form at best only very weak duplexes with either DNA or RNA. The adenine derivative containing a 6-membered aza-sugar (69) was incorporated into DNA, and targeted against RNA and DNA complements.216The duplexes were destabilised against DNA, but against RNA, depending upon the location and number of substitutions, it was more stable. 2’-0-(3-~-Ribofuranosylcytidine and 1-P-D-galactopyranosyl thymine residues have been incorporated into oligonucleotides, which on treatment with sodium periodate undergoes cleavage of the 2’-sugar residue diol to yield a dialdeh~de.~” These have then been used to map the MvaI methyltransferase region that interacts with DNA by cross-linking to amino acid side chains of the protein. An alternative method for introducing an aldehyde function into oligonucleotides is to replace the nucleobase with a protected styrene glycol that is converted into the aldehyde by periodate oxidation.218

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

229

1.3.3 Oligonucleotides Containing ModiJied Buses. By far the most developments in oligonucleotide synthesis are those involving modified base analogues. These analogues fall broadly into three categories. The first are analogues that have been developed for incorporating functional groups, and the main points of attachment are C5 of pyrimidines and the amino groups of both cytosine and adenine. The second include analogues of the naturally occurring nucleotides, which are designed to probe structure or mechanisms of action. The third category is of analogues that are not related to the natural nucleotides, and generally they are non-hydrogen bonding aromatic derivatives. This section will discuss these various analogues, first the pyrimidine analogues, followed by purines and finally those that are not related to naturally occurring nucleotides. In pyrimidines, the C5 position is most frequently used to attach functional groups, largely because substitution at this position has little effect on Watson-Crick base pairing or on the structure of duplexes containing the modification. 5-Benzyloxymethyl- and 5-(N-methylpiperazinyl)-deoxyuridinederivatives have been incorporated into ODNs.’19 The piperazinyl derivative was found to be destabilising, whereas benzyloxymethyl d U was more stabilising. 5-Benzyloxymethyl-dU and -dC derivatives have been incorporated into duplex DNA as shape analogues of naturally occurring C5-glucosylatednucleosides (see 73).z20 However, the analogues were both found to be destabilising, probably as a result of loss of ordered water molecules in the major groove. The templating properties of oligonucleotides containing 5-formyl-2’deoxycytidine (fC), which may be introduced into DNA by oxidative damage of thymidine, have been examined with the Klenow fragment. It was found that fC directed the incorporation of dATP and TTP, thus giving rise to CG + TA transitions as well as CG AT transversions.221 The nucleobase 5-aminouracil, which has H-bonding capability on both sides, has been successfully used as the central base of a DNA triplet.22z,z23 In triplexes, nucleobase 5-aminouracil was recognised by each of the four natural bases, with selectivity based on parallel or antiparallel third strands. C5-Propynyl pyrimidines have often been used to stabilise duplexes. The stabilisation by propynyl units has been studied by UV and CD measurem e n t ~ The . ~ ~addition ~ of a single propynyl unit stabilises a duplex by 0-4 kcal/mol-’ depending on sequence. A propynyl pyrimidine as a dangling end stabilises both natural and propynylated duplexes similarly. In propynylated 0DN:RNA duplexes, there is a long-range cooperativity between propynyl units. ODNs containing 5-methyldC, 2-aminoadenine and 5-propynyldU have been targeted towards tRNAphe,225 and increased binding was observed. Oligonucleotides containing the modified base analogue, 5-propargylamino2’-aminoethoxy-uridine, have been incorporated into T F O S . *The ~ ~ presence of the two amino groups on the same nucleotide greatly enhances triplex stability. Parallel triplexes at oligopurine target sequences are stabilised by interruption with C5-propargylamino-dU at regular i n t e r v a l ~ , 2although ~~ if adjacent to a C+-GC,destabilisation occurs. Two Uridine triphosphates (70, 7 1) which possess additional functionality at the C5position have been prepared for use in in vitro selection.228The analogues

-

230

Organophosphorus Chemistry

were used to replace UTP in transcription reactions with T7 RNA polymerase. The analogues were incorporated less efficiently than UTP, but the authors suggest that these could be used in SELEX procedures to introduce new functionalities into RNA aptamers. By using the thymidine derivative (72),functionalised with either 5-cyanomethylcarbonyl or methoxycarbonyl groups, oligonucleotides may be prepared containing two different modification^.^^^ The reactivity of the two functional groups is significantly different, allowing the functionalisation of each with different amines. Nucleoside triphosphates containing an aminooxy function attached via a linker to either C5of UTP or N6 of ATP have been prepared, and incorporated into oligonucleotides using T7 RNA polymerase.23oOnce incorporated, the aminooxy function reacts with an aldehydic fluorescein derivative for post-amplification labelling.

HN

+

NH2

3

4-09~,~ HO

OH

(70)

HN+SH

‘ - 0 g P 3 0 3

HO

OH (71)

OA H

NI N

h

R

dR (72) R = OCHzCN R = OCH3

Base J (P-D-glucosyl-hydroxymethyluracil) (73) has been found as a minor component in the DNA of Trypanosoma brucei, replacing 0.5-1% of all thymines, a substantial amount being in the telomericic region. More recently, ~~’ J using antibodies to J, it has also found to be present in Euglena g r a ~ i l i c .Base has also been chemically incorporated into ODNs232,233 where it was shown to aid stabilisation of duplexes with DNA and in particular with RNA. A synthesis and incorporation into DNA of the glucosylated hydroxymethyl-2’-deoxycytidine derivative has also been reported.234The galactose modified d U (74) has also been incorporated into DNA duplexes,235 where it caused only a slight increase in duplex stability. Synthesis of the bile acid (75) conjugated to either the 3‘-end of an ODN or via a linker to the C5of dU are When used in vivo in rats, there was an increase in uptake to the liver, and this may be a method of targeting applications, such as antisense, to hepatic cells. The steroid 7-deoxycholic acid has also been incorporated into DNA via the C5of dU.237When used in TFOs, there was an increase in the triplex stability compared to unmodified controls. Various pyrimidines bearing photoreactive groups at C5 have also been studied. 5-Phenylthiomethyl-dU has been incorporated into O D N S . ~ The ~* phenylthiomethyl group undergoes photochemical cleavage to generate a methyl radical to give specific base lesions. The mechanism of photoinduced cleavage of duplex DNA containing 5-bromo- and 5-iodo-deoxyuridine (BrdU, IdU) has been examined.239It was found that cleavage of IdU-containing ODNs was smaller, which may be due to faster dehalogenation of the 5-halopyrimidine radical anion, or competitive carbon-iodine bond homolysis. IdU-containing ODNs do undergo strand scission involving photoinduced single electron trans-

23 1

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides OH

(73)

OH

dR

fer. The factors affecting cleavage of BrdU ODNs include electron transfer, charge recombination and electron migration. In the presence of oxygen the duplex strand break efficiency is decreased, but does not affect the overall strand damage? The photocleavage of ODNs containing 5-bromo-dU have been shown to lead to a 3'-furanyladenine end.241 Analogues of dUTP containing a photoreactive 2-nitro-5-azidobenzoyl group attached to C5via various length linkers have been prepared, and incorporated into DNA using DNA polymerase in place of t h ~ m i d i n e When . ~ ~ ~ irradiated with UV light in the presence of human replication protein A, the photoreactive group formed cross-links to the protein enabling an examination of the interactions between DNA and proteins. To introduce site-specific DNA photoreagents, ODNs, bearing the photoreactive [R~"(tap)~dip]~+ (76) have been prepared, attached to C5of dU via a linker.243The presence of the photoreagent had little or only slight effect on duplex stability when incorporated in the middle of a duplex, and under irradiation induced electron transfer from guanine to the target strand. A series of photolabels based on 4-thiothymine attached to C5 of d U (77), where X is a terminal amino linker of variable length and rigidity, have been incorporated into a hammerhead ribozyme.24 The analogues are able to form long-range photocrosslinks, and have been used to investigate tertiary structures to give proximity data. Shorter, more rigid linkers showed greater selectivity than longer flexible ones. Analogues chelated to metal ions have been incorporated into oligonucleotides. The incorporation into an 11-mer DNA duplex of the bipyridine ligand (bpy), (78), such that two bpy units are complementary, yields a duplex that can be stabilised by copper ions.245In the presence of copper, the duplex melts 10°C higher. In another phenanthroline-based (79) nucleosides have been incorporated into ODNs as hybridisation probes. Hairpin duplexes have been synthesised containing two phenanthroline nucleosides, one containing Ru" which exhibits a long-lived excited state, the other Os", which is non-emissive

232

Organophosphorus Chemistry S

I

tap

dR

(76)

(77)

I

'R

(78)

dR

(79) M = Ru2+ M = OS2+

and acts as a quencher of the Ru" excited state, which may be used as metallobeacons. When the Ru" and 0 s " are in proximity, the Ru" emission is quenched, but when hybridised to a complementary ODN, the Ru" emission is restored. This system has also been used to discriminate mismatches where the luminescence intensity is decreased. The analogue (79) has also been incorporated into ODNs, via a linker, to effect the site-specific formation of thymine glycol in the presence of osmium t e t r ~ x i d e . ~ ~ ~ dUTP labelled at C5with a europium tris-bipyridine cryptate (K-1 1-dUTP) has been prepared, and incorporated into DNA e n ~ y m a t i c a l l yThe . ~ ~ ~incorporation of the analogue was monitored by a FRET based method (Time Resolved Amplification of Cryptate Emission, TRACE), and further TR-FRET bioassays may be possible. The uridine-conjugated ferrocene derivatives, (80-82), have been incorporated into DNA and the Tmsof duplexes containing them measured.249Each analogue showed a marked preference for pairing with dG, and the Tmsof the two duplexes were very similar. The authors conclude that the uridine analogue (80) undergoes rearrangement during DNA synthesis to give the furanopyrimidine derivative (81). Ferrocene has also been introduced into ODNs by the on-column reaction of ferrocenoyl propargylamide with 5-iodod U containing DNA using Pd(0) cross-coupling.250These authors also found that the presence of the ferrocene in DNA duplexes was only slightly destabilising. Ferrocene has also been attached to thymidine via the N3-nitrogen and incorporIn duplexes the ferrocene caused a destabilisation especially ated into ODNs.251 in internal positions of the duplex. In triplexes the ferrocene stabilised the third strand. The phosphoramidite derivatives of A and C have been prepared with a ferrocenyl group attached to the 2'-position through a butoxy linker.252DNA containing these analogues showed no depression of melting temperature com-

233

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

pared to native duplexes. The ferrocene-modified DNA studied by cyclic voltametry showed that the complexes are electrochemically active, and could be used as signalling probes in electronic detection of nucleic acids on bioelectronic sensors. Fc

dR

dR (80)

(81) Fc = ferrocene

0

I

dR

(82)

Two pyrimidine analogues have been incorporated into ODNs to study electron transport. To study DNA-mediated electron transfer, the analogue (83) has been prepared and incorporated into DNA.2s3The analogue is reported to be an excellent chromophore for one-electron oxidation of DNA. In the present study, the analogue has been shown to have little effect on duplex stability. The efficiency of charge transport mediated by DNA n-stacking has been investigated using the analogue (84) which is a strong electron accepting chromoUnder photochemical conditions, the radical cation G was site selectively generated adjacent to the A:84 site, and the hole migrated to a remote GG site. A number of other modified 2’-deoxyuridine analogues have been studied in oligonucleotides. The tetrathiafulvalene derivative (85) has been incorporated into oligoribonucleotides?s6 The analogue was shown to be redox active. The (86) fluorescent analogue benzo [g]quinazoline-2’-O-methyl-~-~-ribofuranoside has been incorporated into the pyrimidine bulge of the HIV-1 TAR stem loop to study the binding of Tat peptide and antisense O D N S .The ~ ~ binding ~ of Tat was found to be 2-3-fold stronger than previously reported by gel shift assays. The role of U + 2 in loop A of the hairpin ribozyme has been studied by replacement with 4-thio-, 2-thio- and 4-O-methyluridine, and measuring the cleavage rates of the modified r i b o ~ y m e These . ~ ~ ~ results, coupled with photocrosslinking data, demonstrated that the O4 of U + 2 is involved in hydrogen bonding in loop A, but O2 is not. 4-Thiothymidine 5’-triphosphate has been shown to be an excellent substrate for Klenow fragment and HIV-1 RT, with kcat/& within a factor of three of those for TTP.2s94-Thio-2’-deoxyuridine and 6-thio-2’-deoxyinosine have also been used to produce disulfide crosslinks in ODNS?~’Duplexes, including hairpins, with base pairs including 4SdUand 6SdI undergo high yield crosslinking in the presence of iodine. An assay has been developed for screening thermostable DNA polymerases for their ability to incorporate modified oligonucleotides.261The assay was exemplified by identifying the best polymerase for incorporating the C-nucleoside pseudothymidine. 2’-Deoxypseudouridine has been functionalised at N’ with methyl acrylate and further functionalised with and incorporated into duplex DNA. Without the fluorescent dye, the analogue had little effect on duplex +

234

Organophosphorus Chemistry

I

2'-OMe rib (86)

stability, but addition of the dye caused destabilisation. 2'-Deoxypseudouridine has advantages over dU due to the ease of modification of the former. A number of cytosine analogues have also been studied. To reduce the possibility of secondary structures in DNA, C-G base-pairs were replaced by N4-ethyldC (d4EtC).Gpairs.263d4EtCpairs specifically with dG, but with reduced stability, thus allowing hybridisation with complementary probes of natural DNA. 2'-Deoxycytidine derivatives with additional functionality at N4, one based on semicarbazide, the other a monoacetylated semicarbazide (87) have been incorporated into TFOs to target selectively a C-G base pair,264though substantial modifications to the DNA synthesis need to be used. The analogues showed favourable Tms with target C-G base pairs, and caused significant destabilisation against G-C base pairs. The introduction of a guanidino group to C4 has been used to mimic the double H-bond donor pattern of protonated cytosines in parallel triple helices.265Guanidino and substituted guanidino nucleosides have been incorporated into ODNs via their H-phosphonate derivatives, though no data have been supplied yet. To investigate the mode of action of RNase P, a disulfide intra-strand crosslink was introduced proximal to the cleavage site.266The disulfide cross-link was introduced by the analogue N4-thioethyl-C, which formed the cross-link with another N4-thioethyl-C in the opposite strand. RNase P was unable to process the duplex with the cross-link, suggesting that helix unwinding near the cleavage site is necessary. NHR

f-N

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

235

6-Formyl-2’-O-methylcytidine was used to replace thymidine in a DNA Myb binding The formyl group was introduced into DNA as a 1,2dihydroxyethyl side chain, which was then subjected to oxidative cleavage using periodate. The incorporation of the C6-formyl group abolished binding to the protein. The effect of the analogue 6-0x0-cytosine in TFOs has been studied, using the ribose and 2’-deoxyribose derivatives, as well as analogues of 6-0x0cytosine bearing a C5-ally1group.268The presence of the C5-ally1group was found to be destabilising, and RNA TFOs did not form triples. When 6-0x0-dC DNA ODNs are used as TFOs they form the most stable triplexes. 2’-Deoxyisocytidine (‘dC) has been introduced into DNA using a (dimethy1amino)methylidene protecting group to stabilise the acid-labile glycosidic bond during synthesis.269In parallel stranded DNA, the stability of duplexes containing ‘dC and the effect of a 5-methyl group (5-MeidC) have been studied where it was shown that the 5-methyl group infers extra stability in the duplex. 5-MeidC and 2’-deoxyisoguanosinehave been incorporated into duplexes opposite dG and dC, re~pectively.~~’ Parallel strand duplexes containing 5methylisocytosine-guanine base pairs were found to be significantly less stable than cytosine-isoguanine pairs. A single-stranded DNA that folds to form duplexes and triplexes analogous to a paper-clip has been studied with and without the modified base pseudoisocytidine in place of dC.271At neutral pH, triplex formation was stabilised by pseudoisocytidine as it can serve as a proton donor without protonation. DNA damage and repair is an area of great interest, in particular because damaged DNA can be a cause of cancerous growths. Alkylating agents can cause damage to DNA leading to mutations. One such alkylated product is 3,N4ethano-dC (88). The synthesis of oligonucleotides containing ethano-dC has been and the templating properties examined using Klenow fragment in comparison with etheno-dC. Ethano-dC is mutagenic, but less so than etheno-dC. A method for the incorporation of thymine glycol into ODNs from its phosphoramidite building block has been The synthesis and incorporhas ation of the UV-damaged analogue, (SR)-5,6-dihydro-5-hydroxythymidine, been Melting studies demonstrated that the analogue destabilises DNA, but still preferentially base pairs with A. However, the analogue disrupts the base pairing at the 5’-nucleotide, resulting in misincorporation of purines opposite the displaced adenosine. The incorporation of the 5R and 5 s diastereoisomers of the 5-hydroxyhydantoin (derived from oxidative damage of dC) derivative (89) has been achieved using phosphoramidite chemistry and mild d e p r ~ t e c t i o nWhilst . ~ ~ ~ the ODNs containing either diastereoisomer were digested with nuclease PI,the hydantoin derivatives were resistant to digestion by calf spleen and bovine intestinal mucosa phosphodiesterases. The preparation of ODNs containing a non-adjacent cis-syn-cyclobutane thymine dimer has been rep0rted.2~~ Triplet-sensitised irradiation of a duplex containing a d(TCT) sequence gave rise to the dimer between the two thymines.

236

Organophosphorus Chemistry

Mutagenesis studies showed that this type of mutation induced a -1 frameshift. A further report describes the incorporation of an (adjacent) cis-syn cyclobutane dimer site specifically into a n u c l e ~ s o m e ?The ~ ~ templating properties of the thymine photoproducts, including the Dewar photoproduct (176), have been examined using the pyrene C-nucleoside tripho~phate.2~' The pyrene nucleotide was inserted in preference to dATP opposite the 3'-T of the photoproducts in all cases except for a trans,syn photoproduct, whereas dATP was preferentially incorporated opposite the 5'-T in all cases. This suggests that the incorporation opposite the 3'-end of the photoproduct takes place via a transient abasic site-like intermediate. tRNA contains a number of hypermodified base analogues, and a number of these analogues have been synthesised and incorporated into oligonucleotides. The anticodon domain of E. coli tRNALYs,which contains the hypermodified nucleoside mnm5s2U(90) and t6A (91) in addition to pseudouridine (Q)(92), has been prepared and studied with the incorporation of each of the modified r i b o n u c l e o ~ i d e sThe . ~ ~NMR ~ ~ ~ ~solution ~ structure shows that the hypermodified nucleotides stabilise a U-turn structure281similar to that in the crystal structure of the yeast tRNAPhestructure.282The anticodon loop of tRNAMetincorporating t6A has also been ~repared.2'~ Also, the tRNALys9'anticodon stem-loop has been synthesised containing mcm5s2U.2g4 The analogues 6-methyl- (m6U) and 5,6dimethyluridine (m'm'U) (93) have been incorporated into various positions in ODNs corresponding to the anticodon loop of tRNApheand TY C domains.285 Both analogues retained the expected syn conformation, but the loss of stability of duplexes containing the analogues was found to be sequence dependent. 0

V O H

0

Rib mnm5s2u (90)

0

Rib t6A (91)

oQH wRib dR

(92)

(93)

x = S, rncm5s2u x = 0, mcm5u

(94)

Pyrimidine analogues lacking one or more heteroatoms or functional groups have been used to investigate the role of hydrogen bonding and steric interactions in oligonucleotides. The nucleoside analogue derived from 4-methylpyridin-2-one (94) has been studied in DNA replication.286As a template base, the analogue directs the incorporation of dGTP, whilst as a triphosphate, the analogue is preferentially incorporated opposite dA. The authors attribute this difference in specificity to the fact that as an incoming triphosphate, the methyl group freely rotates and thus incorporation can occur without steric hindrance, whereas in the template the methyl group is constrained by stacking interactions between neighbouring bases. Recognition of a C-G base pair by a parallel third strand was achieved using

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

237

the base analogue 5-methyl pyrimidin-2-0ne.~~~ The T, of the triplex was slightly increased compared to a third strand containing 5-methyl-dC. Similar results were observed using the LNA derivative of 2-p~ridone.'~' A series of mainly pyrimidine analogues (95-99) incorporated into a conserved d(CTG) site have

4 6,

H3c+H

I

dR d2APy (95)

dR dc3C (96)

dR d5rnOXC (97)

dR dM32P (98)

H3cfj I

dR dH2T (99)

been used to examine the effects of T7 primase reactions.288The analogue d2Apy supported oligoribonucleotide synthesis, but the analogues dc3C (N3-deaza-2'deoxycytidine) and dSmoxC (5-methyl-6-oxo-2'-deoxycytidine) did not, suggesting the importance of the cytidine N3 for enzyme recognition. This is in contrast to that found with Klenow fragment, which incorporated dG opposite dc3Csimilar to dC.289However, the loss of the central H-bond in duplexes containing dc3CdG was strongly destabilised suggesting the importance of the cytidine N3in base pairing. Substitution of thymidine by the analogues dU, dm32P (3-methyl-2pyrimidone) and d2HT(5methylpyrimidone) confirmed the importance of Watson-Crick H-bond interactions. Duplexes containing a base-pair between dm32Pand 3-deazaadenine mimic the dA-T base pair, but lack polar functional groups in the minor groove. The inclusion of this base pair in dA-T rich sequences results in duplex destabilisation, which may be explained by the loss of hydration in the minor groove.290 Lan and McLaughlin have demonstrated that minor groove hydration is critical to the stability of DNA duplexes.291By replacing dA with 3-deaza-dA, and T with 3-methyl-2-pyrimidionethey demonstrated that the N3of dA and O2 of T are involved with hydration in the minor groove, and using the analogues is destabilising in duplex DNA. Eight base analogues have been tested for their ability to stabilise an inverted base pair in an otherwise homopyrimidine strand for their ability to stabilise a third strand of a triplex.292However, no obvious rationale for stabilising an inverted base pair emerged. As with pyrimidine analogues, there are many purine modifications that have been examined. The principal points of attachment to purines are C8and 06/N6 of adenine and guanine, and C2 of adenine, as well as guanine N2.The incorporation of 8-bromo-dG in place of dG into ODNs leads to a destabilisation of duplexes293 as a result of it being preferentially in the syn conformation. However, it is strongly stabilising in Z-DNA. Attachment of propyne to C8of dA residues destabilises DNA duplexes, probably due to the increase in syn conformation.294 However, the modification is stabilising when used in parallel quadruplex structures. 8-Amino-dG has been incorporated into DNA to investigate its mutagenic properties, as it is one of the types of DNA damage found in the liver. In DNA,

238

Organophosphorus Chemistry

8-amino-dG forms base pairs with the natural DNA bases in the order C > T > G > A. Mutagenesis in E. coli showed that the analogue is weakly mutagenic, forming both transition and transversion N2-Methyl-dG, formed by the reaction of formaldehyde with dG, has also been shown to be mutagenic in DNA, giving rise to G A transition Using molecular dynamics calculations, the effect of attaching an amino group to positions 2 and 8 of dI has been examined. As a result, each analogue was prepared and incorporated into DNA.297The 2-amino-dI analogue stabilises both duplexes and triplexes, whilst the 8-amino-dI derivative stabilises triplexes, but destabilises duplexes. Nevertheless, 8-amino-dI is shown to behave as a universal base. In a similar the triplex-stabilising properties of 8amino-dG were calculated and verified by synthesis and incorporation into DNA. The presence of 8-amino-dG stabilises triplex formation at neutral and acid pH, and it is suggested that the stabilisation is due to an additional Hoogsteen H-bond and favourable electrostatic interactions of the 8-amino group in the DNA groove. Using Pd(0) cross-coupling chemistry, dA labelled at C8 with phenothiazine and anthraquinone have been incorporated into DNA as redox ODNs containing these analogues formed stable B-form duplexes, and were only slightly destabilised by the modification. N2-Methylation of guanosine residues of a parallel G-quadruplex was shown to give enhanced thermodynamic ~ t a b i l i t y In . ~ ~addition, an antisense ODN with anti-HIV-1 activity had higher activity with N2-methyl-dG residues, compared to the unmodified ODN. Replacement of the amino group of dG with spermine stabilises DNA duplexes 3°C per m~dification.~" The mutagenic potential of adenosine N6-adducts derived from benzo[c] phenanthrene-3,4-diol- 1,2-epoxide has been studied in O D N S . ~ 'Generally ~ those bulky lesions with S configuration had higher mutation frequencies than those with R configuration. Both isomers were also found to block RNA synthesis by T7 RNA p01ymerase,3'~and led to lower levels of transcription initiation. Oligonucleotides containing the guanine N2 adduct with tetrahydrobenzo[a]pyrene have been prepared post synthesis by incorporation of an 02-triflate modified deoxyxanthosine p h o ~ p h o r a m i d i t eThe . ~ ~incorporation of the dA analogues (100)into a 3-way junction increased the thermal stability of it, particularly with the pyrenylmethyl-dA.305 Post-synthesis modification may be used to introduce a number of 06-alkylated guanosine derivatives into oligonucleotides?06Using a 06-methoxycarbonylmethyl-dG phosphoramidite and different oligonucleotide deprotection conditions leads to a number of different alkylated guanosine derivatives. One of the main modifications to purine analogues is as N7-deaza derivatives. The N7 nitrogen is involved in Hoogsteen base pairing, and removal of this nitrogen provides a new point of attachment. ODNs bearing alkynyl or aminoalkynyl side chains at C7 of 7-deaza-dA have been prepared and their stability in duplexes studied.307Whilst an ethynyl side chain enhances duplex stability a longer chain, or chains with bulky residues are destabilising. The introduction of an amino group into the side chain led to even higher stability, especially at low

-

-

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

239

HN"A~ I

dR (103) X = Br, I

0

0

dR 5-methyl-isodC (106)

dR (108) R = H, Br

salt concentration. C7-Substituted 7-deaza-8-aza-dG analogues have also been .~~~ studied, incorporating Br, I, CN, CONH2 and hexynyl s u b s t i t ~ t i o n sWhen targeted towards complementary DNA there was an increase in duplex stability, but little effect is observed with complementary RNA. The incorporation of 2'-deoxysangivamycin (101) into DNA has been carried out via the 7-cyano (toyocomycin) phosphoramidite deri~afive.3~~ Once incorporated into DNA, the nitrile is converted to the carboxamide under the normal DNA deprotection conditions. The analogue was shown to be stabilising when in duplexes in place of dA. Seela et aL3" have shown that parallel stranded DNA is stabilised by replacing dA and dG with the modified 7-substituted-7-deaza analogues (102-104). Also the N7-glycosylated adenosine derivative aids stabilisation of parallel stranded DNA. The incorporation of 7-chloro-7-deaza-dG in place of dG in a TFO decreases the TFO self-association and slightly increases triplex stability.311The C8-2'-deoxy-~-~-ribofuranoside of 7-deazaguanine (105) has been incorporated into DNA and shown to form stable duplexes with 2'-deoxy-5-methylisocytidine (106)but not with dC in antiparallel O D N S . ~Thus ' ~ the shift in glycosylation site has an effect on its base pairing recognition. The pyrrolopyrimidine derivative (107), in which the sugar is attached to the N8 position (purine numbering), has also been shown to behave as a universal base.313Its unique feature, compared to other universal base analogues,314is that it is able to form bidentate H-bonds with each of the natural DNA bases. The pyrrolo[3,4-d]pyrimidine analogues (108) have been incorporated into DNA, and the stability of duplexes containing them measured. When dA is substituted by the 7-bromo derivative the resulting 'dA-dT' base-pair is as strong as a dG-dC b a ~ e - p a i r This . ~ ~ ~analogue can therefore be used to harmonise the stability of DNA duplexes, as the stability is no longer dependent on base pair composition. The effects of bromo and iodo substituents in the major groove of DNA have been investigated using 7-halo-7-deaza-8-aza-adenosine and 5-halo-dU derivat i v e ~The . ~ ~incorporation ~ of bromo or iodo groups onto the purine derivative always gave higher stability compared to dA or 7-deaza-8-aza-adenosine. However, there was little effect on substitution of dU. The P-linked 8-aza-7-deaza-

240

Organophosphorus Chemistry

A analogue (109) forms strong base pairs with dT in anti-parallel DNA, but in parallel DNA it is less Due to the unusual glycosidic linkage, the N6-amino group points towards the minor groove, so incorporation of bulky groups at C7(such as Br, I) causes duplex destabilisation. Electrospray mass spectrometry has been used to identify and aid characterisation of covalently linked aromatic compounds to guanosine Such adducts are biomarkers used to quantify exposure to mutagenic and carcinogenic environmental substances, and the method described may be used to characterise intact DNA-adducts.

OH

I dR

PN7ap

OH

Various other purine analogues have been reported. Triplex-forming ODNs designed to bind in the antiparallel binding motif were prepared, incorporating single substitutions of the isomeric aN7- (110), pN7- ( l l l ) , aN9- (112) and (3N9-2-aminopurinederivatives (1 13).319,320 The aN7-derivative showed a preference for recognising a TA inversion. The pN7- derivative acts as a replacement for T or A in recognising an AT base pair. The aN9-derivative was not able to discriminate between the target base-pairs, acting as a universal base. The PN9-derivative showed preference for a GC base-pair, and may represent a G replacement in TFOs. The two diastereoisomers of the 5’-8-adenosine cyclonucleoside have been incorporated into DNA and shown to block DNA replication by various polymerases when present in the template strand.321 Both isomers were substrates for the human nucleotide excision-repair enzyme, though the R diastereoisomer was repaired more efficiently. The synthesis and stability of GNRA (R = G or A) hairpin loop structures has been investigated using the purine analogues inosine, 2-aminopurine riboside and n e b ~ l a r i n e .Using ~ ~ ~ UV and CD measurements, the role of hydrogen bonding and base stacking interactions are investigated using the analogues. Exchanging the loop sequence (ANRG) leads towards a UNCG type of base stacking.

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

24 1

Studies to determine the nature of the base pair between 2-aminopurine (2-AP) and cytosine demonstrate that there is an equilibrium between the neutral wobble and protonated W-C pairs.323The pK for the transition between the two forms is 5.9-6.0. The 5'-triphosphate nucleoside derivative of 2-AP has been used for random mutagenesis in PCR.324The analogue induced transition mutations, but at low frequency. At high concentrations of the triphosphate, PCR was inhibited. A comparison of the nucleoside analogues of 2-AP and 8-aza-7-deaza2-AP in DNA duplexes shows that the analogues have similar effect on duplex stability, which is destabilising compared to dA.325However, the 8-aza-7-deaza2-aminopurine analogue is fluorescent, and duplex melting can be monitored using this fluorescent property. 2'-Deoxyisoinosine and 8-aza-7-deaza-2'-deoxyisoinosine form base pairs with 2'-deoxy-5-methylisocytidine in anti-parallel DNA and dC in parallel DNA,326though the base pairs are less stable than Watson-Crick dA-dT or dI-dC pairs. Both analogues are fluorescent, and T, values have been recorded using fluorescence, and found to be the same as that achieved by UV melting. Duplexes prepared from a 2-fluoroinosine protected monomer have been modified with a variety of amines giving N2-modified d G 01igomers.~~~ All modified duplexes had higher thermal stability than with unmodified DNA, the highest stabilisation occurring with ethyl- and propyl-amino groups, which are protonated at physiological pH. An improved method for the incorporation of 2'-deoxyxanthosine (dX) has been reported.328The stability of dX in duplexes opposite each of the natural bases is in the order T > G > A = C at pH 7.5, and A T > C > G at pH 5.5, which is in general agreement with a previous report.3292-Aza-dA (114)when incorporated into duplexes forms the most stable base pair with dG,330almost equivalent to a C.G base pair. It also forms a more stable duplex when present as a dangling end than thymidine. In addition to the hypermodified nucleosides in tRNA discussed earlier, there have been some of the modified purine analogues prepared. I n vitro transcripts of the tRNALySdo not fold into the normal cloverleaf structure. A chimeric tRNALys incorporating a single N'-methyladenosine (m'A) at position 9 folded into a structure that resembled the native tRNA due to Watson-Crick base pair disruption.3317-Methylguanosine (m7G)is used in eukaryotic cells to mark the 5'-end of mRNAs, and is required in key events in gene expression. The structural requirements for the recognition of m7G have been examined by amino acid modifications in m7G protein binding sites.332 Two photoreactive dATP analogues (115, 116) have been incorporated into DNA using Klenow fragment. Subsequent UV irradiation of the primer extension reaction allowed specific cross-linking of the analogues to the polymerase.333 d(GTG)-cisplatin-modifiedDNA has been used to probe the binding site for the human replication protein A (hRPA).334It undergoes specific and efficient photocrosslinking within the ssDNA-binding domain of hRPA. A family of d(GpG)-cisplatin-modified duplexes have been studied by spectroscopy to examine the sequence effect of the lesion.335The cross-link alters the structure of the duplex to a more A-like form, and the nature of the flanking base pairs has an

-

242

Organophosphorus Chemistry

dRTP DB-dATP dRTP = 2'-deoxyribosed'-triphosphate (1 15) (116)

&TP

AB-dATP

effect both on the extent of cross-linking and the change in conformation to an A-like duplex. A number of DNA damage purine analogues have been incorporated into oligonucleotides. 8-Hydroxy-dGTP and 2-hydroxy-dATP9which correspond to two types of oxidative damage in DNA, were incorporated into E . coli strains using E. coli Pol I11 holoenzyme. Using the supF gene as a mutagenesis target, 2-hydroxy-dATP was shown to be highly mutagenic, inducing G T transver~ i o n . ~ ~ ~ The analogue N2-ethyl-dG, formed by the action of acetaldehyde, has been incorporated into ODNs to examine the mutagenicity of the lesion using Klenow fragment.337Primer extension was retarded one base prior to or opposite the lesion, though under forcing conditions full extension occurs. Using steady state kinetics, it was shown that G C transversions occur. The fluorescence and hybridising properties of the a-anomer of l,N(6)-etheno-dA(a-Ed A) in DNA duplexes has been The most stable base pair is a -&dA-dGwhilst with dC it is least stable. Fluorescence anisotropy measurements show that all base pairs except a-EdA-dG show significant conformational flexibility. ODNs containing the oxidatively damaged guanosine oxazolone (117) were prepared by photochemical oxidation, and the mutagenic behaviour of the analogue studied.339The analogue induced misincorporation of dAMP and to a lesser extent dGMP.

-

-

Q I

dR (1 17)

R-a-N6-(adeny1)-styreneoxide (1 18)

HO ----I

S-a-N6-(adeny1)-styreneoxide (1 19)

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

243

Conformational studies of R- and S-a-N6-(adeny1)styreneoxide adducts (118, 119) mismatched with dC have been The S-adduct gave a stable solution structure, whilst the R-adduct was disordered, and a shift towards the minor groove for the A-C mismatch is observed for the S-adduct. The data may suggest why the S-adduct gives rise to A .--, G mutations whilst the R-adduct is non-mutagenic. The effect of binding of Klenow fragment to a primer-template incorporating a bulky lesion in the template strand has been examined. Template strands incorporating the pyrene metabolite anti-BPDE to N2 of a dG residue were used to study the binding and DNA replication past the lesion.342+343 When the 3’-end of the primer is opposite the lesion or at the -1 position, the binding of Klenow fragment is 10-15-fold lower. The replication of both isomers of the lesion has been studied, where it was shown that extension occurs best when dT is opposite the lesion at the 3’-end of the primer, which may correlate with the observation that the lesion causes G + A transition mutations.344 The mutagenic lesions 2-aminofluorene and 2-acetylaminofluorene attached to the C8 of dG have been examined for their mutagenic potential.345The lesions induce G .--, T transversions and G A transitions depending upon the flanking base. The incorporation into anti-parallel DNA of a cross-linked Watson-Crick base pair (120)has been though no data for the duplexes formed are provided. A dissociable covalently bonded base pair (121), modelled to impose minimal distortion of the duplex, was used to replace a Watson-Crick base pair in O D N S . ~The ~ ’ second (complementary) strand was introduced by ligation of appropriate ODNs. The un-natural base pair between 2-amino-N6-dimethylpurine and pyridin-2-one has been developed for specific transcription.348The ribo-triphosphate of pyridin-2-one and the 5-methyl derivative are selectively incorporated opposite 2-amino-N6-dimethyl-purine by T7 RNA polymerase. The bulky dimethyl group prevents recognition and pairing by the natural bases. The abasic site occurs naturally as a result of DNA damage and repair. A number of synthetic analogues of the abasic site have been studied as has the effect of neighbouring bases in duplexes.349 It was found that purines adjacent to

-

an abasic site tend to shift together, creating an overlap which aided stabilisation, which was not found for neighbouring pyrimidines, Belmont et ~ 1 . ~have ~ ’ made use of abasic sites in DNA to design an aminoacridine-based probe to target specifically the abasic site without cleavage. The inhibition of abasic site repair is a strategy to potentiate the action of antitumor DNA alkylating agents.

244

Organophosphorus Chemistry

The presence of the probe in the abasic site is confirmed by hybridisation studies and by NMR. The authors have shown the existence of an apparent synergy with the anticancer agent BCNU. The incorporation of the hydroxyphenylbenzoxazole derivative (122) opposite an abasic site in a duplex is a reasonable mimic of a Watson-Crick b a ~ e - p a i r . ~The ~ ’ ?analogue ~~~ undergoes an excited state intramolecular proton transfer under photolysis conditions, which has been used to study tautomerisation within a DNA duplex. The final part of this section deals with analogues that are not derivatives of the naturally occurring nucleosides, but are generally hydrophobic aromatic nucleoside derivatives. Some of these analogues have been described as universal base analogues as they interact with the native bases with little discrimination between them. The effects of incorporating the universal base 5-nitr0indole~~~ into DNA hairpins has been investigated354by UV and calorimetric melting studies and circular dichroism studies. When two residues are incorporated opposite each other in the stem, the structure still forms a stable hairpin but with reduced stability. The presence of 5-nitroindole in the loop gives a more stable structure (than the un-modified T4 loop), probably due to enhanced stacking and hydrophobic interactions. A set of universal base analogues, including 3-nitropyrrole, 4-, 5- and 6-nitroindole, 5-fluoroindole, benzimidazole, 5-nitroindazole and hypoxanthine have been investigated for stabilising short primers for cycle sequencing.355Of these, a tail of four 5-nitroindole residues was shown to stabilise 8-mers the most efficiently. The effect of nearest neighbour, including mismatches, on the selectivity of the universal base, 3-nitropyrrole, has been investigated by thermal melting.356In most cases the analogue behaves as a universal base, but when there is a G or C 5’ to 3-nitropyrrole, then the specificity is reduced. The analogue (123), nitropiperonyl-2’-deoxyriboside, behaves as a universal base, though it is de~tabilising.~~’ However, UV irradiation of DNA containing the analogue causes strand cleavage leaving the 3’- and 5’-phosphates. The incorporation of the ribonucleosides of 4-fluoro- and 4,6-difluorobenzimidazole and the C-nucleosides of 2-, 3- and 4-fluorobenzene and 2,4-difluorobenzene into RNA duplexes showed that all analogues behaved as universal bases.358Each duplex was found to be A-form from CD measurements. The differences in thermal stability are explained in terms of stacking interactions and solvophobic effects. The 5’-triphosphate deoxynucleoside derivatives of pyrrole-3-carboxamide and pyrrole 3,4-dicarboxamide have been incorporated into DNA with DNA polymera~es.”~They are preferentially incorporated with Klenow fragment where they are incorporated as either dA or dC. The base analogue 1,2,4triazole-3-carboxamide (124) can exist in four different conformations by rotation about the glycosidic or carboxamide bonds, and thus can in principle behave as a universal base. The analogue has been examined by NMR in duplexes opposite G and T where it is anticipated that it would adopt syn and anti conformations, re~pectively.~~’ NMR showed that in both duplexes, the complementary nucleotide adopted a syn conformation, and the carboxamide group is able to adopt two rotational isomers.

245

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

Isocarbostyril nucleoside derivatives are universal base analogues, forming stable base pairs with each of the natural DNA bases without dis~rimination.~~~ Pyrimidones (125) and (126) direct the insertion of each of the natural DNA triphosphates using Klenow fragment with only four-fold lower efficiency. PIMT P (127) is inserted efficiently into DNA, but causes chain termination. The analogue (128) related to PIM, however, showed a marked preference for selfpairing, forming the most stable duplex and the triphosphate preferentially incorporated when paired opposite i t ~ e l f . ~ ~ ~ ? ~ ~ ’ .O

anti

I

dR anti

dR

(123) Me

PIM (127)

The non-polar isostere of dA, 4-methylind0le,3~~ has been studied by the DNA repair enzyme MutY opposite the oxidatively damaged analogue 8 - 0 x o - d G . ~ ~ ~ The 4-methylindole:8-oxo-dG base pair is more efficiently recognised than 7deaza-dA:8-oxo-dG, and the authors speculate that this may be due to the lack of H-bonding in the former base-pair. Kool and co-w~rkers’’~ have examined the effect of duplexes with dangling ends in some detail using the natural DNA bases and the non-hydrogen bonding deoxynucleoside analogues of pyrrole, 4-methylindole, 5-nitroindole and the C-nucleosides of benzene, naphthalene, phenanthrene and pyrene. Using T, studies, they showed that a dangling nucleotide stabilised duplexes; of the natural bases adenine was the most effective, and for the non-hydrogen bonding analogues, the duplex stability increased with the size of the analogue. The exception to this was 5-nitroindole, which was more stabilising than might be expected according to its size. Hydrophobic effects were found to be a major contributor to stacking ability, with the natural bases being less affected than the non-polar analogues. Morales and K001366-368 have used a set of non-polar isosteres of natural DNA bases to probe the interactions at the active site of a number of different polymerases by replacing the deoxynucleoside analogues of difluorotoluene (F) for thymidine and 4-methylbenzimidazole (Z) or 9-methyl-l-H-imidazo[4,5-b] pyridine (Q)(129) for adenosine. Their findings showed that each polymerase, Klenow (exo-) fragment, Taq, T7- and HIV-RT, were all able to efficiently generate the non-natural base-pairs A-F, F-A, F-Z and Z-F. Calf thymus DNA

246

Organophosphorus Chemistry

Pol a and AMV-RT were able to partially synthesise A-F and F-A, but not F-Z and Z-F. When Z was replaced by Q, which possesses a minor groove acceptor nitrogen, then these polymerases were able to synthesise Q-F and F-Q basepairs. This supports the evidence that there is a H-bonding interaction between the polymerase and the incipient base pair for these enzymes. A final set of polymerases, human DNA Pol p and MMLV-RT failed to replicate any of the F-Z or F-Q base pairs which adds to the view that there is hydrogen bonding recognition for template and triphosphate for these enzymes.

Me

Dipic

(130)

PY

Molecular dynamics simulations were performed369on a dsDNA dodecamer in which the adenine residues were replaced by a water-mimicking analogue 2'deoxy-7-(hydroxymethyl)-7-deazaadenine~70 The results showed that incorporation of the analogue did not affect the overall DNA structure, stacking or Hbonding interactions, and that the analogue is a good mimic for ordered water molecules both in the DNA structure itself and at DNA-protein interfaces. As a DNA polymerase incorporates a dNTP, a conformational change from an open to a closed complex occurs. The importance of H-bonding interactions and geometric shape of the nucleobases has been examined for the stability of the closed form of the polymerase.371This has been studied using the incorporation of the TTP isostere derived from difluorotoluene opposite dA, and the 5'-Cnucleoside triphosphate derivative of pyrene opposite an abasic site. In an attempt to design novel DNA base pairs to expand the genetic code, a copper-mediated DNA base pair has been The base pair comprises the nucleobases pyridine-2,6-dicarboxylate (Dipic) as a planar tridentate ligand and pyridine (Py) as the complementary single donor ligand (130). A duplex containing the new base pair showed no melting transition in the absence of metal ions, indicating that the base pair is strongly destabilising. A variety of transition metal ions also failed to increase the duplex stability. However, in the presence of one equivalent of Cu2+ions, a transition was observed. A mismatch within the duplex was also considerably destabilised. Several unnatural nucleobases (131-139) have been studied which make use of interbase hydrophobic interactions to form stable base pairs in hybridisation studies, as well as during DNA r e p l i c a t i ~ n .The ~ ~ analogues ~ . ~ ~ ~ were designed to form new base pairs in efforts towards the expansion of the genetic code. These analogues are orthogonal to the natural DNA bases, with correct pairing being favoured by at least an order of magnitude over mismatches. In particular the base pairs between 7-azaindole (7A1, 137) and isocarbostyril (ICS, 135), and

247

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

I

dR PlCS

$ I {IQJ Qf) I

dR

7AI

dR

I

lmPy

dR

PP

between pyrrolopyrizine (PP, 139) and C3-methylisocarbostyril(125) have been shown to be good candidates for enzyme incorporation into DNA with moderate selectivity, which represent a new generation of stable orthogonal base pairs. DNA-strand exchange between a ssDNA and a duplex in which all G and C residues have been replaced by 2’-deoxyisoguanosine(iG)and 2’-deoxy-5-methylisocytidine MiC) by the E . coli RecA protein in vitro occurred at a similar rate and efficiency to unmodified DNA.375This provides further potential for the role of iG and MiC in an expanded genetic code. Using ODNs rich in isoguanosine residues, Chaput and S w i t ~ e I 3have ~ ~ shown that iG quintet structures may be formed from a metal-assisted hydrogen bond-mediated self-assembly process. The structures were stabilised particularly in the presence of Cs+ ions. Lewis et al. have prepared hairpin DNA containing a central diphenylacetylene-4,4‘-dicarboxamide (DPA) unit (140) in order to study electron transfer in DNA.377Femtosecond time-resolved spectroscopy indicates charge separation via rapid electron transfer to the DPA-localised singlet state from the neighbouring (A or G) nucleobase, creating a contact radical ion pair (DPA-A/G+). In a further the authors have studied hairpin structures containing stilbenediether linkages (141). When the conjugate is a random coil, cis c* trans photoisomerism occurs, but when in a hairpin structure, only cis + trans isomerization occurs, thus acting as a photochemical switch. An azobenzene phosphoramidite linker has been incorporated into DNA for linking two O D N S . The ~ ~ ~linker undergoes trans-cis isomerisation with UV light, though the efficiency of the isomerisation is dependent on the sequence of the flanking ODNs. This may be used as a light switch for nucleic acid structures. A T7 DNA polymerase reaction has been controlled by using ODNs containing an azobenzene unit which photoregulates the polymerase reaction.380The modulator ODN is annealed to the template 3’ to the primer. Before photolysis, the azobenzene is in a trans form, and the polymerase reaction terminates when it reaches the modulator. On photolysis the azobenzene isomerises into the cis form, and is no longer planar, thus weakening the hybridisation of the modulator and allowing the polymerase to pass through.

248

Organophosphorus Chemistry H

H

N-OR

R

(141) R = CONH(CH&OH

'N'

I

-N

b-(

'N-

'0'

Me (142)

DNA has been functionalised at the 5'- and/or 3'-termini with a naphthalene diimide intercalator (a powerful oxidant) (142) to aid triplex ~tabilisation.~'~ Remarkable stability was observed when (142)conjugated third strand DNA was used, with up to 41°C increase in thermal melting using the conjugate at both termini. Naphthalene- and perylene-based linkers have also been used to stabilise triplex formation, enabling them to tether the Watson-Crick and Hoogsteen strands of a triplex.3x2Such systems have also been attached to the centre of a TFO, being able to photo-oxidise guanine residues over at least 25-38 bp in either An acridine attached to the sugar-phosphate backbone was incorporated into a TFO at various positions where it was found to stabilise triplex formation.384 Anthraquinone and naphthalene diimide intercalators containing amino side chains cleave abasic sites in plasmid DNA.385Cleavage using amino compounds, e.g. piperidine, ethylene diamine, is much less efficient. Intercalators containing two amino side chains are also more efficient than one, suggesting a role for two amino groups in the cleavage. The attachment to the 3'-end of an ODN of a tetraphenylporphyrin residue via a lysine linker causes a significant destabilisation when hybridised with a complementary oligomer."' Molecular beacons have also been attached to glass beads.387In buffer solution, the beads (containing FAM and methyl red at the termini) are not fluorescmt until exposed to c:.inplementary DNA. Terminus modifiers based on methoxy oxalamido (MOX) groups (for example the double MOX modifier attached to either a cyclohexane ring (143)or via a 5'-aminothymidine) have been described.'" The modifiers allow for post-synthesis functionalisation of ODNs. The two C-nucleosides derived from 2-aminopyridine (144) and 2aminopyrimidine (145) have been used to enhance base triplets involving C-G and G-C base pairs.3892-Aminopyridine, which has a pK, of 6.8, was shown to recognise the dG-dC base pair better than dC-dG, whilst 2-aminopyrimidine, with a pK, of 3.3, forms more stable triplets with dC-dG. To study the interactions of protein side chains with DNA the amino acid side chains of phenylalanine (146)and asparagine (147)were incorporated into DNA,

249

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

replacing the n u c l e o b a ~ e Both . ~ ~ ~side chains were found to be destabilising, in particular the d(P-Phe) analogue. Both were more destabilising than a glycine residue. The analogue (148),containing a butyl spacer between the sugar and the nucleobase 2-amino-6-vinylpurine, has been incorporated into T F O S . ~2-~ ~ Amino-6-vinylpurine exhibits selective alkylation of cytidine, so the analogue (148) was designed to span a duplex when present in a third strand. Results demonstrated that when the target dC flipped out of the duplex it underwent alkylation by (148).

NH2

v

A

N

,o

I

dR (145)

f'

'

d(P-Phe) (146)

NY HN

0 d(p-Asn) (147)

OH

(148)

New phosphoramidite building blocks for the incorporation of 1-2 histidyl residues into ODNs are reported.392The interstrand cross-link (149) was introduced during solid phase synthesis using a convertible nucleoside to effect the ~ r o s s - l i n k .ODNs ~ ~ ~ containing the interstrand C-C mismatch were shown to form stable duplexes, and were also substrates for T4 DNA ligase, despite the fact that the cross-link would be in the enzyme active site.

2

Aptamers

Systematic Evolution of Ligands by Exponential enrichment (SELEX) is a process using large libraries of random oligonucleotides which are then exposed to the target of interest. Subsets of sequences that have affinity for the target are isolated, amplified and then further rounds of exposure to the target leads to ligands that have increased affinity. Such ligands are called aptamers. Apt amers were originally isolated that bound to a given target, but more recently SELEX

250

Organophosphorus Chemistry

has been used to isolate aptamers that have catalytic activity. In a study of the incorporation of C’-substituted dUTP analogues with side chains of differing flexibility for the incorporation of catalytic groups by SELEX it was found that for PCR products having >200 nucleotides that rigid alkynyl or trans-alkenyl side chains are preferential.394In contrast, when investigating the incorporation of 7-deaza-dATP 7-substituted analogues, the flexibility of the C7-side chain had little effect in PCR 5-(3”-Aminopropynyl)-2’deoxyuridine (150) has been used in an in vitro selection to prepare a library incorporating cationic functional groups to generate receptors that bind ATP.396 After nine rounds of selection, a number of sequences were obtained that bound ATP. Interestingly, the receptors were found to bind co-operatively two ATP molecules. A preliminary report397has described the incorporation into an ODN of the flavin nucleotide (151).The analogue was designed to endow an ODN with catalytic properties.

Using in vitro selection, a set of RNA oligomers with Diels-Alderase activity A 100-nucleotide random region of DNA was randomised have been and then transcribed in the presence of the pyridine-modified dUTP derivative (152). The library of RNA oligomers was then ligated to a short ODN to which was attached, via a PEG linker, the diene. The library was then incubated in the presence of the dienophile (which was biotinylated) and any RNA species that carried out the Diels-Alder reaction would be biotinylated. After twelve rounds of selection, a family of RNAzymes was isolated. I n vitro selection has also been used to prepare RNA aptamers with catalytic activity. Using an RNA ODN containing a 142nt randomised region and a fumaramide attached to the 5’-end of the RNA, selection was carried out for aptamers that would catalyse a Michael reaction.399

Two modified deoxynucleoside triphosphates, an adenosine derivative modi-

251

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

fied with imidazole (153), and uridine with a cationic amine (154) have been used in an in vitro selection protocol to prepare a DNAzyme to mimic RNase A.400 After several rounds of selection, a DNAzyme was isolated and sequenced. It was shown to be metal-independent, and had a k,,, of 0.044 min-', with a maximum cleavage of 60% and a catalytic optimum at pH 7.4. In a similar report,40' a dUTP derivative was used incorporating an imidazole on a modified side chain. Again selection was for RNA cleavage. After sixteen rounds of selection, a DNAzyme was isolated which contained a twelve nucleotide catalytic core, incorporating three imidazole units, and required 10 pM Zn2+.The catalytic efficiency of the enzyme was lo8M-' min-'. A DNA aptamer with N-glycosylase activity has been isolated by in vitro selection.402The catalytic rate enhancement is of the order of lo6, and the aptamer catalyses the N-glycosidic cleavage of a specific dG residue. It is dependent on divalent metal cations, and has optimal activity at pH 5. DNA aptamers that catalyse the capping of DNA with AMP to the 5'-end of the DNA, thus creating a 5',5'-pyrophosphate linkage, have been The aptamers require Cu2+and have a catalytic efficiency of lo4M-' min-' using either ATP or dATP. Kore et d 4 0 4 have used mutagenic PCR with the triphosphates dPTP (155) and 8-0x0-dGTP to isolate purine-specific hammerhead ribozymes. After five rounds of selection, new ribozymes were isolated with up to 90 times higher in trans cleavage than the starting ribozyme. An RNA aptamer has been selected to activate the carboxylic acid of amino acids that mimics the formation of a mixed phosphate anhydride synthesis of aminoacyl tRNA ~ynthetases."'~ The optimal aptamer requires only Ca2+for the reaction, and operates at low pH with KM 50 mM and kcat 1.1 min-' for the activation of leucine. This lends support to the concept of translation in an RNA-based world. An RNA-cleaving DNAzyme406has been used to target a chemokine receptor required by HIV-1 for entry into susceptible cells.407The DNAzyme was found to be very efficient, and specifically interfered with the fusion of cells that harboured the T-lymphocytotropic HIV-1 envelope. From a randomised 40 nucleotide region using twelve rounds of in vitro selection, a number of RNA cleaving deoxyribozymes were identified.408Each had a common motif, and are Zn(I1) dependent. Novel nuclease-resistant ribozymes capable of trans-cleaving target RNA at physiological Mg2 concentrations have been achieved by in vitro selection.409The selection was carried out by using 2'-aminopyrimidine nucleosides in a randomised 40 nucleotide region. RNA aptamers have been developed to inhibit the in vitro phosphorylation activity of extracellular regulated kinase 2 (ERK2)!1° Using randomised regions of 134 nucleotides and several rounds of selection, three families of competitive inhibitors were isolated. Using the catalytic core of the ligase ribozyme using in vitro selection, a RNA aptamer was obtained that can use an RNA template to replicate the template, with the successive addition of up to 14 nucleotides!ll The catalytic effect was general and copying fidelity quite high. A series of allosteric hammerhead ribozymes that are activated by theophylThe ribozymes show a 3000-fold line have been evolved by in vitro

-

+

252

Organophosphorus Chemistry

enhancement in cleavage in the presence of the effector which is equivalent to the unmodified hammerhead ribozyme. A variant allosteric ribozyme that is activated by 3-methylxanthine has also been evolved that is able to distinguish between the two effectors. Hammerhead ribozymes cleaving 3' to GAC triplets have been evolved using ribozymes with ten random nucleotides in the catalytic core.413After seven rounds of selection, ribozymes were isolated that were active for cis cleavage of GAC, though the rate for trans cleavage was slower than for the parent sequence. Replacement of all uridine residues in the Tetrahymena group I ribozyme with 5-bromouridine results in a 13-fold reduction in catalytic efficiency.414Using a library of 1013 ribozymes with 5-bromouridine instead of uridine gave after 5 rounds of selection a 27-fold increase in catalytic efficiency compared to the uridine ribozyme. DNA aptamers binding to hematoporphyrin IX (HPIX) were obtained from an in vitro selection method.41sAfter seven and ten rounds of selection, G-rich sequences were obtained. Binding assays and CD measurements revealed a guanine quartet structure that binds to HPIX. By a similar method, aptamers were obtained after eight rounds of selection that bind to The structures were again G-rich, containing G-rich loop clusters. Using an aptamer previously described for binding to NF-KB;'~ improved binding, including one sequence that bound to a single NF-KB dimer in cell culture extracts, was obtained by substituting thymidine for thymidine 3'0-pho~phorodithioates.~'* Two separate selections (69-mer and 109-mer libraries) were carried out to isolate RNA aptamers that bind to the 16s ribosomal RNA decoding region.419 After ten rounds of selection, aptamers were isolated and characterised. Each set of aptamers showed a similar core motif. After five rounds of selection, two classes of RNA aptamers binding to 3',5'-cyclic-AMP (CAMP)were isolated.420 Each class is composed of a similar stem-loop and single-stranded structural elements. Class I1 require divalent cations and display a KDfor cAMP of 10 pM. Whilst specificity for cAMP compared to ATP and AMP was high, both adenine and adenosine were bound, suggesting that the nucleobase is a significant determinant for binding. An 18-mer DNA derived from in vitro selection to bind hemin has been previously reported.42'In a further report,"22the authors have prepared the RNA analogue of the aptamer to examine the peroxidative properties of each. Whilst both RNA and DNA aptamers displayed peroxidase activity, the RNA analogue bound with 30-fold weaker affinity. An RNA aptamer selected to inhibit the Drosophila B52 protein binds to B52 and inhibits B52-stimulated pre-mRNA splicing.423It has been expressed in cell culture and animals, and binds B52 in vivo, suppressing all phenotypes. Starting from a library of lOI4 ODNs comprising a 60 nucleotide randomised region, RNA aptamers were selected for binding to S-adenosylhomocysteine (SAH).424 The Hoogsteen face was critical for binding in addition to the thioether linkage. In the presence of Mn2+ ions, the binding approached that of an anti-SAH antibody. The stability of a thrombin aptamer containing sequence modifications in one or more of the loops has been studied.42sThe aptamer is a

-

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

253

15-mer which forms a quadruplex of two stacking G-quartets. Addition of a single guanine at the 5'-end decreases stability of the quadruplex, whilst an addition at the 3'-end increases stability. I n vitro selection was used to examine the cyanobacterial transcription factor NtcA binding A randomised (N13) region was passaged through five rounds of selection, and the resulting binding motifs examined. The most frequently occurring sequence was similar to a naturally occurring binding motif.

3

Oligonucleotide Conjugates

Oligonucleotide conjugates are a fast growing area of research. One of the main areas is in the synthesis of peptide-oligonucleotide conjugates, but apart from this there are still many other conjugates that have been prepared. A new method for native ligation of ODNs to peptides has been reported in which the 5'-end of an ODN is modified with the cysteinyl derivative (156).427>428 After deprotection of the ODN, the t-butyl group is removed with tris(2-carboxyethy1)phosphine (TCEP) and then reacted with an N-terminal thioester-functionalised peptide. A range of peptide-ODN conjugates was reported using this method. The direct synthesis of ODNs bearing dipeptides at either the 3'- or 5'-terminus has also been though the methodology appears to require amino acids that need little or no protection for DNA synthesis. A new method for the synthesis of ODN-peptide conjugates has been described in which the two components are linked directly between the terminal hydroxyl group of an ODN (3'- or 5'-) and the hydroxyl group of a peptide serine or threonine via a phosphate linkage.430 The conjugation occurs between the ODN whilst still on the solid support and a phosphoramidite modified Ser or Thr on the peptide. The method requires that the amidite and nucleoside building blocks have allyloxycarbonyl protecting groups. A method for the solid phase synthesis of cyclic peptide-DNA conjugates is The peptide portion is prepared using Fmoc/Alloc protection on an a-hydroxylauric acid derivatised support. After incorporation of nucleoside phosphoramidites, peptide synthesis is continued by coupling to a 5'-deoxy-5'aminothymidine group. The synthesis and characterisation of photocleavable peptide-DNA conjugates have been The peptide portions have been used as mass tags, released during ionisation by UV-M ALDI to identify unique DNA sequences. The conjugates were evaluated as hybridisation probes, and the photocleavable peptide had no effect on the thermal stability of DNA duplexes. A method for preparing ODNs conjugated to sugars, termed nucleoglycoconjugates, has been r e p ~ r t e d . "Three ~ ~ different conjugates were prepared, at either termini and in the centre of an ODN, and T , studies showed that the presence of the sugar was destabilising. DNA has been labelled with carbohydrate conjugates by a diazo-co~pling."~~ It is suggested that the conjugation occurs via guanine residues, as the extent of conjugation is proportional to the guanine content. ODNs modified with either lactose or cellobiose were shown to bind to galactose-specific lectin with high affinity.

254

Organophosphorus Chemistry

The attachment of DNA to the backbone of defined organic polymers derived from ring-opening metathetic polymerisation (ROMP) has been Starting from the norbornenol derivative (157), polymerisation of the ringstrained olefin was carried out, and the product converted into its phosphoramidite derivative and conjugated to DNA. Bu‘S

\

A number of methods to attach reactive functional groups to oligonucleotides have been reported. Dempcy et al. have investigated a series of linkers attached to a triplex forming oligonucleotide terminating in an electrophilic moiety, which is the reactive unit of the antibiotic CC-1065.436 They determined that the optimal linker contained aromatic units as these probably aided stabilisation by a threading mechanism in which the aromatic unit is intercalated into the dsDNA. A method for functionalisation of ODNs is reported which makes use of a 5’-linker containing a trityl protected aminooxy group, which is attached to the oligomer during DNA Derivatisation with aldehyde-containing groups, such as fluorescein derivatives, is described. The phosphoramidite monomer (158) has been used to prepare ODNs with a thiol terminus for the synthesis of DNA conjugate^."^^ Removal of the trityl group with silver ions affords the free thiol which has been coupled to a cysteine via a disulfide bond. Methods for terminal functionalisation of ODNs by amino, sulfydryl, thiophosphate and carboxyl groups in both organic and aqueous media have been extensively studied.439Optimal conditions for conjugating ODNs with reactive nucleophilic and electrophilic groups, including linkage to other ODNs, have been described. The three ribonucleoside triphosphates (159-161) have been prepared and incorporated into RNA using T7 RNA p01yrnerase.4~~ The analogues each bear a linker with a terminal methyl ketone group which has been used for post-synthesis labelling using a fluorescein derivative containing an aminooxy group. Another principal interest is the conjugation of fluorophores and dyes to oligonucleotides. The novel Fmoc-protected modified dU derivative (162) has been used for the efficient conjugation of reporter groups, e.g. dyes for FRET assay.44*The Fmoc group may be selectively removed during or after DNA synthesis to allow coupling of phosphoramidite derivatives. A four-colour set of FRET dideoxy terminators has been and shown to be excellent reagents for high-throughput DNA sequencing. Coumarin has also been intro-

6: Nucleotides and Nucleic Acids: Oligo- and Polynucleotides

255

0 HN

duced into DNA by attachment to a 2’-amino group, as a FRET donor, and evaluated with fluorescein in FRET analysis of DNA The fluorescent ddA 5’-triphosphate derivative (163) was shown to be an effective substrate for terminal transferase, and various DNA po1ymerases!4 The resultant DNA could then be detected by fluorescence spectroscopy. A molecular beacon DNA probe incorporating a donor and a quencher dye has been which shows high sensitivity and dynamic range. Such molecular beacons are anticipated to have use in DNA/RNA and protein/DNA/RNA interactions. A set of fluorophores derived from naphthalene, phenanthrene, pyrene, phenazine and fluorene have been conjugated to the 5’-ends of DNA and RNA to compare their physico-chemical properties.48 Decreasing the n-electron density led to an enhancement in thermal stability, attributable to more favourable n-n interactions. Stability is further enhanced by using nitrated fluorophores. Fluorescent labelling of ODNs using oxyamino modified fluorescein has been reported by the incorporation into DNA of aldehyde functions.449The aldehyde function was attached either at the 5’-end via a phosphate linker or internally via 8-mercaptobutanal. Reduction of the resulting oxime was not necessary. Lyttle et ~ 1 . ~have ~ ’ reported an improved synthesis of 5’-TAMRA-conjugated DNA. A method for preparing, on a solid phase, rhodamine-conjugated ODNs attached via a 5’-amino group is reported, by in situ activation of rhodamine carboxylic A benzotriazole azo dye (164) has been used as a nonfluorescent active label for surface enhanced resonance Raman scattering (SERRS)>52The dye has been conjugated to both DNA and PNA and SERRS obtained for both. The authors report that SERRS detection of PNA was easier than for DNA. A new method for labelling ODNs using pyrylium cyanine dyes (165) has been reported in which amino-linker modified ODNs react, converting them into pyridinium derivatives.453 The anilino-acridine anti-tumour drug amsacrine-4-carboxamide has been conjugated to the phosphorylated termini of TFO to assess the affect with human topoisomerase II.454Although the effects were found to depend upon sequence, when attached to the 3’-end of a TFO via a

256

Organophosphorus Chemistry 0 II

H

hexaethylene glycol linker, the conjugate was shown to modulate the extent of DNA cleavage by topoisomerase 11. A method for labelling ODNs with radioactive halogens has been reported using the conjugate (166).4s5The reaction of ODNs containing a 3’-phosphorothioate with the conjugate occurs in moderate yield. As with nucleotides containing modified bases, there have been a number of reports on the attachment of metal ions to oligonucleotides. A general method for easy 2’-O-modification of nucleosides is described. 19-mer-ODNs carrying an aminoalkyl linker at the 2’-position of cytidine residues are covalently attached to a metalloporphyrin moiety (167). The site of conjugation of the manganese cationic porphyrin within the 19-mer vector sequence was selected taking into account the linker length so that the tethered nuclease residue would be close to an (AT)3site in the duplex region. The cleavage of the target DNA by these new metalloporphyrin-ODN conjugates was compared with that of the 19-mer-ODN conjugate carrying the metalloporphyrin at the 5’-end.456 Schmidt et al. have prepared by solid phase synthesis a monofunctional trans-Pt” complex tethered to a homopyrimidine ODN4j7useful for antisense cross-linking. The platinum species was attached to the 5’-end of the oligonucleotide during DNA synthesis (168).This methodology was subsequently used to cross-link two ODNs to give parallel-stranded DNA.458In the latter case, the platinum species was linked via the N7 positions of 3’-end guanine bases. The platinum antitumor compound [{ ~ ~ ~ ~ S - P ~ C I ( N H ~ ) ~ } ~ H ~ N ( C H ~ (l,l/t,t) coordinates to DNA bases and forms various cross-links. It also forms a 1,2-d(GpG) intrastrand adduct analogous to that formed by cis-platin. The adduct formed by (l,l/t,t) has been studied by thermal denaturation in comparison to that formed by ~is-platin.~~’ The (l,l/t,t) adduct showed reduced stability

257

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

(166) X = halogen

(167)

a

f

a OH a = NH3 or arnine

I

0 I

0 =P-0-DNAI

OH

OH (168)

compared to cis-platin, and suggests different binding modes for the two DNAbinding drugs. A 2’-O-methylribooligonucleotide containing a G U G sequence modified by trans-diamminedichloro-platinum(I1) has also been used to investigate the effect of Pt-induced crosslink^.^^^ The modified oligomer was targeted to the RNA region responsible for the gag-pol frameshifting during translation of HIV- 1 mRNA. The binding of the platinated oligomer resulted in a rearrangement of the intramolecular G-G cross-link, resulting in an intermolecular G-A cross-link. This resulted in selective arrest of translation of a luciferase gene downstream of the HIV-1 frameshift signal. Ossipov et al.461have prepared ODNs with a ruthenium complex ([R~(phen)~dppz]’+, phen = 1,lO-phenanthroline, dppz = dipyrid0[3,2-~:2’,3’-c]phenazine)tethered at defined positions. Conjugation at either termini led to a significant increase in thermal stability, but less so in the centre of the duplex. When conjugated at the centre of the duplex the resulting diastereoisomers could be resolved and used to examine the nature of threading of the Ru complex. ODNs containing dppz have been shown to stabilise duplexes with both DNA and RNA as well as triplexes when incorporated at the t e ~ m i n i . 4However, ~ ~ ’ ~ ~ ~internal substitutions are destabilising. Using 3’- and/or 5’-amino modified ODNs, metallointercalators have been conjugated to the termini of DNA via the active ester of the ligand on solid By this method 0 s and Rh metallointercalators have been introduced to probe DNA charge transfer. The zinc-neocuproine probe (169) has been incorporated into DNA to act as an artificial ribon~clease.4~~ The probe is incorporated into DNA via a spacer unit which takes the place of a nucleotide. When targeted to RNA the probe gives 5’-site-specific cleavage of the target RNA. In another an acridine unit is attached to the 5‘-end of a DNA probe, which when hybridised to target RNA, and in the presence of free Lu(II1) ions, carried out efficient and site-selectivecleavage of the target RNA. The conjugation of glutamic acid to a 5’-aminohexyl-modifiedO D N has been used to prepare copper ion-directed triple helices.467Using ODNs with a twofold axis of symmetry, the Glu-modified pyrimidine strand was shown to form a symmetrical triplex in the presence of Cu2 . Tetraphenylcyclobutadiene(cyc1opentadieny1)cobalt complexes (170) and phenylene-ethynylene trimers (171) +

258

Organophosphorus Chemistry

were prepared and modified at each end with O D N S . ~The ~ * resulting ODNmodified organics (OMOs) were characterised by UV and C D measurements. Using the OMOs, defined oligomers could be prepared, demonstrating that DNA can self-assemble modules of interest independent of the module itself. The microgravimetric quartz crystal microbalance (QCM) has been used to

1

NH

(169)

0

(170) CoCp = Cobalt cyclopentadiene

OMe

give an amplified response for the detection of DNA.469An ODN with a 3’hexanethiol linker, which has a complementary sequence to the target DNA, is attached to a gold electrode of the QCM. This is then allowed to hybridise to the target DNA, after which a gold nanoparticle, which has a complementary sequence to the 3’-end of the target sequence, is hybridised to the complex. Target DNA at sub-nanomolar concentration can be detected. Non-linear amplification can be obtained by using a second gold nanoparticle, which then forms dendrimer structures with the target DNA sandwich complex.47oAnother method of amplification made use of either ODN-functionalised liposomes or biotinylated liposomes to amplify the target DNA signa1.471,472 Oligonucleotides are only very poorly taken up into cells, and a variety of conjugates have been studied with the aim of improving cellular uptake. The cellular uptake of the ISIS ICAM-1-specific phosphorothioate ODN conjugated to cholesterol (ISIS-9388) has been studied in vivo for uptake into liver cells in The presence of the 3’-cholesterol on the ODN resulted in a two-fold increase in accumulation of the ODN in various liver cell types, and the authors conclude that conjugation of ODNs with cholesterol is likely to be beneficial for antisense therapy of liver-associated diseases. ODNs which have 3’-linked cholesterol have been shown to interact with cell membranes in macrophages, and

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

259

were internalised more efficiently than un-derivatised DNA.474Cholesterol was attached to DNA via positions 3, 7 or 22 of the steroid, and most efficient internalisation was observed with DNA attached to positions 3 or 7. Antisense phosphorothioate thymidine ODNs do not reach the target RNA in In the absence of cellular proteins, vitro in the presence of cellular RNA targeting was successful, suggesting that therapeutic properties of such phosphorothioate ODNs derive from an aptamer effect. To study the cleavage mechanism for RNase P, precursor tRNAs (ptRNAs) bearing either an Rp or Sp phosphorothioate at the RNase P cleavage site were prepared.476RNase P enzymes from three species exclusively cleaved the ptRNA one nucleotide upstream from a Sp-phosphorothioate modification. The Rp diastereoisomer was inefficiently cleaved at different positions depending on the RNase P enzyme. Two conjugates of an anti-HIV ODN with differing high molecular weight monomethoxy polyethylene glycols (MPEG) have been prepared, and tested for their activity as substrates for RNase H.477Both conjugates were found to form regular duplexes with the target ODN and were substrates for RNase H. A high molecular weight polymer of N-acryloylmorpholine (PacM) has been conjugated to an antisense ODN against an HIV-1 The presence of the polymer did not affect hybridisation properties, and it was still a substrate for RNase H, though less so than the MPEG conjugate. There were purification problems, and the conjugate exhibited no antisense effect. ODNs conjugated at the 3’-end with hexadecylglycerol have been used to improve cellular The presence of the 3’-conjugate (introduced as a DMT protected CPG) had little effect on hybridisation properties, enhanced nuclease resistance, and the ODN exerted an antisense effect without the use of cellular uptake enhancers. An ODN covalently linked through a heterobifunctional linker to streptavidin via a genetically engineered variant containing a solvent-accessiblecysteine has been conjugated to ~ o ~ ~ N I P A A M PolyNIPAAM .~~’ (poly-N-isopropylacrylamide) is a temperature responsive polymer, and the ODN-streptavidin-NIPAAM conjugate could be used to affinity precipitate biotinylated reagents above 32°C. DNA-protein aggregates have been prepared by conjugation of an ODN with a 5’-SH group to streptavidin, which was then reacted with duplex DNA with biotin attached to each 5’-end.481 It was used to immobilise DNA at a functionalised surface. There is a large therapeutic interest in bisphosphonate derivatives, which are stable analogues of the metabolite of pyrophosphate. The bisphosphonate derivative alendonate (172)has been conjugated to either termini of O D N S .Such ~~~ conjugates may be of use for the delivery of bisphosphonate to target a variety of bone disorders.

260

Organophosphorus Chemistry

The conjugation of octreotide, a cyclic octapeptide analogue of somatostatin, using a maleimido-modified peptide and an O D N with a 5'-SH has been s t ~ d i e d . The 4 ~ ~presence of the peptide had little effect on hybridisation affinity of the conjugate with DNA, and had specific nanomolar binding affinity to the somatostatin receptor. Using the same conjugation chemistry, peptide-ODN conjugates carrying nuclear localisation sequences were also prepared.484Peptide-ODN conjugates with membrane translocation and carrying nuclear localisation sequences have also been prepared uia disulfide bond formation involving ODN and peptides with 2-pyridyl sulfide functional group^."^ In an attempt to study DNA minor groove binders for increasing sequence selectivity, the preparation of functionalised fullerene derivatives has been rep ~ r t e d . ~DNA " was first modified through its 3'-phosphate with 6-aminocaproic acid to give a phosphoramidate derivative. Bis-functionalised fullerenes containing the minor groove binder (trimethoxyindole-2-carboxylate)and a linker arm were conjugated with the modified DNA. Further results are anticipated. The use of ethylene glycol linkers as non-nucleotidic loop replacements for short hairpin RNA has been It was shown that the optimum linker is a heptakis- or hexakis-(ethylene glycol) unit. The stability is independent of the counter-ion. The phosphoramidite building block (173) has been prepared for modification of ODNs with hydrophobic octyl The octyl groups are stable to the normal deprotection step of O D N synthesis. Incorporation of (173) at the termini of ODNs (3'-, 5'- or both) in a duplex led to a slight stabilisation, and improved stabilisation was observed when incorporated into a triplex. An anthraquinone linked to the 5'-phosphate of an O D N containing 4 separate GG steps has been used to serve as a trap for a migrating radical cation.489 Irradiation of the quinone leads to electron transfer from the DNA to the quinone, generating a quinone radical anion and a base radical cation. The radical cation migrates along the DNA and causes strand breaks at the GG steps.

4

Nucleic Acid Structures

With recent advances in the field of NMR spectroscopy there have been many new solution structural studies of increasingly complex systems. Structural studies of oligonucleotides has been another major growth area. NMR has been used to solve the solution structure of a decamer duplex containing a central TAATTA tract.490Dynamics calculations show that the minor groove of the central AATT core fluctuates between wide and narrow conformations, and is not as highly pre-organised as regarded for recoghition and binding by small molecules. A large roll at the TpA step appears to be important for widening of the minor groove. NMR has been used to study the structure of the Dickerson dodecamer in an aqueous liquid crystalline medium containing 5% w/v bicelle~.~ The ~ l phospholipid imposes a degree of orientation on the DNA with respect to the magnetic field, and allows for measurement of dipolar interactions.

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

26 1

The structure was shown to be a regular B-form duplex without any significant bending or kinks, and is in agreement with the X-ray structure.492 The DNA heptamer d(GCGTAGC) has been studied by NMR,493and shown to exist in a temperature and salt-dependent equilibrium between a monoloop hairpin (with the central T forming the loop) and a duplex. In the duplex the unpaired thymidines from opposite strands intercalate and stack between shared G:A pairs. The self-complementary duplex d(G4C4)demonstrates the propensity for guanine runs to stack in an A-like duplex even within the framework of a B-form The solution structure of a duplex incorporating a five adenine bulge in one strand has been studied by NMR, IR and Raman spectros~opy.4~~ The two stems form normal B-form duplexes, while the adenine bulge, which is localised at intrahelical positions, induces a local kink in the DNA of about 73". The solution structure of the duplex d(GGCAAAAAACGG). d(CCGTTTTTTGCC) shows a helix axis bend of 19", with a decreasing minor groove width (5'-3') within the A tract as a result of propeller twist in the AT ~ a i r s . 4NMR ~ ~ studies of the DNA sequence AGCTTATCGACGATAAGCT show that the ODN forms a hairpin structure with a single residue The central G C forms a distorted base pair in a wedge shape geometry, with the bases stacked on each other in the minor groove. Homopurine-homopyrimidine mirror repeats occur frequently in nature, and in vitro studies have shown that these regions form triple-helical structures called H-DNA. H-DNA forms when half the Watson-Crick duplex dissociates and the released pyrimidine strand folds back onto the duplex to form a triplex. There are two isomers that can arise, H-y3 and H-y5, depending on whether the 3'-Py or the 5'-Py strand folds back. A solution structure of a DNA fragment representing the H-y5 triple helix has been solved, giving an insight to the mechanism of H-DNA formation.498 NMR has been used to solve the structure of a 22-mer hairpin DNA having a TTTU tetra-lo0p.4~~ The structure was chosen to examine the mode of action of uracil DNA glycosylase (UDG) enzymes, as the tetra-loop may offer the U in a flipped-out form, which would then be recognised by UDG's. The uridine in position 4 of the loop has been found to be the best substrate for UDG compared to each of the other position^.^^ The structure showed that the stereochemistry of the uridine mimics the situation in which it would stack into ds-DNA as it stacks in between the adjacent nucleotides. The solution structure of two cyclic octamers, d(pTGCTCGT) and d(pCATTCATT) have been The two octamers dimerize at high concentrations to form a four-stranded symmetrical structure. The central nucleotides from each form two G:C:G:C or A:T:A:T tetrads respectively,which are connected by short loops of two residues. The first residue of the loop acts as a cap at both ends of the stack. The smallest unimolecular G-quadruplex belongs to the family d(GlN,GlNnG2NnG2),and forms two stacked G-tetrads. The solution structure of such a G-quadruplex in which the first loops are diagonal has been solved.502A similar structure of a guanosine- and adenosine-rich sequence, but which forms a dimeric structure with two G-tetrads has also been solved by NMR.503In determining the solution structure of a DNA 3-way junction, van Buuren et al.jo4

262

Organophosphorus Chemistry

have determined the sequence features that determine conformer selection. These deal with the nature of the nucleotide in the crossover strand, and stacking interactions in the loop. The effect of substitution of guanine residues by 6-thioguanine in duplex- and quadruplex-forming oligomers has been investigated by NMR.jo5 The data demonstrated that 6-thioguanosine is a disruptive substitution of both Watson-Crick and Hoogsteen base-pairings. It is a weaker H-bond acceptor than the corresponding 0x0 group, and may also disrupt interactions with water molecules and cations. 6-Thioguanosine substitutions cause destabilisation in duplex structures, with greater destabilisation in quadruplex structures. The NMR structure of a 17-mer containing hydroxymethyluracil (hmU), that closely resembles the cognate site for transcription factor 1 (TF-l), has been reported.'06 The B-DNA structure showed base unstacking at the 2 hmU-A steps, and the authors suggest that this unstacking may play a role in the recognition process for TF-1. A decamer duplex structure containing a central 3-nitropyrrole-A base pair has been solved by NMR.jo7The structure was found to be very similar to the unmodified duplex, but with minor perturbations caused by reduced stacking interactions due to the small size of the ring. The bulky nitro group protruded into the major groove. The authors conclude that the pyrrole ring did not stack as well as expected. The DNA base 5,6-dihydrouracil (DHU) has been studied by NMR in the Dickerson dodecamer, where it replaced an internal dC to form a DHU-dG wobble pair.50*The findings suggested that the duplex was not distorted from the usual B form DNA, and that the DHU was contained within the duplex. A trimethylene interstrand cross-link (174) has been introduced into a selfcomplementary duplex as a model for the mutagenic cross-link agent malondialdehyde.jo9 The structure has been studied by NMR. The cross-link causes minimal distortion to the duplex, with slight unwinding at the lesion site producing a bulge. The linked guanosines and the tether are almost planar. The distortion does not lead to significant bending of the duplex as confirmed by PAGE. The NMR structure of a duplex containing a difluorotoluene (F) and 4methylbenzimidazole (Z) has been F and Z are non-hydrogen bonding H

0

0

I

dR

H

A- G-G -C -G -C -C -T T-

C -C-

/

G-C -G- G - A (174)

I

dR

6: Nucleotides and Nucleic Acids; Oligo-and Polynucleotides

263

nonpolar isosteres of thymine and adenine respectively, and their triphosphate derivatives have been shown to be incorporated efficiently opposite their natural DNA Despite the absence of hydrogen bonds, the Z:F pair structurally resembles an A:T pair in the same context, which supports the authors' view that shape complementarity is an important feature in replication. The solution structure of a dumbbell DNA with a 10-base stem and a nick in the centre with PEG6linkers at either end has been r e p ~ r t e d .The ~ ' ~duplex forms a stable structure despite the nick, and the stability of the stems are enhanced by the PEG loops. The solution structure of the tryptophan aminoacyl-capped duplex d(W-TGCGACh (175) has been reported.514The duplex has an overhanging dC residue at each end opposite the tryptophan residue. The tryptophan residue stacks against the adjacent T.A base pair without hydrogen bonding, leaving a dangling base at each end. The presence of the end cap does not appear to reduce fraying at the termini. The solution structure of the duplex d(ATGCAT)2in a stoichiometric complex with the anthracycline antibiotic nogalamycin has been determined.515The antibiotic intercalates into the 5'-TpG with the nogalose in the minor groove towards the centre of the duplex. Steric occlusion prevents a second nogalamycin binding at the symmetry site, as has been observed in other structures, suggesting that the drug is bound in its preferred orientation. The DNA sequence 5'GCGAAGCAGAAGT has been demonstrated by NMR to form an intramolecular double hairpin structure with GAA The two hairpins are co-axially stacked which gives enhanced stability. The antibiotic nogalamycin is able to intercalate between the two hairpins in a 1:1 complex, where it acts as a surrogate base pair. A DNA structure containing an interstrand transplatin GN7-CN3cross-link has been studied by NMR.517The structure proved the syn conformation of the G residue, and that the helix is slightly bent towards the minor groove. The effect of 1,3-GTG intrastrand cross-link, as caused by cisplatin, has been studied by NMR in the duplex d(CTCTgtgCTC)-d(GAGACACAGAG)?" The structure showed considerable distortion with no base pairing for the 5'-9-C and t-A, and the central thymine is extruded into the minor groove. In a further NMR study of an intra-strand cross-link, as caused by cisplatin containing the cross-link at a GpG site in a 14-mer duplex,519the two guanosine residues were shown to roll toward one another, causing a large helix bend (52"). There was also considerable helix unwinding at the platination site, and a widening and flattening of the minor groove opposite the lesion was observed. The effect of damaged DNA, in particular polynuclear aromatic hydrocarbon (PAH) adducts, has been studied quite extensively. The solution structure of a DNA duplex containing a 3'-T*Tcis-syn cyclobutane dimer containing a wobble pair between the 3'-T of the dimer and the opposite T residue has been reported.520The results may be used to explain why the frequency of the transversion T + A during transcription is relatively low. The solution structure of a DNA duplex containing the thymine dimer Dewar photoproduct (176) opposite GA has been Although the 3'-T formed stable H-bonds with the opposing dG, there is a poorer stacking interaction of the Dewar lesion with the

264

Organophosphorus Chemistry

adjacent base pair, compared with the fully complementary duplex. This may account for the low level of T += C mutations observed with this type of lesion. The solution structure of 3,N4-ethenocytosine(EdC) opposite dC in the centre of an 11-mer duplex showed a regular B-form duplex with only a slight bend at the lesion The EdC-dCpair is displaced towards opposite grooves, and the resulting base pair is highly sheared, but stabilised by a single hydrogen-bond. The solution structures of DNA duplexes containing the mutagenic lesions of benz~[a]pyrene-dA?~~ trihydroxybenz[a]anthra~ene,5~~~~~~ aminopyrene-dG,526 aminoflu~rene-dG~~’ and malondialdehyde-dGS2* derivatives have been reported. In each case the lesion was shown to intercalate into the duplex causing only minimal disruption to the duplex structure. These structures have been used to study the nucleotide excision repair (NER) by the UvrABC nuclease system from E . coli of the bulky purine lesions.s29 A solution structure of a duplex containing an adenosine N6-amino adduct of the trans (10R)-tetrahydrobenzo[a]pyrene shows that the hydrocarbon is intercalated into the duplex on the 5’-side of the modified base.530From 2D exchange data, it can be observed that the modified base inter-converts between the usual anti-conformation into the less populated syn-conformation. The 10s isomer, however, adopts a syn conformation as the major conformer.s31The solution structure of a S-cis-tamoxifen-W-guanine adduct in the middle of an 11-mer duplex has been The lesion is accommodated in a widened minor groove without disruption of the neighbouring base pairs, though the helix axis is bent by 30” away from the minor groove adduct site. A duplex containing the mutagenic lesion N6-(+ )-trans-anti-benzocg] chrysene-dA opposite thymidine has been studied by NMR.s33The lesion intercalates into the duplex on the 5’-side of the dA residue, and the strain associated with the chrysenyl ring is relieved by the adoption of a non-planar propeller-like geometry within the chrysenyl ring system. The hydration of a DNA-RNA chimera [d(CGC)r(aaa)d(TTTGCG)I2showed A long-lived water molecule retention close to the adenine H2and H” pr0t0ns.j~~ further water molecule is found close to the methyl group of the thymine residue at the RNA-DNA junction. The solution structure of the chimeric self-complementary O D N d(CGC)r(AAA)d(TTTGCG)adopts a structure in between an Aand B-form The solution structure of the DNA-RNAhybrid d(ATGG3’-3’-aT-5’-5’-GCTC).r(gagcaccau), which incorporates an a-anomeric thymidine and polariversals, has been reported.s36The duplex adopts an A-form structure with an increase in S-puckering for two nucleotides upstream of the 3’-3’ linkage, with associated narrowing of the minor groove. The presence of the a T produces only localised distortions. As modified nucleotides have been shown to have advantages over native nucleotides, so the structures of oligonucleotides incorporating these modifications have been very informative. NMR has been used to study a decamer duplex containing L-deoxynucleotides (CLpGL) in its central core.s37The duplex was expected to form a right-left-right handed B-DNA structure, but it actually formed a fully right-handed duplex, with the central CLpGLcore adopting a Z-DNA helix to maintain stacking continuity along the full duplex. The first

6: Nucleotides and Nucleic Acids; Oligo- and Polynucleotides

265

NMR structure of a 2’-deoxy-2’-fluoro-~-arabinose(aF) nucleic acid duplex has been The structure is a hybrid hairpin duplex containing a ribose-aF stem duplex and a four-residue DNA loop (177). The RNA strand adopted the classical A-form structure with C3’endo sugar puckers, whilst the a F strand contained 04-endo puckers and was intermediate between A- and B-form, similar to that found in DNA-RNA structures. 0

dT- dC / \ d\T /dG rC - - aFG I

I

rA--aFT I

I

I

I

rG - - aFC rG - - aFC

A palindromic 10-mer DNA strand containing one LNA thymine monomer has been solved by X-ray ~ r y s t a l l o g r a p h ywhich , ~ ~ ~ shows the duplex adopting an A form structure induced by the LNA structure in each strand. A duplex containing four LNA thymine modifications in one strand has been studied by NMR.540The furanose rings of the un-modified strand are almost all in the S conformation, whilst the structure confirmed that the LNA residues were all C3’-endo.There was structural strain between the A-like modified and the B-like unmodified strands, and the high stability of the duplex arises from a change in the backbone geometry that allows a high degree of base stacking. In further NMR studies of structures containing one LNA thymidine residue in a DNA strand targeted towards RNA,541the duplex was shown to exist in A-form, and the DNA sugar residues were in an equilibrium with N - and S-type conformations. However, the introduction of three LNA thymidine residues changes the DNA sugar into the N-type conformation except for the terminal residues. An RNA-HNA (hexitol) hybrid duplex structure has been studied by NMR.542 The P-P distances across the minor groove are a determinant for cleavage by RNase H. In the structure, the duplex is in an A-form, and the P-P bond distance similar to that for an RNA-RNA duplex, which may explain the resistance of HNA duplexes to RNase H. A self-complementary HNA duplex h(GCGCTTTTGCGC) containing a central T-tract has been studied by NMR.543The duplex exists in the A-form in the stem regions, with minor distortions in the T-tract causing a 9 A displacement of the helical axes. The T-tract is stabilised by wobble pairs enhancing the overall stability of the duplex. The structure of a hybrid DNA-RNA duplex containing a single MMI (3’CH2N(CH3)-0-5’)linker in the centre of the DNA strand has been studied by NMR.s44The lipophilic N-methyl group is peripheral to the duplex and the linker promotes a 3’-endo conformation for both adjacent sugar moieties. The solution structure of a DNA aptamer selected for binding to arginine revealed a hairpin loop with residues critical for binding in the Binding arises from contact between the guanidino group and the phosphate backbone. The NMR characterisation of a kissing complex between an 18-nucleotide RNA

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HO

OH

hairpin and a DNA aptamer selected against the TAR element from HIV-1 has been reported.546The aptamer contains a region complementary to the TAR loop sequence, which is incorporated into the RNA hairpin loop. The H3 stem loop of the Moloney murine leukemia viral RNA, which includes a conserved non-self-complementary GACG tetraloop, has been solved by NMR.547It forms a stable homo-dimeric kissing complex through only two intermolecular G-C base pairs. The solution structure of a 28-mer RNA, being the conserved region of the signal recognition particle (SRP), has been The central feature of this structure is a six nucleotide internal loop which has a novel Mg2 dependent structure with unusual cross-strand interactions. A solution structure of an RNA duplex containing a C-U mismatch showed that the mismatch was stacked into the duplex rather than being flipped The presence of a H-bond in the C-U base pair was confirmed by substitution of 15N at the exocyclic amino group of cytidine. A solution structure of a self-complementary RNA duplex in which there is a A G-G base pair is more stable than other G-G base pair has been non-canonical base pairs, and can form two-H-bond pairs in four different ways. The structure described shows the two guanosines with alternate syn glycosidic conformations. The solution structure of a hairpin complexed with Co(NH3)2 (which may be used as a probe for binding sites of solvated Mg(H20)$+)has been The binding site for Co(NH3)b3 was determined by titration experiments. The CO(NH&~+ was found to bind in the major groove of the (GAAA) tetraloop, with H-bonds to guanine N7 and phosphate oxygen atoms of the tetraloop. Similar observations were made in the NMR structure of an RNA hairpin modelling the P5 helix of a group I intron complexed with C O ( N H ~ ) ~ ~ + . ~ ~ The solution structure of the self-complementary RNA duplex r(GCGA*AUUCGC), where A* is the 2’-O-P-~-ribofuranosylderivative (178), which is found in lower eukaryotic methionine initiator tRNAs (tRNAsIMet), has been solved by NMR.553The additional ribose moiety has no effect on thermal stability, and takes a well-defined position in the minor groove, where it is stabilised by water bridges to the phosphate backbone. An NMR structure of the tRNALYsanticodon stem and loop domain, containing the hypermodified nucleoside t6A (91), has been reported.554The structure of the anticodon loop UUUt6A is significantly different from the unmodified (UUU) sequence, where the t6A residue adopts the form of a tricyclic nucleoside with an intraresidue H-bond, and enhanced stacking interactions on the 3’-sideof the anticodon loop. The NMR structure of a self-complementary hexamer RNA duplex incorporating an isoguanosine-isocytidine base pair has been Whilst the struc+

+

+

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ture adopted an A-form duplex there were some deviations, but the structure was in accordance with the native equivalent duplex. An RNA duplex incorporating an additional adenosine in one strand has been studied by NMR.556The structure showed that the extra adenosine stacked into the duplex, with little perturbation around the bulge region. The duplex was A-form, with the sugar residues C3'-endoexcept for the adenosine and flanking nucleotides which were C2'-endo.The crystal structure of a DNA/RNA hybrid containing an additional adenosine in the polypurine RNA strand showed that the additional adenosine is looped out of the structure.557The duplex was in the A-form, with all sugar residues in the C3'-endoconformation, and the looped out base forms a C.g.a base triple with the terminal base pair. This has been observed previously in the case of the tridecamer duplex d(CGCAGAATTCGCG)z,where X-ray crystallography showed that the additional A lies out of the whilst the NMR structure shows an in-c~nformation.~~~ Clearly the two conformations cannot be energetically very different. There are several significant X-ray crystal structures, the details of which are beyond the scope of this review, but are nonetheless worthy of mention. These include the complete atomic structure of the large ribosomal subunit a t 2.4 A r e s o l ~ t i o n , 5the ~ ~ .ribosome ~~~ at 5.5 A,562the central domain of the ribosome the 30S5643565 and the 5 0 P 6 incorporating the S15, S6 and S18-rRNA at 2.6 ribosomal subunits and the 30s ribosomal subunit in complex with cognate tRNA?67The S15 rRNA complex has also been solved at 2.8 A resolution.568The minimal catalytic domain of a group I self-splicing intron RNA has been reported.569A solution structure of the A loop of the 23s rRNA has also been A crystal structure of the Holliday and the Holliday junction complex with a single E . coli RuvA tetramer at 3.1 A is reported.572A 2.4 A resolution crystal structure of tRNAG1"complex with glutamyl-tRNA synthetase has also been together with that of the hepatitis delta virus ribozyme bound to the U1A RNA binding The crystal structure of a decamer DNA duplex at high resolution (0.74 A) reveals conformations of sugar and phosphate residues that are not observed at lower The structure also shows two bound calcium ions and hydration of the duplex. Crystal structures of B-DNA duplexes binding with Mg2+ and Ca2+ show sequence-specific binding to both major and minor grooves.576Binding of Mg2+and Ca2+to the major groove causes DNA bending by base-roll compression towards the major groove. Binding in the minor groove has negligible effect on helix curvature. The DNA duplex d(CATGGGCCCATG) has been crystallised in a conformation intermediate between A- and B - f ~ r mThe . ~ ~structure ~ supports a base-centred rather than backbonecentred mechanism for the A B transition, mediated in this case by the G-tract. The crystal structure of a very short patch repair (Vsr) endonuclease complex with DNA containing a TG mismatch shows novel interactions of intercalated aromatic side chains which recognise the mismatch The enzyme also distorts the DNA backbone, and many protein side chain interactions stabilise the complex. Crystallographic studies of duplexes containing the mutagenic

-

268

Organophosphorus Chemistry

analogue N6-methoxyadenosine opposite cytosine and thymine demonstrate that the analogue is able to form stable Watson-Crick base pairs with both pyrimidines without distortion from the B-form duplex.579. 580 Endonuclease IV repairs damaged DNA at abasic sites. The crystal structure of Endonuclease IV with DNA containing an abasic site has been The enzyme side chains bend the DNA at the abasic site to -90" and promote double-nucleotide flipping to sequester the abasic site into an enzyme pocket. Three Zn2+ions are involved in the phosphodiester cleavage. The crystal structure of the duplex d(GGCCAATTGG) complexes with the minor groove binder 4',6-diamidino-2-phenylindole (DAPI) shows that DAPI is off-centred with a unique H-bond between the DAPI and a CG base pair.582The d G amino group is believed to prevent drug binding in the minor groove, but the structure shows that the amino group is non-planar, and does not prevent complexation. The crystal structure of the duplex d(CG5-BRUACG)2bound to the topoisomerase poison 9-bromophenazine-4-carboxamide shows a novel binding mode of the intercalated drug in the presence of Co2+ions.583A cavity is formed by the terminal cytosine rotated to form a pseudo-Holliday junction, with two such cavities forming a quadruplex-like structure. The crystal structure of the duplex d(CCAGGCCTGG)2 with a cross-link in the minor groove, via ethylene thiol linkers attached to N2,between the central d G residues shows the duplex in two different conformational states to relieve torsional One duplex contains a strained cross-link stabilised by Ca2+ion binding in the major groove. The other shows relief of strain by partial rupture of a base pair and partial extrusion of a cytosine residue. The crystal structure of a self-complementary duplex d(CCGCTAGCGG), in which the thymine bases are cross-linked by psoralen forms a Holliday junction at the cro~s-link.~*~ In contrast, the psoralen cross-linked duplex d(CCGGTACCGG) forms a sequence dependent junction which is highly distorted at the thymine cross-link. The two structures contrast the drug- and sequence-dependent interactions on the structure of a Holliday junction. A DNA duplex containing an interstrand dithio-bis-propane cross-link between two central adenosine residues has been solved by c r y s t a l l ~ g r a p h yThe .~~~ cross-link is long enough so that it does not cause helical bending. The crystal structure of the first triple helix has been The structure has a parallel third strand and whilst it has similarity with B-form DNA, it is distinct from both A- and B-DNA. There are large changes in the phosphate backbone torsion angles which result in a narrowing of the minor groove of the purine-Hoogsteen strands. DNA-RNA hybrid duplexes are substrates for RNase H and reverse transcriptase. The crystal structure of a hybrid deoxy-polypyrimidine with polypurine RNA has been solved.588The structure showed an A-form duplex, and the terminal base pair abuts the minor groove of another duplex creating a bend. RNase H is believed to interact through the minor groove but of an intermediate width between an A- and B-form duplex. The present structure did not exhibit an intermediate width of minor groove. A crystal structure of the chimeric ODN d(CCACTAGTG)rG shows that the presence of the 3'-ribonucleotide induces a

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conformational change towards the 5'-end such that duplex adopts an A-like conformation.589 The crystal structure of a 108-nucleotide RNA-DNA Holliday junction has been solved at 3.1 and differs from a previously solved 'stacked-X' conform a t i ~ n . The ~ ~ ' present structure differs due to a 135" rotation of the branches, and comparison of the two structures gives an insight into factors contributing to the flexibility of four-way junctions. The crystal structure of the duplex [r(guauaca)dC12,which would be expected to form a self-complementary duplex with an AC mismatch, has been solved and instead shown to form only six Watson-Crick base pairs with two 3'-overhanging bases.s92There are two independent duplexes, each of which is bent, and which stack end to end to form a right-handed super-helix. The overhanging nucleotides are looped out of the structure, with the penultimate adenosine residues forming A-GC base triples. The 2.8 A resolution crystal structure of an aptamer that binds to the chromophore malachite green593shows the binding site as an asymmetric internal loop flanked by a pair of helices.594There are several tiers of stacked nucleotides arranged in pairs, triples and a novel quadruple that encapsulates the ligand. An aptamer isolated by in vitro selection to bind to biotin has been studied by ~rystallography.~~~ The aptamer binds to biotin several orders of magnitude weaker than streptavidin. The aptamer contains a pseudoknot and binds biotin around the biotin head group, making little contact with the tail, unlike streptavidin. Also, biotin binds within the hydrophobic core of streptavidin, whereas in the aptamer complex there is a shell of water and magnesium ions surrounding the ligand. A 3 resolution crystal structure of RNA aptamer binding to vitamin BI2shows a RNA triplex stabilised by a novel three-stranded zipper.s96Perpendicular stacking of a duplex on the triplex creates a cleft that functions as the B12 binding site. A mutant tRNA''" in which the variable loop sequence 5'-44CAUUC48is replaced by AGGU binds to the glutaminyl-tRNA-synthetase with 30-fold improved affinity. A crystal structure of the mutant tRNA with its synthetase reveals major rearrangements of the central tertiary core, whilst maintaining the RNA-protein interface as the wild type.597The crystal structure of a UUCG tetraloop motif has recently been and found to be in general agreement with the previous solution However, the crystal structure gives a more detailed picture of the role of the 2'-OH groups in stabilising the structure.

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7 Ylides and Related Species ~

BY N. BRICKLEBANK

1

Introduction

This review covers the ylide literature over the period June 2000 to June 2001 with an emphasis on the organophosphorus compounds themselves, with only a cursory look at their myriad of applications in synthesis. Particular highlights include the first structurally authenticated example of a phosphonium diylide and the use of ionic liquids as a novel medium for performing Wittig reactions. Ylides, particularly their iminophosphorane counterparts, continue to provide a strikingly rich avenue of coordination chemistry research. A useful study by Pandolfo et al. reports the solid state NMR spectra of several ylides and their complexes, showing that this technique can provide valuable structural information in situations where it is difficult to obtain solution data due to solubility problems or decomposition.

2

Phosphonium Ylides

2.1 Mechanistic and Theoretical Sudies of Phosphonium Ylides and the Wittig Reaction. - A study of the mechanism of the Wittig reaction of pyridyl-substituted phosphoranes (1) with benzaldehyde shows that the reaction pathway, and the E:Z ratio of the products, is dependent upon the choice of base. With n-butyllithium, betaine intermediates (2) are favoured which results in lower product yields and poor selectivity. In contrast, using sodium bis(trimethy1silylamide) (NaHMDS) as base gives significantly higher yields of the phenylpropene with a much greater 2-selectivity. It is proposed that the pyridyl rings help to stabilise the betaine intermediates (2), by chelating the lithium ions, relative to the oxaphosphetane intermediate (3). Sodium ions are not chelated in the same way and so the reactions with NaHMDS proceed via the typical oxaphosphetane route.' Lledos et al. have carried out a theoretical DFT study (at the B3LYP level) on a series of hypothetical a-keto-stabilised ylides (4) and (5),in order to model the conformational preferences and rotational barriers of these compounds. As has Organophosphorus Chemistry, Volume 33

0The Royal Society of Chemistry, 2003 289

Organophosphorus Chemistry

290

M---C-Me I

(1) a n = l bn=2

(3)

cn=3

p’

0

H\ H-‘P=C 4 ‘ H C-R2

Hx\

H-P=C\

d’

,c\

H

’

,C=P‘-H \ H H

(4) R’ = H, R2 = Me

H

(5)

R ’ = H , R2=OMe R’ = H , R 2 = F R’ = H, R2 = NH2 R’ = R2 = Me

been shown by previous experimental studies on similar a-keto-ylides, ylides (4) and (5) show strong preferences for cis-conformations which facilitate the formation of P - - 0 intermolecular interactions.2Dransfield et al. have carried out an ab initio study (using the B3LYP/631 +G(d) method), of ‘electron poor’ boranesubstituted ylides (6) and (7), ‘dication’ (8) and ‘classical’ ylides ( 9 x 11) with the aim of shedding more light on the electronic nature of the P-Cylidic bond. The results indicate that compounds (6) and (8)require at least one amino substituent on the Cylide to form minimum structures with ylidic character, otherwise the compounds are unstable and susceptible to rearrangement. Compound (7a) is a model system for (7b), the structure of which has been determined previously. The calculations on (7a) confirm the suggestion that electron density from the carbene centre in (7a) and (7b) is delocalised towards the electron-deficient phosphonio-borane m ~ i e t i e sAn . ~ electron localization function investigation of the covalent and ionic contributions to the bonding in four-coordinte nitrogen and phosphorus compounds, including simple ylides such as (12) has been rep~rted.~ *

(6)R = R’ = H, NH3 R = H , R’=NH3

(7) a R = H bR=Ph

(8)

(10) R = R’ = H

R = H R1=NH3 R = Ri = NH3 R, R’ = -CH2CH2-

Ustynyuk and co-workers continue to describe their studies of the structures and reactivities of silicon-containing phosphorus betaines and ylides. In their

7: Hides and Related Species

29 1

latest contribution they use DFT calculations to model the thermal decomposition of betaines with the molecular backbone illustrated in structure (13). The authors conclude that thermal degradation of (13) through the formation of a ‘Wittig-type ylide’ and silanethione is the favoured route.’ R2 R3 I I +/ s i c -P - R ~ A2 R’

H H \ / H--P=C, / H

-s-

A2

‘R3

2.2 Synthesis and Characterisation of Phosphonium Ylides. - We start this section with a phosphanylidene-d-phosphorane (14) which, although not strictly an ylide, has a P-P bond which displays many of the properties of more conventional phosphonium ylides. A crystal structure of (14) revealed a P-P bond length of 2.084(2) A, which is similar to those found in other phosphanylidene-d-phosphoranes and is certainly shorter than a typical P-P single bond (ca. 2.22 A), indicative of multiple bond character. Compound (14) undergoes reactions with electrophiles (Scheme 1) which demonstrate its nucleophilic

Me Ar-P=P/--Me

Ar=

\

BH,.THF

or BH,-SMe, Me

/BH3 Ar -P

\+ PMe3

I..;..[

E

Scheme 1

E

-Me,P

X- *

Ar-P’ \ +Me,P

X E = Me3Si, X = OTf E = H , X=OTf E = M e , X=OTf E = Me3Si, X = l E=Me, X = I E=H, X=CI E=Ph, X = O H

character.6 Another atypical ylide that we review in this section is a new phosphonium diylide. Treatment of dimethylbis(fluoreny1)phosphoniumiodide (15) with either potassium hydride or potassium (hexamethyldisilazide) in T H F generates the corresponding ylide (16) in yields greater than 70%. A crystal structure of (16) reveals a distorted tetrahedral environment around the phosphorus atom. The P-C bonds between the phosphorus atom and fluorenyl groups are unequal, that between the phosphorus and the fluorenyl ring [1.847(2)A] is appropriate for a P-C single bond and is significantly longer than the bond between the phosphorus and the fluorenylide ring [1.724(2) A], reflecting the partial multiple bond character in the latter. Treatment of (15) with calcium (hexamethyldisilazide) generates salt (17). Alternatively, compound (17)

Organophosphorus Chemistry

292

m

1

+,-

KH or K[N(SiMe,),],

THF b

5)

~

H

F-L~I

,

. Gal,, THF

can also obtained by treating (15)with n-butyllithium followed by reaction in situ with calcium iodide. A single crystal X-ray investigation of (17) revealed that the diylide anion is not in the coordination sphere of the cation and thus represents the first structurally authenticated example of a phosphonium diylide. The P-C(ylidic) bond lengths [1.750(3) A, 1.746(3) A] are comparable with the P-C(fluorenylide)distance of (1 6), confirming multiple-bond character. The formation of this apparently discrete anionic diylide in an otherwise highly ionic system was attributed to the unusual preference of calcium to coordinate to a single iodide and the oxygen atoms of several T H F molecules rather than the diylide.' Heterocyclic phosphorus ylides provide the topic for a comprehensive review by Aitken and MassiL8 Aitken and co-workers also continue to make new contributions to the field of heterocyclic phosphorus ylides and in their latest paper they report the synthesis of a series of new ylides from amino acid derived ylides using their established flash vacuum pyrolysis (FVP) route operating at 6OO0C, Torr. Thus, hydrogenolytic removal of the N-benzyloxycarbonyl group from ylides (18) using normal wet chemical methods produces (19), which readily undergo FVP with loss of ethanol, producing tetramic acid substituted ylides (20) as crystalline solids (Scheme 2). Similarly, when proline derived ylide (21) is subjected to the same FVP conditions then bicyclic ylide (22) is obtained in 67% yield. Previous FVP studies of protected amino acid-derived ylides such as (18) had shown that the reactions proceeded via extrusion of triphenylphosphine oxide affording a$-acetylenic-y-amino acids. Deprotection of the amino acid function prior to FVP therefore completely changes the pyrolysis behaviour and produces new stabilised ylides. Considering the above reactions only take place under extreme conditions, it is perhaps surprising that the cyclisation of ylide (23) derived from methyl glutamate occurs spontaneously (no FVP required), with the competing elimination of ethanol and methanol, producing (24) and (25) in

7: Ylides and Related Species

293

HP, P d C - p

h

3

p

~

ph3z

~ ~ 2 FVP, 600 "C

-EtOH

p h03 p ~R'~ ~ C 0 2 C H ~ F ' h

0

R'

(19) Scheme 2

(18)

p

h

3

P

0

*

R'

(20) R' = H, Me, Pr'

FVP, ~ 600 "C w P

h s l P .

-EtOH

0

H

P h 3 P V 0

NO FVP

NH

t

0 ph3p\2

(23)

NOFVP

I

C02Me -MeOH

-MeOH

+ RT, several months

-EtOH

*

ph3p% 0

yields of 20% and 12% respectively (Scheme 3). Moreover, upon standing at room temperature for several months (25),but not (24), was found to undergo a further cyclisation producing (26). The reasons for these apparently anomalous cyclisation were not explained. Another amino acid derived ylide (27),in this case obtained from p-alanine, undergoes FVP with loss of ethanol, producing ylide (28) in 42% yield, although product (29) was also obtained in appreciable yield (190/,)through the extrusion of triphenylphosphine oxide from (27) (Scheme 4). Finally, a series of extended amino acid analogues, (a-aminoacyl)(ethoxycarbonyletheny1)ylides (30) was prepared and subjected to FVP and similarly these underwent cyclisation with loss of ethanol and the N-benzoyloxycarbonyl protecting group still in place, to afford azepine-2,6-dione ylides (31).9

FVP

600 "C

(27)

ph3pfiNH

0 (28) Scheme 4

Et02C

+

\NH2 (29)

Ylides containing fluorine atoms are of obvious utility, considering the importance of fluorine-containing compounds and materials. Kolodiazhnyi and Schmutzler have reviewed the synthesis, properties and applications of ylides

Organophosphorus Chemistry

294

p co2 + iEt

h3

FVP, 600 "C -EK)H

0%

NHC02CH2Ph

1 'C02CH2Ph R' (31) R' = H, Me, Pr'

R'

(i) Bu'Li, THF, 0 "C, N,

* Ph,P=C/ (ii) RFC=CP(0)(OEt)2,0 "C,30 min

P(OEt)* R'

\

/

c=c,

R/F

R2

(32)a R' = R2 = Me, RF = CF2CF3 b R' = R2 = H, RF = CF2CF3 c R' ,R2 = --(CH&-, RF = CF2CF3 d R' ,R2 = -(CH2)6-, RF = CFpCF3 e R' = R2 = Me, RF = CF3 f R' R2 = -(CH2)5-, RF = CF3 g R':R2 = -(cti2)6-, RF = CF3 Scheme 5

which contain fluorine atoms bonded to the ylidic phosphorus atom." The synthesis and reactivity of a series of perfluoroalkylated diethoxyphosphinyl triphenylphosphoranes (32a-g) has been reported (Scheme 5). The crystal structure of one of these ylides (32a) was determined and found to have a short P-Cylidic bond length 1.699(5) A. It was observed that perfluoroalkyl ylides (32a-g) did not react with benzaldehyde, even in boiling toluene, and this low reactivity was attributed to the short, and consequently very stable, P-C ylide bond." The condensation reactions between ylidyl chlorophosphines and tertiary phosphines have proved a fruitful avenue of research for Schmidpeter and co-workers. In their latest contribution to this area, this group describe the reactions of ylide-containing chlorophosphines with trimethylsilylphosphines, lithium diphosphinylmethanide and lithium diphosphinylamide. The reaction between ylidyl chlorophosphines (33) and trimethylsilylphosphines produces ylidyl diphosphines (34)-(36) whereas treatment of (33) with lithium diphosphinylmethanide or lithium diphosphinylamide yields diphosphonium ylides (37) or ylidyl diphosphinimine (38) respectively (Scheme 6). The diphosphonium ylides (37) rearrange to give ylidyl triphosphinylmethanes (39) whereas chloromethyl diphosphinimine (38) undergoes a further cyclisation generating 1,2,3,5azatriphosphole derivative (40), the structure of which was determined by X-ray crystallography. Unusual phosphine selenides (41) and (42) are obtained from the reaction of ylidyl chlorophosphine (33) or diphosphinimine (38) with elemental selenium. Ylidyl dichlorophosphines (43) react with diphenyl(trimethy1sily1)phosphine to produce 2-ylidyl triphosphines (44). Treatment of (44b) with elemental selenium, yields mixtures of phosphine-phosphine selenides (Scheme 7). Reaction of ylidyl bis(ch1orophosphine) (45) with lithium diphosphinylmethanide or lithium diphosphinylamide produces 1,2,4,5tetraphosphinine (46) and 1,2,3,5,6-azatetraphosphinine(47) respectively (Scheme 8). Similarly, the reaction between ylidyl bis(ch1orophosphine) (48) and lithium diphosphinylamide produces 1,2,3,5,6-azatetraphosphinine(49) (Scheme 9).12Clearly, these reac-

7: Hides and Related Species

295 R3

Ph

I

PI Ap , R4

Ph3PA

R’

////-

R1 = Me, Et, R2 = Ph +R3R4PSiMe3 -Me,SiCI

= Me, R3 = R4 = Ph = Et, R3 = R4 = Ph = Et, R3 = Ph, R4 = SiMe3 = Me, R3 = R4 = SiMe3 = Et, R3 = R4 = SiMe3

(34) R’ R’ R’ R’ R’

R’ = CH2CI, R2 = Ph

Ph

A

Ph p Jr,

+Ph,PSiMe,

Ph3P

Ph3PAP’

t

-Me,SiCI

+Ph/

~2

PPh2

(35)

Ph3P

PPh2

I

(36)

PPh2

R2

-

Ph3PAPAPPh2 I R’ (39)

(37)

Ph3P

Ph

A

Ph3P

7h2 Ph2 p paN I

Ph3P

‘+se

(42)

77

Ph2P+ :PPh2 CIN (40)

Me

Scheme 6

Me

I

Q.-

PPh2 II

A Ph3P

p,cI I

CI (43)

Ph3P

R’

R’

a = Me b = pMec6H4-

2 Ph,PSiMe, -2 Me,SiCI

p’ PPh2 I

PPh2 (44) a = Me b = pMeC6H4-

Scheme 7

Se

PPh2

I

Ph2

296

Organophosphorus Chemistry PPh3

PPh3

PhxpAp’p\lI

Ph-P++P\P i

* LiCH(PPh,),

Ph,p/C’

Ph,pKp’Ph

LiN(PPh,),

I

I

Ph Ph

-LiCI

A p / C l Ph3P

-LICI

I

(46)

I

* Ph-P+

(45) Ph

‘P-Ph P i N 0 ‘Ph (47)

c1-

Scheme 8

I

Ph Ph\+ N Ph-P’ ?-‘P/-Ph

2 LiN(PPh,), D

-2 LiCl

Ph-P+ Ph/

(z;

+P,-Ph Ph

Scheme 9

Ph3P +

(50) R’ = Me, Et, Pr’

Scheme 10

(51) R2 = Me, Et

tions produce a fascinating variety of ylide-containing phosphines and related species which might be expected to display an equally varied coordination chemistry. Stable phosphorus ylides (50)and (51) have been prepared from the reaction of electron-deficient acetylenic esters, such as dialkyl acetylenedicarboxylates or alkyl propiolates and triphenylphosphine in the presence of 3-chlorotetrahydrofuran-2,4-dione (Scheme 10). These reactions are thought to proceed via vinylphosphonium salt intermediates which undergo Michael addition with the conjugate base of the CH-acid.13Similar methodology has been used to prepare phosphonium ylide (52)from triphenylphosphine, isatin (indoline-2,3-dione) and dimethyl acetylenedi~arboxylate.’~ 0 CN

H Ph3P=C,

C

I

H I

,OEt

II

HC ,,

,OCH&H=CHp

:

0 (53)

Other new ylides that have been reported recently include (53),which is useful for the conversion of aldehydes into y,&unsaturated ally1 ~ - k e t o e ~ t e r sand , ’ ~(54),

7: Ylides and Related Species

297

obtained from 3-cyanochromone and methylenetriphenylphosphorane. Variable temperature ‘H NMR indicates that (54) undergoes rapid conformational interconversion in solution; however, X-ray crystallography shows that in the solid state (54) exists as the E-isomer.’6

Ph3P=CHR1 + R2CH0

R’

(55)

R2

R1-=-R2

Olefin Yield

COMe Ph 4-CI-CeH4COMe 4-NO2-CeH4COMe COMe 4-MeO-C6H42-Me-CeH4COMe COMe Cyclohexyl COMe FsHl I COMe Butyl COMe (€)-Ph-CH=CHCOMe (0-Me-CH=CHPh C02Me Ph CN

86 44 82 95 80 82 84 86 88 90 79

+ Ph3PO

€12 9713 9812 9614 9614 85115 9812 9812 90110 9515 9713 50150

Scheme 11

2.3 Reactions of Phosphonium Ylides. - 2.3.1 Reactions with Carbonyl Compounds. The traditional Wittig reaction between phosphonium ylides and carbony1 compounds remains a widely used tool for the synthesis of alkenes in a wide variety of compounds. One important new development that we can report in this volume is the use of ionic liquids as a medium for Wittig reactions. Ionic liquids are a relatively new class of solvent consisting of poorly coordinating ion pairs, such as 1-butyl-3-methylimidazolium tetrafluoroborate [bmim] [BF4] (55), which is a colourless, odourless, non-volatile mobile liquid. Such solvents are of interest in organic synthesis because they facilitate easy separation of products and are re-usable, thus reducing solvent waste. In a preliminary communication, Le Boulaire and Gree outline the use of (55) as a solvent for the Wittig reaction between stabilised ylides and a variety of aldehydes (Scheme 11). Important aspects of this work are that the same solvent can be used for repeated identical reactions. For example, the reaction between triphenylphosphoranylidene-2-propanone and benzaldehyde was repeated six consecutive times in the same solvent and all six reactions gave greater than 80% yield of alkene. Moreover, the same solvent was used for different reactions with no appreciable cross contamination of products.” A detailed study of the Wittig reactions of novel semi-stabilised ylide (56) has appeared. Unlike other semi-stabilised ylides, which typically give mixtures of E-

298

Organophosphorus Chemistry

and 2-alkenes, (56) reacts with aldehydes with very high E-selectivity. Moreover, the selectivity is maintained irrespective of the metal ion of the base, the solvent, and the reaction temperature. For example, (56) reacts with a variety of aliphatic or aromatic aldehydes, the latter bearing electron-donating or electron-withdrawing subsitutuents, to give the E-alkenes, typically in 90% yield. Only the reaction with acetophenone was poor, giving a low yield and mixture of isomers, and cyclohexanone does not react with (56) at all. Similarly (56) reacts with benzaldehyde using either KHMDS, Bu'OK, LiHMDS or lithium diisopropylamide as base, producing exclusively the E-alkene in yields greater than 80%. The remarkable stereoselectivity of this reagent is clearly linked to its rigid cage structure which affects the stereochemical arrangement of the oxaphosphetane intermediates formed during the course of the Wittig reactions.'* Tertiary phosphines containing long perfluoroalkyl chains, so called 'pony tails', are of considerable interest in view of their application in fluorous-phase catalysis. Gladysz and co-workers have reported the synthesis of fluorous phosphonium salts (57),19 which they have subsequently used to prepare fluorousphosphines. The first step in their protocol is the Wittig reaction of (57) with bromobenzaldehyde, producing fluorous bromostyrenes (58) as mixtures of the E- and 2-isomers in 86-93% yield (Scheme 12).*'

H

(59)

H

(60)

(61)

R' = CN, R2 = Et, X = Br R' = C02Et, R2 = Et, X = Br R' = NO2, R2 = Et, X = Br R'=CN, R2=Et, X = l R' = C02Et, R2 = Et, X = I R' = NO2, R2 = Et, X = I R'=CN, R2=Me, X = I R' = N02, R2 = Me, X = I

Treatment of fluorinated amides (59) with phosphoranes has been shown to proceed at room temperature to give mixtures of enamines (60) and imine (61) tautomers through competing pathways.21 A new route for the synthesis of monofluorinated allyl alcohols involves a Wittig olefination reaction of (afluoroviny1)triphenylphosphonium triflate (62) with caesium allylate and aldehydes in trimethyl orthoformate, which gave the corresponding mono-fluorinated allyl ethers with good stereoselectivity; the resulting ethers were readily transformed into the corresponding mono-fluorinated allyl alcohols.22 So-called tandem, domino or cascade reactions provide powerful tools for the

7 : Hides and Related Species

299

-; ]

[Ph3b

=CH2 O T f

ooL I

(i)

, reflux, 24 h

/ R

BU‘OK Et20, rt., 0.5 h*

Ph/ ‘Ph

R

R = Ph, Me, P i , n-Pentyl

(64)

Scheme 13

synthesis of complex molecules. Tandem Michael-Intramolecular Wittig reactions of cyclic ylide (63) with 8-phenylmenthyl enolates have been used to prepare cyclic ketones (64) which can be converted into their diastereomeric ketals through treatment with (2R,3R)-2,3-butanediol(Scheme 13). The reaction proceeds with high yields and high stereo~electivity.~~ Wittig olefinations continue to be exploited for the synthesis of heterocyclic species. For example, acylphosphoranes (65), formed as intermediates in the condensation of (trimethylsily1)methylenetriphenylphosphorane and the silyl esters of 0-acyl(aroy1)salicylic acids, undergo intramolecular Wittig reactions producing substituted chromenones (66) (Scheme 14).24Treatment of dioxolanones (67) with (carbethoxymethy1ene)triphenylphosphoraneproduces the corresponding a$-unsaturated esters (68), which are useful precursors to 0

R’&OSiMe2CMe3 R2

0

R’ H H H H H H H H H H CI CI

l*

0

300

Organophosphorus Chemistry

butyrolactones, which are themselves important components of many natural A variety of heterocyclic species has been obtained from the reaction of acetyl-furan or -thiophene compounds with phosphonium ylides,26whereas nitrogen-containing heterocycles have been obtained from the reaction of indolinone and azaindolinone with ylides.*' Ylide (69) was obtained from the reaction of 1-benzenesulfonylindole-2,3-dicarboxylic anhydride and methylenetriphenylphosphorane. After esterification of the carboxyl function and removal of the benzenesulfonyl group of (69), the ylide was treated with aldehydes to give a$-unsaturated ketones which were subsequently converted into pyrrolo[ 1,2-a] indoles.**Phosphonium salt (70) has been prepared and treated with aromatic aldehydes under phase-transfer conditions to furnish substituted-tria~oles.~~

(67) (68) R = Ph, CH2Ph, Me2CH, MeCH2CHMe

%PPh3 Ph02S

[Ph3bCH2CH2CH2-N, R

0 (69)

, JN

Br-

N

(70)

Wittig olefination reactions continue to play important roles in the synthesis of a wide variety of biologically active molecules and here we review a small selection of examples. Dolastatin-14 is a very potent anti-cancer agent first isolated from the Indian Ocean sea hare Dolabella auricuaria in 7.5 x 10 7 % yield! In their quest for a total synthesis of dolastatin, Duffield and Pettit have prepared the (7&15s)- and (7R,15S)-diastereoisomers of dolatrienoic acid in which the Wittig reactions of phosphonium salts (71) and (72)played an important role.3oAs part of their approach for the total synthesis of plaunotol, a component of the Thai folk medicinal plant Plau-noi, which shows remarkable anti-gastric ulcer properties, Kogen and co-workers have developed a highly Z-selective Wittig olefination of a-acetal ketones. Reaction of phosphonium salts (73) with a-acetal ketones (74)generally proceeded with greater than 90% Z-selectivity under the conditions employed, with the 18-crown-6 playing a pivotal role in ylide formation (Scheme 15). The synthesis of plaunotol was achieved using similar methodology, utilising phosphonium salt (75).3' Wit tig reactions have played a prominent role in the evolution of a gram-scale synthesis of (+)-discoderolide, an anti-tumour agent derived from the marine sponge, Disaderia d i s ~ o l u t a .In ~ ~order to synthesise radio-labelled testosterone and

7 : Ylides and Related Species Br-

+

301 (i) BU'OK, 18-crown-6,THF, rt.

Ph3P-

* R2

R' (73)

(ii)

, -78

O

to -40

R1

"C

R2

(74) (iii) H+

R' = -(CH2),-Me, Bu', (CH2)20Bn,(CH2)2C=CH R2 = (CH,)2C=CHCH2CH2C(CH3)=CHCH2-, -(CH2)4-Me, Bu', Ph

Scheme 15

OTBDMS (75)

progesterone, labelled triphenylphosphoranylidenepropan-2-one (76) has been prepared from commercially available 13C-acetyl chloride and 13C-methyltriphenylphosphonium iodide (Scheme 16).33Oligosacccharide mimics have been obtained using a stereoselective iterative process starting from galactopyranose phosphonium iodide (77) (Scheme 17).34A combined Wittig-dehydroxylation protocol, utilising stabilised ylides (78) and (79), has been used to transform unprotected carbohydrates into higher sugars. The bulky tertiary butyl or diphenylmethyl substituents on these phosphoranes reduce the likelihood of unwanted Michael addition side reactions.35

Scheme 16

0 (76)

n= 1,2 Reagents: i, BuLi, 3: THF, HMPA, -20 "C, 4 h; ii, TBAF, THF, reflux, 1.5 h; iii, 12, PPh3, imidazole, toluene, reflux, 1 h; iv, PPh3. 110 "C, 4 h Scheme 17

Finally, Shah and Protasiewicz have reviewed what they term 'phosphavariations' of the Wittig and aza-Wittig olefination reactions where a phosphaWittig is one that uses 'phospha-ylides', such as phosphoranylidene-d-phos-

302

Organophosphorus Chemistry

phoranes (SO), to convert carbonyl compounds into new materials possessing P-C double bonds, i.e. phosphalkenes (81).36 H

H Ph3P=d,

C

,OBu'

Ph3P=d,

6

(78)

(79)

0

R:

9

R'

+ Ph3P=(

H 'X

R2

-

-

R:

I1

P=PPh3 + R2C ,,

(80)

,0CHPh2

80

R2

,R2 P=C,

ZH

+ Ph3PO

(81)

+

R'

irx

R 2 ~ ' 0

R

,

H

x R2H

+ X-0J-Y

'H

X = Y = Ph, Me; X = Ph, Y = H, Me; X = pCF3-C6H4--; R' = H, R2 = C02CH2Ph, C02Et, C02Me, COMe, C(0)H; R' = Me, R2 = C02Et; R' = COCF3, R2 = C02E Scheme 18

R2 = C02Me, COPh, C02CHPh, C02Bu', CHO, Ph Scheme 19

2.3.2 Miscellaneous Reactions. In two comprehensive publications, Taylor and co-workers detail the reactions of 1,2-dioxineswith stabilised ylides as a route to diastereomerically pure cyclopropanes (Scheme 18).37,38 The reaction of ozonides with stabilised ylides produces a$-unsaturated carbonyl compounds (Scheme 19). The E/Z isomeric ratio of the final products is affected by the identity and position of heteroatom substituents on the ozonide h e t e r o ~ y c l e . ~ ~ The interaction of phosphonium ylides with oxidising agents is the theme of a number of recent papers. Dioxiranes (82) are a new and versatile group of oxidising agents which have recently been applied to the synthesis of a-keto esters by the oxidative cleavage of cyanoketophosphoranes (Scheme 20).40A one-pot oxidation/Wittig olefination process using ortho-iodoxybenzoic acid and stabilised ylides facilitates the conversion of benzylic, allylic and propargylic alcohols into a$-unsaturated esters."' A relatively simple procedure for the oxidation of keto-ylides to vicinal tricarbonyls in high yields using unsupported, moist magnesium monoperoxophthalate has been reported (Scheme 21).42Vide (83) was obtained from the reaction of methacryloyl isocyanate with (carbethoxymethy1)triphenylphosphorane;similar compounds were obtained with sulfonium ~lides.4~ The reaction between phosphorus ylides and elemental sulfur or selenium has been used to prepare chalcogen-containing heterocyclic species. For example,

7: Hides and Related Species

303

x

0-0

0

0 (82) MeCH, acetone, rt. *

R-"KoMe

0

PPh3 $0

R=-,-

\

t

Me(CH2)7C=C(CH2)7-, Me0

An,u,n,-,

q, Br

L

O

Scheme 20

0.H20

PPh3

Scheme 21

sequential treatment of (diphenylmethy1ene)triphenylphosphoranes (84) with sulfur and maleic anhydride in refluxing xylene affords 1,2-dithiolanes (85). However, if the reaction is carried out in the presence of 2-adamantanethione, then spiro-adamantane- 1,2,4-trithiolane (86) and spiro-diadamantane- 1,2,4trithiolane (87) are obtained in yields of 15% and 44% respectively, together with substantial quantities of thiobenzophenone and triphenylphosphine sulfide.44 Similarly, treatment of t-butyl (ary1)methylenetriphenylphosphoranes (88) with selenium affords 1,2,4-triselenolanes(89) and 1,3-diselenetanes (90) together with triphenylphosphine ~ e l e n i d e . ~ ~ Taillefer et al. have reported a one-pot method for the preparation of a$unsaturated organophosphorus compounds through the reaction of lithium diphenylphosphonium diylides with phosphorus electrophiles and aldehydes. In the first step, treatment of diylides (91)with chlorodiphenylphosphine results in the formation of mono-ylide intermediates (92) and (93). Subsequent addition of aldehyde (94) produces either alkenes (95) or phosphines (96) (Scheme 22). The product obtained is critically dependent upon the nature of the ylide substituents and the aldehyde employed. For example, non-stabilised ylide (91a) reacts with chlorodiphenylphosphine and aromatic, heteroaromatic or enolisable aldehydes (94a-f) producing the corresponding phosphines (96), predominantly as the 2 isomer. However, with 4-phenylcyclohexanone the only product obtained from (91a) is the alkene, (4-methylenecyclohex-1-y1)benzene.Non-stabilised ylide (91b) reacts with chlorodiphenylphosphine and benzaldehyde (94a) to give primarily alkene product whereas para-nitrobenzaldehyde (94c) yields only the phosphine product. Semi-stabilised ylide (91c), and stabilised ylide (91d), react

Organophosphorus Chemistry

304

s,, xylene, *

R

y

R

R

R

PhMe, reflux

PPh3 + Se

+

t

(88) R = MeO, PhO

R

(89)

+/-CHR’ Ph2P, Li+

-CHR’

Ph,PCI

CHR’ (91) a R ] = H b R’ = Me c R’ = Ph d R’ = COPh

THFy

CH-PPhP

p’

R:

C=C

1

2o ”‘

2

R3 (92) a-d

I

R

]. (94)a-f

[h2‘(A,

(90)

3

H (95)

‘I

-CH2R’ +/ Ph2P,C-PPh2

.

(93) a-d

.

A’

Scheme 22

with benzaldehyde to give alkene product (95) only. Using a similar methodology, treatment of ylide (9la) with either chlorodiphenylphosphine oxide, sulfide or diethylchlorophosphate and benzaldehyde allowed the synthesis of styrylphosphine oxide (97), styrylphosphine sulfide (98) and diethyl styrylphosphonate (99).46

7: Hides and Related Species

305 R:

c=o

R3 (94) a R2 = Ph, R3 = H b R2 = pMeC&-, R3 = H C R2 = pN0&6H4-, R3 = H

cR i 2=),f

R3=H

e R2 = PhCH(Me)CH2-, R3 = H f R2 = R3 = H +JCH2 Ph2P, Li+ -CH2

fi

i, R ~ P C ITHF, , 20c

*

Ph,

H'

ii, PhCHO, 25 "C

(91)a

H ,

c=c

'PR1 II

X

(97) R'=Ph, X = O (98) R1=Ph, X = S (99) R1 =OEt, X = O

Phosphonium ylides can be used to effect the reduction of the phosphodecamolybdate anion through a consecutive series of single-electron transfers (Scheme 23). The reactions utilising tributyl(methy1ene)phosphorane apparently proceed most cleanly, triphenylphosphoranes leading to precipitates containing mixtures of oxidised and reduced phosphadecamolybdates. The reductions are accompanied by strong blue colouration of the resulting solution~.~' Carbonyl-stabilised ylides have proved effective for the reduction of platinum(1V) imines to the corresponding platinum(I1) complexes which are difficult to obtain from the usual platinum(I1) precursors.48

Bu,P=CH~

3[Bun4fi][PMOI2O40l3-

MeCN

Bu,P

-

CH2, MeCN

[PM012040]4-+ Bu36Me

[PM012040]5-+ 2 Bu36Me

Scheme 23

R2

R2

R2

.

R2

The crystal structures of two phosphonium aryloxides (loo), produced by the protonation of the corresponding ylides, have been determined. The compounds contain unusually short C-H - 0 hydrogen Phosphonium ylides have previously been used as latent catalysts for the addition of bisphenol A diglycidyl ether with bisphenol A. In their latest contribution to this topic, Endo and co-workers have carried out a detailed kinetic study on the effect of different ylide-substituents on the reaction of glycidyl phenyl ether with 2$-dimethylphenol (Scheme 24), and the polyaddition of bisphenol A diglycidyl ether with bisphenol A.50 *

306

67

Organophosphorus Chemistry

Ph,P=(

H

C-R

+

6 R = H, Me, Ph, But

w

OH

Scheme 24

0,N

2.4 Synthesisand Reactions of Aza-WittigReagents.- We begin this section by looking at some of the new aza-Wittig phosphoranes that have been reported recently. Five new phosphoranes (101), all derivatives of 1,2,3-triazoles, have been prepared and ~haracterised.~~ Christau et al. have developed two routes to diaminophosphonium diazaylides (102) (Scheme 25). The first route involves treating acylazides with sodium diphenylphosphide whereas the second route involves the deprotonation of mono-azaylide intermediates with butyl lithium. No comparison of the relative merits of the two routes was reported although it was noted that the latter is significantly faster.52 Deprotonation of cyclopropyl(tripheny1)phosphonium bromide (103) with sodium amide did not yield the expected triphenylphosphonium cyclopropylylide but rather the unusual N-phosphino-substituted imino-phosphorane (104), the structure of which has been determined by X-ray crystallography. A mechanism, based on in situ NMR data, was proposed to account for the formation of ( 104).53Treatment of optically active azides (105) and (106), derived from quinine and penta-0-acetylglycose tartaric acid respectively, with aminophosphine (107), has been used to prepare highly basic iminophosphoranes (108) and (109), which have potential application as asymmetric catalysts and l i g a n d ~ . ~ ~ Regarding the application of iminophosphoranes and aza-Wittig reagents to synthesis, polymer-supported aza-Wittig reactions have been used to prepare nitrogen-containing compounds including a m i n e ~ , ~i~m i n e ~ , ~and ~ bi~(guanidines).~’ Furthermore, iminophosphoranes continue to play important roles in the synthesis of biologically active alkaloids, such as the indole-alkaloids rhopaladin A58and cryptotackienine, the latter utilizing phosphorane (1 and the aza-analogues of naturally occurring ellipticine alkaloids which required compounds (111) and (112).60Other biologically active compounds prepared using aza-Wittig chemistry include benzodiazepins and benzothiadiazepines, which are accessed from iminophosphoranyl thiazine-S-oxides (113).61

7: Ylides and Related Species

307 H I

2 RN3 N, acetone, 20 "C, 48 h

+

N-R M+ N-R (102)

Ph2Na

Bu"Li, THF, -50 "C, 1 h

1;

* Ph2P<,,;

.

N-R

N., acetone 4

4

N-R.

2 RN3

+

-5"C, 3 h Ph2PH

Scheme 25

J?

4

C - ~H..-4,rt..., 1. _5 .h.

TNJT

'N =P(MeNC2H4)3N

Other heterocycles prepared using iminophosphoranes include novel pyrimidinone and quinazoline derivatives, obtained from in situ aza-Wittig reactions of N' aryl-N-(triphenylphosphoranylidene)carboxidamides (114) and ketenes,62 and pyrido thienopyridazines and pyrimidothienopyridazines, accessed from aza-Wittig/electrocyclic-ring closure reactions between phosphoranes (115) and (116) and heteroc~mulenes.6~

2.5 Ylides Coordinated to Metals. - Bailey et al. have described the coordination behaviour and unusual structural features of lithiated phosphonium ylides. Treatment of phenyltribenzylphosphonium chloride with two or three equival-

Organophosphorus Chemistry

308

(y;$phYN PR3 II 0- R'

(113)

X = S02, CO,

P

h

phs

c

?PPh3

(114) R = H, Me

N."

s

R

(1 15) R = C02Et, CN

(116) R = Ph, 4-MeOC6H4-

R = Bu", Ph; R' = H, Me; R'-R' = -[CH*CH2]-

nents of n-butyllithium leads to the formation of mono- and di-lithiated phosphonium ylides (117) and (118) respectively (Scheme 26). The X-ray crystal structure of the TMEDA adduct of the monolithiated compound was determined and revealed that the lithium atom is not coordinated by both P-CHPh groups, as might be anticipated, but through the carbon atom of one of the

(1 17)

P-CHPh groups and the ipso-ortho bond of the phenyl ring of the second P-CHPh group. Therefore, not surprisingly, the bonds between the phosphorus atom and the benzylic-carbons are all of different lengths. The P-C ylidic bond [1.712(3) A] was assigned as a double bond, and is clearly shorter than that between phosphorus and the uncoordinated benzylic methylene group [1.845(3) A], The third P-CHPh bond, which bears the negative charge, has a length of 1.743(3) A which was interpreted as a phosphorus-carbon single bond shortened

7: Ylides and Related Species

309

by its polar nature. Unfortunately the authors were not able to grow crystals of dilithiated species (118) which would have surely displayed equally interesting structural features. Treatment of dimeric, halide-bridged, rhodium and chromium complexes [(q5-C5Me5)RhCl2I2 and [q5-C5Me5)CrBr2I2 with (118), generated in situ, leads to complexes (119)and (120),containing monoanionic, chelated phosphonium ylide moieties. Complexes (119) and (120) are thought to be hydrolysis products of the target complexes [{ PhP(CHPh),)M(q5-C5Me5)](M = Rh, Cr).64 NMR studies show that fullerene derivative (121)exists as mixtures of E and 2 isomers. Treatment of (121)with either magnesium bromide or lithium iodide, in deuterated chloroform with ultrasonic agitation, produces a single isomeric form of a complex in which (121) coordinates to the metal through the ylide carbonyl function.65 Cave11 and co-workers have disclosed more of their studies of the chemistry of

‘OMe

Ph\ Ph --P

Ph, Ph-P=N

,SiMe3

=N’ \ +

/SiMe3

\

/CI C=M-CI f‘t Ph-P=N\ L ph/ SiMe3 M=HF. L = T H F M=HF; L = A d C N M = Zr, L = 2,6-Me2C6H4CN

C=M

/

,CH2Bu‘

‘CH2Bu‘ Ph-P=N\ ph/ SiMe3 M = HF

/

\

f

1

2 LiCH,Bu‘, -LiCI

Ph,

/SiMe3

Ph, P =N, ’SiMe3 \x=C=Y

Me3Si, P” Phi N L . LC.;X Ph-P’i N” . ;M :/ I Y Me3Si’ cI CI M=HF, X = Y = O M = H F , X = O , Y=NAd M = HF, X = Y = N(pt0lyl) M = Zr, X = Y = N(ptoly1) M=Zr, X = Y = N C y

Ph-P=N‘

”

\ +

/CI C=M-CI / f‘x Ph-P=N\ ph/ SiMe3 M = HF, E = H, X = HN(pt0lyl) M = Zr, E = H, X = O A d M = HF, E = M e , X = l

’

Scheme 27

310

Organophosphorus Chemistry

chelating iminophosphorane ligands and their complexes. The high-valent metal alkylidene character of bis(iminophosphorano)methanediide (carbene) complexes (122) has been demonstrated through their reactions with a variety of electrophiles and nucleophiles. Thus complexes (122) form Lewis acid-base adducts with THF, nitriles and isonitriles, and undergo 1,2-addition reactions with amines, alcohols and alkyl halides and [2 + 21-cycloaddition reactions with heteroallenes. Furthermore, the halide complexes can be alkylated without attack at the carbene centre (Scheme 27).66 Treatment of N-alkylated bis(dipheny1phosphino)amines (123) with trimethylsilylazide in the absence of solvent yields trimethylsilyliminophosphoranes(124) as crystalline solids. It is worthy of note that the reactions of N-methyl and N-phenyl bis(dipheny1phosphino)amines did not proceed cleanly under these conditions, giving mixtures of products that could not be characterised. The compounds were characterised spectroscopically and, in the case of the propyl derivative (124b), the X-ray crystal structure was determined. Compounds (124) act as bifunctional ligands, readily forming chelate complexes with a variety of rhodium, platinum and palladium species (Scheme 28). The oxidation of (124b) with elemental sulfur, selenium or phosphoryl azide produces the corresponding moisture sensitive phosphoranes (129, (126) and (127)respectively, which desilylate readily in moist (undistilled) acetonitrile producing phosphinimines (12 8 H 130). Compounds (124b),(125)and (126) readily react with [(qS-C5H5)TiCl3] with the elimination of chlorotrimethylsilane generating titanium(1V) metallated phosphinimines ( 13l), (132) and (133) respectively (Scheme 29).67In another comprehensive study,

? R

N,SiMe3. . . A, 130-1 35 “C

*

PhPP’ PPh2 (123)

Ph,p”’FPh2 “SiMe3 (124) a R = Et

b R=Pr” c R=Bu”

SiMea [Rh(CO),CI],,

MeCN

t

I -co

wet MeCN

wet MeCN

Ph2 P-NR

H

Scheme 28

H

7: Ylides and Related Species Pr I

Ph2P' II

'PPh2 II

-

311 Pr

moist MeCN

S NH (128)

Pr I

CpTiCI,, CHzC12,25 "C

* Ph2PyNx;Ph2 I1 I1 S

'PPh2

Ph2P

II

II

@

'Ti' CI,, 'cl (132)

Pr I

moist MeCN

(124) b

t

0

CpTiCI,

(127)

Ph2P' 'PPh; II II PhO, N NH P' PhO' I I 0 (130)

Pr Pr I

Se

N, (126) SiMe3

CI' \cI (131)

CpTiCI,, CHzCIz,25 "C

Pr

Scheme 29

Bochmann and co-workers report the coordination chemistry of a family of chelating iminophosphorane ligands. The iminophosphoranes (134), (1 35) and (136) form a variety of complexes with first row transition metals (137)-(140).68 The a-keto ylide, [(2-thiazoylcarbonyl)methylene]triphenylphosphorane (141),readily coordinates with titanium and zirconium tetrachlorides, generating simple complexes (142) in which the ylide acts as a bidentate chelating ligand. The zirconium derivative of (142) undergoes transmetallation reactions producing a variety of organometallic species including the pentamethylcyclopentadiene-containing complexes (143) and (144).Moreover, treatment of complexes (142) and (143) with silver triflate yields heterometallic species (145) and (146) respectively. All of these complexes were characterised spectroscopically and the molecular structures of ylide (141) and complex (143) were determined by X-ray ~rystallography.6~ Rhodium complexes containing chiral organophosphorus ligands are of interest in view of their potential use as catalysts. With this application in mind, Viau et aE. have prepared and characterised complex (148)(Scheme 30), which contains an ylide derivative (147) of the well-known R-BINAP ligand.70

312

Organophosphorus Chemistry

p’

R’-P

P-R’ II

I

VCI,(THF),

MX,,THF

R1-P

II

I

P-R’ II

Fe CI Ph C6H2Me3 Fe Br Ph C6H2Me3 Fe Br Ph SiMe3

The interaction of ylidic species with palladium and platinum centres continues to be a key area of activity. New palladium complexes of stabilised ylides include (149),” (150) and (151),72all of which have been structurally characterised by X-ray crystallography. In a particularly useful study, Pandolfo e t al. have reported the solid state 13C and 31PCP/MAS NMR spectra of ylides (152) and (153) and their complexes (154H156). For example, ketenylidene(tripheny1)phosphorane (152) has a solid state 31Pchemical shift of 4.5 ppm (compared with a CDC13 solution value of 5.45 ppm), which shifts to lower frequency in complexes (154) (27.7 ppm) and (155)

313

7: Ylides and Related Species

CF3SO3I

,

(142) M =Ti, Zr

I

LiCp', -LEI

@q+ PPh2Me BF4-

(145)

Bu'LLi

WPPh2 (147)

i [Rh(COD)CI], ii AgBF,

Organophosphorus Chemistry

3 14 Ph2

O=C,

Ph2

2+

H H

(22.6 ppm). The 13Csignal for the ylidic carbon in (152),which is observed at -7.9 ppm (lJCp= 220 Hz), is shifted to -9.2 ppm ('JCp = 70 Hz, lJCpt= 850 Hz) in (154) and -12.9 ppm ('JCp= 100 Hz, 'JCpt= 750 Hz) in (155). Similar trends were observed for (153) and its complexes (156) and (157).73Thus, solid state NMR thus provides valuable structural information in cases where it is difficult to obtain solution data due to solubility problems or decomposition. An example of the latter is provided by complex (158) which was initially obtained serendipitously from the reaction of [Pt(Cl)(Me)(dppe)] and ketenylidene(tripheny1)phosphorane (152), and subsequently prepared directly from carboethoxymethylene(tripheny1)phosphorane (Scheme 3 1).74The synthesis and reactivity of platinum(I1) complexes (159), containing an ortho-metallated ylide ligand, provides the subject of a comprehensive study by Navarro and co-~orkers.~~ Ph3P=C,

/H

C'

<

Me

,CI

; Me

(156) Me i +AgBF,, -AgCI + Ph3P=C=C=O

11,

1'

Ph2

/-----\

Ph2

u i +AgBF,, -AgCI ii, + Ph,PCHCO,Et

Scheme 31

Ylide (160)can be selectively alkylated generating salt (161).The ylidic carbon of (161) was found not to react readily with common organic electrophiles but does coordinate to gold(1) forming complex (162)(Scheme 32).76 Turning now to p-block complexes, isostructural tin and lead complexes (163) have been prepared (Scheme 33), in which the iminophosphorane 'side arms' of the ortho-metallated ligands help to stabilise the fragile diarystannylene and plumbylene

7: Hides and Related Species

315

Finally, we draw this section to a close by mentioning nitrilium phosphine ylide complex (164), which is perhaps more accurately described as a low-valent organophosphorus species (see Chapter 1) rather than a conventional ylide. Complex (164) has been identified as an intermediate in the thermally induced conversion of 7-phosphanorbornadiene complexes into 2H-1,2-azaphosphole complexes (Scheme 34).78 2+

2(C104-)

H Ph2P"'PPh2Me (160)

2 Ph3P=N

/SiMe3

2 MeLi, Et20, 25°C

-

[Li(eC6H4PPh2NSiMe3)]2*Et20 MCIZ, EtzO, -30 "C

SiMe3

SiMe3

I

I

P h ' b Ph/,,p//N--.M*--Nc S P ,,\Phh

\ /

\ /

(163) M = Sn or Pb Scheme 33 (OC)5W, C02Me

pipCN, MeO2CC=CCO2Me

,R

R

A

Me C02Me

(164) Scheme 34

3

Wittig-Horner Reactions of Metallated Phosphine Oxide Anions

A series of N-(alk-1-enyl) nucleobase compounds has been prepared by Wittig-Horner reaction of phosphine oxides (165H167) or the Horner-Wadsworth-Emmons reaction of the analogous phosphonates (168) and ( 169).79Horner-Wittig reactions have been utilised for the stereoselective synthesis of single

Organophosphorus Chemistry

316

enantiomers of E- 1,5-diarylpentene-4,5-diols.80 The synthesis of (fluoromethy1)diphenylphosphine oxide (170) has been described, the anion of which reacts readily with carbonyl compounds yielding diastereomeric mixtures of a-fluoro-fb(hydroxyalky1)phosphineoxides, which were easily separated and converted into E- or Z-l-fluoroalkenes.8' Similarly, the stereoselective synthesis of E-vinyl sulfoxides has been accomplished by the Horner-Wittig reaction of sulfinylmethyl-substituted phosphine oxides (171).82 0

0 PhCH2-NyMe

OAN

0 (165) R = Ph (168) R = OEt

4

IFR2

I

PPh2 II

0

(166) R = Ph (169) R = OEt

0 (167)

Horner-Wadsworth-Emmons Reaction of Phosphonate Anions

The Horner-Wadsworth-Emmons modification of the Wittig reaction continues to find wide application in contemporary organic synthesis. Two reviews, looking at different aspects of the stereoselectivity of this procedure, have been p ~ b l i s h e d . ~One " ~ ~ considers approaches to improve the 2-selectivity of the Horner-Wadsworth-Emmons reaction, and the other the use of heteroatoms to improve the stereoselectivity of the Horner-Wadsworth-Emmons reaction. A combined experimental and computational study of the selectivity of the Horner-Wadsworth-Emmons reaction of a series of phosphonoacetates (172) has EtOiP, EtO

O , CH2C<

OR

(172) R = (CF&CH-, CFsCH2--, CC13CH2-, CBr3CH2--, Ph, 2,4-F&H3--, 2,4-PeC~H3-, PhS

2,6-F,c~H3-, 2,6-Me2C&-,

been reported which shows a dependence of the 2-selectivity on the electronwithdrawing ability of the phosphonoacetate s u b s t i t ~ e n t s .Ando ~ ~ and coworkers have demonstrated that the 2-selectivity of the Horner-Wadsworth-Emmons reaction between ethyl(diary1phosphono)acetates and functionalised aldehydes can be improved by using sodium iodide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base,86 whereas Petroski et al. have reported an improved route for the E-selective synthesis of a-methyl- or aAlternatively, the reduced pyrimidine (173) has ethyl-a$-unsaturated been used as a base-promoter to effect Wittig reactions, and their Horner-Wadsworth-Emmons counterparts, under mild conditions with high efficiency (Scheme 35).88

7: nides and Related Species

317

Horner-Wadsworth-Emmons procedures have been used to prepare a variety of compounds including chiral tetrahydrofuran- and tetrahydropyran-derivat i ~ e s , 8novel ~ organo-sulfur electron donors containing dithiole and azulene

Ph36CH2RBror

f

EtOiP, EtO

+R ~ H O

A(173)

R-CH=CH--R~ or R~-CH=CH-COR

50 CH2Cxp

I ,

Scheme 35

moieties:' nitroalkanes:' and rare examples of synthetically useful vinyl selenides, a-phenylseleno-a$-unsaturated esters, which were obtained from phosphonoacetate (174) and phosphorane ( 175y2 Tandem reactions have emerged as promising procedures for the synthesis of highly functionalised compounds in a single step. Horner-Wadsworth-Emmons reactions have been coupled with 1,4-Michael additions to prepare &substituted a$-unsaturated carboxylic acids derivative^:^ and with Diels-Alder reactions, which utilised sugar-derived phosphonate (176) to prepare enantiomerically pure bicyclo[4.3.O]nonane~?~ 0 I I ,OMe 0 II EtOiP, EtO

,SePh

SePh

c:

A

,OEt

Ph3P=C,

C

Go

II

C'OR

0

(174)

(175)

(176)

0

I1

I

R

CFSCH20/y'-.(Co2Me CF&HzO

Br

(177) Ar

OMe OMe OMe OMe NMe2 NMe2 NMe2 NMe2 NMe2 OSiMe3 OSiMe3 OSiMe3 OSiMe3 OSiMe3

New phosphonates that have been prepared specifically for Horner-Wadsworth-Emmons processes include a new series of a-substituted phosphonates ( 177p5and (178), designed for the synthesis of E-brorn~acrylates.~~

Organophosphorus Chemistry

3 18

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7: Hides and Related Species

37. 38. 39. 40. 41. 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. 71. 72. 73.

319

T.D. Avery, B.W. Greatrex, D.K. Taylor and E.R.T. Tiekink, J . Chem. Soc., Perkin Trans. I , 2000,1319. T.D. Avery, D.K. Taylor and E.R.T. Tiekink, J . Org. Chem., 2000,65,5531. Y-S. Hon, L. Lu, R-C. Chang, S-W. Lin, P.P. Sun and C-F. Lee, Tetrahedron, 2000, 56,9269. M-K. Wong, C-W. Yu, W-H. Yuen and D. Yang, J . Org. Chem., 2001,66,3606. A. Maiti and J.S. Yadav, Synth. Commun., 2001,31,1499. K. Lee and J-M, Im, Tetrahedron Lett., 2001,42,1539. T. Hatta, S. Ishibashi and 0.Tsuge, Org. Prep. Proced. Int., 2001,33, 173. K. Okuma, K. Kojima and S. Shibata, Heterocycles, 2000,53,2753. K. Okuma and T. Kubota, Tetrahedron Lett., 2001,42,3881. M. Taillefer, H.J. Christau, A. Fruchier and V. Vicente, J . Organornet. Chem., 2001, 624,307. V. Artero and A. Proust, Eur. J . Inorg. Chem., 2000,2393. G. Wagner, T.B. Pakhomova, N.A. Bokach, J.J.R. Frausto da Silva, J. Vicente, A.J.L. Pombeiro and V. Yu. Kukushkin, Inorg. Chem., 2001,40,1683. M.G. Davidson, A.E. Goeta, J.A.K. Howard, S. Lamb and S.A. Mason, New J . Chem., 2000,24,477. M. Kobayashi, F. Sanda and T. Endo, Macromolecules, 2000,33,5384. M-D. Chen, G-P. Yuan and S-Y. Yang, Hecheng Huaxue, 2000, 8, 234 (Chern. Abstr., 2001,134,71636). H.J. Christau, M. Taillefer and I. Jouanin, Synthesis, 2001,69. A.S. Batsanov, M.G. Davidson, I. Fernanez, J.A.K. Howard, F. Lopez-Ortiz and R.D. Price, J . Chem. Soc., Perkin 1,2000,4237. P. Ilankumaran, G. Zhang and J.G. Verkade, Heteroat. Chem., 2000,11,251. K. Hemming, M.J. Bevan, C. Loukou, S.D. Pate1 and D. Renaudeau, Synlett, 2000, 1565. A.B. Charette, A.A. Boezio and M.K. Janes, Org. Lett., 2000,2,3777. P. Lopez-Cremades, P. Moina, E. Aller and A. Lorenzo, Synlett, 2000,141 1. P.M. Fresneda, P. Molina and M.A. Sanz, Synlett, 2000, 1190. P.M. Fresneda, P. Molina and S. Delgado, Tetrahedron, 2001,57,6197. Q. Zhang, C. Shi, H-R. Zhang and K.K. Wang, J . Org. Chem., 2000,65,7977. B. Anwar, P. Grimsey, K. Hemming, M. Krakniewski and C . Loukou, Tetrahedron Lett., 2000,41, 10107. S. Jayakumar, V. Kumar and M.P. Mahajan, Tetrahedron Lett., 2001,42,2235. R. Alvarez-Sarandes, C. Peinador and J.M. Quintela, Tetrahedron, 2001,57,5413. P.J. Bailey, T. Barrett and S. Parsons, J . Organornet Chem., 2001,625,236. S-C. Chuang, H-T. Shih and C-H. Cheng, Fullerene Sci. Technol., 2001,9,233. R.P.K. Babu, R. McDonald and R.G. Cavell, Organometallics, 2000,19,3462. M.S. Balakrishna, S. Teipel, A.A. Pinkerton and R.G. Cavell, Inorg. Chem., 2001, 40, 1802. S. Al-Benna, M.J. Sarsfield, M. Thornton-Pett, D.L. Ormsby, P.J. Maddox, P.Br&s and M. Bochmann, J . Chem. Soc., Dalton Trans., 2000,4247. A Otero, J. Fernandez-Baeza, A. Antiiiolo, F. Carillo-Hermosilla, J. Tejeda, A. Lara-Sanchez and I. Lopez-Solera, J . Organomet. Chern., 2001,629,68. L. Viau, C. Lepetit, G. Commenges and R. Chauvin, Organometallics, 2001,20,808. L.R. Falvello, S.Fernandez, R. Navarro and E.P. Urriolabeitia, Inorg. Chem., 2000, 39,2957. A. Spannenberg, W. Baumann and U. Rosenthal, Organometalics, 2000,19,3991. L. Pandolfo, A. Sassi and L. Zanotto, Inorg. Chem. Commun., 2001,4, 145.

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74.

E. Benetollo, R. Bertani, P. Ganis, L. Pandolfo and L. Zanotto, J . Organomet. Chem., 2001,629,201. C. Larraz, R. Navarro and E.P. Urriolabeitia, New J . Chem., 2000,24,623. I. Romeo, M. Bardaji, M.C. Gimeno and M. Laguna, Polyhedron, 2000,19,1837. S. Wingerter, H. Gornitzka, R. Bertermann, S.K. Pandey, J. Rocha and D. Stalke, Organometallics, 2000, 19,3890. R. Streubel, U. Schiemann, P.G. Jones, N.H. Tran Huy and F. Mathey, Angew Chem., Int. Ed., 2000,39, 3686. T. Boesen, C. Madsen, U. Henriksen and 0. Dahl, J . Chem. SOC.,Perkin Trans. I , 2000,2015. T. Boesen, N. Feeder, M.D. Eastgate, D.J. Fox, J.A. Medlock, C.R. Tyzack and S. Warren, J . Chem. SOC.,Perkin Trans. I, 2001, 118. J.H. van Steenis and A. van der Gen, Eur. J . Org. Chem., 2001,897. J.H. van Steenis, J. Johannes, G.S. van Es and A. van der Gen, Eur. J . Org. Chem., 2000,2787. K. Ando, Yuki Gosei Kagaku Kyokaishi, 2000, 58, 869 (Chem. Abstr., 2000, 133, 207396). S. Shigeki, Yakugaku Zasshi, 2000,120,432 (Chem. Abstr., 2000,133, 58343). J. Motoyoshiya, T. Kusaura, K. Kokin, S. Yokoya, Y. Takaguchi, S. Narita and H. Aoyama, Tetrahedron, 2001,57, 1715. K. Ando, T. Oishi, M. Hirama, H. Ohno and T. Ibuka, J . Org. Chem., 2000,65,4745. R.J. Petroski and D. Weisleder, Synth. Commun., 2001,31, 89. D. Simoni, M. Rossi, R. Rondanin, A. Mazzali, R. Baruchello, C. Malagutti, M. Roberti and F.P. Invidiata, Org. Lett., 2000,2, 3765. L. Vares and T. Rein, Org. Lett., 2000,2,2611. A. Ohta, K. Yamaguchi, N. Fujisawa, Y. Yamashita and K. Fujimori, Heterocycles, 2001,54, 377. A.S. Franklin, Synlett, 2000, 1154. C.C. Silveira, M.R.S. Nunes, E. Wendling and A.L. Braga, J . Organomet. Chtim., 2001,623,131. 0.Piva and S. Comesse, Eur. J . Org. Chem., 2000,2417. S. Jarosz and S. Skora, Tetrahedron Asymmetry, 2000,11,1425. K.P. Kumar, C. Muthiah, S. Kumaraswamy and K.C.K. Swamy, Tetrahedron Lett., 2001,42,3219. K. Tag0 and H. Kogen, Org. Lett., 2000,2,1975.

75. 76. 77. 78. 79. 80. 81. 82. 83. 84.

85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.

8 Phosphazenes BY J. C. VAN DE GRAMPEL

1

Introduction

This review covers phosphazene literature over the period June 2000 to June 2001 (Chemical Abstracts Vols. 133 and 134) and discusses linear phosphazenes including compounds derived thereof (Section 2), cyclophosphazenes (Section 3) and polyphosphazenes (Section 4). Structural data have been summarized in Section 5.

2

Linear Phosphazenes

The reaction of an azide RN3 and a phosphine PR’3 yields the reactive phosphoranimine (iminophosphorane) RN=PR’3 under elimination of a nitrogen molecule. Phosphoranimines play an important role in synthetic organic chemistry and are useful precursors for a subsequent aza-Wittig approach, leading to various nitrogen-containing compounds. A theoretical study shows the polarity, and consequently, the reactivity of the N=P bond to be dependent on the nature of the phosphorus substituents.’ The initial reaction product in the Staudinger reaction is a phosphazide, which can be isolated in some cases. An example has been provided by the reaction product ( 2 ) of (2-azidophenyl)-N-[(4-methylphenyl)carbonyl]carboxamide (1) with triphenylphosphine. The unusual stability of (2) arises from its zwitterion character, resulting in a strong hydrogen bonding between the amide proton and the nitrogen linked to the phenyl ring. In refluxing toluene compound (2) can be converted into the phosphoranimine (3), which reacts further to give (4) by an intramolecular aza-Wittig pathway.2 The stability of (2) even allows an azaWittig reaction with ArNCO at the N=PPh3 side without loss of nitrogen, resulting in the formation of 1,2,3-benzotriazine-4-one (5). A similar reaction of (1) with the more reactive PhzMeP yields (6) and (4) in a ratio depending on the reaction time: the longer the reaction time the larger the yield of (4).2 The importance of the Staudinger procedure as intermediate step in the synthesis of N-containing organic molecules can be illustrated by many Organophosphorus Chemistry, Volume 33 0 The Royal Society of Chemistry, 2003

32 1

322

Organophosphorus Chemistry 0

0

0

0

Me

1

Ph,MeP

PPh3

-ArNHCN

(3)

examples, viz.synthesis of 2-aminomethyloxolane-3-thiol from its corresponding azido precur~or,~ conversion of azides into guanidines? reduction of azidopiperidinones: synthesis of the alkaloid rhopaladin D,6 synthesis of naphthyridin-2-one derivatives from azidopyridones' or synthesis of silylated dendrimers.' The Staudinger reaction involving the azido derivative N3P(S)[N(Me)-NH2I2has been applied to the synthesis of dendrimers with N,N-disubstituted hydrazines as end groups.' The cyclic phosphine l-methylphospholane easily reacts with Me3SiN3to form the corresponding N-(trimethylsilyl)-l-methylphospholanimine.l" P,N-Difunctional ligands (8) can be obtained by the Staudinger reaction of (7) with (2)-1,2-bis(diphenylphosphanyl)ethene. Complexation with PdC12 leads to complexes (9)." In addition to Na[Ph2P(NCN)2] new phosphonium diylides with general formula [Ph2P(NEw)z]M+ (Ew = electron-withdrawing group; M = Na, Li) have been prepared from acylazides either by the Staudinger reaction of PhzPNa with two equivalents EwN3 or by the reaction of Ph2PHwith two equivalents EwN3followed by deprotonation with Bu"Li." -

AYco2Et

PPh, ~

Ayco2Et N,

PdC12.2C,jH&N

* Q ;, Ph2

.N,

Ph2P

N3

PhzPJph2 (8)

(7)

R1 = R2 = H R1=RZ=H R1=R3=H R2=R3=H

(9)

R3 = Me R3=OMe R2=OMe R1=OMe

Reactions of the bis(dipheny1phosphine)amines Ph2PN(R)PPh2(R = Et, Pr", Bun)with a 10% excess of N3SiMe3have been reported to give the corresponding

323

8: Phosphazenes

phosphoranimines Me3SiN=PPh*N(R)PPh2. The trivalent phosphorus in compound Me3SiN=PPh2N(Prn)PPh2 can been oxidized with elemental sulfur, selenium or N3P(0)(OPh)2 to afford Me3SiN=PPh2N(Pr")P(S)Ph2, Me3SiN=PPh2N(Pr")P(Se)Ph2 and Me3SiN=PPh2N(Prn)P(Ph2)=P(0)( OPh)2, respectively. Complexes of Me3SiN=PPh2N(R)PPhzwith Rh(I), Pd(I1) and Pt(I1) have been de~cribed.'~ Three methods have been given for the preparation of ArN=P(Phz)CHIP(Phz)O from PhPCH2PPh, viz. (a) Staudinger reaction with ArN3 followed by oxidation with H202,(b) Staudinger reaction with ArN3, oxidation with Br2or I2followed by treatment with Et3Nand deprotonation with NaNH2 and (c) oxidation of PhPCH2PPh to PhPCH2P(O)Ph followed by a Staudinger reaction with ArN3.14 Two other procedures for the synthesis of phosphoranimines have been described, which are totally different from the Staudinger approach. Microwave irradiation of a mixture of l-aryl-4-ethoxycarbonyl-5-amino1,2,3-triazoles (lo), PPh3 and Et3N in C2C16provides the corresponding 5-phosphoraniminato deA chiral N-phosphine substituted phosrivatives (11) in excellent ~ie1ds.I~ phoranimine (13) has been prepared by deprotonation of cyclopropyl(tripheny1)phosphonium bromide (12) with NaNH2 via a complicated reaction mechanism.16

PPh3, Et3N, C2C16

N=PPh3 microwave

[

PhP"2PPh,

NaNH2

P h 3 P d ]IBr-

(12)

*

A

k

h

(13)

Phosphoranimines have also been obtained as Al-N Lewis acid-base adducts from the reaction of (Cy2N)2PNH2(Cy = cyclohexyl) and R3Al (R = Me, Et, But) or R2AlH (R = Me, Et). In the case of R3Al linear compounds (CY,N)~P(H)=N(H).R~A~ were formed, whereas the reaction with R2AlH results in the formation of A12N2 four-membered rings with formula (Cy2N)2P(H~NAl(R2>NC=P(H)(Cy2N)2PIA l(R2).l 7 It has been shown that amides can be formed by the reaction of a phosphoranimine nitrogen and an acyl group in which the acyl group originates from the phosphine itself;" e.g. the reaction of the triarylphosphine (14) with the azidonucleoside (15 ) yielded the amide-linked phosphine oxide (16) after hydrolysis.'' Similar examples of the Staudinger ligation concern the preparation of peptides.20,2' The reaction between a-azido protected amino acids and Me3Pforms an important step in the synthesis of tri- and tetrapeptides.22 Staudinger reactions have been described as part of synthetic routes to

324

Organophosphorus Chemistry Ph2P

Me

e0

(14)

NHBz

0

K,y

C6H11NH

i Ph,P

NHAc

___)

ii Ac20

A o H&c13

-NHC(O)This is exemplified by the synthesis of compound (18) from the azide (17), triphenylphosphine and acetic acid anhydride.23 The reaction of Ph*PCH=CH2 and RN3 has been reported to yield compounds RN=P(Ph2)CH=CH2, which can undergo a base-catalyzed Michael addition with Ph2PH to form N,P-ligands with general formula RN=P(Ph2)CH2CH2PPh2.26 1,3,2h5-Oxazaphosphetidines(20) have been synthesized from the phosphoranimines (19)and benzaldehyde or the ketones PhC(0)CF3or CF3C(0)CF3. Thermolysis of compound (20c) showed the formation of the corresponding imine (21)and the cyclic phosphinate (22),which means that compound (20c)can be considered as the cyclic intermediate in the aza-Wittig reaction of (19) with aldehydes or ketone^.^' An one-pot reaction to transform primary alkyl bromides R'Br into their corresponding imines R'N=CR2R3has been reported. The reaction is based on a three-step procedure, a substitution reaction with NaN3 to form R'N3, a Staudinger reaction with PPh3 followed by an intermolecular aza-Wittig reaction with an aldehyde or ketone, R2C(0)R3.'*A chloroimine has been claimed as intermediate in the aza-Wittig reaction of Me02C(N=PPh3)=CHC02Mewith RC(O)Cl, yielding oxaline derivative^.^^ Compounds 2-amino-3H-4-quinazolin4-ones (24) have been prepared by the aza-Wittig reaction of the phosphoranimine (23) with aromatic isocyanates, followed by treatment with piperidine or morpholine and subsequent cy~lization.~' The aromatic phosphoranimines CSH4N(N=PPh3-3) and CsH4N(N=PPh3-4) have been used as starting materials for the synthesis of naphthyridine~.~' Compounds R'R2C-P(Ph)2=NC02Mehave been used for the preparation of di-,

8: Phosphazenes

325 R1R2C=0

h @ A'P+ NPh I ZF3 .R1 (19)

A Pr' =

J($,

(20a) R' = Ph, R2 = H (20b) R'=Ph, R2=CF3 (20c) R' = CF3, R2 = CF3

Prl

0

(23)

C02Et

C02Et

N=C=NAr

N=C:

Am = piperidino, morpholino

NHAr Am

tri- and tetrasubstituted a l k e n e ~ It . ~ has ~ been shown that the P-C bond in compounds ArN=P(Phz)CH2P(X)Phz(X = 0, S) can be cleaved under acidcatalyzed conditions, yielding Ph2P(X)Meand Ph2P(0)NHAr?3 Numerous compounds have been prepared from polymer-supported phosphoranimines. These are versatile starting materials for solid-phase methods based on the aza-Wittig r e a ~ t i o n . ~ ~ - ~ ~ Not only intermolecular, but also intramolecular aza-Wittig pathways lead to nitrogen-containing organic heterocycles. For instance, a quinazoline system (27) could be synthesized by Staudinger reaction of (25) with B u ~ Pyielding , (26) as intermediate, followed by intramolecular aza-Wittig c y ~ l i z a t i o n . ~ ~ The multi-step preparations of pyrazoloisoquinolines?' benzodiazepines and benz~thiadiazepines~' also occur via a Staudinger and intramolecular aza-Wittig protocol. The versatility of the N=P bond in organic syntheses has been illustrated by other synthetic procedures. An 1,3 diaza-2-phosphetine derivative has been formed by the addition reaction of Pr1N=PC13with ArN=C=NPr' (Ar = 2-fl~oropheny1).4~ The bromobis(ary1imino)phosphorane (28) reacts with one equivalent p-dimethylaminopyridine to yield the monoadduct (29), whereas addition of two equivalents of amine gives the bis-adduct (30). The N-P bond lengths (149-153 pm) in these adducts point to a high double bond character.43 Interesting chemistry has been carried out with the similar N P N system, uiz. P(NHSiMe3)(NSiMe3)Pyz(Py = 2-pyrimidyl) (31). This compound reacts with Sr2+and Ba2+to form complexes (32) and (33), in which two pyridyl nitrogens and one imino nitrogen per ligand act as coordination sides for metal complexa-

326

Organophosphorus Chemistry

Ar = 9

0

0

(25)

(26)

O

M

J

e

f

Me0

Me

Ar'

H

+

NMe2

NMe2

Br-

\ (28) R = 2,4,6-But3C6H2

.Br

-

(30)

-

tion. Coordination to Zn2+(34) occurs via one pyridine and one imino nitrogen per ligand.@ Lithiation of (31) leads to an unexpected phenomenon of N P bond cleavage and, consequently, to the reduction of phosphorus to oxidation state three from five. One N P bond is cleaved by reaction of (31) with LiN(SiMe3)2,giving the lithium adduct (35). Additionally, two N P bonds are cleaved by the reaction with MeLi or Bu"Li, leading to the previously reported compound (36).@ Metal phosphoraniminato complexes formed by the reaction of silylated phosphoranimines with metal salts form an attractive class of compounds from a theoretical, synthetic and structural point of view. A computational study of transition metal-phosphoraniminato complexes with a heterocubane structure has shown that metal-nitrogen bonds are based on ionic interactions, whereas the N P bonds can be described as strongly polar single bonds. Moreover it turned out that the heterocubanes concerned are clusters of high-spin ~omplexes.4~A dimeric tantalum complex [TaCL,(N=PCl3)I2(37) has been synthesized by a 1:l molar ratio reaction of Me3SiN=PC13and TaC15 in CH2C12as a solvent. The dimeric structure can be cleaved by the addition of thf, leading to the formation of the monomeric adduct TaC&(N=PCl,).thf (38). The reaction of (37) with Me3SiN=P(C12)N(SiMe3)2

8: Phosphazenes

327

//

Sr{N(SiMe3)d2.2thf

/ Me3Si-N H

/

4,4'-bipyridine I

'* N-SiMe3

\

I

\ ZnMe2

4,4'-bipyridine

'SiMe3

Me$i

(35) I MeLi

-Bu"Li

Me3Si -N

H

'*N-

(31)

SiMe3

-h ft

QPD thf

; Li 'thf (36)

resulted in a four-membered tantalum-phosphazene ring (39a),which also can be synthesized directly from TaC15. An interesting perchlorinated phosphazenium salt (40) has been obtained by the reaction of (39b) with HCl.46 Metal complexes have been prepared using Me3SiN=PEt3 as starting material!' 49 The synthesis and crystal structure of two molybdenum complexes RN[R = Mo(C&)N=PPh3] and [(N=PPh3)4Mo][BF4]2}have been rep~rted.~' The tungsten complex W(S)2(N=PPh3)2 has been obtained from the reaction of WN(N=PPh3)3with CS2 in presence of traces of water." The ortho-

Organophosphorus Chemistry

328

TaCI4R

HCI t

Me3Si, Me3Si

, N-

I

P =NSiMe3 I

CI

/.

CI %I (39a) R = CI (39b) R = NPC13

for R = NPCl3 L

(40)

'

metalated compound (41), prepared by the reaction of Me3SiN=PPh3 with MeLi, reacts with the metal chlorides, SnC12 and PbC12, to yield the organometallic complexes (42a) and (42b), respectively. In these complexes the metal atoms are linked to the phenyl groups by cr-bonds combined with an additional coordination to the imine-nitrogen atoms5'

(42a) M =Sn (42b) M = P b

Ultrasound treatment of a reaction mixture of metallic europium and N-iodo phosphoranimine IN=PPh3 in 1,2-dimethoxyethane (DME) has been described to afford the compounds E U I ~ ( D M Eand ) ~ EuJ(N=PPh&(DME) (43). The core of the structure of (43) consists of a planar Eu2N2 four-membered ring. One of the europium atoms has a distorted tetrahedral surrounding, the other a distorted A mixture of yttrium and IN=PPh3 in thf, subjected octahedral s~rrounding.'~ to the similar treatment, yields the compound [YzI(NPPh3)4(thf),]+13-(44).52 N=PPh3 thf, ,thf Ph P-N-Y--I-Y-N=PPh3 thf' 'thf N=PPh3

+

/\

\/

13-

(44)

The compounds [E(N=PPh3]+[0.5 1 3 , 0.5 I-].thf (E = S, Se) and [Te(N=PPh3]+13-have been obtained by the reaction of IN=PPh3 with sulfur, selenium and tellurium, re~pectively.'~ A new method for the synthesis of the compounds MN=PPh3 (M = Na, K, Rb, Cs) has been reported, consisting of the reaction of Ph3P12and MNH2 in liquid ammonia. The molecular structure of

8: Phosphazenes

329

(RbN=PPh3), (45) can be characterized as double cube, whereas (CsN=PPh3), (46) possesses a heterocubane structure.54

\

PPh3

PPh3

(45)

(46)

The complexes [La(N=PPh3)3]2and [Y b(N=PPh3)3]2can be easily prepared from the metal chlorides and NaN=PPh3. A four-membered metal-nitrogen ring forms the basic element of the dimeric molecular structure and is non-planar for La and planar for Yb. Both compounds exhibit catalytic activity in the ring-opening polymerization of E-caprolactam to poly(e-caprolactam)~sOn the contrary, no activity has been observed for the salt-like complex [CsYb(N=PPh3)&, which has been ascribed to steric constraint^.^^ Non-ionic phosphazene bases still find their application in the synthetic organic chemistry. Reactions of icosahedral carboranes with HN=P(NMe2)3 have been reviewed.57The electronic structure of a number of the phosphazene bases has been investigated by UV spectroscopy and compared with those of guanidine bases. In both cases the imine nitrogen acts as protonation site.58 Basicity measurements suggest some contribution of the ylidic structure (RN P +R'3) for the phosphoranimines ArN=PPyr3 (Pyr = pyrrolidino) and ArN=P(NMe2)Pyr3.59 A 13C NMR study of the base strength of compounds RN=PPyr3 (R = NH2, Ar) in acetonitrile has been reported.6@ The phosphazene base ButN=PPyr3 (BTPP) has been successfully used as non-ionic base in the synthesis of 2H-indoles,6' pyrrolic compounds,62and a poly(viny1 alcohol)-based polymer.63Mono- and difluoromethylation of diethyl N-acetylaminimalonate proceeds under mild conditions in presence of MeN=PEt3.64The But-P4-phosphazene B u ' N = P [ N = P ( N M ~ ~ )(P4-t-Bu) ~]~ has been used as base in a large variety of organic s y n t h e s e ~ . ~ ~ - ~The ~ bases BTPP, Bu'N=P(NM~~)~[N=P(NM (But-P2) ~ ~ ) ~ ] have been applied to the rearrangement of N-alkyl-0-benzoyl hydroxamic acid derivatives to 2-benzoyl a m i d e ~ . ~ ~ The polymerization of 1-hydroxypentamethylcyclotrisiloxaneto high-molecular weight hyperbranched polysiloxanes has been reported to proceed more effectively in the presence of P4-t-Bu than in the presence of the usual lithium silanolates.'@Another process for the preparation of polysiloxanes has been carried out with ButN=P[N=P(NMe2)3]3-,(Nme2), as base ~atalyst.~' Anionic polymerization of methyl methacrylate (MMA) has been carried out with the phosphonium salt { P[N=P(Nme2)3]4} [n-C5H11CPh2]-as initiator. The polymerization process is very fast and follows first-order kinetics, yielding polymers with a narrow molecular weight distribution. No conclusive explanation can be given for the low initiator effi~iency.~~ Other polymerization pro+

3 30

Organophosphorus Chemistry

cesses in the presence of phosphonium salts have been covered by patents.73The preparation of phosphine oxides O=P[N=P(NR&J from POC13 and HN=P(NR2)3and their application in the preparation of polymers and resins have been described.74New patents have been issued covering the use of compounds [C13P(=NPC12),PC13] + [cl or PC&] as catalysts for the equilibration and/or condensation of organosiloxane~.~~ The phosphazene PhN=PPh3 has been claimed as an fireproofing agent.76 The coordination chemistry of compounds R2P(E)NHP(E)R’, (R, R’ = alkyl, aryl; E = 0,S, Se) has received considerable interest in recent years. Compounds R2P(S)NHP(S)R’2(R = Ph, OPh, R’ = Et, Pr’, OEt) have been prepared by a co ing reaction of the corresponding amines R2P(S)NH2with NaH.77The coEding reaction between the amines can also be carried out by KOBU~.~’

S,S-complexation of R2P(S)NP(S)R; with divalent metal ions leads to either tetrahedral complexes as Zn[R2P(S)NP(S)R’2-S,S]2or square-planar complexes Pd[R2P(S)NP(S)R’2-S,S]2 and Pt[R2P(S)NP(S)R’2].77 The complexes Pd[ Ph2P(S)NP(S)Ph2-S,S’]* and its selenium analogue Pd[ Ph2P(Se)NP(Se)Ph212 have been used as catalysts for the carbonylation of phenol to diphenyl carbonate by CO and 02.The complex Pd[Ph2P(S)NP(S)Ph2-S,S’]2appears to be a useful catalyst, even better than PdC12under similar reaction conditions. On the contrary the selenium derivative showed a very low Whereas the symmetrical anions [Ph2P(E)NP(E)Ph2] exclusively react with PdC12and PtC12 complexes to give bis-homoleptic complexes M[Ph2P(E)NP(E)Ph,-E,E’l2(E = S or Se), non-symmetrical ions [Ph*P(O)NP(E)PhJ (E = S, Se) react to give E-unidentate complexes (47, 49 and 50). In the case of the more sterically hindered complex PdC12(tmda) O,E chelation (48) has been The complexes VO[ Ph2P(Se)NP(Se)Phz-Se,Se’]2, V[ Ph2P(Se)NP(Se)Ph2Se,Se’13and Cr[Ph2P(Se)NP(Se)Ph2-Se,Se’]3 have been prepared from the metal chlorides and K[Ph2P(Se)NP(Se)Ph2].A square-pyramidal geometry around vanadium formed by a apical oxygen and four selenium atoms has been observed for VO complex, whereas six selenium atoms form a distorted octahedron in the other two compounds.’0 Several Ru(I1) complexes with Ph2P(E)NP(E)PhZ ligands have been reported. Two new complexes (51) and (52) have been isolated from the reaction mixture of R U ~ ( C Oand ) ~ ~Ph2P(S)NP(S)Ph2. In these complexes, one of the P=S bonds appears to be broken, leaving only one Ph2P-S moiety. Different from (52), where only one sulfur atom is present, compound (51) contains a second sulfur atom connected in a p3-position to three Ru atoms.81 Chlorine abstraction from (R-RuC1)2(p-C1)2(R = C6H6, p-C6H4Pr’)by AgBF4, followed by complexation with Ph2P(E)N(H)P(E)Ph2(E = S, Se) led to the formation of ruthenium complexes (53).82Chlorine abstraction from (C6H6-

331

8: Phosphazenes

RuC1)2(p-C1)2 with subsequent complexation with Ph*P(E)N(H)P(E)Ph,(E or Se) and pyridine yields the cationic complexes (54).*,

=

P(Phi)NP(O)Ph2

(47a) (47b) (47c) (47d)

E = S, M = Pd E = Se, M = Pd E = S, M = Pt E = Se, M = Pt

\

t

(48a) E = S (48b) E = Se M = Pd, Pt

M e 2 N - d y !

+

S

332

Organophosphorus Chemistry

The ruthenium complex Ru[Ph2P(E)NP(E)Ph2-Se,Se']Pph3(55b) has been reported to react with pyridine, SO2,NH3 and hydrazines, forming complexes which obey the 18 electron rule. The reaction (55b) with pyridine yields the kinetic trans-isomer (56), which in solution slowly isomerizes to the thermodynamic cis-isomer. For the reaction of (55b) with SO2both isomers of (57) are present in the reaction mixture.83This is in contrast with the reaction of (55a) with SO2, where only the cis-isomer could be isolated. Both the sulfur and selenium analogues of (55) react with NH3 and hydrazines to a mixture of cisand trans-isomers of (58) and (59), re~pectively.'~ Ph2P-Se \T:yP/Ph2

N

Ru

I

\

N

\

1

Ph2P-Sel Se -PPh2

TPh3

Ph2P-Se Se-PPh2 \

N

/

Ru

\

f

\

pyridine

\

N

*

N

I

/

PhpP-Sel Se-PPh2

I

Ph2P-E

R;

N \

I

PPh3 02S ISe-PPh2

E-PPhZ

I55b) E = S e \

\

I

'

I

N

R;

ie ISe -PPh2 I

I I \

1 ,Se Ph2P N, PPh2

(56) trans-is0me r

(57) cis-isomer

' /

Ph2P-E TPEyPPh2 \ I

N

Ru

\

Ph2P--E/

1

Ph2P-E Tpl?-PPh2 N' \ / \ Ru N

N

'E-Pbh,

NH3 (58a) E = S (58b) E = S e trans-isomer

H3N\ yp2yPPh2 / \ N

Ph;P--E/

NH~

Ph2P-E \pz3PPh2 N

\

'Ru/

'N

I

I

\

Ph2P-E E-PPh2 (55a) E = S (55b) E = S e

I

\E--Pbh2 NH2R

(59a) E = S (59b) E = S e trans-isomer

RNH2

* R = NH,, BU'NH, C~H,,,N

'

RH2N\ Tpi/!yPPh2

N E-PPh2 Ph2P ' N, PPh2

(58a) E = S (58b) E = S e cis-isomer

(59a) E = S (59b) E = S e cis-isomer

8: Phosphazenes

333

Surprisingly, the reaction of (55a) with hydrazine monohydrate leads to the formation of cis-(58a) and trans-Ru[Ph2P(S)NP(S)Ph2-S,S’](Pph3)(NH3)(H20) (60). The difference in reaction products between the reaction with aqueous hydrazine [formation of the cis- and trans-isomer of (59a)l and hydrazine monohydrate has been ascribed to a concentration effect.83Reactions of the complex [ R u ( = C H P ~ ) ] ( P C Y ~ ) ~ (61) C ~ ~ with two equivalents of K[Ph2P(S)NP(S)Ph2] yielded a complex (62), whereas the reaction with the selenium analogue gave [Ru(=CHPh)] [Ph2PNP(Se)Ph2-Se,P]2(64) in addition (63). The difference in reaction to [Ru(=CHPh)] [Ph2P(Se)NP(Se)Ph2-Se,Se’I2 mode can be explained by the weaker P-Se bond in comparison with the P-S bond.84The complex (62) appears to be active as catalyst in the ring opening polymerization of n ~ r b o r n e n e . ~ ~ H\ /Ph C Ph2P-Se Se-PPhp \ / N Ru N

II

H

H\ /Ph

Ph

\C’

I I ‘-‘Ph2

ph2p-s

N

\

Ph2P-S

\R,/ I

\

C

K[Ph2P(S)NP(S)Ph21 N

4

II

\

/

\

f

Ph2P-Se Se-PPhp pcy3 K[Ph2P(Se)NP(Se)Ph21 (63) t

1

S-PPhp (62) \p/

\

I

S e -PPh2

Ph2

(64)

By analogous procedures as described for the preparation of the complexes (53) and (54), the Rh(II1) and Ir(II1) complexes (CsMe5-MCl)(Ph2P(E)NP(E)Ph2E,E’) (M = Rh, Ir; E = E’ = S or Se) and [(CsMe5-M)(Ph2P(E)NP(E)Ph2E,E’)PPh3]PF6 (M = Rh, Ir; E = E’ = S or Se) can be synthesized. Complexes trans-Os02[R2P(E)NP(E)R2-E,E’I2(65) have been synthesized from transK2[OsV102(0H)4] and two equivalents of R2P(E)NHP(E)R2(E = S with R = Pr’ or Ph; E = Se with R = Ph). In these complexes the Os(V1) atom has a pseudo (distorted) octahedral environment. A similar geometry around osmium has been found for the complexes Os[R2P(S)NP(S)R2-S,S’13 (66a) and (66b).85In addition to the dioxoosmium complexes, new nitridoosmium(II1) complexes OsNCl[R2P(S)NP(S)R2-E,E’] (67a) and (67c)have also been reported. Reduction of (65a) or (65b) by N2H4 leads to the formation of osmium dinitrogen complexes (68).85Compound (67b) has been used as starting material for the preparation of a bimetallic complex (69).85 The interesting chemistry of bis[(trimethylsilyl)phosphoraniminato]methandiide complexes of early transition metals and lanthanides has been reviewed.86 Recent investigations concern the reactivity of the C=MC12center in zirconium and hafnium complexes, (70a) and (70b),respectively.” The insertion of heteroallenes in the A1-C bond of the dimetallic spirocyclic complex (71) gave two fused sixmembered metallocycles (72a) and (72b).88 A theoretical study has been performed for the dilithium methanide dimer

334

Organophosphorus Chemistry

-

M

[NH4]2[Os'vCld I PPh, OS"'[R~P(S)NP(S)R~]~ (66a) R = Pr' (66b) R=Ph

forM=K, E = S and R = Pr' or Ph

R2P II

0 tran~-K~[Os~lO~(OH)~] R?P-E\ 0s * N

II /E-TR2

-FR2

E

E E = S, R = P i , Ph E = Se, R = Ph M=H,K

for M = H

R2P-E

N

\

I

E-PR2

[Bun4N][0sV1NCI4] for M = K

N

112

R2P-S

'0;

N \

R2P-S 111

11

0 (65a) E = S, R = P i (65b) E = S, R = Ph (65c) E = Se, R = Ph

I

I

/

/

/

S-yR2 \

'N

I

S-PR2

(68a) R = P S (68b) R = P h

(67a) E = S, R = Pr' (67b) E = S, R = Ph (67c) E = Se, R = Ph

SiMe3 I

Ph2P=N, C=MC12 I / Ph2P=N

Me2

A1

Ph2 P

SiMe3

RN=C=E

Me3SiN/ '\CH I

Me2A1,

I

(70a) M = Hf (70b) M = Z r

Ph2

Ph2

Me2 (71)

II

C ,,

Ph2 p , NSiMe3 I

N' R

AIMe2

(72a) E = 0, R = Ad (Ad = adamantyl) (72b) E = NCy, R = Cy

{ Cli2[Ph2P=N(SiMe3)]2}2 and its hypothetical monomer. Calculations show the dimerization process to be exothermic, resulting in a very stable di~ner.8~ Reaction of CH2[Ph2P=N(SiMe3)I2with one equivalent of MN(SiMe3)Z (M = Li, Na) leads to the formation of dimeric mono deprotonated species (73) and (74), respectively. Different bridging modes for the coordination of the ligand CH[Ph2P=N(SiMe3)]-have been found in these compounds with a preference for bridging by nitrogen rather than carbon for the sodium containing compound (74).90Double deprotonation with two equivalents of MN(SiMe3)has not been observed, even by using prolonged reaction times. This is in contrast to reactions with RLi (R = alkyl, aryl) and has been explained from the more basic character of RLi in comparison to MN(SiMe3).90Also the reaction of CH2[Ph2P=N(SiMe3)I2 with NaH is limited to the formation of a monomethanide complex (75a,b).9'The extent of deprotonation does not depend only on the nature of the alkali metal reagent, but also on the substituent on phosphorus, This has been demonstrated by the reaction CHz[Cy2P=N(SiMe3)l2 with MeLi where only the monomethanide derivative (76) could be isolated.'' Complexes with general formula (77a, MX = CoC1) and (77b, MX = NiBr) have been prepared from CH[Ph2P=NAr2I2Li and MX2. Molecular orbital calculations suggested that the bonding in (77b, Ar = C6H3Prt2-2,6)can be described by a combination of 0-and x-bonding models as Numerous complexes with general formula (78) have been reported which are prepared by the reaction of the metal halides CoCl2 or NiBr2 and (CH2)n[R2P=NAr2]2 (R = Me, Ph) in absence of a lithium precursor. Complexa-

8: Phosphazenes

335 Me3Si

SiMe3

I

I

N N, Ph2P’, \Li/ PPh2 H-C: >(-H or

iLiN, PPh2

Ph26,

.I

I.

Me3Si

SiMe3 (74)

(73)

H2 II II Ph2PNC‘PPh2

..

..

Me3SiAN

N

-

S

i

M

e

3

H C Ph2P,c--
x

‘I

I0

Me3Si /

M

‘SiMe3

f Z

thf thf (75a) M = N a (75b) M = K SiMe3

H2

MeLi Me3SiAN

“SiMe3

Et20

-

CY2PPN, H-C$----Li/ Cy2P“N

-*\

Et

Et

tion of the metal atom in these complexes occurs via nitrogen atoms. For 2,6-bis(phosphoraniminato)pyridine complexes (79), both the imino nitrogens as well as the pyridine nitrogen are involved in metal bonding. The activity of some of the above-described complexes in ethene polymerization has been investigated.92 Chlorine atoms in C13P=N-P(O)C12 can be easily replaced by nucleophilic substitution with RONa, yielding compounds (R0)3P=N-P(0)(OR)2(R = i-propyl, allyl, benzyl and furfuryl). The biological properties of these compounds have been investigated and compared with those of their chlorine p r e c ~ r s o r . ~The ~ ~ ~ preparation ~ of the linear thiazylphosphazenes (R0)3P=N-S(02)0R and (R0)3P=N-S(02)-N=P(OR)3 has been described95

Organophosphorus Chemistry

336

as well as their a p p l i ~ a t i o nas~ ~a flame-retardant in non-aqueous electrolyte batteries.

.

"iI

II

N N Ar' \Ar n=1,2 R = Me, Ph

R' = SiMej, Ar

b

thf MX2 = CoCI2, NiBr2

Ar'

N

II

\ M / ~ \ A ~ x2

(78)

(79)

X-Ray structure determinations of some miscellaneous linear compounds containing a N=P entity are summarized in Section 5.97-102

3

Cyclophosphazenes

Cyclophosphazenes with macrocyclic ligands form a part of a general review about supramolecular interactions in synthetic procedure^.'^^ The correlation between structure and NMR (13C and 3'P) parameters for tris(2,3-naphtha1enedioxy)cyclotriphosphazene and t ris(o-phenylenedioxy)cyclot ripho sphazene has been reviewed.lM Ab initio calculations have revealed that the TC and IT' bonding in planar phosphazene rings ( 2 ) n (n = 2,3,4; X = H, F, Cl) are governed by p orbitals, and that contribution of d orbitals (d,-pn bonding) can be negle~ted.'~' Moreover, it turned out that properties of cyclotriphosphazenes, e.g. the atomic charge on nitrogen, can not directly related to the ligand electronegativity.'06Theoretical studies of the structure of metallacyclotriphosphazenes with transition metals incorporated in the ring, viz. NP(X2)NM(C13)NP(X2) (X = H, F, Cl), have shown that the phosphazene units act as o and TC donors toward the transition metal. The existence of bimetallic compounds NP(X*)NM(C&)NM(C13) has been predicted."' A molecular modeling approach for cyclophosphazene structures has been described."' Structural data of [NP(CF3)2]3in the gas-phase have been determined and compared to crystal structure data and results of quantum mechanical calculations.' O9 Mesomorphic phase transition and mesogenicity of the cyclotetraphosphazenes (80)and (81) have been studied and compared with their cyclotriphosphazene analogues. Compound (81) appears to be the first cyclotetraphosphazene that exhibits mesogenetic behavior.'" A related study of the mesomorphism of cyclotriphosphazenes has shown that relatively small changes of the mesogenic side groups have a considerable effect on the mesomorphic properties."

8: Phosphazenes

337 RO,

,OR

Conductivity studies have been carried out for the salt of (NPC12)3and 4methylpyridine N-oxide, i.e. (NPC12)3NPCl(0-NC5H4Me-4)]-tC1,'12 and for the hexa(azopheno1) derivative'I3 of cyclotriphosphazene. A new method for the preparation (NPPh2)3from KNPPh3 in the presence of Moo3 and 18-crown-6 has been de~cribed."~ Novel 1,2,5,6-tetrahydro-l,3oxaza-4-phospha-2-phosphorine-2-oxides have been synthesized by metallation of linear phosphazenes R'R2C-P(Ph2)=N-P(0)(OPh)2with Bu"Li and subsequent quenching by aldehydes or ketones.'ls An interesting synthetic and structural investigation deals with the chiral configuration of cyclotriphosphazenes carrying macrocyclic substituents. Two configurations of compound (83) could be isolated from a reaction mixture of (82) and piperazine, uiz. a meso- and racemate-form as proven by X-ray analysis. Further aminolysis yielded two meso-forms of (84), one with a plane of symmetry, the other with a center of symmetry. The results are consistent with inversion of configuration at a P(0R)Cl center for each substitution step going from (82) to (84). The patterns of the 31PNMR spectra are consistent with the X-ray structures. ''

Several chromium(II1) complexes have been prepared with NPMorph2(NPC1Morph)2 (Morph = morpholino) as ligand.' l7 Another study

338

Organophosphorus Chemistry

deals with synthesis and characterization of Fe(III), Co(II), Ni(I1) and Cu(I1) complexes with (NPAm2)3and (NPAm2)4in which Am represents an amino group."' It has been shown that the reactivity of the trifluoroethoxy derivatives N3P3(0CH2CF3),[(NHCH2CH2(CSH4N-2)l6 ,, (n = 3-5) in complexation reactions with transition metal chlorides is substantially lower than that of the corresponding derivatives in which the trifluoroethoxy has been replaced by phenoxy groups."' Compounds [NP(OR)2]3 [R = -(CH2)2SMe,-(CHJ4SMe, -(CH2)2CH(SMe)S(CH2)2Me and -CH2C6H4(SMe-4)]have been prepared and investigated with respect to their complex formation with metal ions.'2o The oxidation-reduction behavior of the new compounds [NP(OPh)2] ,NP(OPh)[ OC6H4(CH2CN)] .FeC12PF6 and { NP[OC6H4(CH2CN)I 2}3.(FeC12PF6)6 have been investigated.I2l The highly innovative technique continuous-flow laser-polarized 129XeNMR spectroscopy has been used to study the diffusion of xenon-helium mixtures into the pseudo-hexagonal channels in tris(o-pheny1enedioxy)cyclotriphosphazene [N3P3(OC6H40-2)3],which was obtained by careful evaporation of benzene from the N3P3(0C6H40-2)3-benzeneinclusion compound. It turned out that the shape of the NMR signal is dependent on two competing interactions, xenon-xenon and xenon-wall (n-electron rich). At high Xe concentration the xenon-xenon interaction dominates, at low concentration the xenon-wall interaction prevailed.122The synthesis and properties of the new clathrate tris(9,lO-phenanthrenedioxy)cyclotriphosphazene (85) have been described. X-ray powder diffraction of crystalline inclusion adducts of (85) with a large variety of organic solvents such as 1,2-dichloroethane and p-xylene has shown clearly the influence of the guest on the host-guest structure. Inclusion adducts containing 1,2dichlorobenzene or 0-and p-xylene appear to be more stable than those with thf, benzene or hexane.'23

9.10-dihydroxyphenanthrene

EtsN

The reaction of the dilithiated diols RCH2P(S)(CH20Li),[R = ferrocenyl (Fc) or Ph] with (NPF2)3in a molar ratio 1:l has been described to yield a mixture of the endo and exo isomers of the ansa-substituted derivatives (86, R = Fc) and (87, R = Ph), the ratio of the isomers being dependent on the reaction temperature. The ansa isomers can be converted into their corresponding spiro derivatives (88) and (89) in the presence of catalytic amounts of CsF using thf as the solvent. This behavior is in line with the exclusive formation of the spiro derivative (88) in the reaction of (NPF2)3and F c C H ~ P ( S ) ( C H ~ O S ~inMthe ~ ~ presence )~ of C S F . ' ~ ~

8: Phosphazenes

339

X-ray structure determinations of the ansa derivatives show that the nitrogen atom in the ring segment P(O,F)NP(O,F) deviates significantly from the plane formed by the other ring

F

+

thf

II

S endo-(86) R = Fc endo-(87) R = Ph CsF

1

exo-(86) R = Fc exo-(87) R = Ph thf

2 (88) R = Fc ( 8 9 ) R = Ph

Treatment of (NPF2)4with (CF2)n(CH20SiMe3)2 ( n = 2,3) in the presence of CsF resulted in the formation of the spiro compounds (90)and (91)in addition to the bridged compounds (92) and (93). Reaction of (NPF2)4with dilithiated propane-1,3-diol yields the 1,3 ansa compound (94) with small amounts of the spiro compound (95).Only a spirocyclic compound (96)is formed in the reaction with dilithiated propane-1,3-dithiol. As already observed for the trimeric case, compound (94) can be transformed into a spirocyclic compound (95) when treated with catalytic amounts of CsF. Also the bridged compound (92) changes slowly into (90) in the presence of CsF.12' gem-NPC12[(NP(OC6C1s)2]2has been obtained in 20% yield by the reaction of (NPC12)3with a twelve-fold excess of NaOC6C15in refluxing thf and a reaction period of ten days. The hexasubstituted pentachlorophenoxy derivative could be obtained in 8% yield from refluxing diglyme, using again the 1:12 molar ratio between the reactants.'26NaOC6FSproved to be a more reactive reagent because [NP(OC6Fs)2]3was obtained in 70% yield from a 1:7 reaction mixture in refluxing thf after four hours. A predominantly geminal substitution pattern has been suggested for the reaction of (NPC12)3 with NaOC6ClSand The (97) has been studied reactivity of the OH groups in N3P~[oc6H3(Bu'-3)(oH-4)] by reactions with acetic anhydride and alkyl halides. A high reactivity was observed for the reaction of (97) towards acetic anhydride in 1,4-dioxane, yielding (98) in good yield. Lower reactivities were found for the reactions with alkyl halides, 1-chloropentane or 1-iodopentane and 1-bromohexane, yielding (99) and (loo), re~pectively.'~~ Esterification of the hydroxyl functionalities in

340

Organophosphorus Chemistry

N3P3[OC6H3(But-3)(0H-4)] (97) by dicarboxylic acid anhydrides or acid chlorides can lead to the formation of cyclomatrix polymers (Section 4).

F.

'F (90) n = 2 (91) n = 3

CsF, thf n=2,3

F\ /F

N=P\

P/ II

N I I/F

R ,'/ P\= N F F

N\

(93j n = 3

(100)

8: Phosphazenes

34 1

342

Organophosphorus Chemistry

Hexakis(4-pyridylmethoxy)cyclotriphosphazene(101) appears to be a versatile compound to undergo self-assembling in exchange with other compounds. Self-assembling has been observed with naphthalene- 1,4-dicarboxylic acid in dimethylformamide to yield needle-like crystals with one cyclophosphazene molecule per three carboxylic acid molecules. FT-IR and fluorescence spectroscopy in combination with X-ray powder diffractometry point to assemblies of alternating layers of cyclophosphazene and carboxylic acid molecules held together by hydrogen bonding. In this way cylinders (102) are formed in which iodine molecules can be included.12*An analogous structure has been formed by the coordination of (101) with AgN03 in a ratio 1:3.'29 The complex formation as described above also depends on the solvent used. Compound (101)and terephthalic acid have been found to assemble in a mixture of dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) with as major product the 1:2 adduct (104), even using a molar ratio 1:3 between the reactants. In D M F only the 1:3 adduct (105) has been formed. The difference in reactivity has been explained from the stronger solvating ability of DMSO in comparison to that of DMF. Bonding between the pyridyl group and the acid functionalities occurs via hydrogen bridge formation [NH - - - OH distance in (104) is equal to 2.66 New polymers with an organic backbone and pendant cyclophosphazene groups have been reported. Radical polymerizations of the styryloxy derivatives (106a-b) in bulk and (108a-b) in solution give the hybrid inorganic-organic polymers (107a-b) and (109a-b),respectively. Efforts to polymerize (108a)in bulk failed. All polymers are stable beyond 400°C with an onset degradation temperature at about 500°C.'31 A new method for the preparation of hybrid inorganic-organic polymers has been found by applying the Staudinger reaction to an azido cyclophosphazene and a phosphine derivative of an organic (co)polymer. Both poly(4-diphenylphosphinostyrene) (110) and poly(4-diphenylphosphinostyrene-co-methyl methacrylate) (111) react almost quantitatively with the mono-azido cyclotriphos4phazenes (112) and (113) to give the corresponding diphenylphosphinophosphazenyl derivatives (114), (11 9 , (116) and (117), respectively. The use of higher azido derivatives opens the possibility for the preparation of crosslinked material^.'^^ The polynorbornenes (119a-d)'33 and (119e-g)'34 with pendant cyclotriphosphazene groups have been prepared from (118a-d) and (118e-g) by ring opening polymerization of the norbornenyl group. Ionic conductivity of polymers (119fg)-salt complexes with LiS03CF3or LiN(S02CF3)2 increases with increasing salt concentration with highest conductivities for LiN(S02CF3)*having a larger anion. Conductivities are of the same order of magnitude S cm-' at 30°C)as those of [NP(OCH2CH20CH2CH20Me)2]n-salt c ~ m p l e x e s . 'Another ~~ approach describes the polymerization of a mixture of (120)and (121),resulting in a branched or slightly crosslinked material. Ionic conductivities of polymer-salt complexes with LiS03CF3or LiN(S02CF3)2 can be compared with those mentioned above. Addition of propylene carbonate enhances the cond~ctivity."~

343

8: Phosphazenes

DMFiD/4H\

COOH

‘“6 4 ?

C=O

I

H

?

I

H I

H

0

0

c=o

c=o I

c=o I

? I

H

?

I

c=o I 0

? I

H

o=c I 0

c=o I

? I

H

Organophosphorus Chemistry

344

x, ,x N X,II 0

-

N I,X

p, "'p,

X

X = F, CI

X = F, CI

x. ,o

x , ,OCGH~CH=CH~ N"+N

NaOC6H4-CH=CH2

X,II 0

AlBN

I,X p , NI'p,

X (106a) X = F (106b) X =CI

polymn. in bulk

(108a) X = F (108b) X = C l

"3,

X,II I,X P, N5P, X (107a) X = F (107b) X = C I

(109a) X = F (109b) X = C I

Monobenzyl poly(ethy1eneglycol) BnO-(CH2CH20),H (Bn = benzyl) reacted with (NPC12)3in the presence of KH to give the star polymer [NP{O(CH2CH20),Bn}2l3,which can be transformed by H2/Pt/C reduction into the star polymer [NP{ O-(CH2CH20),H)2l3.The precipitation behavior of the star polymer makes this compound very suitable for applications in organic synThe mixed ring system (NPC12)2NSOC1(122) proves to be an interesting starting material in synthetic chemistry. In attempts to isolate the ionic structure [(NPC12)2NSO]+X-, (NPC12)2NSOClhas been treated with AlC13, AgBF4 and Ag[OS(02)CF3].The reaction of (NPC12)2NSOCl with two equivalents of AlC13 in 1,2-dichloroethane surprisingly resulted in the quantitative formation of the dichloroethyl derivative (123).The reaction of (NPC12)2NSOCl with AgBF4gave (NPC12)*NS(0)F(124), presumably via [(NPC12)2NSO] [BF4]- as intermediate, whereas treatment with Ag[OS(02)CF3] afforded (NPC12)2NS(O)[OS(02)CF3] (125). Reaction of (125) with diethyl ether gave (NPC12)2NS(O)OEt ( 126).'37 Ring-opening polymerization of (NPC12)2NSOClwill be discussed in Section 4. It has been shown that by a proper choice of reaction conditions, chlorine substitution in (NPC12)3 by sodium salts of poly(ethy1ene glyco1)s can be achieved, to yield cis-non-gerninalcompounds N3P3C13(OR)3. The group R represents (CH2CH20)2Me,(CH2CH20)2Et,(CH2CH20)2Bu", and the larger side groups (CH2CH20),Mewith n = 7,12 and 16. Subsequent substitution with amino acid esters gave derivatives with an octopus-shaped structure with three hydrophilic groups at one side of the phosphazene ring plane and three hydrophobic groups +

8: Phosphazenes

345

C(0)OMe

PPh2 I1

N, ,OPh /+N Ph0,II I,OPh PhO'P\N5P\OPh (114) n # 0 , rn = O (115) n # O , r n # O Me C(0)OMe

m

PPh2

(116) n # 0 , m = O (117) n # O , m # O

at the other side. The compounds belong to the class of thermosensitive cyclophosphazenes with interesting lower critical solution temperatures (LCST).13' Water-soluble cyclotriphosphazene-diamine Pt(I1) complexes (127a-c) have been prepared. All compounds showed in vitro and in vivo activity towards cancer cell lines, in particular the glutamate derivative (127c) with trans-1,2diaminocyclohexane as the other platinum ligand.'39 The use of cyclophosphazenes as additive in lubricants is a matter of continuing interest. All investigations conclude that the presence of N3P3(OC6H4CF33),(OC6H4F-4)6, (industrial name X-lP)i40-'42or N3P3[OCH2(CF&H]6 (industrial name X-100)142,143 significantly improves the lubricant performance of perfluoroethers. Moreover X-1P does not initiate the formation of silicon oxides at head-disk interfaces when contaminated with siloxanes, thus improving the flyability perf~rmance.'~~ Analogous fluorine-containing cyclophosphazenes have been claimed to be useful lubricant additive^.'^^-'^^ The compound ( N P A z ~ ) ~ (Az = aziridinyl), which is in fact a biologically very active compound, has been used as a postcuring agent towards aqueous-based polyurethane to improve the flame retardancy. Postcuring takes place via ring opening of the aziridino groups.148[NP(OCH2CF3)2]3has been applied in a fire retardant solvent for the preparation of a graphite anode.149Flame retardancy has been studied for 10-20

346

Organophosphorus Chemistry

I (7.42

RO, ,CI N/'+N RO,ll I,OR

NaOR

Ro'p\N;p\

OR

CH20Na

RO, ,o NlP+N R0,II I,OR

CIZRU(P C Y ~ ) ~ = C H C ~ H S

(118a-g)

*

RO, ,OCH2 NNP+N R0,II I,OR Ro,p\N;p\

(119a) (119b) (119c) (119d) (119e) (119Q (119g)

(120)

R = (CH2CH20),Me with x = 7.2

OR R = Et R = CH2CF3 R=Ph R = CeH4C02Et-4 R = CH2CH20Me R = (CH2CH20)2Me R = (CH2CH20)3Me

Ro'p\N;p\

(118a) (118b) (118c) (118d) (118e) (1180 (1189)

OR R = Et R = CH2CF3 R=Ph R = CeH4C02Et-4 R = CH2CH20Me R = (CH2CH20)2Me R = (CH2CH20)3Me

(121)

wt% mixtures of [NP(OPh),],, [NP(NHPh)& [NP(OC6H4O-4)I3, [NP(NHC6H4NH-4)I3,or [NP(NHC6H40-4)I3 and poly(buty1ene terephthalate).15' Many flame retardant phosphazene preparations and formulations based on linear and cyclic phenoxy-substituted phosphazenes, either crosslinked or not and lacking halogen, have been covered by patent^.'^^ Phosphorylation of [NP(OC6H40H-4)2]3 with diphenylchlorophosphate ClP(O)(OPh), has been reported to yield almost quantitatively the compound { NP[OC6H4(0P(0)(OPh2-4)2]2}3. The flame retardancy of this phosphorylated product, when added to polystyrene, can be compared with that of triphenyl phosphate. The plasticizing effect on polystyrene, however, is far 10wer.I~~ Poss-

347

8: Phosphazenes

~

(CH2),C02Li N+p,NHCHC02Li I

-+ .

\

(CH2,"EO'

0

"'"0

Am = N H ~ C H Z C H ~ N H ~

0

\NHCHCH2~0,

nAm

pt

u

Am = ffanS

H2N

Am = H Z N C H ~ C ( M ~ ~ ) C H ~ N H ~

(127a) n = O (127b) n = l (127c) n = 2

ible application of NP(NH2)2[NP(N3)2]2 as pyrotechnic material in an electrically driven igniter has been disclo~ed.'~~ The preparation of 1,5-diamino-1,3,3,5,7,7hexa(azid0)-cyclotetraphosphazene'54 has been described, as well as the preparation of l,l-diamino-3,3,5,5,7,7-hexa(azido)-cyclotetraphospha~en~~~ and their application as energetic compounds. Hexakis(ally1amino)cyclotriphosphazene has been used as sensitizer (crosslinkingagent) for the crosslinkingof low-density polyethylene by 6oCoy r a d i a t i ~ n . ' ~ ~ 4

Polyphosphazenes

general reviews on syntheses, properties and applications of polyphosphazenes have Moreover, polyphosphazenes form part of a general review on inorganic p01ymers.l~~ Special reviews have appeared on phosphazene based polymer electrolytes160 and polyphosphazene microspheres.'61 Polyphosphazenes are suitable materials to be used as carriers for nonlinear optical (NLO) chromophores. Second order NLO properties have been studied for the polymer (128)and blends of (129)with the free chromophore (130) or the cyclophosphazene (131). All systems have glass transition temperatures higher than 135°Cand a wide transparency window. The system (129H130) appears to exhibit the highest second-harmonic generation (SHG) response. For possible applications the SHG capability has to be e n h a n ~ e d . ' ~ ~ . ' ~ ~

Organophosphorus Chemistry

348

Q

NO, (128)

02N

'o\

N=N

The synthesis and photo-induced charge separation properties of (NPC9-(2ethoxy)carbazolyl]2}flhave been described.164The analogous polyphosphazenes (132a-b) contain carbazolylalkoxy and ethoxy substituents in combination with chromophore~.'~~ It has been shown that [NP(OC6H4C02H-4)2], forms a predominantly onehanded helical conformation in solution, when complexed to the optical amine (R)-l-phenylethylamine.'66 Spectroscopic and solution properties of phosphazene copolymers with phenoxy and optically active binaphthoxy side groups have been inve~tigated.'~' Dilute solution properties of poly(diphenoxyphosphazene) in thf have been investigated by size exclusion chromatography (SEC) and multi-angle light scattering (MALLS). Molecular dynamics simulations point to a preferred trans-

349

8: Phosphazenes

conformation of the polymer backbone.16' Dilute solutions of poly(dipiperidinoph0sphazene) in thf have also been subjected to SEC and MALLS A combined XPS and DSC study of solvent cast films of [NP(OPh)J, and polystyrene has shown that the polymers are not compatible. The polyphosphazene tends to migrate to the ~urface.'~'

Me

L

x+y+z=2 (132a) p = 2 (132b) p = 6

J n

Gas permeability of poly(bis-n-dibutoxyphosphazene) and poly(bis-sC& and C02 has been simulated using the butoxyphosphazene) for He, Ne, 02, COMPASS molecular mechanics force field.'71Poly(bis-trifluoroethoxyphosphazene) and blends of this polymer with poly[(trifluoroethoxy)(adamantane amino)phosphazene] have been applied in gas permeability experiments. In general, the incorporation of the adamantane amino derivative leads to a reduction of the permeability. The permeability ratios of H2, 0 2 and N2 appear to decrease with increasing size of the penetrant. For C02, CH4, C2H6 and C3H8 both the solubility of the penetrant in the polymer matrix and the diffusity seem to determine changes in ~ermeabi1ity.I~~ It has been shown, by phosphorescence quenching, that the diffusion coefficient of oxygen in polymers poly(n-alkylaminothionylphosphazene)(133) increases with decreasing value of the glass transition temperature. The solubility of oxygen is not very sensitive to the nature of the alkyl The influence of silica particles on oxygen diffusion in polymer films of poly(n-butylaminothionylphosphazene)has been investigated by luminescence experiment^.'^^ Diffusion coefficients for methanol (concentration range 1.0-5.0 M) in ionexchange membranes of UV-crosslinked sulfonated poly(bis-3methoxyphenoxyphosphazene)(134) have been reported to be much smaller than those in Nafion perfluorosulfonicion-exchange membrane^.'^^ Application of polyphosphazene-based membranes in met hanol-based fuel cells has been re~0rted.I~~ A wide- and small angle X-ray diffraction study of crosslinked (134)has shown the presence of two phases, uiz. an amorphous phase and a two-dimensional ordered phase. Changes of the ordered structure depend on the ion-exchange capacity of the polymer and extent of water ~wel1ing.l~~ Pervaporation membranes have been prepared by thermally crosslinking of polyphosphazenes bearing p-methoxyphenoxy,methoxyethoxyethoxyand o-allylphenoxygroups in the presence of a radical initiat~r.'~'

Organophosphorus Chemistry

3 50

Am = n-alkylamino

Me (134)

(133)

Novel synthetic approaches were not reported in the period covered by this review, only refinements to well-known procedures have been published. A solvent-free procedure has been developed for the preparation of welldefined block copolymers [NPC12],[NPRR'], (136a+) with narrow polydispersities by cationic condensation polymerization of phosphoranimines XP(RR')=NSiMe3 (X = C1, F) initiated by the living polymer {C13P=N[P(C12)=N],-PC13} PC16-(135). Polymer (137) has been synthesized analogously from C1P(MeEt)=NSiMe3and ClP(MePh)P=NSiMe~.'79~'80 Chlorine substitution in (136a-d) by the nucleophile CF3CH20 results in a full replacement of the halogen atoms. The difference in reactivity of chlorine and fluorine towards nucleophiles opens the possibility for selective substitution as visualized by the preparation of (139) via ( 138).'79 +

[

C13P=Nf;N~PC13]

+ [PCI, ] -

XRRP=NSiMe3

CI (136a) (136b) (136c) (136d) (136e)

(135)

CIP(MeEt)=NSiMe3

(136a) R = Ph, R = CI (136c) R = R = Me (136d) R = R = Ph

{T=NHy=Nk-,

i PCIB ii CIMePhP=NSiMe3

*

R R = Ph, R = CI, X=CI R = Me, R = Et, X = CI R = R' = Me, X= CI R = R = Ph, X = CI R = Ph, R = F, X = F

Q N H F N k

(140a) R = Ph, R = R" (140c) R = R = Me (140d) R = R = Ph

8: Phosphazenes

351

Introduction of Me(OCH2CH2)20-groups gives polymers (140a, 140c-d), in which both hydrophilic and hydrophobic properties are combined.'79Characteristics of micelles of polymer (140a),formed by self-assembly in aqueous solution, have been investigated.181 A triblock polymer (142) has been obtained by polymerization of C1P(MeEt)=NSiMe3 initiated by the difunctional initiator (141) in CHzClz solution, followed by chlorine substitution in dioxane by trifluoroethoxy Cationic condensation polymerizations of C13P=NSiMe3 and PhC12P=NSiMe3in the solvents benzene, toluene and dioxane, and initiated by PC15, appear to be reproducible and result in polymers with a low polydispersity.182Diblock and triblock polyphosphazene-polystyrenecopolymers have been synthesized by quenching the living polymer (135) by a polystyrene phos-

ii

NaOR

(143)

P

ii

NaOR

(143)

iB

Organophosphorus Chemistry

352

phoranimine (143) using a molar ratio polyphosphazene: polystyrene equal to 1:1 and 1:2, respectively. Subsequent nucleophilic substitution of chlorine by CF3CH20 leads to the fully trifluoroethoxy-substituted derivatives (144) and (145).'80,'83 Radical polymerization of a mixture of styrene and the vinylaniline derivative (146)has been reported to give graft copolymers (147) in high yield^.'^^.^^^ Di- and triblock phosphazene-siloxane copolymers have been synthesized from phosphoranimine terminated poly~iloxanes.'~~ Polymers with composition [NP(O2C12H8)]nSX(OC4H8)n have been formed in the reaction of (NPCl2), with 2,2'-diphenol in thf. Polytetrahydrofurane (OC4H8), arises from acid-catalyzed ring opening polymerization of thf.'85 Analogous to the phosphorylation of [NP(OC6H40H-4)2]3the reaction of [NP(OC6H4OH-4)2]n with diphenylchlorophosphate ClP(O)(OPh)2 has been reported to yield well-defined polymers { NP[OC6H4(OP(0)(OPh2-4)2]2}n.'52 Aromatic poly(ether ketones) have been prepared in which phosphazene units (148)in cyclolinear positions are coupled to diphenyl ether or diphenoxybenzene (A) using Eaton's reagent (P205/MeOS020H).Ternary systems (149) could be obtained by the addition of 4,4'-dicarboxydiphenyl ether.'86 HC=CH2

HC=CH;!

0. I

OR (147)

(146) R = CHzCF3

I

Eaton's reagent

The 'small molecule approach' has been applied to synthesize polymers [NP(ORh]n [R = (CH2)2SMe,(CH2)4SMe, (CH2)2CH(SMe)S(CH2)2Meand CH2C6H4(SMe-4)].'20 Films of these polymers have the highest affinity to silver cation for the range of the metal salts AgN03,Cd(N03)2and Hg12.The synthesis

353

8: Phosphazenes

and characterization of polyphosphazenes with -S-C = NCH2CH2S as P-bonded groups have been de~cribed."~ Cyclolinear polyphosphazenes have been prepared by acyclic diene metathesis (ADMET) polymerization of NP(OR)2NP(OR)[ O(CH2)5CH=CH2] [R = C6H4(0CH2C&-4)], using Grubb's catalyst [C12Ru(PCy3)2=CHC6H4].188 Cyclomatrix polymers (150a-c) have been prepared by the reaction of (97) with difunctional acid chlorides in 1,4-dioxane.NMR data suggest that each phosphazene unit has three side-groups participating in crosslinking and three free g r 0 ~ p s . Both l ~ ~ [NP(OC6H40H-4)2]3 and (97) have been investigated for their application in a polyphosphazene binder ~ y s t e m . ' ~ ~ - ' ~ ~ A cyclomatrix structure has been proposed for the product obtained from the reaction of [NP(OC6H40H-4)2], and formaldehyde, and subsequent curing at 120oc.191

/

A"' (150a) n = 2 (150b) n = 4 (150c) R = 12

Ring-opening polymerization of cyclic compound (NPCl2)2NSOCl (122) at ambient conditions by means of GaC13as initiator has been reported to result in the polymer [(NPC12)2NSOCl],together with higher cyclic systems. GaC13appears to be a more efficient initiator than SbCls or AlC13. Poly[(amino)thionylphosphazenes] (133) have been prepared by aminolysis of the chloro precursor [(NPC12)2NSOC1],.'92 The medical application of polyphosphazenes still attracts the interest of several research groups, although anaphylactic effects have been observed in some in vivo experiment^.'^^ Fluorinated polymers, among which are fluorinated polyphosphazenes with general formula { NP(OCH2CF3)x[OCH2(CF2)3CF2H] l - x } n (x = 0.90, 0.95) and {NP(OCH2CF3)x[OCH2(CF2)6CF3]l-x}n (x = 0.95), have been evaluated as a coronary stent ~ 0 a t i n g .It l ~has ~ been shown by in vitro and in vivo experiments that high quality [NP(OCH2CF3)2],exhibits a high

Organophosphorus Chemistry

354

biocompatibility and a low thr~mbogenicity.”~Polyphosphazenes with imidazolyl and amino ester groups have been studied as biodegradable membrane~’’~ or as microspheres in controlled drug-release experiment^."^^"^ Side group chemistry at poly[bis(glycinato ethyl ester)phosphazene] by NhZOH, followed by treatment with benzoylchloride, has been reported to give the biodegradable polymer (15 1).’97

Biodegradable polymers with methoxy poly(ethy1ene glycol) (MPEG350), amino acid ethyl esters and depsipeptide ethyl esters as side groups have been rep~rted.’’~ and surfactant200 effects on the LCST of polymers [NP(MPEG350),(amino acid Et e ~ t e r ) ~ -have J ~ been investigated. Water-soluble polyphosphazenes (152) have been prepared aiming at carrier systems for bioactive agents2”

IN= [

N [

,

?CH2CH20Me J OCH2CH20Me

I1

1

[

1 f 1 ,

OeNHk3H2N(H)CMe

=

OCH2CH20Me

(152)

High molecular weight, water-soluble polyphosphazenes possessing LCST characteristics, e.g. { NP[O(CH2CH20)2Me]2}.,can be isolate and purified, making use of their phase transition behavior.202Blends of [NP(NHCH2C02Et)2InZo3 with polyesters or polyanhydrides or [NP(NHCH2CO2Et)(OC6H4Me-4)InZo4 have been evaluated to obtain materials with desirable mechanical properties and degradation characteristics. Formulation and application of poly(dicarboxylatophenoxyphosphazene) microspheres containing antigens have been covered by a patent.205 Cyclolinear polymers with cyclotriphosphazene, pyrimidine and triazine units have been applied to enhance the durability of fabrics.*06The use of polyphosphazene membranes for the separation of dyes from waste streams has been patented.207

5

Crystal Structures of Phosphazenes and Related Compounds

The following compounds have been examined by diffraction methods. Distances are given in picometres and angles in degrees. Standard deviations are given in parentheses. Endo (exo) means endo (exo)cyclic.

8: Phosphazenes

355

Compound

Comments

Ref.

9,A = C5HSFeCSH4CH Me3SiN=PPh2N(Prn)PPh2

N P 160.5(3) N(SiMe3)P 152.1(3) N(Pr')P 169.4(2) L NPN 110.7(1) L P N P 118.2(1) N P 156.3(2) NP(Ph2) 157.2(3) NPPh(cyc1o-Pr) 168.9(3) L P N P 123.4(2) N(A1)P 158.6(2) mean N(Cy2)P164.6(4) L N(CyJPN(Cy2) 106.4(1) L N(cyJPN(A1) 111.5(1), 118.2(1) two independent mols. in unit cell mean N(A1)P 158.9(2) N(Cy2)P 163.9(2)-16542) L N(Cy2)PN(Cy2) 106.5(1), 113.9(1) L N(cy2)PN(Al)111.0( 1) - 118.7(1) N(A1)P 155.9(1) mean N(Cy2)P 166.3(2) R = Me L N(Cy2)PN(Cy2)107.3(1) L N(cy2)PN(Al)114.1(1), 118.6(1) N(A1)P 155.6(2) mean N(Cy2)P 166.0(2) L N(CyJPN(Cy2) 105.6(1) L N(cyJPN(A1) 114.6(l), 120.0(1) N P 168.8(2) NP(C13) 178.3(3) NP(Pr') 165.0(3) L NPN 75.7(2) N(R)P 148.6(5),152.8(5) N(Pyr)P 181.5(5) L N(R)PN(R) 130.6(3) mean N(R)P 152.7(3) N(Pyr)P 181.2(4),183.0(4) L N(R)PN(R)135.9(2) N(H)P 164.9(2) N P 152.9(3) L NPN 111.9(1) mean N(coord.)P 158.8(6) mean N(non-coord.)P 154.0(3) L NPN 122.3(2),124.4(3) mol. Ci symmetry N(coord.)P 158.1(2) N(non-coord.)P 156.2(2) L NPN 125.8(1) mean N(coord.)P 161.6(3) mean N(non-coord.)P 154.0(6)

11 13

PhN=P(Ph2)CH2P(O)Ph2 13

LNAl(R2)N(L)A1(R2) L = (CY2N)2P(HF LNA1(R2)N(L)A1(R2) L = (Cy2N2PWF R = Et 20, R' = R2 = CF3 = NPr' P+N=P(C13)N(Ar)C

29

30

31

32

33

34

14 16

17

17

17

17

27

43

43

44

44 44

44

356

Organophosphorus Chemistry

Compound

Comments

mean L NPN 123.2(2) N P 165.8(1) N P 154.7(8) N P 149(2) mean N P 159.2(4) L NPN 101.1(3) 39b N(Si)P 155.9(5), 159.8(4) NP(C1,) 153.7(4) L NPN 103.8(2) 40 N(H2)P 162.9(2) NP(N,Cl) 155.3(3) L NPN 109.7(3) L PNP 138.2(5) [MeC(O)N(H)PEt3]2[ Cu2(02CMe),C12] N P 165.5(6) .4CH2C12 [Ag, 2F(NPEt3)8](SiF6)1.5.2.4MeCN N P 158(1)-161(1) [CO~(NPE~~)~(HNPE~,)~O~CM N(H)P ~ ) ~ 158.8(4),N(Co)P 159.7(3)49 .[OSi(Me2)OSi(Me2)0] RNS -, R = Mo(C&)N=PPh, N P 168(1) C(N=PPh3)4MolCBF412 mean N P 160.2(3) [Ph,PNH2][ SCNJ N P 160.1(2) W(S2)(N=PPh3)2 N P 162(1) 42a mean N P 157.3(1) 42b mean N P 157.0(4) 43.2DME (DME = 1,2-dimethoxyethane)NP 153.5(6)-156.5(4) 4.6.5 thf mean N P 155.6(4) N P 160.1(2) [S(N=PPh,] C0.5 I<, 0.5 I-].thf N P 160.7(3) [Se(N=PPh,]+[0.5 I3 ,0.5 I-].thf [Te(N=PPh3] + 1, meanNP 158.8(4) 45.4.5C6H~Me mean N P 153.3(4) 46.(2C6H5Me,3.75C6H14) N P 153.6(9) 46.2C6H5Me mean N P 153.0(2) [La(N=PPh3)J2.2thf mean N P 154.5(7) CYb(N=PPh,),l2 N P 152.8(5)-157.2(4) CS[Yb(N=PPh3)4],.6thf mean N P 155.3(4) [Ph2P(S)NP(S)Pr‘2-S’]2Pt mean N P 158.8(2) L PNP 133.4(2) [(PhO)2P(S)NP(S)Pri2-S,S’]2Pd N P 155.1(5), 161.5(5) L PNP 123.9(3) [( P hOhP(S)NP( S)Prl2-S,S’I2Pt N P 155.2(4), 160.5(4) L PNP 131.4(3) [(PhO)2P(S)NP(S)Et2-S,S’]2Pd N P 155.8(2), 160.2(2) L PNP 132.8(1) 47a N P 155(1)-159(1) mean L P N P 137.7(6) 47b mean N P 160.1(4) L PNP 129.8(3)

35 37 38 39a

+

Re5

44 46 46 46 46

46

47 48

50 50 50 51 51 52 52 53 53 54 54 54 54 55 55 56 77

77 77

77 77 79

8: Phosphazenes

Compound

357

Comments

mean N P 159.9(2) L P N P 126.9(1), 130.9(1) N P 157.3(3), 158.7(3) L P N P 128.0(2) 49a. H 2 0 two independent mols. in unit cell N P 155.7(6b160.2(6) L P N P 132.6(5)-138.4(4) [Ph2P(Se)NP(Se)Ph2-Se,Se’I2VO.CH2Cl2 mean N P 160.0(4) mean L P N P 125.0(1) [Ph2P(Se)NP(Se)Ph2-Se,Se’] 3V.CH2C12 N P 159.4(3-1 6 1.1(3) L P N P 124.6(2), 127.4(2) mean N P 159.5(2) [Ph2P(Se)NP(Se)Ph2-Se,Se’I3Cr.CH2Cl2 L P N P 126.4(4b130.7(4) 51 N P 159.1(9), 163(1) L P N P no data available 52 N P 158(1), 162(1) L P N P no data available (C5Me5-RhC1)( Ph2P(Se)NP(Se)Ph2-Se,Se’)mean N P 159.6(4) L P N P 127.7(3) (CsMeS-IrC1)(Ph2P(Se)NP(Se)Ph2-Se,Se‘) mean N P 159.9(5) L P N P 128.1(5) 55b mean N P 159.2(3) L P N P 127.5(2), 137.0(2) cis-58b.Ch2C12 mean N P 159.7(3) L P N P 127.2(2),133.8(2) cis-59a.Ch2C12,R = ButNH N P 158.9(3)-160.4(3) L P N P 126.9(2),129.3(2) cis-59a, R = piperidino mean N P 159.8(3) L P N P 126.9(2),130.8(2) 60 mean N P 159.2(3) L P N P 128.3(3),129.5(3) Ru[Ph2P(S)NP(S)PPh2-S,S’](PPh3)(N2H2) mean N P 159(1) L P N P 124.6(8),140.0(9) 62 mean N P 160(1) mean L P N P 129(2) mean NP(Se) 156.1(7) 64 mean N P 164.7(4) L P N P 117.8(4), 121.9(4) Ru(%=CHPh)[ Ph*P(S)NP(S)Ph2-S,S’] mean N P 158.8(5) mean L PNP 133.1(4) 2pcy3 65a.CH2C12 mean N P 158.8(4)85 mean L P N P 126.8(4) 65b mean N P 159.4(3) 85 L P N P 127.6(3) 6% mean N P 158.9(2)85 L P N P 130.7(2)

Ref. 79 79

79

80 80

83 83 83 83 83 84

84

84

85 85

Organophosphorus Chemistry

358 Compound

Comments

Ref:

66b

mean N P 158.8(2)85 L PNP 131.7(3b136.1(3) mean Np 159.1(6)85 L PNP 127.9(8),130.0(6) N P 162.8(4)

85

mean N P 161.5(4)

87

N P 161.8(3), 163.3(3)

87

N P 161.4(2), 162.1(2) N P 161.6(2), 162.4(2) mean N P 158.8(5) N P 157.3(3), 160.4(3) mean N P 158.2(2) mean N P 157.2(1) mean N P 159.1(2) mean N P 160.6(1) mean N P 161.1(5)

88 88 90 90 91 91 91 92 92

two independent mols. in unit cell N P 154.6(6b157.4(5) mean N P 161.6(2)

92 92 97

N P 165.1(1) two independent mols. in unit cell mean N P 160.9(3) mean N P 159.3(5) mean L PNP 122.1(3) N P 158.2(.3)-159.4(3) L PNP 130.4(2), 131.4(2) NP(OR),(0)158.6(3) NP(OR)3 151.7(3) L PNP 146.0(2) mean N P 160.1(1) mean L NPN 117.2(1) mean L PNP 122.6(4) mean N P 159.2(2)

98 99

N P (endo) 154.5(4)-160.1(4) mean N P (exo) 162.5(5) L NPN (endo)l13.6(2k120.5(2) L PNP (endo) 118.2(3)-124.6(3) NP(endo)154.4(4b159.6(4) mean N P (exo) 160.2(3) L NPN (endo) 114.1(2t121.0(2) L PNP(endo) 119.0(3b124.2(2)

116

69.MeOH Hf (N=CAd)Cl,[C(Ph2P=NSiMe3),C,”I Ad = adamantyl HfC12(HNC6H4Me-4)[HC(Ph2P=NSiMe3),-C,N,N’] ZrC12{[C(NCy)NCy]C[(Ph2P=NSiMe3), -C,N,N””]}.thf, 1.5PhMe 72a 72b 73. C6HsMe 74. C6H5Me 75a 75b 76 77b.CH2C12,Ar = C6H3Pri2-2,6 78.3.5CH2C12,MX2 = CoCl,, R = Ph, n =1 79.Ch2C12,MX2 = FeBr,, R = Ph, R’ = %Me3 triazole derivatives with a N=PPh3 or N=P(C6H4Cl-4)3 moiety [C6HSCH=NN(H)=PCy3] + [Ph3P=NHJ+.EtO, [Ph,P(S)NP(S)Ph,-S,S’] 2Pd [P~~P(S)NP(S)P~~-S,S’]~CO

(RO)2P(0)-N=P(0R)3 R = C6H2(Me3-2,4,6) (NPPh&.thf

0CH(R)CH(Me)P(Ph,)=N-P (O)(0Ph), R = 4-MeOC6H4 83 (meso)

83 (racemate)

85 87

100 101 102

114

115

116

8: Phosphazenes

Compound

359 Comments

N P (endo) 156.6(3)-161.2(3) N P (exo) 164.7(3), 166.3(3) L N P N endo) 115.2(2)-121.9(2) L P N P (endo) 120.2(2)-126.1(2) 84 (meso, triclinic) N P (endo) 153(1)-166(2) N P (exo) 161(2)-170(2) L N P N (endo) 115(1)-125( 1) L P N P (endo) 118(1)-126(1) in segment P(O,)NP(N,O) mean NP(N,O) 159.4(1) mean NP(02) 157.0(2) in segment P(O,)NP(O,) mean N P 158.0(2) NP(exo) 162.7(2) L NP(N,O)N (endo)l15.8(1) L NP(02)N 117.2(1), 118.4(1) L P N P (endo) 120.6(1)-123.0(1) CoC12R2,complexation via pyrimidyl N; NP(endo)l53( 1)-159.0(9) R = [NP(0Ph),] ,NP( 0P h) NP(exo) 158.3(9), 163.7(9) L NPN (endo) 115.1(5)-119.5(5) C(NHCH2(C5H4N-3)l L P N P (endo) 120.1(5)-122.1(7) NP(endo) 156.0(5)-167.3(4) mean NP(exo) 162.7(3) L NPN(endo) 108.8(2k112.8(2) L PNP(endo) 127.7(2)-130.3(2) mean N P 157(1) mean L NPN 116.5(5) mean L P N P 123.5(3) N P 153.7(9)-161.4(10) 84.p-xylene mean L NPN 116.5(6) mean L P N P 123.2(5) endo-86, R = Fc in segment P(O,F)NP(O,F) Fc = ferrocenyl mean N P 157.1(4) in segment P(O,F)NP(F,) mean NP(0,F) 156.3(4) mean NP(F2)155.1(8) mean L NP(0,F)N 118.1(2) L NP(F2)N 120.3(3) L P(O,F)NP(O,F) 114.9(3) mean L P(O,F)NP(F,) 119.0(3) exo-86, R = Fc two independent mols. in unit cell Fc = ferrocenyl in segment P(O,F)NP(O,F) N P 156.7(3)-158.2(3) in segment P(0,F)NP(F2) mean NP(0,F) 157.0(2) mean NP(F2) 155.9(2) L NP(0,F)N 117.8(2)-119.0(2) mean L NP(F,)N 120.6(3)

84 (meso, monoclinic)

Ref: 116

116

119

119

119

123

123 124

124

Organophosphorus Chemistry

360 Comments

Compound

endo-87,R

=

Ph

88,R = FC

90

94

gem-NPC12[(NP(OC6C15)2]2

L P(O,F)NP(O, F) 119.5(2), 120.3(2) mean L P(0,F)NP(F2)120.2(2) in segment P(O,F)NP(O,F) N P 155.8(3), 157.0(4) in segment P(0,F)NP(F2) NP(0, F) 155.4(4)-156.7(4) mean NP(F2) 155.5(3) mean L NP(0,F)N 117.9(2) L NP(F2)N 120.2(2) L P(O,F)NP(O,F) 114.7(2) mean L P(0,F)NP(F2)118.8(1) in segment P(02)NP(F2) mean N P ( 0 3 158.6(2) mean NP(F2)155.2(3) in segment P(FJNP(F2) mean N P 156.0(4) L NP(02)N 117.2(1) L NP(F2)N 119.0(2), 120.3(2) L P(OJNP(F2) 120.7(2), 122.0(2) L P(F2)NP(F2) 120.6(2) mean N P ( 0 3 156.3(2) mean NP(F2) 154.5(2) L NP(02)N 120.2(2) L NP(F2)N 122.5(2)-124.1(2) L PNP 135.1(2)-140.3(2) in segment P(O,F)NP(O,F) NP(0,F) 155.8(2) in segment P(0,F)NP(F2) NP(0,F) 155.7(4) NP(F2) 152.0(4) in segment P(F2)NP(F2) N P 154.1(2) L NP(0,F)N 120.4(2) L NP(F2)N 123.0(2) L P(O,F)NP(O,F)126.1(3) remaining L PNP 135.6(3), 136.6(3) in segment P(02)nP(C12) mean NP(C12)158.3(2) mean NP(02)158.0(2) in segment P(02)NP(02) mean N P 157.9(3) L NP(C12)N 118.5(2) L NP(02)N 117.2(2), 118.6(2) L PNP 120.3(2)-121.7(2) mean N P 156.8(1) L NPN 115.9(2~119.1(1) L PNP 119.9(1k120.8(1)

Ref.

124

124

125

125

126

126

8: Phosphazenes

361

Compound

Comments

Ref.

104

mean N P 158.0(2) bond angles (endo) not available two independent mols. in unit cell in segment P N P mean N P 156.4(3) in segment PNS mean N P 158.7(4) mean NS 152.5(5) mean L NPN 116.6(1) mean L NSN 116.8(2) mean L PNP 121.5(2) mean L PNS 123.4(4)

130

124

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74.

363

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364

75. 76. 77. 78. 79. 80.

81. 82. 83. 84. 85.

86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100.

Organophosphorus Chemistry

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